prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/7563/1/... · IV DECLARATION I, Shahid Rasool, Reg. No. 2012-GCU-PHD-CHEM-09, student of PhD in the subject of Chemistry, Session

I

SYNTHESIS, CHARACTERIZATION AND

PHARMACOLOGICAL SCREENING OF SOME

DERIVATIVES OF 1,3,4-OXADIAZOL-2-YL

AZOMETHINE AND BENZO-2-PYRONE

BY

SHAHID RASOOL

REG. NO. 2 0 1 2 GCU PHD CHEM 0 9

Session 2012-2015

Department of Chemistry

Government College University Lahore

II

SYNTHESIS, CHARACTERIZATION AND

PHARMACOLOGICAL SCREENING OF SOME

DERIVATIVES OF 1,3,4-OXADIAZOL-2-YL

AZOMETHINE AND BENZO-2-PYRONE

Submitted to GC University, Lahore in

partial fulfillment of the requirements for

the

award of degree of

PhD In Chemistry

BY

SHAHID RASOOL

REG. NO. 2 0 1 2 GCU PHD CHEM 0 9

Session 2012-2015


Government College University Lahore

III

IV

DECLARATION

I, Shahid Rasool, Reg. No. 2012-GCU-PHD-CHEM-09, student of PhD in the subject

of Chemistry, Session 2012-2015, hereby declare that the material printed in the thesis

titled “Synthesis, Characterization and Pharmacological Screening of Some

Derivatives of 1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone” is my own

work and has not been printed, published and submitted as research work, thesis or

publication in any University, Research Institution etc, in Pakistan or abroad.

Dated: __________________________

__________________ Signature of Deponent

SHAHID RASOOL

V

GC UNIVERSITY LAHORE

RESEARCH COMPLETION CERTIFICATE

SESSION (2012-2015)

It is certified that Mr. Shahid Rasool, student of PhD Chemistry (Reg. No. 2012-

GCU-PHD-CHEM-09) has completed the research work contained in the thesis

entitled “Synthesis, Characterization and Pharmacological Screening of Some

Derivatives of 1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone”.

Date:_______________

_________________

Dr. Aziz-ur-Rehman

Associate Professor Supervisor

Submitted Through:

____________________

Prof. Dr. Ahmad Adnan

Chairperson


_______________________

Controller of Examinations

GC University, Lahore

VI

DEDICATION

To my

“all those loving

personalities who prayed

for my success”

VII

ACKNOWLEDGEMENTS

I am thankful to Almighty Allah who bestowed me such an ability to make a little

contribution in the world of knowledge and also to the teacher of mankind, Hazrat

Muhammad (PBUH) who is a candle for every researcher.

I have no words to pay thanks to my all teachers who guided me during my

studies specially my supervisor, Dr. Aziz-ur-Rehman, Associate Professor, whose

great encouragement and support remained with me at every step during my research

work. I also want to mention the name of Dr. Muhammad Athar Abbasi, Associate

Professor, for his guidance and encouragement during my stay in GC University,

Lahore.

I pay thanks to Prof. Dr. Ahmad Adnan, Chairperson Department of

Chemistry, and Prof. Dr. Islam Ullah Khan, Dean Faculty of Science and

Technology GC University Lahore, for their cooperation during course and research

work regarding official and laboratory matters.

Thanks are paid to Prof. Dr. Khaleeq-ur-Rehman, Vice Chancellor GC

University Lahore for his efforts for the betterment of students, especially research.

I acknowledge Prof. Dr. Khalid Mohammad Khan, HEJ-University of

Karachi, and Dr. Muhammad Nadeem Akhtar, FIST-University Malaysia Pahang,

for providing assistance in spectroscopic analysis; and Dr. Irshad Ahmad and his co-

workers, The Islamia University of Bahawalpur, for screening the synthesized

molecules for antibacterial activity and enzyme inhibition analysis.

I appreciate all my lab fellows for the everything which they provided me

regarding my course or research work and cannot help to mention their names,

Sabahat Zahra Siddiqui, Hira Khalid, Samreen Gul, Misbah Irshad, Asia

Siddiqa, Kaniz Rubab, Khadija Nafeesa, Almas Sattar, Muhammad Shahid

Ramzan, Majid Nazir and my dearest friend, Ghulam Hussain.

I pray a lot for the good health of my Parents who encouraged me at every

step of my education and especially my dear wife, Aasma Mukhtar, without her

countless efforts & sacrifices I was not able at all to achieve this goal in my life.

May Allah bestow his blessings to all of above infinitely!

I also want to pay thanks to Higher Education Commission (HEC) of Pakistan

for financial assistance by awarding me Indigenous PhD Fellowships for 5000

scholars-HEC, Phase-II, Batch-I.

Shahid Rasool

VIII

ABSTRACT

The synthetic chemistry has gained much attention because of the broad spectrum of

biological activities related to structural features of various synthesized molecules.

The synthetic chemistry has prominent application in the field of pharmaceutical or

medicinal chemistry regarding new drug candidates. In this regard, the three

concerned functionalities; 1,3,4-oxadiazole, azomethine and benzo-2-pyrone; have

gained much attention because of their notable biological activities. The current

research work was an effort to synthesize different molecules bearing these

functionalities; 1,3,4-oxadiazole derivatives bearing azomethine functionality and

benzo-2-pyrone derivatives bearing acetamide functionality; and to evaluate their

antibacterial and enzyme inhibition potential.

Eight (8) different carboxylic acids (I1-8) were employed to synthesize one

hundred thirty three (133) azomethine compounds (VIII1-133, Scheme-1) by

converting them to corresponding ethyl esters (II1-8) by ethanol on reflux,

carbohydrazides (III1-8) by hydrazine on stirring at RT (room temperature) or reflux,

1,3,4-oxadiazoles (IV1-8) by carbon disulfide on reflux, ethyl esters (V1-8) by ethyl 2-

bromoethanoate (EBE) on stirring at RT, again carbohydrazides (VI1-8) with

hydrazine on stirring at RT and finally azomethine derivatives (VIII1-133) with aryl

carboxaldehydes (VII1-19) on stirring at RT. 2,4-Dimethylphenol (IX) was also

converted to thirteen (13) compounds (XV1-13, Scheme-2) of such type through the

same steps except first one for the synthesis of ethyl ester (X) by ethyl 2-

bromoethanoate (EBE) on reflux.

4-Chloro-1,3-dihydroxybenzene (XVI) was converted to heterocyclic 6-

chloro-7-hydroxy-4-methylbenzo-2-pyrone (coumarin, XVII) by reaction with ethyl

2-ethanoylethanoate (EEE) in concentrated sulfuric acid. The synthesized benzo-2-

pyrone molecule was O-substituted by alkyl halides (XVIII1-9) to synthesize XIX1-9

and by acyl halides (XX1-8) to synthesize XXI1-8 (Scheme-3). The different

alkyl/aralkyl/aryl amines (XXII1-27) were made to react with 2-bromoethanoyl

bromide (BEB) on stirring to synthesize a number of new electrophiles (XXIII1-27,

Scheme-4). These synthesized electrophiles were subjected to react with XVII to

synthesize N-substituted acetamide derivatives (XXIV1-26, Scheme-5) and then with

4-hydroxybenzo-2-pyrone (XXV) to synthesize XXVI1-18 (Scheme-6) on stirring at

RT. The N-substituted 1,3,4-oxadiazole acetamide derivatives (XXX1-27, Scheme-7)

of benzo-2-pyrone were synthesized by stirring XXIII1-27 with 5-{[(6-chloro-4-

IX

methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-thiol (XXIX), prepared by

the same steps as that for 5-[(2,4-Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-thiol

(XII) in Scheme-2.

All the proposed structures of synthesized compounds were characterized by

IR (Infra Red), PNMR (Proton Nuclear Magnetic Resonance) and EIMS (Electron

Impact Mass Spectrometry) spectral data. Ring formation of 1,3,4-oxadiazole and

benzo-2-pyrone was confirmed through CNMR (Carbon-13 Nuclear Magnetic

Resonance). The compounds have been enriched by their physical data also. All the

synthesized compounds were screened against two Gram-positive and three Gram-

negative bacteria to evaluate their antibacterial potential with reference of

Ciprofloxacin, the reference drug. Along with antibacterial potential, these were also

evaluated for their LOX (Lipoxygenase) inhibition potential with reference to

Baicalein.

Among the 1,3,4-oxadiazole bearing azomethine compounds (Scheme-1 and

Scheme-2), VIII5,7,48,53 & XV1,8-10, were the most active against both of the Gram-

positive bacterial strains and the compounds, VIII5,53,90,124, were the most active

against all the three Gram-negative bacterial strains. Also against all the five bacterial

strains, VIII5,53, were the best inhibitors. Against LOX, the compound, XV9 bearing

5-[(2,4-Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl and 3-nitrobenzylidene, was

better inhibitor even than Baicalein, as evident from its four times low IC50 value.

Among the benzo-2-pyrone derivatives (Scheme-3 to Scheme-7), the

compounds obtained after alkylation (XIX1-9) of benzo-2-pyrone were relatively more

efficient against the bacterial strains taken into account than the acylated (XXI1-8)

ones. The compounds, XIX1,2,8,9, were the active inhibitors of all the bacterial strains.

The acetamidic compounds, XXIV4,15,23,26 presented notably valuable inhibitory

potential for all the bacterial strains. The LOX inhibition potential was too much low

for these compounds. All the compounds, XXVI1-18, were notably active against all

the strains but two compounds, XXVI16,17, were the most efficient ones. Among the

compounds, XXX1-27, the Gram-negative strains were efficiently inhibited than Gram-

positive ones. The best activity was presented by XXX5,6,10,22. Among the acetamidic

1,3,4-oxadiazole compounds, the molecules bearing alkyl substituted phenyl rings and

aralkyl groups with long aliphatic chain resulted in moderate to good activity. The

molecules bearing ortho substituted phenyl rings remained active against all the

strains, also good to excellent and more efficient against the Gram negative strains.

The meta substituted phenyl rings were also good against negative strains but the para

X

substituted ones presented varying moderate activities. For the LOX inhibition, the

most of compounds remained inactive and the active ones depicted too much low

potential.

The structure activity relationship (SAR) is discussed in detail in discussion

section (Chapter-4) for all the series of compounds. Overall a number of compounds

among all the series executed valuable antibacterial potential and a few ones with

valuable anti-enzymatic potential. The most active compounds might be subjected to

in vivo study for further analysis as drug candidates. The pharmacological industries

may consider these compounds as new drug candidates for drug discovery pathway.

XI

Overall Reaction Schemes:

N

O

N

SHCH2 OC2H5

O

N

O

N

SCH2 NH

O

NCH

R1

OH OOC2H5

O

ONHNH2

O

O

N

O

N

SO

CH2 NHNH2

O

N

O

N

SO O

COH

O

R

R

R

R R

R R

R n n

n n

n n

HO OHO

C2H5O CH3

O O O

CH3

HO

O O

CH3

OR2

Cl Cl

Cl

O O

CH3

OC

Cl

R3

O

NH2

C

O

Br

R4

R4

O O

CH3

O

Cl

HN

O

R4

O O

OHO O

ONH

O

R4

O O

CH3

HO

Cl

C2H5O

O

O O

CH3

O

Cl

H2NHN

O

O O

CH3

O

Cl

N

O

N

O O

CH3

O

Cl

HS

N

O

N

O O

CH3

O

Cl

SHN

O

R4

NH

R = Different substituents, R1 = Aryl groups, R2 = Alkyl/aralkyl groups, R3 =

Alkyl/aryl groups, R4 = Alkyl/aralkyl/aryl groups, n = 1 or 0.

XII

TABLE OF CONTENTS

Topic Page

Declaration IV

Research Completion Certificate V

Dedication VI

Acknowledgement VII

Abstract VIII

List of Schemes XVI

List of Tables XVII

List of Figures XVIII

List of Abbreviations XXI

Chapter-1 Introduction 1-21

1.0 General 2

1.1 Oxadiazole compounds 2

1.1.1 Nomenclature of oxadiazole ring 2

1.1.2 1,3,4-Oxadiazole 2

1.1.3 Biological activities 3

1.1.4 Importance of 1,3,4-oxadiazole 3

1.2 Azomethine compounds 3


1.3 Benzo-2-pyrone compounds 4


1.4 Acetamide compounds 5


1.5 Antibacterial activity 5

1.5.1 Antibacterial assays 5

1.5.2 Antibacterial mechanism 6

1.5.3 Gram-bacteria 7

1.6 Enzyme inhibition activity 8

1.6.1 Inhibition mechanism 8

1.6.2 Lipoxygenase enzyme 8

1.6.3 Active site of lipoxygenase enzyme 8

1.6.4 Baicalein 9

1.7 Aim of work 9

1.8 Plan of work 10

Chapter-2 Literature Survey 22-32

2.0 1,3,4-Oxadiazole derivatives 23

2.1 Azomethine derivatives 26

2.2 Benzo-2-pyrone derivatives 28

XIII

2.3 Acetamide derivatives 31

Chapter-3 Experimental Work 33-43

3.0 General 34

3.1 Synthesis of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1-133, XV1-13)

34

3.1.1 General procedure for the synthesis of Ethyl carboxylates (II1-8)

34

3.1.2 Procedure for the synthesis of Ethyl 2-(2,4-dimethylphenoxy)acetate (X)

35

3.1.3 General procedure for the synthesis of carbohydrazides (III1-8, XI)

35

3.1.4 General procedure for the synthesis of 5-Substituted-1,3,4-oxadiazol-2-thiol (IV1-8, XII)

35

3.1.5 General procedure for the synthesis of Ethyl 2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetate (V1-8,

XIII)

36

3.1.6 General procedure for the synthesis of 2-[(5-Substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VI1-8, XIV)

36

3.1.7 General procedure for the synthesis of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)

thio]acetohydrazide (VIII1-133, XV1-13)

37

3.2 Synthesis of 7-Substituted-6-chloro-4-methylbenzo-2-pyrone (XIX1-9, XXI1-8)

37

3.2.1 Procedure for the synthesis of 7-Hydroxy-6-chloro-4-methylbenzo-2-pyrone (XVII)

37

3.2.2 General procedure for the synthesis of 7-Alkoxy/aralkoxy-6-chloro-4-methylbenzo-2-pyrone (XIX1-9)

38

3.2.3 General procedure for the synthesis of 7-Acyloxy-6-chloro-4-methylbenzo-2-pyrone (XXI1-8)

38

3.3 Synthesis of N-Substituted-2-substitutedacetamide (XXIV1-26, XXVI1-18, XXX1-27)

39

3.3.1 General procedure for the synthesis of N-Substituted-2-bromoacetamide (XXIII1-27)

39

3.3.2 General procedure for the synthesis of N-Substituted-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy] acetamide (XXIV1-26)

39

3.3.3 General procedure for the synthesis of N-substituted-

2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI1-18)

40

3.3.4 Procedure for the synthesis of Ethyl 2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetate (XXVII)

40

3.3.5 Procedure for the synthesis of 2-[(6-Chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetohydrazide (XXVIII)

40

XIV

3.3.6 Procedure for the synthesis of 5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-thiol (XXIX)

41

3.3.7 General procedure for the synthesis of N-Substituted-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy] methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX1-

27)

41

3.4 Antibacterial activity assay 42

3.5 Lipoxygenase (LOX) enzyme inhibition activity assay 42

3.6 Statistical analysis 42

Chapter-4 Results & Discussion 44-204

4.0 Results of organic synthesis 45

4.0.1 Physical and spectral data of N'-Substituted-2-[(5-

phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1-16)

45

4.0.2 Physical and spectral data of N'-Substituted-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydraz -ide (VIII17-32)

52

4.0.3 Physical and spectral data of N'-Substituted-2-{[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydra-zide (VIII33-48)

60

4.0.4 Physical and spectral data of N'-Substituted-2-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydra-zide (VIII49-64)

68

4.0.5 Physical and spectral data of N'-Substituted-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydr-azide (VIII65-83)

76

4.0.6 Physical and spectral data of N'-Substituted-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohyd-

razide (VIII84-102)

85

4.0.7 Physical and spectral data of N'-Substituted-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}aceto hydrazide (VIII103-117)

94

4.0.8 Physical and spectral data of N'-Substituted-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]

thio}acetohydrazide (VIII118-133)

102

4.0.9 Physical and spectral data of N'-Substituted-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio)acetohydrazide (XV1-13)

110

4.0.10 Physical and spectral data of 7-Alkoxy/aralkoxy-6-chloro-4-methylbenzo-2-pyrone (XIX1-9)

117

4.0.11 Physical and spectral data of 7-Acyloxy-6-chloro-4-methylbenzo-2-pyrone (XXI1-8)

120

4.0.12 Physical and spectral data of N-Substituted-2-[(6-

chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1-26)

123

XV

4.0.13 Physical and spectral data of N-Substituted-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI1-18)

136

4.0.14 Physical and spectral data of N-Substituted-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl

}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX1-27)

145

4.1 Results of biological activities (in vitro) 159

4.1.1 Antibacterial and enzyme inhibition data of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)

thio]acetohydrazide (VIII1-133, XV1-13)

159

4.1.2 Antibacterial data of 7-Alkoxy/aralkoxy/acyloxy-6-chloro-4-methylbenzo-2-pyrone (XIX1-9, XXI1-8)

163

4.1.3 Antibacterial and enzyme inhibition data of N-Substituted-2-[(6-chloro-4-methylbenzo-2-pyron-7-

yl)oxy]acetamide (XXIV1-26)

163

4.1.4 Antibacterial data of N-substituted-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI1-18)

164

4.1.5 Antibacterial and enzyme inhibition data of N-substituted-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]

acetamide (XXX1-27)

165

4.2 Discussion of chemistry of organic synthesis 166

4.2.1 N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1-133, XV1-13)

166

4.2.2 7-Substituted-6-chloro-4-methylbenzo-2-pyrone

(XIX1-9, XXI1-8)

178

4.2.3 N-Substituted-2-substitutedacetamide (XXIV1-26, XXVI1-18, XXX1-27)

184

4.3 Discussion of biological activities (in vitro) 193

4.3.1 N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-

yl)thio]acetohydrazide (VIII1-133, XV1-13)

193

4.3.2 7-Substituted-6-chloro-4-methylbenzo-2-pyrone

(XIX1-9, XXI1-8)

201


201

4.4 Conclusion 203

Chapter-5 References 205-216

Chapter-6 Appendices 217-222

6.0 Appendix-I (List of Carboxylic acids) 218

6.1 Appendix-II (List of Alkyl halides) 218

6.2 Appendix-III (List of Acyl halides) 218

6.3 Appendix-IV (List of Aldehydes) 219

6.4 Appendix-V (List of Miscellaneous) 219

6.5 Appendix-VI (List of Amines) 220

6.6 Appendix-VII (List of Publications) 221

XVI

LIST OF SCHEMES

Number Title Page

1 Synthesis of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1-133)

11

2 Synthesis of N'-Substituted-2-({5-[(2,4-dimethylphenoxy) methyl]-1,3,4-oxadiazol-2-yl}thio)acetohydrazide (XV1-13)

14

3 Synthesis of 7-Substituted-6-chloro-4-methylbenzo-2-pyrone (XIX1-9, XXI1-8)

16

4 Synthesis of N-Substituted-2-bromoacetamide (XXIII1-27) 18

5 Synthesis of N-Substituted-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1-26)

18

6 Synthesis of N-Substituted-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI1-18)

18

7 Synthesis of N-Substituted-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]

acetamide (XXX1-27)

19

XVII

LIST OF TABLES

Topic Page

1.1 List of publications on 1,3,4-oxadiazole 3

1.2 List of R- and R1-groups for VIII1-16 12








1.10 List of R1-groups for XV1-13 15

1.11 List of R2-groups 17



2.1 Examples of bioactive molecules bearing 1,3,4-oxadiazole 25

2.2 Examples of bioactive molecules bearing azomethine 27

2.3 Examples of bioactive molecules bearing benzo-2-pyrone 30

2.4 Examples of bioactive molecules bearing acetamide 32

4.1 The MIC values of antibacterial activity for VIII1-32 159



4.4 The MIC values of antibacterial activity for VIII130-133, XV1-13 162

4.5 The IC50 values of enzyme inhibition activity for VIII1-102 162

4.6 The IC50 values of enzyme inhibition activity for VIII103-133, XV1-13

163

4.7 The MIC values of antibacterial activity for XIX1-9 163

4.8 The MIC values of antibacterial activity for XXIV1-26 164

4.9 The IC50 values of enzyme inhibition activity for XXIV1-26 164

4.10 The MIC values for antibacterial activity for XXVI1-18 165

4.11 The MIC values of antibacterial activity for XXX1-16 165

4.12 The MIC values of antibacterial activity for XXX17-27 166

4.13 The IC50 values of enzyme inhibition activity for XXX1-27 166

XVIII

LIST OF FIGURES

Topic Page

1.1 Isomeric forms of oxadiazole 2

1.2 Biological activities of 1,3,4-oxadiazole 3

1.3 Azomethine moiety 4

1.4 Basic skeleton of Benzo-2-pyrone 4

1.5 Derivatives of Benzo-2-pyrone 5

1.6 Acetamoyl moiety 5

1.7 Phases of bacterial growth 6

1.8 Target molecules 10

2.1 Synthesis of heterocyclic rings from N'-substituted thiosemicarbazide

23

2.2 Structure of L-Tartaric acid 23

2.3 General structure of imidazole derivatives 23

2.4 Synthesis of pyridine derivatives 24

2.5 Synthesis of furan derivatives 24

2.6 Synthesis of Thiazolidine derivatives 26

2.7 Synthesis of Azomethine derivatives 26

2.8 General structure of benzo-2-pyrone azomethine derivatives 26

2.9 General structure of acetamidic derivatives of benzo-2-pyrone

28

2.10 Synthesis of amide derivatives of benzo-2-pyrone 28

2.11 Synthesis of 3,6-substituted derivatives of benzo-2-pyrone 28

2.12 Structure of 4-chlorobenzo-2-pyrone 28

2.13 Structure of 7-hydroxy-3-nitrobenzo-2-pyrone 29

2.14 Synthesis of new derivatives of benzo-2-pyrone 29

2.15 Structure of 7-amino-4-methylbenzo-2-pyrone 29

2.16 General structure of N-substituted acetamide derivatives 31

2.17 General structure of acetamide derivatives bearing 1,3,4-oxadiazole

31

2.18 General structure of pyrazole derivatives 31

3.1 Esterification of carboxylic acids 34

3.2 O-Substitution of phenol 35

3.3 Carbohydrazide formation 35

3.4 1,3,4-Oxadiazole formation from carbohydrazide 36

3.5 S-Substitution of 1,3,4-oxadiazole 36

3.6 Carbohydrazide formation from ester 36

3.7 N-Substitution of hydrazone 37

3.8 Synthesis of benzo-2-pyrone 38

XIX

3.9 Alkylation of benzo-2-pyrone 38

3.10 Acylation of benzo-2-pyrone 38

3.11 Acetamide formation 39

3.12 7-Substituted acetamide derivatives of benzo-2-pyrone 39

3.13 4-Substituted acetamide derivatives of benzo-2-pyrone 40

3.14 O-Substitution of benzo-2-pyrone 40

3.15 Carbohydrazide from benzo-2-pyrone 40

3.16 Synthesis of 1,3,4-oxadiazole bearing benzo-2-pyrone 41

3.17 S-Substitution of 1,3,4-Oxadiazole bearing benzo-2-pyrone 41

4.1 General mechanism for ester formation 167

4.2 General mechanism for carbohydrazide formation 168

4.3 General mechanism for 1,3,4-oxadiazole formation 169

4.4 General mechanism for S-substitution 169

4.5 General mechanism for azomethine formation 170

4.6 Mechanism for O-substitution 171

4.7 Aromatic region of PNMR spectrum of VIII79 171

4.8 Aliphatic region of PNMR spectrum of VIII79 172

4.9 DEPT135 of CNMR spectrum of VIII126 173

4.10 DEPT90 of CNMR spectrum of VIII126 174

4.11(a) BB of CNMR spectrum of VIII126 175

4.11(b) BB of CNMR spectrum of VIII126 175

4.12 EIMS spectrum of VIII71 176

4.13 Mass fragmentation pattern of VIII71 177

4.14(a) PNMR spectrum of XII 178

4.14(b) PNMR spectrum of XII 178

4.15 Mechanism for benzo-2-pyrone ring formation 179

4.16 PNMR spectrum of XIX1 180

4.17 DEPT135 of CNMR spectrum of XIX1 181

4.18 DEPT90 of CNMR spectrum of XIX1 181

4.19 BB of CNMR spectrum of XIX1 182

4.20 EIMS spectrum of XIX9 182

4.21 Mass fragmentation pattern of XIX9 183

4.22 PNMR spectrum of XXI1 184

4.23(a) PNMR spectrum of XXIV26 185

4.23(b) PNMR spectrum of XXIV26 185

4.24 EIMS spectrum of XXIV13 186

4.25 Mass fragmentation pattern of XXIV13 187

4.26(a) PNMR spectrum of XXVI18 188

4.26(b) PNMR spectrum of XXVI18 188

4.26(c) PNMR spectrum of XXVI18 189

XX

4.27 EIMS spectrum of XXVI5 189

4.28 Mass fragmentation pattern of XXVI5 190

4.29(a) PNMR spectrum of XXX6 190

4.29(b) PNMR spectrum of XXX6 191

4.30 EIMS spectrum of XXX16 191

4.31 Mass fragmentation pattern of XXX16 192

4.32 Inhibition potential against B. subtilis for VIII1-133, XV1-13 197

4.33 Inhibition potential against S. aureus for VIII1-133, XV1-13 198

4.34 Inhibition potential against S. typhi for VIII1-133, XV1-13 199

4.35 Inhibition potential against E. coli for VIII1-133, XV1-13 199

4.36 Inhibition potential against P. aeruginosa for VIII1-133, XV1-

13

200

4.37 Inhibition potential against LOX for VIII1-133, XV1-13 200

XXI

LIST OF ABBREVIATIONS

BEB 2-Bromoethanoyl bromide

% percent

& and

µL Micro liter

AcOH Acetic acid

Aq. Aqueous

Ar Aromatic

BB Broad Band

BP Base peak in mass spectrum

CH3CN Acetonitrile

CHCl3-d1 Deuterated chloroform

CNMR Carbon-13 Nuclear Magnetic Resonance

Conc. Concentrated

CS2 Carbon disulfide

d Doublet

dd Doublet of doublet

DEE Diethylether

DEPT Distorsionless Enhancement by Polarization Transfer

Dist. Distilled

DMF N,N-Dimethylformamide

DMSO-d6 Deuterated dimethylsulfoxide

DNA Deribonucleic acid

dt Doublet of triplet

EBE Ethyl 2-bromoethanoate

EEE Ethyl 2-ethanoylethanoate

EIMS Electron impact mass spectrometry

Et Ethyl

Etc etcetera

EtOAc Ethyl acetate

EtOH Ethanol

Glac. Glacial

H2O Water

H2SO4 Sulfuric acid

HIV Human immunodeficiency virus

hr hour

HRMS High resolution mass spectrometry

hrs hours

XXII

Hz Hertz

i.e. that is

IC50 Inhibitory Concentration for 50% inhibition

IR Infra red

KOH Potassium hydroxide

LiH Lithium hydride

LOX Lipoxygenase

m Multiplet

[M]+ Molecular ion peak in mass spectrum

M.P. Melting point

m/z Mass to charge ratio

ME Microsoft Excel

MeOH Methanol

MHz Mega Hertz

MIC Minimum inhibitory concentration

mins minutes

mL Milli liter

mm millimeter

mRNA Messenger ribonucleic acid

N2H4.H2O Hydrated hydrazine

Na2CO3 Sodium carbonate

NaOH Sodium hydroxide oC Degree Celsius

pH Power of hydrogen

PNMR Proton Nuclear Magnetic Resonance

ppm Parts per million

q Quartet

qui Quintet

RB flask Round Bottom flask

RT Room temperature

s Singlet

SAR Structure Activity Relationship

SEM Standard Error of Mean

soln. solution

str. Stretching

t Triplet

TLC Thin Layer Chromatography

1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone Introduction

Page 1

CHAPTER ONE

Introduction


Page 2

1.0 General

Organic synthesis is extensively applied to synthesize new molecules followed by

pharmacological evaluation in search of new drug candidates. Two modes are

generally applied to synthesize new molecules, one by using the already known

methodology and other by using some new methodologies. My research project is

related to the first one because the valuable biological activities of 1,3,4-oxadiazole,

azomethine, benzo-2-pyrone and acetamide functionalities prompted me to synthesize

new compounds bearing these ones.

As my objective was to introduce some new compounds with pharmacological

evaluation, so my introduction in this dissertation is strictly emphasizing on different

pharmacological activities shown by the discussed functionalities and not the various

synthetic routes for these moieties along with their physical/chemical properties.

Furthermore, references have been provided for the different reaction procedures

employed for the synthesis of target molecules in experimental section.

1.1 Oxadiazole compounds

Oxadiazole is a heterocyclic five membered ring with resemblance to furan except

two nitrogen atoms instead of two carbons. It is an isomeric ring with four different

isomers which differ due to the position of two nitrogen atoms relative to that of

oxygen [1], see Figure-1.1.

O

N

N

1,2,3-Oxadiazole

N

O

N N

O

N

1,2,5-Oxadiazole

N

O

N

1,3,4-Oxadiazole1,2,4-Oxadiazole

Figure-1.1: Isomeric forms of oxadiazole

1.1.1 Nomenclature of oxadiazole ring

The name of oxadiazole is a mixture of different symbols such as oxa+di+az+ole.

Here ‘oxa’ for ‘oxygen’, ‘di’ for ‘two’, ‘az’ for ‘nitrogen’ and ‘ole’ for ‘five

membered ring’. Oxygen is preferably mentioned first in the name and then nitrogen

with prefix ‘di’ for two [2].

1.1.2 1,3,4-Oxadiazole

Among all the four isomeric forms, 1,3,4-oxadiazole is known to cover a wide range

of biological activities of pharmacological importance. Therefore the scient ists are

trying to incorporate new molecules derived from or bearing 1,3,4-oxadiazole moiety

to achieve more valuable biological results.


Page 3

1.1.3 Biological activities

The biological activities of a large number of 1,3,4-oxadiazole derivatives have been

investigated [3-64]. A number of references are included here to emphasize on the

synthetic work on this 1,3,4-oxadiazole heterocyclic ring regarding its biological

activities. To avoid complication, only a few of these biological activities have been

listed in Figure-1.2.

N

O

N

1,3,4-Oxadiazole

antibacterial anti-enzymatic

anti-inflammatory

antifungal antiviral

anticancer antitumor

antioxidant

Figure-1.2: Biological activities of 1,3,4-oxadiazole

1.1.4 Importance of 1,3,4-oxadiazole

Again to emphasize the synthetic work on this ring and its importance in

pharmacology, the number of publications has been given in Table-1.1 for 2000 to

2012. The given data clearly demonstrates the increment in the number of

publications till 2011 from 2000 with a few ups and downs. There is some ups and

down between 2002 to 2007 but there is rise from 2000 to 2002, 2005 to 2006 and

then 2007 to 2011 [65].

Table-1.1: List of publications on 1,3,4-oxadiazole

Year Publications Year Publications Year Publications

2000 95 2005 190 2010 307 2001 120 2006 219 2011 319

2002 169 2007 214 2012 166 2003 146 2008 229 2004 149 2009 254

1.2 Azomethine compounds

The doubly bonded carbon and nitrogen (-CH=N-) on the whole are called

azomethine moiety (Figure-1.3). This linkage is created by the reaction of carbonyl

compounds (including aldehydes & ketones) with primary amines (R-NH2). The


Page 4

compounds bearing this moiety are also called Schiff bases. This moiety has been

known to possess a stretching vibration in IR spectrum in the range of 1690-1640 cm-1

[66-68]. Such type of compounds synthesized by the reaction of carbohydrazides and

carbonyl compounds are usually referred as hydrazones instead of Schiff bases.

R N CH R1

Figure-1.3: Azomethine moiety

In the general structure of azomethine given in Figure-1.3, R and R1 are different

aliphatic or aromatic substitutents.


Such type of compounds is also valuable because of a large number of biological

activities including antimicrobial, anti-enzymatic, anticancer, anti- inflammatory etc

[66-82]. Although compounds incorporating this moiety are not still commercialized

as drug molecules yet literature review has demonstrated much of their valuable

activities.

1.3 Benzo-2-pyrone compounds

Benzo-2-pyrone, also known as benzo-α-pyrone or coumarin, consists of two six

membered rings fused together. One of them is benzene ring and the other is oxane

containing an ‘oxo’ (ketonic) group. The basic skeleton is shown in Figure-1.4.

O O

Figure-1.4: Basic skeleton of benzo-2-pyrone

The derivatives of this moiety are also found naturally in many plants including

licorice, strawberries, vanilla grass woodruff, sweet clover etc in different forms,

known as its classification [83].


The different derivatives of benzo-2-pyrone have been also investigated for a number

of biological activities including antimicrobial, anticancer, antioxidant, anti-enzymatic

(including tyrosinase, monoamine oxidase-B etc), anti- inflammatory activities etc

[84-153].

The molecules bearing this moiety which are incorporated in the presented

research work are given in Figure-1.5.


Page 5

O OHO

Cl

CH3

O O

OH

6-chloro-7-hydroxy-4-methylbenzo-2-pyrone 4-hydroxybenzo-2-pyrone

Figure-1.5: Derivatives of benzo-2-pyrone

1.4 Acetamide compounds

The acetamide compounds bear acetamoyl moiety in which a carbonyl group is

attached to a nitrogen atom (-CO-N<, Figure-1.6). This linkage can be generated by

the reaction of carbonyl containing compounds (except aldehydes and ketones which

do not have good leaving group so no nucleophilic substitution but nucleophilic

addition) with primary or secondary amines.

R N C R2

OR1

Figure-1.6: Acetamoyl moiety


The molecules with acetamoyl group have also been known to possess a variety of

biological activities including antimicrobial, anti-enzymatic etc. This linkage has also

been employed as intermediate to synthesize molecules with multiple functionalities

[154-167].

1.5 Antibacterial activity

Antibiotics are microbial metabolites with low mol. wt. which inhibit the growth of

other microorganisms at low conc. The inhibition mode can be bacteriostatic

(inhibition only in the presence of antibiotic) or bactericidal (permanent inhibition).

The antibiotic as therapeutic agent should be [168],

1. Stable & effective

2. Less toxic

3. Completely metabolized and eliminated from body

1.5.1 Antibacterial assays

A number of methods are employed to investigate the antibacterial behavior of a drug

but commonly two are in use [168].

1. Turbidometric (tube dilution) assay: The organisms are allowed to grow in

test tubes with different conc. of antibiotics. The inhibition is indicated by the


Page 6

disappearance of turbidity. The lowest conc. inhibiting completely the growth

of organisms is called minimum inhibitory conc. (MIC).

2. Plate assay: Filter paper discs impregnated with different conc. of antibiotics

are dried and placed on agar medium seeded with organism and incubated.

Because of diffusion of antibiotic to agar medium, the size of clear zone

increases whose diameter is measured in millimeters (mm).

1.5.2 Antibacterial mechanism

The kinetics of bacterial growth has been studied and is known to compose of four

different phases named as lag phase, log phase, stationary phase and death phase, as

illustrated below [168]. Also see the Figure-1.7.

Time

Log c

ell

num

ber

Lag phase

Log phase

Stationary phase

Death phase

Figure-1.7: Phases of bacterial growth

1. Lag phase: When bacteria are transferred to another medium, they take time

to adjust to the conditions or environment of the surrounding. This duration is

related to the physiological conditions including temperature, nature of

medium, contents of the medium etc.

2. Log phase: Now growth of cell mass increases rapidly and roughly double of

cell number per unit time. This organism growth phase is termed as

trophophase and antibiotic production phase is called idiophase.

3. Stationary phase: The growth of microorganism is stopped although

composition of cell may change. This phase is present because of the

production of antibiotics, the idiophase.

4. Death phase: Reserved energy of organism cells is used up and death starts.

The antibacterial action of different drugs involves the disruption of bacterial cell

growth and has five different modes [168].


Page 7

1. Inhibition of cell wall synthesis: This mode disrupts mucopeptide

(constituting the major part of bacteria cell wall) synthesis.

2. Disruption of DNA metabolism: This mode involves the interruption in

replication & synthesis of DNA, transcription of genetic mode, synthesis of

mRNA or synthesis & assembly of ribosomes.

3. Inhibition of protein synthesis: This mode directly influences the normal

assembly of amino acids for protein synthesis at the surface of mRNA.

4. Alteration of cell membrane permeability: This mode involves the direct

interaction with cell membrane and results the leakage of cytoplasmic solute.

5. Inhibition of cell metabolism: This mode inhibits the synthesis of different

metabolites required for cell growth.

1.5.3 Gram-bacteria

Bacteria are grouped as Gram-positive and Gram-negative bacteria. This grouping is

based upon Gram-staining method, introduced by Christian Gram. In this method, the

bacterial culture is treated with a solution of a dye crystal violet, iodine solution and

washed with an alcohol. The bacteria which retain the violet color are called Gram-

positive bacteria and that which appear red are called Gram-negative bacteria [168].

Gram-positive and Gram-negative differ by their different cell wall structure.

The Gram-negative bacteria have a thinner but more complex cell wall as compared

to that of the Gram-positive bacteria [168].

Five bacterial strains (two Gram-positive bacteria, listed as 1 & 2, and three

Gram-negative bacteria, listed 3 to 5) are used to investigate the antibacterial potential

of all the synthesized molecules listed and discussed in this dissertation. The general

introduction, regarding their role in different diseases, for these five strains taken into

account is given below.

1. Bacillus subtilis (B. subtilis): It is believed to be harmless but is the source of

an enzyme named ‘subtilisin’ which causes dermal allergic or hypersensitivity

reactions because of long exposure [169].

2. Staphylococcus aureus (S. aureus): It is pathogenic bacteria because of its

ability to adhere to the extracellular matrix and plasma proteins on the

biomaterials [170].

3. Salmonella typhi (S. typhi): This bacterial strain is pertained to enteric fever

and some other diseases [171].

4. Escherichia coli (E. coli): It is also considered to be harmless but it can cause

food poisoning [172].


Page 8

5. Pseudomonas aeruginosa (P. aeruginosa): This bacterial strain can be the

cause of chronic infection and some other diseases [173].

1.6 Enzyme inhibition activity

The different enzymes are involved in various biological processes happening in the

body. The abnormal behavior of some of enzymes causes different diseases. So the

inhibition of such enzymes is used to cure the caused diseases.

1.6.1 Inhibition mechanism

The molecules which can decrease or stop the enzyme activity by some type of

interactions are called inhibitors. Inhibition of enzymes can be of two modes

including competitive or non-competitive and so the inhibitors can be classified as

well. The effects of both types of inhibitors on rate and how to minimize them can be

summarized as below [174].

1. Competitive inhibitors: These inhibitors compete with substrate for the

active site of enzyme and this can be minimized by increasing the conc. of

substrate.

2. Non-competitive inhibitors: These inhibitors bind to enzyme at different site

from that of substrate. These can bind to either free enzyme or the enzyme-

substrate complex and hence reaction is prevented.

1.6.2 Lipoxygenase enzyme

Lipoxygenase (EC 1.13.11.12) enzyme is extensively spread in animals & plants. It is

a non-haem iron dioxygenase. Lipoxygenases are responsible for biosynthetic route

producing a number of bio-regulatory molecules in mammals [175-181].

Among various products of lipoxygenases, one is leukotriene, the mediator of

different inflammatory disorders like bronchial asthma. These enzymes are known to

take part in thrombosis & tumor angiogenesis, organization of newly capillary

vessels, many physiological processes and development of many pathological

conditions. Hence, these enzymes are thought to be the objective for introduction of

new inhibitors to cure different disorders like bronchial asthma, inflammation etc

[175-181].

1.6.3 Active site of lipoxygenase enzyme

Iron of lipoxygenase is known to attach the histidine ligands, responsible for the

activity of this enzyme. Three nitrogen atoms and one oxygen atom of histidine

residues are coordinated to iron. Some additional coordinate bonds are also observed

for iron in different types of lipoxygenase enzymes [182-184].


Page 9

1.6.4 Baicalein

Baicalein belongs to the class of flavonoid and is used as reference drug in the

presented dissertation for comparison of the results of lipoxygenase enzyme inhibition

activity of the synthesized molecules, as shown and discussed in results and

discussion section.

This flavonoid is known as inhibitor of lipoxygenase enzymes [185] and so as

anti- inflammatory drug [186]. In addition to this activity, it has shown anti-

proliferative effects [187] and antidepressant effects [188].

1.7 Aim of work

The synthesis of new compounds by using working methodologies is going on

research. Such compounds are extensively evaluated for different biological activities

including antimicrobial, anti-enzymatic etc. in search of new drug candidates for the

different diseases.

The heterocyclic compounds, restricting myself to five membered ring and

then to oxadiazole particularly 1,3,4-oxadiazole, demonstrated the pharmacological

importance because of a broad spectrum of biological activities (as referenced in

introduction section). In addition to this heterocyclic moiety, benzo-2-pyrone,

commonly known as coumarin, has also gained much importance in the field of

medicinal chemistry.

The aim or prime objective of this demonstrated work was to inaugurate some

new molecules with more considerable and valuable results of biological activities.

Owing to the known biological activities of 1,3,4-oxadizole, azomethine, benzo-2-

pyrone and acetamide derivatives, it was decided to synthesize some new compounds

bearing multiple functionalities as one unit. To boost up the potential of 1,3,4-

oxadiazole, azomethine moiety was assembled with it through a multiple step

synthesis and likewise the benzo-2-pyrone was assembled with acetamoyl moiety.

Moreover, the synthesized compounds were investigated for their potential as new

drug candidates against certain bacterial strains and enzymes. The general view of the

target molecules is given below in Figure-1.8.

The target molecules were decided to include 1,3,4-oxadiazole ring with

variation at 2nd and 5th position incorporating the azomethine functionality and benzo-

2-pyrone ring with variation at 4th, 6th and 7th positions incorporating the acetamoyl

functionalities. Both the azomethine and acetamoyl functionalities have been varied

through different N-substituents.


Page 10

R O

NN

S

O

HN N

HC R1

1,3,4-oxadiazole and azomethine derivatives

R = aryl

R1 = aryl

O OR2

R3

R4

Benzo-2-pyrone and acetamide derivatives

R2 = H or = (alkyl/aralkyl/acyl)oxy or = N-substituted-2-acetamoyloxy or = 2-(N-substituted-2-acetamoylthio)- 1,3,4-oxadiazol-5-ylmethyloxy

R3 = H or Cl

R4 = methyl or N-substituted-2-acetamoyloxy

Figure-1.8: Target molecules

1.8 Plan of work

The synthesis of two hundred and thirty four (234) compounds has been presented in

this dissertation and their protocol is elaborated in different seven (7) schemes,

sketched below.

Scheme-1 is about the synthesis of one hundred and thirty three (133) 1,3,4-

oxadiazole bearing azomethine derivatives from different eight (8) carboxylic acids.

Scheme-2 is about the synthesis of thirteen (13) 1,3,4-oxadiazole bearing azomethine

derivatives from a di-substituted phenol.

Scheme-3 is about the synthesis of seventeen (17) 7-substituted benzo-2-pyrone

derivatives through O-alkylation or acylation of benzo-2-pyrone.

Scheme-4 is about the synthesis of twenty seven (27) acetamidic electrophiles from

different alkyl/aralkyl/aryl amines.

Scheme-5 and Scheme-6 is about the synthesis of forty four (44) acetamide

derivatives of benzo-2-pyrone by using two different starting compounds bearing this

moiety.

Scheme-7 is about the synthesis of twenty seven (27) 1,3,4-oxadiazole-acetamide

derivatives of benzo-2-pyrone.


Page 11

I1-8

COOH

R

COOEt

R

CONHNH2

R

II1-8 III1-8

RO

NN

SH

IV1-8

RO

NN

S

V1-8

OEt

O

RO

NN

S

VI1-8

NHNH2

O

RO

NN

S

VIII1-133

NH

O

N

CH

A B

C

D

E

F

1

34

1'3'

5'

1''2''

7'''

R1

1'''

3'''

5'''

Scheme-1: Synthesis of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-

yl)thio]acetohydrazide (VIII1-133). Reagents and conditions: (A) EtOH, conc.

H2SO4, reflux for 6-8 hrs (B) 80% N2H4.H2O, MeOH, stir for 6-8 hrs or reflux for 4-6

hrs (C) CS2, KOH, EtOH, reflux for 6-8 hrs (D) Ethyl 2-bromoethanoate (EBE), LiH,

DMF, stir for 4-6 hrs (E) 80% N2H4.H2O, MeOH, stir for 4-6 hrs (F) R1C6HxCHO

(VII1-19), Glac. AcOH, MeOH, stir for 2-4 hrs.


Page 12

Table-1.2: List of R- and R1-groups for VIII1-16

R Compound R1 Compound R1

H

VIII1 H VIII9 3-NO2

VIII2 2-CH3 VIII10 4-NO2 VIII3 3-CH3 VIII11 4-N(CH3)2

VIII4 4-CH3 VIII12 4-N(C2H5)2 VIII5 2-OH VIII13 2-OCH3, 3-OCH3 VIII6 3-OH VIII14 2-OCH3, 4-OCH3

VIII7 4-OH VIII15 2-OCH3, 5-OCH3 VIII8 2-NO2 VIII16 3-OCH3, 4-OCH3



2-Cl

VIII17 H VIII25 3-NO2

VIII18 2-CH3 VIII26 4-NO2 VIII19 3-CH3 VIII27 4-N(CH3)2 VIII20 4-CH3 VIII28 4-N(C2H5)2

VIII21 2-OH VIII29 2-OCH3, 3-OCH3 VIII22 3-OH VIII30 2-OCH3, 4-OCH3




3-Cl

VIII33 H VIII41 3-NO2 VIII34 2-CH3 VIII42 4-NO2

VIII35 3-CH3 VIII43 4-N(CH3)2 VIII36 4-CH3 VIII44 4-N(C2H5)2 VIII37 2-OH VIII45 2-OCH3, 3-OCH3


VIII40 2-NO2 VIII48 3-OCH3, 4-OCH3



4-Cl

VIII49 H VIII57 3-NO2 VIII50 2-CH3 VIII58 4-NO2 VIII51 3-CH3 VIII59 4-N(CH3)2

VIII52 4-CH3 VIII60 4-N(C2H5)2 VIII53 2-OH VIII61 2-OCH3, 3-OCH3

VIII54 3-OH VIII62 2-OCH3, 4-OCH3 VIII55 4-OH VIII63 2-OCH3, 5-OCH3 VIII56 2-NO2 VIII64 3-OCH3, 4-OCH3


Page 13



4-CH3

VIII65 H VIII75 4-N(CH3)2

VIII66 2-CH3 VIII76 4-N(C2H5)2 VIII67 3-CH3 VIII77 2-OCH3, 3-OCH3

VIII68 4-CH3 VIII78 2-OCH3, 4-OCH3 VIII69 2-OH VIII79 2-OCH3, 5-OCH3 VIII70 3-OH VIII80 3-OCH3, 4-OCH3

VIII71 4-OH VIII81 4-OCH3 VIII72 2-NO2 VIII82 2-Cl, 4-Cl

VIII73 3-NO2 VIII83 2-Cl, 6-Cl VIII74 4-NO2



4-OH

VIII84 H VIII94 4-N(CH3)2 VIII85 2-CH3 VIII95 4-N(C2H5)2

VIII86 3-CH3 VIII96 2-OCH3, 3-OCH3 VIII87 4-CH3 VIII97 2-OCH3, 4-OCH3

VIII88 2-OH VIII98 2-OCH3, 5-OCH3 VIII89 3-OH VIII99 3-OCH3, 4-OCH3 VIII90 4-OH VIII100 4-OCH3

VIII91 2-NO2 VIII101 2-Cl, 4-Cl VIII92 3-NO2 VIII102 2-Cl, 6-Cl VIII93 4-NO2



2-Cl, 4-Cl

VIII103 H VIII111 4-N(CH3)2

VIII104 2-CH3 VIII112 2-OCH3, 3-OCH3 VIII105 3-CH3 VIII113 2-OCH3, 4-OCH3

VIII106 4-CH3 VIII114 2-OCH3, 5-OCH3 VIII107 3-OH VIII115 3-OCH3, 4-OCH3 VIII108 4-OH VIII116 2-Cl, 4-Cl

VIII109 2-NO2 VIII117 2-Cl, 6-Cl VIII110 4-NO2



3,4-OCH2O

VIII118 H VIII126 3-NO2

VIII119 2-CH3 VIII127 4-NO2 VIII120 3-CH3 VIII128 4-N(CH3)2 VIII121 4-CH3 VIII129 4-N(C2H5)2




Page 14

OH OCH2COOEt OCH2CONHNH2

O

NN

SH

O

NN

SOEt

O

O

NN

S

NHNH2

O

O

NN

S

XV1-13

NH

O

N

CH

A B

C

D

E

CH3H3C

IX X XI

XII

XIII

XIV

CH3H3C CH3H3C

CH3H3C

H3C CH3

CH3H3C

H3C CH3

O

O

O

O

F

1

34

1'

3'

5'

1''2''

7'''

7'1'''

3'''

5'''R1

Scheme-2: Synthesis of N'-Substituted-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-

oxadiazol-2-yl}thio)acetohydrazide (XV1-13). Reagents and conditions: (A) Ethyl 2-

bromoethanoate (EBE), KOH, EtOH, reflux for 10-12 hrs (B) 80% N2H4.H2O,

MeOH, reflux for 4-6 hrs (C) CS2, KOH, EtOH, reflux for 6-8 hrs (D) Ethyl 2-

bromoethanoate (EBE), LiH, DMF, stir for 4-6 hrs (E) 80% N2H4.H2O, MeOH, stir

for 4-6 hrs (F) R1C6HxCHO (VII1-12,17), Glac. AcOH, MeOH, stir for 2-4 hrs.


Page 15

Table-1.10: List R1-groups for XV1-13

Compound R1 Compound R1

XV1 H XV8 2-NO2

XV2 2-CH3 XV9 3-NO2 XV3 3-CH3 XV10 4-NO2

XV4 4-CH3 XV11 4-N(CH3)2 XV5 2-OH XV12 4-N(C2H5)2 XV6 3-OH XV13 4-OCH3

XV7 4-OH


Page 16

OH

A

C B

Cl

XVI

HO

OHO

Cl

O

CH3XVII

OO

Cl

O

CH3XIX1-9

R2

OO

Cl

O

CH3XXI1-8

C

R3

O

1

35

7

11

1

35

71

35

7

11 11

Scheme-3: Synthesis of 7-Substituted-6-chloro-4-methylbenzo-2-pyrone (XIX1-9,

XXI1-8). Reagents and conditions: (A) Ethyl 2-ethanoylethanoate (EEE), conc.

H2SO4, age for 12 hrs (B) R2X (XVIII1-9), LiH, DMF, stir for 4-6 hrs (C) R3COX

(XX1-8), NaOH, H2O, stir for 1 hr.


Page 17

Table-1.11: List of R2-groups

Compound R2-group Compound R2-group

XIX1 1'

H3C XIX6 1'

H3C3'5'7'

XIX2 1'

H3C3'

XIX7

1'

3'

5' 7'

CH3

8'

XIX3 1'

H3C

3' XIX8

1'

3'

5'7'

Br

XIX4 1'

H3C3'

CH34'

XIX9

1'

3'

5'7'

Br

XIX5 1'

H3C3'

5'



XXI1 1'

H3C XXI5 1'

3'

5'

Cl

XXI2 1'

Br

XXI6

1'

3'

5'

ClCl

XXI3

O

1'

3'

5'

XXI7 1'

3'

5'

S

XXI4 1'

3'

5'

XXI8 1'3'

5'O

N


Page 18

A

XXIII1-27XXII1-27

C

HN

O

BrR4NH2R4

Scheme-4: Synthesis of N-Substituted-2-bromoacetamide (XXIII1-27). Reagents and

conditions: (A) 2-bromoethanoylbromide (BEB), Na2CO3, H2O, stir for 2 hrs.

A

OO

Cl

O

CH3XXIV1-26

1

35

7

OHO

Cl

O

CH3XVII

HN

O

R4

1' 2'

11

Scheme-5: Synthesis of N-Substituted-2-[(6-chloro-4-methylbenzo-2-pyron-7-

yl)oxy]acetamide (XXIV1-26). Reagents and conditions: (A) N-substituted-2-

bromoacetamide (XXIII1-26), LiH, DMF, stir for 4-6 hrs.

A

XXVI1-18

1

35

7

O O

OHXXV

1'2'

O O

O

NH

O

R4

Scheme-6: Synthesis of N-Substituted-2-[(benzo-2-pyron-4-yl)oxy]acetamide

(XXVI1-18). Reagents and conditions: (A) N-substituted-2-bromoacetamide (XXIII3-

5,7-13,16-19,21,22,25,26), LiH, DMF, stir for 4-6 hrs.


Page 19

OH

O

NN

S

XXX1-27

NH

O

R4

A

Cl

XVII

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7'

OO

CH3

OCH2COOEt

Cl

XXVII

OO

CH3

OCH2CONHNH2

Cl

XXVIII

OO

CH3

O

NN

SH

Cl

OOO

CH3

B

C

D

XXIX

12'

Scheme-7: Synthesis of N-Substituted-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-

yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX1-27). Reagents and

conditions: (A) Ethyl 2-bromoethanoate (EBE), LiH, DMF, stir for 4-6 hrs (B) 80%

N2H4.H2O, MeOH, stir for 4-6 hrs (C) CS2, KOH, EtOH, reflux for 6-8 hrs (D) N-

substituted-2-bromoacetamide (XXIII1-27), LiH, DMF, stir for 4-6 hrs.


Page 20



XXIV1, XXX1 1''

3''

5''

XXIV13, XXVI10,

XXX13

1''

3''

5''

COOCH3

7'' 8''

XXIV2, XXX2 1''

3''

5''

7''

XXIV14, XXX14 1''

3''

5''

Br

XXIV3, XXVI1,

XXX3 1''

3''

5''

7''

8''

XXIV15, XXX15 1''

3''

5''

O2N

XXIV4, XXVI2,

XXX4 1''

3''

5''

XXIV16, XXVI11,

XXX16

1''

3''

5''

CH3

CH3

7''

8''

XXIV5, XXVI3,

XXX5

1''

3''

5''

CH3

7''

XXIV17, XXVI12,

XXX17

1''

3''

5''

CH3H3C7''8''

XXIV6, XXX6

1''

3''

5''

CH3

7''

XXIV18, XXVI13,

XXX18 1''

3''

5''

CH3

H3C

7''

8''

XXIV7, XXVI4,

XXX7

1''

3''

5''

H3C7''

XXIV19, XXVI14,

XXX19 1''

3''

5''

CH3

CH3

7''

8''

XXIV8, XXVI5,

XXX8

1''

3''

5''

CH2CH3

7'' 8''

XXIV20, XXX20

1''

3''

5''

CH3

H3C

7''

8''

XXIV9, XXVI6,

XXX9

1''

3''

5''

H3CH2C7''8''

XXIV21, XXVI15,

XXX21

1''

3''

5''

CH3

H3C

7''

8''

XXIV10, XXVI7,

XXX10

1''

3''

5''

OCH3

7''

XXIV22, XXVI16,

XXX22 1''

3''

5''

CH2CH3

CH3

7'' 8''

9''

XXIV11, XXVI8,

XXX11

1''

3''

5''

OCH2CH3

7'' 8''

XXIV23, XXX23 1''

3''

5''

Br CH3

7''

XXIV12, XXVI9,

XXX12

1''

3''

5''

H3CH2CO7''8''

XXIV24, XXX24 1''

3''

5''

O2N CH3

7''


Page 21

Table-1.13: (continued)


XXIV25, XXVI17,

XXX25 1''

3''

5''

CH3

NO2

7''

XXX27 N

1''

3''

5''

H3C7''

XXIV26, XXVI18,

XXX26 1''

3''

5''

OCH3

7''

Cl

1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone Literature Survey

Page 22

CHAPTER TWO

Literature Survey


Page 23

2.0 1,3,4-Oxadiazole derivatives

A brief survey is elaborated here otherwise majority of references have been provided

in Chapter one. Andrews and Ahmed synthesized 1,3,4-oxadiazole, 1,3,4-thiadiazole

and 1,3,4-triazole from a N'-substituted thiosemicarbazide derivative [189].

R NH

O

NH NH2

S

N

S

N

R NH2

N

NH

N

R SH

NH3

NaOH

NaOH

N

O

N

R NH2

conc. H2SO4

I2 / KI

1,3,4-Thiadiazole

1,3,4-Triazole

1,3,4-Oxadiazole

Figure-2.1: Synthesis of heterocyclic rings from N'-substituted thiosemicarbazide

Khiati et al. started with L-tartaric acid to synthesize 1,3,4-oxadiazole and 1,3,4-

triazole derivatives and evaluated these compounds for the antimicrobial activity

against certain microorganisms with considerable results [3].

COOH

COOH

OHH

OH H

Figure-2.2: Structure of L-Tartaric acid

Rashid et al. converted 1,2-diaminobenzene into benzimidazole nucleus and then into

1,3,4-oxadiazole derivatives through different steps. All the compounds were

evaluated for their anticancer activity and found valuable anticancer agents [4].

NH

N

O N

N

O

R

NH

N

O N

N

O

N

R

Figure-2.3: General structure of imidazole derivatives


Page 24

Rani et al. prepared 1,3,4-oxadiazole and some other cyclic compounds from

azomethine derivatives of pyridin-4-ylcarbohydrazide and evaluated for the

antibacterial potential [5].

N

O

HN

NH2

N

O

HN

N

CH

R

N

O

NN

R

O

CH3

N

O

NN

R

N

O

HN N Cl

R

O

N-[3-chloro-2-substituted-4-oxoazetidin-1-yl]isonicotinamide

4-[5-substituted-1,3,4-oxadiazol-2-yl]pyridine

RCHO Ac2OMeOHconc. H2SO4

ClCH2COCl

Figure-2.4: Synthesis of pyridine derivatives

Cui et al. synthesized 1,3,4-oxadiazole derivatives bearing substituted furan moiety

from diacylhydrazine and acylhydrazone as intermediates by microwave irradiation as

fast method of synthesis. All the compounds demonstrated valuable antifungal

activity against some certain fungal strains [6].

COOH

R

CONHNH2

R

NH2

R1

R1

O

COOH

R1

O O

NN

R

Figure-2.5: Synthesis of furan derivatives


Page 25

Some of the bioactive compounds incorporating 1,3,4-oxadiazole nucleus are listed in

Table-2.1.

Table-2.1: Examples of bioactive molecules bearing 1,3,4-oxadiazole

Structure Biological

activities Reference

N

O

NHO

OO

Antibacterial

activity [11]

N

O

NCl

Cl

O

ON

Cl

Cl

Anti-inflammatory

activity [12]

N

O

NF

S

H3C

OO

Antifungal activity

[16]

N

O

NCl

H2N

Antibacterial

activity [65]

N

O

NHO

H2N

Br

Antimicrobial activity

[65]

N

O

NO

H2N

F

Anticonvulsant

activity [65]

N

O

N

NH

H3C

HO

F

F

Anti-inflammatory

activity

[65]

N

O

N

NH

F

HN

Cl

Cl

Analgesic

activity [65]


Page 26

2.1 Azomethine derivatives:

Narsibhai et al. yielded acetohydrazide from 1H-1,2,3-benzotriazol-5-yl(phenyl)

methanone and then synthesized its azomethine and further thiazolidinone derivatives.

Compounds were evaluated for antibacterial and antifungal activities [66].

NH

N

N1. BrCH2CO2Et

2. NH2NH2

3. RCHO

N

N

N

CONHN=CHR1H-1,2,3-benzotriazol-5-yl(phenyl)methanone

Azomethine derivatives

SHCH2COOH

N

N

N

HN

O

N S

R

O

Thiazolidine derivatives

PhCO PhCO

PhCO

Figure-2.6: Synthesis of Thiazolidine derivatives

Somani et al. synthesized azomethine compounds from carbohydrazide of nicotinic

acid and screened them for antibacterial, antifungal, antiviral, cytotoxic and anti-HIV

activities [67].

N N

O

NN

SHCONHNH2

N

O

NN

S

O

HN N

HC R

Figure-2.7: Synthesis of Azomethine derivatives

Zhang et al. presented the synthesis of 4-azomethine substituted coumarin derivatives

from 5-substituted resorcinol and further studied their antioxidant activity [68].

O O

R

OPh

N

R1

Figure-2.8: General structure of benzo-2-pyrone azomethine derivatives


Page 27

Some of the bioactive compounds have been listed in Table-2.2 to emphasize the

pharmacology of compounds bearing this moiety.

Table-2.2: Examples of bioactive molecules bearing azomethine



N NH

NO

Anti-inflammatory

activity

[69]

N NH

N

HO

Antimalarial

activity [69]

O

NH

N

Cl

N

N

O2N

Antimalarial

activity [69]

O

NH

N

OH

N

N

OCH3

CH3

N

Antimycobacterial

activity [69]

O

NH

NHN OH

COOH

N

Antimycobacterial

activity [69]

NH

N

OH

NO2

O2N

Antitumoral

activity [69]

O

NH

NO

F

NO2

Antibacterial activity

[69]

N

N

OO

W

CO

CO

COCO

Antioxidant activity

[71]


Page 28

2.2 Benzo-2-pyrone derivatives:

Olomola et al. synthesized various new derivatives of benzo-2-pyrone which was

prepared from 2-hydroxybenzaldehyde and evaluated their potential as dual-action

HIV-1 protease and reverse transcriptase inhibitors [84].

O O

R1

R

N

Cl

Ph

O

Figure-2.9: General structure of acetamidic derivatives of benzo-2-pyrone

Matos et al. synthesized coumarin-3-ylcarbamates as selective monoamine oxidase-B

inhibitors in one step synthesis [85].

O O

NH

O

O

R

O O

NH2

ROCOCl

Figure-2.10: Synthesis of amide derivatives of benzo-2-pyrone

Aggarwal et al. yielded 6-substituted-3-acetyl-benzo-2-pyrone to synthesize further

derivatives and evaluated for anti- inflammatory and antibacterial activities [86].

O O

OH

C

CH3COCH2COOEtH

O

R R

CH3

O

Figure-2.11: Synthesis of 3,6-substituted derivatives of benzo-2-pyrone

Behrami and Krasniqi used 4-chlorobenzo-2-pyrone as starting material to synthesize

various sulfamoyl derivatives and screened them for antibacterial activity [87].

O O

Cl

Figure-2.12: Structure of 4-chlorobenzo-2-pyrone


Page 29

Krasniqi and Behrami used 7-hydroxy-3-nitrobenzo-2-pyrone as precursor to

synthesize its different derivatives in the form of esters and demonstrated their

antibacterial potential [88].

O O

NO2

HO

Figure-2.13: Structure of 7-hydroxy-3-nitrobenzo-2-pyrone

Liu et al. synthesized various derivatives of benzo-2-pyrone from substituted

salicylaldehyde by reaction with ethyl acetoacetate and diethylmalonate to evaluate

their anti-tyrosinase potential [89].

O O

OH

CHO

R

CH3

O

R

O O

OEt

O

R

OEt

O

EtO

O

OEt

O

H3C

O

Figure-2.14: Synthesis of new derivatives of benzo-2-pyrone

Al-Rifai et al. demonstrated the synthesis of such molecules by coupling 7-amino-4-

methylbnezo-2-pyrone with various other reagents and finally tested them for

antibacterial activity (in vitro) [90].

O OH2N

CH3

Figure-2.15: Structure of 7-amino-4-methylbenzo-2-pyrone

Ingale et al. synthesized various 5-substituted-1,3,4-oxadiazol-2-thiol from carboxylic

acids and coupled them with 3-(2-bromoacetyl)benzo-2-pyrone. All the molecules

were tested for anti- inflammatory and analgesic activities [91].


Page 30

Some of bioactive compounds bearing benzo-2-pyrone moiety are listed in Table-2.3.

Table-2.3: Examples of bioactive molecules bearing benzo-2-pyrone



OO

NH

C4H9

Antibacterial activity

[87]

OO

HN

HO

OH

Antibacterial

activity [88]

OO

CH3

Br

H3CO

H3CO

Antioxidant

activity [98]

OO

O

O

C2H5

CH3

H3C

O

CH3

Anticancer activity

[100]

OO

CH3 O

O

NN

N

. 2 HCl

NN

N


[101]

OO

CH3

O

NN

N

. HCl

Antimicrobial

activity [101]

OO

CH3 HO

OH

N

NNH

O

F

Anti-inflammatory

activity

[110]

OO

CH3

S N Cl

Cytotoxic agent [115]


Page 31

2.3 Acetamide derivatives:

Khalid et al. demonstrated synthesis of various N-substituted 1,3,4-oxadiazole

acetamide derivatives and also their potential as anti-bacterial activity [154].

N

O

NN

S

S

O

HN R

OO

Figure-2.16: General structure of N-substituted acetamide derivatives

Aziz-ur-Rehman et al. synthesized different 5-substituted-1,3,4-oxadiazol-2-thiols

and coupled with N-(4-chloroanisol-2-yl)-2-bromoacetamide to evaluate their anti-

enzymatic activity [155].

R O

NN

S

O

HN

H3CO

Cl

Figure-2.17: General structure of acetamide derivatives bearing 1,3,4-oxadiazole

Chambers et al. presented the synthesis of N-substituted-2-(3,5-dimethyl-1-phenyl-

1H-pyrazol-4-yl)acetamides as antagonists of the P2X7 receptor [156].

N

N

O

HN R

CH3

CH3

N-substituted-2-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)acetamides

Figure-2.18: General structure of pyrazole derivatives

Jagessar and Rampersaud evaluated the antimicrobial potential of a series of amides

by Stokes Disc diffusion sensitivity technique and the pour plate method. The

antibacterial and antifungal activities were investigated and found valuable and

pharmacologically important results [157].


Page 32

Some of bioactive compounds bearing acetamide moiety are listed in Table-2.4.

Table-2.4: Examples of bioactive molecules bearing acetamide



Cl

F

NH

O

N

NH

H3C

CH3

Antagonists of

the P2X7 receptor

[156]

HN CH3

O

Antimicrobial

activity [157]

HN CH3

O

Br


[157]

NH2

O

Antimicrobial

activity [157]

NH2

ONO2

Antimicrobial

activity [157]

O

N

O

NH

O

Cl

S. aureus

inhibitor [159]

NH2

O

F

F

Anti-inflammatory

and analgesic activity

[165]

1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone Experimental Work

Page 33

CHAPTER THREE

Experimental Work


Page 34

3.0 General

The manufacturing company and physical characteristics of all the reagents and the

analytical grade solvents, employed in the whole synthetic work, are provided in the

appendices I to VI (Chapter Six). The synthesized compounds were initially affirmed

through customary Thin Layer Chromatography (TLC) and finally through spectral

data analysis. TLC was performed on silica (G-25-UV254) coated aluminum plates

dipped in solvent system of varying concentration of EtOAc and n-Hexane. The

spectral data analysis included PNMR at 300, 400 & 600 MHz and CNMR at 75, 100

& 125 MHz operated through Bruker spectrometers in CHCl3-d1 & DMSO-d6. It also

included IR performed by KBr pellet method operated through Jasco-320-A

spectrophotometer and HRMS/EIMS operated through JMS-HX-110 spectrometer

with a data system. The various abbreviations/symbols used in PNMR, IR & EIMS

are provided in the list of abbreviations.

3.1 Synthesis of N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-

yl)thio]acetohydrazide (VIII1-133, XV1-13)

This scheme consists of nine series with different starting compounds which were

subjected to the synthesis of corresponding ethyl esters, carbohydrazides, 1,3,4-

oxadiazoles, ethyl esters of 1,3,4-oxadiazole, carbohydrazides of 1,3,4-oxadiazole and

finally azomethine derivatives. Eight of these starting compounds were different

carboxylic acids and one was 2,4-dimethylphenol.

3.1.1 General procedure for synthesis of Ethyl carboxylates (II1-8)

The different aryl carboxylic acids (I1-8; 0.1 mol) were taken in a 250 mL round

bottom (RB) flask containing 40 mL EtOH. The mixture was acidified by conc.

H2SO4 in catalytic amount (0.5 mL for 1 g acid). The whole mixture was refluxed for

6-8 hours and monitored through TLC. After maximal completion, because of

reversibility of reaction, the reaction mixture was shifted to 250 mL separating funnel

containing 70 mL H2O and basified for pH 8-10 by conc. aq. Na2CO3 soln. The ethyl

esters, II1-8, were extracted by DEE and collected after distillation [67, 91].

I1-8

COOH

R

COOEt

R

II1-8

EtOH

conc. H2SO4

reflux 6-8 hrs

Figure-3.1: Esterification of carboxylic acids


Page 35

3.1.2 Procedure for the synthesis of Ethyl 2-(2,4-dimethylphenoxy)acetate (X)

2,4-Dimethylphenol (IX; 0.1 mol) was dissolved in 25 mL EtOH in a 100 mL RB

flask. The mixture was basified by solid KOH (0.1 mol) followed by EBE (0.1 mol).

The mixture was refluxed for 10-12 hours and supervised through TLC. Excess of

cold distilled H2O and conc. aq. Na2CO3 soln. were added till pH of 8-10 was

adjusted. The title compound was extracted by DEE and acquired after distillation

[190].

OH OCH2COOEt

EtOH/KOHCH3H3C

IX X

CH3H3Creflux 10-12 hrs

EBE

Figure-3.2: O-Substitution of phenol

3.1.3 General procedure for synthesis of carbohydrazides (III1-8, XI)

The ethyl esters (II1-8, X; 0.1 mol) were mixed with 25 mL MeOH in a 100 mL RB

flask. After addition of N2H4.H2O (0.1 mol), the reaction contents were stirred for 6-8

hrs or refluxed for 4-6 hrs. After single spot by TLC, excess of water was added to

precipitate the products which were filtered. The water soluble products were

obtained after complete evaporation of MeOH and washed with n-hexane [67, 91].

R

II1-8, X

N2H4.H2O

MeOH

stir 6-8 hrs

or reflux 4-6 hrs

OCH2 COOEt

R

III1-8, XI

OCH2 NHNH2

n n

n = 0 or 1

Figure-3.3: Carbohydrazide formation

3.1.4 General procedure for the synthesis of 5-Substituted-1,3,4-oxadiazol-2-

thiol (IV1-8, XII)

The carbohydrazides (III1-8, XI; 0.1 mol) were mixed with 45 mL EtOH in a 100 mL

RB flask. The reaction contents were basified by solid KOH (0.1 mol) on reflux. Then

CS2 (0.2 mol) was added at RT and refluxed for 6-8 hrs. At single spot by TLC,

excess of dist. water was added to form a clear solution. Dil. HCl (a few drops) was

added to adjust pH 5-6 and aged for 1 hr. The precipitated products were collected

through filtration and washed with dist. water. The obtained molecules were re-

crystallized from MeOH [67, 91].


Page 36

RO

NN

SHO

EtOH/KOH

CS2

reflux 6-8 hrs

R

III1-8, XI

OCH2 NHNH2

nn

IV1-8, XII

Figure-3.4: 1,3,4-Oxadiazole formation from carbohydrazide

3.1.5 General procedure for the synthesis of Ethyl 2-[(5-substituted-1,3,4-

oxadiazol-2-yl)thio]acetate (V1-8, XIII)

The 1,3,4-oxadiazoles (IV1-8, XII; 0.1 mol) were dissolved in 25 mL DMF followed

by addition of LiH (0.1 mol) and stirring for 0.5 hr to activate IV1-8 and XII for S-

substitution by replacing acidic proton by lithium. Then EBE (0.1 mol) was added to

the stirred mixture and monitored through TLC. Excess of cold dist. water was added

gradually to mixture and aged for 0.25 hr. Final products were filtered off, washed

with water and re-crystallized from MeOH [154, 155].

RO

NN

SHO

DMF/LiH

EBE

stir 4-6 hrs

n

IV1-8, XII

RO

NN

SO

n

V1-8, XIII

CH2COOEt

Figure-3.5: S-Substitution of 1,3,4-oxadiazole

3.1.6 General procedure for the synthesis of 2-[(5-Substituted-1,3,4-oxadiazol-

2-yl)thio]acetohydrazide (VI1-8, XIV)

The ethyl esters (V1-8, XIII; 0.1 mol) were treated with N2H4.H2O (0.1 mol) by the

same procedure as discussed in section 3.1.3 (page-35). The additional thing in this

procedure was that the products were geared up strictly only on stirring at room

temperature (RT) to avoid decomposition.

MeOH

N2H4.H2O

stir 4-6 hrsR

O

NN

SO

n

V1-8, XIII

CH2COOEt

RO

NN

SO

n

VI1-8, XIV

CH2CONHNH2

Figure-3.6: Carbohydrazide formation from ester


Page 37

3.1.7 General procedure for the synthesis of N'-Substituted-2-[(5-substituted-

1,3,4-oxadiazol-2-yl) thio]acetohydrazide (VIII1-133, XV1-13)

The carbohydrazides (VI1-8, XIV; 0.002 mol) were dissolved in 10 mL MeOH in a 50

mL RB flask. The different aryl carboxaldehydes (R1C6HxCHO, VII1-19; 0.002 mol)

were added along with a few drops of Glac. AcOH. The reaction contents were stirred

for 2-4 hrs and supervised through TLC. Excess of dist. water was added to

precipitate out the final products which were separated through filtration and washed

with dist. water. All the final products were re-crystallized from MeOH [67].

R

VI1-8, XIV

R

VIII1-133, XV1-13

R1

O

NN

S

NHNH2

O

O

NN

S

NH

O

N

CH

O

O

R1C6HxCHO

n

Stir 2-4 hrs

MeOH

n

VII1-19

Figure-3.7: N-Substitution of hydrazone

3.2 Synthesis of 7-Substituted-6-chloro-4-methylbenzo-2-pyrone

(XIX1-9, XXI1-8)

The current scheme demonstrates the synthesis of 7-hydroxy-6-chloro-4-

methylbenzo-2-pyrone nucleus from 4-chloro-1,3-dihydroxybenzene and Ethyl 2-

ethanoylethanoate (EEE) and then its O-substitution by different alkyl/aralkyl/acyl

halides to yield 7-substituted derivatives.

3.2.1 Procedure for the synthesis of 7-Hydroxy-6-chloro-4-methylbenzo-2-

pyrone (XVII)

4-Chloro-1,3-dihydroxybenzene (XVI; 0.1 mol) was completely dissolved in EEE

(0.1 mol) upon gentle heating and shaking in a 500 mL iodine flask. Then 45 mL

conc. H2SO4 was added gradually to the reaction mixture in ice bath at 0 oC. The

whole mixture was aged for 12 hrs at RT. The ice cold dist. water was added to flask

and shook to generate the precipitates of title compound. The solid product was

filtered off and washed by the dist. water. The compound was re-crystallized from

methanol [86, 89].


Page 38

OH

EEE

Cl

XVI

HO OHO

Cl

O

CH3XVII

conc. H2SO4

age 12 hrs

Figure-3.8: Synthesis of benzo-2-pyrone

3.2.2 General procedure for the synthesis of 7-Alkoxy/aralkoxy-6-chloro-4-

methylbenzo-2-pyrone (XIX1-9)

The molecule XVII (0.001 mol) was made to react with different alkyl/aralkyl halides

(R2X, XVIII1-9; 0.001 mol) by same procedure discussed in section 3.1.5 (page-36).

R2XOHO

Cl

O

CH3XVII

OO

Cl

O

CH3XIX1-9

R2XVIII1-9

DMF/LiH

Stir 4-6 hrs

Figure-3.9: Alkylation of benzo-2-pyrone

3.2.3 General procedure for the synthesis of 7-Acyloxy-6-chloro-4-

methylbenzo-2-pyrone (XXI1-8)

The molecule XVII (0.001 mol) was dispersed in 15 mL dist. water in a 100 mL

iodine flask and completely dissolved by the addition of aq. 10% NaOH soln. Then

the different acyl halides (R3COX, XX1-8; 0.001 mol) were added followed by

vigorous shaking for 15 mins and further stirring for 45 mins. TLC was developed to

verify reaction completion. The title compounds were precipitated and collected after

filtration and washing by dist. water [191]. The products were recrystallized in

MeOH.

R3COXOHO

Cl

O

CH3XVIIOO

Cl

O

CH3XXI1-8

C

XX1-8

H2O/NaOH

Shake/Stir 1 hrR3

O

Figure-3.10: Acylation of benzo-2-pyrone


Page 39

3.3 Synthesis of N-Substituted-2-substitutedacetamide (XXIV1-26,

XXVI1-18, XXX1-27)

This heading is comprised of four different schemes including the synthesis of N-

substituted-2-bromoacetamides as electrophiles from different alkyl/aralkyl/aryl

amines and then their reaction with three different nucleophiles to synthesize three

different series of compounds.

3.3.1 General procedure for the synthesis of N-Substituted-2-bromoacetamide

(XXIII1-27)

Various alkyl/aralkyl/aryl amines (XXII1-27; 0.1 mol) were dispersed in 35 mL dist.

water in a 250 mL iodine flask. The pH of reaction was kept strictly 8-10 by aq. 10%

Na2CO3 soln. Then BEB (0.15 mol) was added and shaken vigorously for 15 mins.

The mixture was set to stir for further 1.75 hrs. The precipitated products were

collected after filtration and washed by dist. water [154, 155].

BEB

XXIII1-27XXII1-27

C

HN

O

BrR4NH2R4

H2O/Na2CO3

Shake/Stir 2 hrs

Figure-3.11: Acetamide formation

3.3.2 General procedure for the synthesis of N-Substituted-2-[(6-chloro-4-

methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1-26)

The molecule XVII (0.001 mol) was treated with the synthesized electrophiles

(XXIII1-26; 0.001 mol) and the final products were obtained by the discussed

procedure in section 3.1.5 (page-36).

R4NHCOCH2Br

OO

Cl

O

CH3XXIV1-26

OHO

Cl

O

CH3XVII

HN

O

R4

XXIII1-26

DMF/LiH

Stir 4-6 hrs

Figure-3.12: 7-Substituted acetamide derivatives of benzo-2-pyrone


Page 40

3.3.3 General procedure for the synthesis of N-substituted-2-[(benzo-2-pyron-4-

yl)oxy]acetamide (XXVI1-18)

The molecule, 4-hydroxybenzo-2-pyrone (XXV; 0.001 mol) was made to react with

certain synthesized electrophiles (XXIII3-5,7-13,16-19,21,22,25,26; 0.001 mol) to acquire

different compounds, using the similar method as previously elaborated in section

3.1.5 (page-36).

XXVI1-18

O O

OHXXV

O O

O

NH

O

R4

R4NHCOCH 2Br

XXIII3-5,7-13,16-19,21,22,25,26

DMF/LiH

Stir 4-6 hrs

Figure-3.13: 4-Substituted acetamide derivatives of benzo-2-pyrone

3.3.4 Procedure for the synthesis of Ethyl 2-[(6-chloro-4-methylbenzo-2-pyron-

7-yl)oxy]acetate (XXVII)

The molecule XVII (0.1 mol) was stepped to XXVII (an ethyl ester) by O-

substitution on reaction with EBE (0.1 mol) using the same method discussed in

section 3.1.5 (page-36).

OH

Cl

XVII

OO

CH3

OCH2COOEt

Cl

XXVII

OO

CH3

DMF/LiH

EBE

stir 4-6 hrs

Figure-3.14: O-Substitution of benzo-2-pyrone

3.3.5 Procedure for the synthesis of 2-[(6-Chloro-4-methylbenzo-2-pyron-7-

yl)oxy]acetohydrazide (XXVIII)

The ethyl ester (XXVII; 0.1 mol) was converted to corresponding carbohydrazide,

XXVIII, on stirring in MeOH by the same procedure mentioned in section 3.1.3

(page-35).

OCH2COOEt

Cl

XXVII

OO

CH3

OCH2CONHNH2

Cl

XXVIII

OO

CH3

MeOH

N2H4.H2O

stir 4-6 hrs

Figure-3.15: Carbohydrazide from benzo-2-pyrone


Page 41

3.3.6 Procedure for the synthesis of 5-{[(6-chloro-4-methylbenzo-2-pyron-7-

yl)oxy]methyl}-1,3,4-oxadiazol-2-thiol (XXIX)

The carbohydrazide (XXVIII; 0.1 mol) was subjected to intermolecular cyclization to

corresponding 2,5-disubstituted-1,3,4-oxadiazole by the procedure of section 3.1.4

(page-35).

OCH2CONHNH2

Cl

XXVIII

OO

CH3

O

NN

SH

Cl

OOO

CH3

XXIX

EtOH/KOH

CS2

reflux 6-8 hrs

Figure-3.16: Synthesis of 1,3,4-oxadiazole bearing benzo-2-pyrone

3.3.7 General procedure for the synthesis of N-Substituted-2-[(5-{[(6-chloro-4-

methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide

(XXX1-27)

The 1,3,4-oxadiazole (XXIX; 0.001 mol) was subjected to S-substitution by reaction

with all the synthesized electrophiles (XXIII1-27; 0.001 mol) by the method explicated

in section 3.1.5 (page-36).

O

NN

S

XXX1-27

NH

O

R4

Cl

OOO

CH3

O

NN

SH

Cl

OOO

CH3

XXIX

R4NHCOCH2Br

XXIII1-27

DMF/LiH

Stir 4-6 hrs

Figure-3.17: S-Substitution of 1,3,4-Oxadiazole bearing benzo-2-pyrone


Page 42

3.4 Antibacterial activity assay

The sterilized 96-wells micro-plates were utilized under sterile circumstances. The

basic principle is based upon the fact that the number of cells increases with the

microbial growth but in a log phase which results in enhanced broth medium

absorbance [154, 192, 193]. The included bacterial strains are of two Gram-positive

and four Gram-negative bacteria which were stocked on stock culture agar medium.

Each micro-plate well was filled by 200 µL containing sample to be tested as 20 µg

(suitably diluted) and bacterial culture as 180 µL (reasonably diluted). Before

incubation, the absorbance should be between 0.12-0.19 at 540 nm. The micro-plate

was covered by lid followed by incubation prolonged for 16-24 hrs at 37 oC and then

absorbance was noted. The difference of absorbance at 540 nm before and after

incubation was directly related to the bacterial growth. The %age inhibition was noted

by the formula given below.

Where Control = Absorbance in control with bacterial culture

Test = Absorbance in test sample

3.5 Lipoxygenase (LOX) enzyme inhibition activity assay

The reported method was employed with a little alteration [175-181]. Sodium

phosphate buffer (with specifications of 100 mM & pH 8.0) as 175 μL, test compound

as 10 μL and purified lipoxygenase enzyme (Sigma, USA) as 15 μL were mixed up to

make a net volume of 200 μL of assay mixture. The assay mixture was homogenized,

pre-read at 234 nm and pre- incubated for 10 min at 25 oC. Substrate solution as 25 μL

was added to initiate the reaction. The variation in absorbance was noted after 6 min

at 234 nm. The 96-well plate reader (Synergy HT, BioTek, USA) was utilized in all

experiments executed in triplicates. The positive and negative controls were included

in the assay. The used positive control was baicalein and the %age inhibition was

noted by the same formula used above. But here,

Control = Total enzyme activity without inhibitor

Test = Activity in the presence of test compound

3.6 Statistical analysis

The statistical analysis was executed by ME 2010. The results are given as mean ±

SEM. The tabulated results as MIC (Minimum Inhibitory Concentration) for

antibacterial activity and IC50 values (conc. for 50% enzyme inhibition) for LOX


Page 43

inhibition are mean of triplicate values (n = 3, ± SEM). The reference drug for

antibacterial results was the famous antibiotic ciprofloxacin and for LOX inhibition

was Baicalein. MIC was noted after suited dilutions ranging 5-30 µg/well and

calculated using EZ-Fit Perrella Scientific Inc. Amherst USA software and the IC50

values were also calculated using the same software.

1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone Results & Discussion

Page 44

CHAPTER FOUR

Results & Discussion


Page 45

4.0 Results of organic synthesis

This part of the running chapter includes the physical and spectral data for all the

synthesized target molecules. The spectral data for the precursors is omitted which

might be understood from target molecules but their physical data is given.

4.0.1 Physical and spectral data of N'-Substituted-2-[(5-phenyl-1,3,4-

oxadiazol-2-yl)thio]acetohydrazide (VIII1-16)

Ethyl benzoate (II1)

Light yellow liquid; Yield: 89%; HRMS: [M]•+ 150.0685 (Calcd. for C9H10O2;

150.0693).

Benzohydrazide (III1)

White amorphous solid; Yield: 83%; M.P.: 112-114 oC; HRMS: [M]•+ 136.0639

(Calcd. for C7H8N2O; 136.0648).

5-Phenyl-1,3,4-oxadiazol-2-thiol (IV1)


(Calcd. for C8H6N2OS; 178.0219).

Ethyl 2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetate (V1)

White amorphous solid; Yield: 81%; M.P.: 88-90 oC; HRMS: [M]•+ 264.0569 (Calcd.

for C12H12N2O3S; 264.0581).

2-[(5-Phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VI1)


(Calcd. for C10H10N4O2S; 250.0532).

N'-Benzylidene-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cream white amorphous solid; Yield: 79%; M.P.: 136-138 oC; HRMS: [M]•+

338.0843 (Calcd. for C17H14N4O2S; 338.0857); IR (KBr, υmax, cm-1): 3415 (N-H),

3054 (Ar C-H), 1653 (C=N), 1641 (C=O), 1612 (Ar C=C), 1091 (C-O); 1H-NMR

(600 MHz, DMSO-d6, δ, ppm): 11.72 (s, 1H, CONH), 8.16 (s, 1H, H-7'''), 7.93 (d, J =

7.8 Hz, 2H, H-2' & H-6'), 7.74 (dd, J = 7.2, 1.8 Hz, 2H, H-2''' & H-6'''), 7.53-7.49 (m,

3H, H-3' to H-5'), 7.44-7.41 (m, 3H, H-3''' to H-5'''), 4.66 (s, 2H, H-2''); EIMS (m/z):

338 [M]•+ (25%), 219 (11%), 191 (9%), 178 (13%), 147 (14%), 145 (14%), 119

(63%), 105 (BP, 100%), 103 (31%), 91 (27%), 77 (47%), 65 (42%), 51 (59%).


Page 46

N'-(2-Methylbenzylidene)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide

(VIII2)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Shiny white crystalline solid; Yield: 83%; M.P.: 142-144 oC; HRMS: [M]•+ 352.0998

(Calcd. for C18H16N4O2S; 352.1012); IR (KBr, υmax, cm-1): 3418 (N-H), 3069 (Ar C-

H), 1655 (C=N), 1647 (C=O), 1605 (Ar C=C), 1089 (C-O); 1H-NMR (600 MHz,

DMSO-d6, δ, ppm): 11.73 (s, 1H, CONH), 8.34 (s, 1H, H-7'''), 7.95 (d, J = 8.4 Hz,

2H, H-2' & H-6'), 7.72 (dd, J = 8.4, 1.2 Hz, 1H, H-6'''), 7.57-7.55 (m, 3H, H-3' to H-

5'), 7.36-7.32 (m, 2H, H-4''' & H-5'''), 7.24 (d, J = 7.2 Hz, 1H, H-3'''), 4.64 (s, 2H, H-

2''), 2.46 (s, 3H, CH3-2'''); EIMS (m/z): 352 [M]•+ (13%), 219 (6%), 191 (11%), 178

(13%), 161 (6%), 145 (17%), 133 (8%), 119 (38%), 105 (BP, 100%), 103 (43%), 77

(48%), 65 (38%), 51 (45%).


(VIII3)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3





2H, H-2' & H-6'), 7.59-7.56 (m, 3H, H-3' to H-5'), 7.43 (d, J = 7.8 Hz, 1H, H-6'''),

7.31 (t, J = 7.8 Hz, 1H, H-5'''), 7.25 (s, 1H, H-2'''), 7.22 (d, J = 7.2 Hz, 1H, H-4'''),

4.64 (s, 2H, H-2''), 2.31 (s, 3H, CH3-3'''); EIMS (m/z): EIMS (m/z): 352 [M]•+ (18%),

219 (2%), 191 (7%), 178 (16%), 161 (7%), 145 (19%), 133 (6%), 119 (41%), 105

(BP, 100%), 103 (46%), 77 (38%), 65 (35%), 51 (55%).


(VIII4)




Page 47

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3



2H, H-2' & H-6'), 7.59 (d, J = 7.8 Hz, 2H, H-2''' & H-6'''), 7.51-7.48 (m, 3H, H-3' to

H-5'), 7.25 (d, J = 7.8 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H, H-2''), 2.35 (s, 3H, CH3-

4'''); EIMS (m/z): 352 [M]•+ (11%), 219 (7%), 191 (10%), 178 (8%), 161 (2%), 145

(21%), 133 (5%), 119 (45%), 105 (BP, 100%), 103 (44%), 77 (52%), 65 (38%), 51

(41%).

N'-(2-Hydroxybenzylidene)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazid-

e (VIII5)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Light yellow amorphous solid; Yield: 89%; M.P.: 188-190 oC; HRMS: [M]•+


3213 (O-H), 3067 (Ar C-H), 1675 (C=N), 1647 (C=O), 1601 (Ar C=C), 1098 (C-O);

1H-NMR (600 MHz, DMSO-d6, δ, ppm): 11.75 (s, 1H, CONH), 8.32 (s, 1H, H-7'''),

7.96 (d, J = 9.0 Hz, 2H, H-2' & H-6'), 7.73 (dd, J = 7.8, 1.8 Hz, 1H, H-6'''), 7.59-7.55

(m, 3H, H-3' to H-5'), 7.52 (dd, J = 7.2, 1.8 Hz, 1H, H-3'''), 7.23 (dt, J = 7.2, 1.8 Hz,

1H, H-4'''), 6.82 (t, J = 7.2 Hz, 1H, H-5'''), 4.65 (s, 2H, H-2''); EIMS (m/z): 354 [M]•+

(23%), 219 (2%), 191 (6%), 178 (16%), 163 (11%), 145 (20%), 135 (8%), 119 (29%),

107 (17%), 105 (BP, 100%), 103 (44%), 77 (60%), 65 (43%), 51 (38%).


e (VIII6)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH



Page 48

(Calcd. for C17H14N4O3S; 354.0799); IR (KBr, υmax, cm-1): 3429 (N-H), 3215 (O-H),


(600 MHz, DMSO-d6, δ, ppm): 11.75 (s, 1H, CONH), 9.61 (s, 1H, HO-3'''), 8.11 (s,

1H, H-7'''), 7.96 (d, J = 7.8 Hz, 2H, H-2' & H-6'), 7.56-7.54 (m, 3H, H-3' to H-5'),

7.23 (t, J = 7.8 Hz, 1H, H-5'''), 7.16 (s, 1H, H-2'''), 7.07 (d, J = 7.8 Hz, 1H, H-6'''),

6.85 (dd, J = 7.8, 2.4 Hz, 1H, H-4'''), 4.67 (s, 2H, H-2''); EIMS (m/z): 354 [M]•+

(27%), 219 (5%), 191 (8%), 178 (11%), 163 (16%), 145 (26%), 135 (9%), 119 (25%),

107 (11%), 105 (BP, 100%), 103 (30%), 77 (56%), 65 (41%), 51 (53%).


e (VIII7)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Shiny cream white crystalline solid; Yield: 79%; M.P.: 210-212 oC; HRMS: [M]•+




7.96 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.53 (d, J = 9.0 Hz, 2H, H-2''' & H-6'''), 7.46-

7.42 (m, 3H, H-3' to H-5'), 6.82 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H, H-2'');

EIMS (m/z): 354 [M]•+ (20%), 219 (4%), 191 (4%), 178 (14%), 163 (8%), 145 (16%),

135 (12%), 119 (32%), 107 (15%), 105 (BP, 100%), 103 (36%), 77 (49%), 65 (47%),

51 (47%).

N'-(2-Nitrobenzylidene)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydrazide

(VIII8)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Light pink amorphous solid; Yield: 77%; M.P.: 190-192 oC; HRMS: [M]•+ 383.0693




1H, H-6'''), 8.27 (d, J = 9.0 Hz, 2H, H-2' & H-6'), 7.97 (dd, J = 9.0, 1.8 Hz, 1H, H-


Page 49

3'''), 7.96-7.94 (m, 2H, H-4''' & H-5'''), 7.56-7.52 (m, 3H, H-3' to H-5'), 4.71 (s, 2H, H-

2''); EIMS (m/z): 383 [M]•+ (12%), 219 (8%), 192 (13%), 191 (5%), 178 (9%), 164

(16%), 145 (24%), 136 (15%), 119 (26%), 105 (BP, 100%), 103 (33%), 77 (58%), 65

(31%), 51 (45%).


(VIII9)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Shiny cream white crystalline solid; Yield: 77%; M.P.: 198-200 oC; HRMS: [M]•+



(600 MHz, DMSO-d6, δ, ppm): 12.03 (s, 1H, CONH), 8.46 (t, J = 1.8 Hz, 1H, H-2'''),

8.37 (s, 1H, H-7'''), 8.24 (dd, J = 8.4, 1.8 Hz, 1H, H-6'''), 8.15 (d, J = 7.8 Hz, 1H, H-

4'''), 7.96 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.71 (t, J = 8.4 Hz, 1H, H-5'''), 7.44-7.41

(m, 3H, H-3' to H-5'), 4.73 (s, 2H, H-2''); EIMS (m/z): 383 [M]•+ (17%), 219 (3%),

192 (9%), 191 (7%), 178 (13%), 164 (8%), 145 (19%), 136 (13%), 119 (34%), 105

(BP, 100%), 103 (47%), 77 (50%), 65 (34%), 51 (41%).


(VIII10)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2





7.8 Hz, 2H, H-3''' & H-5'''), 8.03 (d, J = 7.8 Hz, 2H, H-2''' & H-6'''), 7.94 (d, J = 7.8

Hz, 2H, H-2' & H-6'), 7.56-7.52 (m, H-3' to H-5'), 4.61 (s, 2H, H-2''); EIMS (m/z):

383 [M]•+ (21%), 219 (6%), 192 (12%), 191 (8%), 178 (9%), 164 (13%), 145 (23%),

136 (27%), 119 (38%), 105 (BP, 100%), 103 (29%), 77 (43%), 65 (36%), 51 (39%).


Page 50

N'-[4-(Dimethylamino)benzylidene]-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]aceto-

hydrazide (VIII11)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2





8.4 Hz, 2H, H-2' & H-6'), 7.54-7.50 (m, 3H, H-3' to H-5'), 7.48 (d, J = 8.4 Hz, 2H, H-

2''' & H-6'''), 6.64 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.53 (s, 2H, H-2''), 2.92 (s, 6H,

(CH3)2N-4'''); EIMS (m/z): 381 [M]•+ (13%), 219 (8%), 191 (4%), 190 (11%), 178

(16%), 162 (14%), 145 (18%), 133 (25%), 119 (42%), 105 (BP, 100%), 103 (45%),

77 (37%), 65 (37%), 51 (46%).

N'-[4-(Diethylamino)benzylidene]-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohy-

drazide (VIII12)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2






2''' & H-6'''), 6.61 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.59 (s, 2H, H-2''), 2.61 (q, J =

7.2 Hz, 4H, (CH3CH2)2N-4'''), 1.03 (t, J = 7.2 Hz, 6H, (CH3CH2)2N-4'''); EIMS (m/z):

409 [M]•+ (16%), 219 (6%), 218 (13%), 191 (5%), 190 (18%), 178 (17%), 162 (3%),

145 (21%), 119 (46%), 105 (BP, 100%), 103 (32%), 77 (48%), 65 (44%), 51 (62%).

N'-(2,3-Dimethoxybenzylidene)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetohydr-

azide (VIII13)



Page 51

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3





7.47 (dd, J = 7.8, 1.8 Hz, 1H, H-4'''), 7.13 (t, J = 7.8 Hz, 1H, H-5'''), 4.63 (s, 2H, H-

2''), 3.81 (s, 3H, CH3O-3'''), 3.74 (s, 3H, CH3O-2'''); EIMS (m/z): 398 [M]•+ (9%), 219

(6%), 207 (15%), 191 (4%), 179 (10%), 178 (13%), 151 (13%), 145 (17%), 119

(43%), 105 (BP, 100%), 103 (34%), 77 (54%), 51 (64%).


azide (VIII14)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3





2H, H-2' & H-6'), 7.72 (d, J = 8.4 Hz, 1H, H-6'''), 7.53-7.50 (m, 3H, H-3' to H-5'),

6.64 (d, J = 2.4 Hz, 1H, H-3'''), 6.58 (dd, J = 8.4, 1.8 Hz, 1H, H-5'''), 4.63 (s, 2H, H-

2''), 3.84 (s, 3H, CH3O-2'''), 3.81 (s, 3H, CH3O-4'''); EIMS (m/z): 398 [M]•+ (7%), 219

(9%), 207 (12%), 191 (7%), 179 (9%), 178 (8%), 151 (7%), 145 (18%), 119 (49%),

105 (BP, 100%), 103 (28%), 77 (53%), 51 (58%).


azide (VIII15)







Page 52

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

6'''), 7.07 (d, J = 7.8 Hz, 1H, H-3'''), 7.02 (dd, J = 9.0, 3.0 Hz, 1H, H-4'''), 4.64 (s, 2H,

H-2''), 3.81 (s, 3H, CH3O-5'''), 3.78 (s, 3H, CH3O-2'''); EIMS (m/z): 398 [M]•+ (7%),

219 (2%), 207 (21%), 191 (9%), 179 (15%), 178 (14%), 151 (11%), 145 (23%), 119

(37%), 105 (BP, 100%), 103 (42%), 77 (40%), 51 (47%).


azide (VIII16)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

White crystalline solid; Yield: 83%; M.P.: 138-140 oC; HRMS: [M]•+ 398.1049





7.19 (dd, J = 8.4, 1.8 Hz, 1H, H-6'''), 6.96 (d, J = 8.4 Hz, 1H, H-5'''), 4.63 (s, 2H, H-

2''), 3.81 (s, 3H, CH3O-3'''), 3.79 (s, 3H, CH3O-4'''); EIMS (m/z): 398 [M]•+ (12%),

219 (7%), 207 (12%), 191 (7%), 179 (14%), 178 (10%), 151 (17%), 145 (19%), 119

(46%), 105 (BP, 100%), 103 (32%), 77 (58%), 51 (56%).

4.0.2 Physical and spectral data of N'-Substituted-2-{[5-(2-

chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VIII17-32)

Ethyl 2-chlorobenzoate (II2)

Yellow liquid; Yield: 83%; HRMS: [M]•+ 184.0291 (Calcd. for C9H9ClO2; 184.0304).

2-Chlorobenzohydrazide (III2)


(Calcd. for C7H7ClN2O; 170.0253).

5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-thiol (IV2)


Page 53


(Calcd. for C8H5ClN2OS; 211.9826).

Ethyl 2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetate (V2)


(Calcd. for C12H11ClN2O3S; 298.0185).

2-{[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VI2)



N'-Benzylidene-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide

(VIII17)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl


(Calcd. for C17H13ClN4O2S; 372.0462); IR (KBr, υmax, cm-1): 3427 (N-H), 3058 (Ar

C-H), 1663 (C=N), 1647 (C=O), 1618 (Ar C=C), 1086 (C-O), 696 (C-Cl); 1H-NMR

(600 MHz, DMSO-d6, δ, ppm): 11.84 (s, 1H, CONH), 8.08 (s, 1H, H-7'''), 7.97 (dd, J

= 7.8, 1.2 Hz, 2H, H-2''' & H-6'''), 7.91 (dd, J = 8.4, 1.8 Hz, 1H, H-6'), 7.74-7.68 (m,

3H, H-3''' to H-5'''), 7.60 (d, J = 7.8 Hz, 1H, H-3'), 7.44 (dt, J = 7.2, 1.8 Hz, 1H, H-

5'), 7.40 (t, J = 7.8 Hz, 1H, H-4'), 4.66 (s, 2H, H-2''); EIMS (m/z): 374 (2%), 372

[M]•+ (7%), 253 (8%), 225 (11%), 212 (13%), 179 (16%), 153 (24%), 147 (12%), 139

(BP, 100%), 137 (23%), 119 (17%),

111 (35%), 91 (25%), 65 (52%), 51 (26%).

N'-(2-Methylbenzylidene)-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}aceto-

hydrazide (VIII18)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3Cl





Page 54


= 8.4, 1.8 Hz, 1H, H-6'), 7.77 (dt, J = 9.0, 1.2 Hz, 1H, H-5'''), 7.74 (d, J = 7.2 Hz, 1H,

H-6'''), 7.63 (d, J = 8.4 Hz, 1H, H-3'), 7.43 (dt, J = 7.8, 1.2 Hz, 1H, H-5'), 7.31 (dt, J

= 7.8, 1.2 Hz, 1H, H-4'''), 7.27 (t, J = 7.8 Hz, 1H, H-4'), 7.21 (d, J = 7.2 Hz, 1H, H-

3'''), 4.69 (s, 2H, H-2''), 2.43 (s, 3H, CH3-2'''); EIMS (m/z): 388 (3%), 386 [M]•+ (9%),

253 (3%), 225 (6%), 212 (21%), 179 (14%), 161 (10%), 153 (24%), 139 (BP, 100%),

137 (18%), 133 (13%), 111 (39%), 105 (17%), 65 (34%), 51 (29%).


hydrazide (VIII19)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl





8.4 Hz, 1H, H-6'), 7.60 (d, J = 7.8 Hz, 1H, H-6'''), 7.49 (d, J = 7.8 Hz, 1H, H-3'), 7.34

(t, J = 7.8 Hz, 1H, H-5'), 7.26 (t, J = 8.4 Hz, 1H, H-5'''), 7.17 (d, J = 8.4 Hz, 1H, H-

4'''), 7.10 (t, J = 8.4 Hz, 1H, H-4'), 6.74 (s, 1H, H-2'''), 4.64 (s, 2H, H-2''), 2.33 (s, 3H,

CH3-3'''); EIMS (m/z): 388 (2%), 386 [M]•+ (7%), 253 (6%), 225 (8%), 212 (25%),

179 (12%), 161 (17%), 153 (20%), 139 (BP, 100%), 137 (15%), 133 (11%), 111

(37%), 105 (15%), 65 (39%), 51 (32%).


hydrazide (VIII20)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl






Page 55

8.4 Hz, 1H, H-6'), 7.72 (d, J = 7.8 Hz, 1H, H-3'), 7.67 (t, J = 8.4 Hz, 1H, H-5'), 7.62

(d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.57 (t, J = 8.4 Hz, 1H, H-4'), 7.22 (d, J = 8.4 Hz,

2H, H-3''' & H-5'''), 4.65 (s, 2H, H-2''), 2.35 (s, 3H, CH3-4'''); EIMS (m/z): 388 (1%),

386 [M]•+ (5%), 253 (4%), 225 (9%), 212 (19%), 179 (19%), 161 (10%), 153 (24%),

139 (BP, 100%), 137 (18%), 133 (13%), 111 (39%), 105 (21%), 65 (28%), 51 (26%).

N'-(2-Hydroxybenzylidene)-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acet-

ohydrazide (VIII21)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHCl


388.0399 (Calcd. for C17H13ClN4O3S; 387.0412); IR (KBr, υmax, cm-1): 3439 (N-H),

3228 (O-H), 3065 (Ar C-H), 1677 (C=N), 1653 (C=O), 1616 (Ar C=C), 1096 (C-O),

694 (C-Cl); 1H-NMR (600 MHz, DMSO-d6, δ, ppm): 11.75 (s, 1H, CONH), 8.34 (s,

1H, H-7'''), 7.97 (d, J = 7.8 Hz, 1H, H-6'), 7.92 (d, J = 7.8 Hz, 1H, H-6'''), 7.71 (d, J =

8.4 Hz, 1H, H-3'), 7.62 (t, J = 8.4 Hz, 1H, H-5'), 7.59 (t, J = 7.8 Hz, 1H, H-4'), 7.54

(dd, J = 7.8, 1.8 Hz, 1H, H-3'''), 7.23 (dt, J = 7.8, 1.8 Hz, 1H, H-4'''), 6.90 (dt, J = 7.2,

1.8 Hz, 1H, H-5'''), 4.67 (s, 2H, H-2''); EIMS (m/z): 390 (2%), 388 [M]•+ (7%), 253

(7%), 225 (4%), 212 (17%), 179 (23%), 163 (16%), 153 (25%), 139 (BP, 100%), 137

(26%), 135 (9%), 111 (38%), 107 (16%), 65 (35%), 51 (31%).


ohydrazide (VIII22)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl





1H, HO-3'''), 8.13 (s, 1H, H-7'''), 7.95 (dd, J = 8.4, 1.8 Hz, 1H, H-6'), 7.69 (dd, J =

7.8, 1.2 Hz, 1H, H-6'''), 7.60 (d, J = 7.8 Hz, 1H, H-3'), 7.23 (t, J = 7.8 Hz, 1H, H-5'''),

7.14 (t, J = 8.4 Hz, 1H, H-5'), 7.11 (t, J = 7.8 Hz, 1H, H-4'), 6.85 (dd, J = 9.6, 1.8 Hz,


Page 56

1H, H-4'''), 6.79 (s, 1H, H-2'''), 4.68 (s, 2H, H-2''); EIMS (m/z): 390 (2%), 388 [M]•+

(9%), 253 (10%), 225 (7%), 212 (15%), 179 (22%), 163 (17%), 153 (28%), 139 (BP,

100%), 137 (27%), 135 (8%), 111 (42%), 107 (18%), 65 (37%), 51 (33%).


ohydrazide (VIII23)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl

Shiny white crystalline solid; Yield: 78%; M.P.: 230-232 oC; HRMS: [M]•+ 388.0399

(Calcd. for C17H13ClN4O3S; 387.0412); IR (KBr, υmax, cm-1): 3429 (N-H), 3217 (O-

H), 3073 (Ar C-H), 1679 (C=N), 1656 (C=O), 1601 (Ar C=C), 1089 (C-O), 705 (C-

Cl); 1H-NMR (600 MHz, DMSO-d6, δ, ppm): 11.61 (s, 1H, CONH), 9.94 (s, 1H, HO-

4'''), 8.12 (s, 1H, H-7'''), 7.96 (dd, J = 8.4, 1.8 Hz, 1H, H-6'), 7.62 (d, J = 7.8 Hz, 1H,

H-3'), 7.54 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.36 (t, J = 8.4 Hz, 1H, H-5'), 7.17 (t, J

= 9.0 Hz, 1H, H-4'), 6.78 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 4.64 (s, 2H, H-2'');

EIMS (m/z): 390 (3%), 388 [M]•+ (11%), 253 (5%), 225 (9%), 212 (13%), 179 (24%),

163 (13%), 153 (26%), 139 (BP, 100%), 137 (24%), 135 (8%), 111 (32%), 107

(19%), 65 (33%), 51 (27%).

N'-(2-Nitrobenzylidene)-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohy-

drazide (VIII24)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2Cl

Shiny light yellow crystalline solid; Yield: 77%; M.P.: 208-210 oC; HRMS: [M]•+


3083 (Ar C-H), 1672 (C=N), 1643 (C=O), 1613 (Ar C=C), 1094 (C-O), 701 (C-Cl);


8.05 (d, J = 8.4 Hz, 1H, H-6'), 8.00 (d, J = 7.8 Hz, 1H, H-6'''), 7.91 (d, J = 7.8 Hz,

1H, H-3'''), 7.78 (d, J = 7.8 Hz, 1H, H-3'), 7.67 (t, J = 7.8 Hz, 1H, H-5'), 7.62 (t, J =

8.4 Hz, 1H, H-4'), 7.60-7.56 (m, 2H, H-4''', H-5'''), 4.65 (s, 2H, H-2''); EIMS (m/z):

419 (1%), 417 [M]•+ (5%), 253 (6%), 225 (8%), 212 (15%), 192 (3%), 179 (18%),


Page 57

164 (7%), 153 (6%), 139 (BP, 100%), 137 (24%), 136 (16%), 111 (43%), 65 (27%),

51 (23%).


drazide (VIII25)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl





8.37 (s, 1H, H-7'''), 8.20 (d, J = 8.4 Hz, 1H, H-6'''), 8.12 (d, J = 7.8 Hz, 1H, H-6'),

8.06 (d, J = 8.4 Hz, 1H, H-4'''), 7.85 (t, J = 8.4 Hz, 1H, H-5'''), 7.72 (d, J = 7.8 Hz,

1H, H-3'), 7.58 (d, J = 7.8 Hz, 1H, H-5'), 7.53 (t, J = 7.8 Hz, 1H, H-4'), 4.71 (s, 2H,

H-2''); EIMS (m/z): 419 (1%), 417 [M]•+ (6%), 253 (7%), 225 (9%), 212 (14%), 192

(6%), 179 (17%), 164 (8%), 153 (9%), 139 (BP, 100%), 137 (22%), 136 (12%), 111

(40%), 65 (23%), 51 (21%).


drazide (VIII26)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl

Yellow amorphous solid; Yield: 83%; M.P.: 236-238 oC; HRMS: [M]•+ 417.0302




8.4 Hz, 1H, H-6'), 8.17 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.92 (d, J = 8.4 Hz, 2H, H-

3''' & H-5'''), 7.67 (d, J = 7.8 Hz, 1H, H-3'), 7.61 (t, J = 8.4 Hz, 1H, H-5'), 7.58 (t, J =

7.8 Hz, 1H, H-4'), 4.74 (s, 2H, H-2''); EIMS (m/z): 419 (2%), 417 [M]•+ (6%), 253

(7%), 225 (9%), 212 (13%), 192 (4%), 179 (15%), 164 (9%), 153 (7%), 139 (BP,

100%), 137 (21%), 136 (19%), 111 (41%), 65 (26%), 51 (25%).


Page 58

N'-[4-(Dimethylamino)benzylidene]-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]-

thio}acetohydrazide (VIII27)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2

Cl

Yellow white amorphous solid; Yield: 83%; M.P.: 164-166 oC; HRMS: [M]•+




7.94 (dd, J = 7.8, 2.4 Hz, 1H, H-6'), 7.63 (d, J = 7.8 Hz, 1H, H-3'), 7.49 (d, J = 9.0

Hz, 2H, H-2''' & H-6'''), 7.31 (t, J = 8.4 Hz, 1H, H-5'), 7.20 (t, J = 8.4 Hz, 1H, H-4'),

6.71 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H, H-2''), 3.04 (s, 6H, (CH3)2N-4''');

EIMS (m/z): 417 (3%), 415 [M]•+ (8%), 253 (4%), 225 (9%), 212 (18%), 190 (14%),

179 (17%), 162 (6%), 153 (29%), 139 (BP, 100%), 137 (26%), 133 (12%), 111

(34%), 65 (36%), 51 (36%).

N'-[4-(Diethylamino)benzylidene]-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]th-

io}acetohydrazide (VIII28)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2

Cl





7.97 (d, J = 8.4 Hz, 1H, H-6'), 7.61 (d, J = 7.8 Hz, 1H, H-3'), 7.49 (d, J = 9.0 Hz, 2H,

H-2''' & H-6'''), 7.25 (t, J = 7.8 Hz, 1H, H-5'), 7.11 (t, J = 7.8 Hz, 1H, H-4'), 6.67 (d, J

= 9.0 Hz, 2H, H-3''' & H-5'''), 4.64 (s, 2H, H-2''), 3.39 (q, J = 7.2 Hz, 4H,

(CH3CH2)2N-4'''), 1.13 (t, J = 7.2 Hz, 6H, (CH3CH2)2N-4'''); EIMS (m/z): 445 (1%),

443 [M]•+ (4%), 253 (6%), 225 (8%), 218 (4%), 212 (17%), 190 (7%), 179 (16%),

162 (14%), 153 (22%), 139 (BP, 100%), 137 (24%), 111 (27%), 65 (39%), 51 (24%).


Page 59

N'-(2,3-Dimethoxybenzylidene)-2-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}-

acetohydrazide (VIII29)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl





= 9.0, 1.8 Hz, 1H, H-6'), 7.72 (d, J = 8.4 Hz, 1H, H-3'), 7.66 (t, J = 7.8 Hz, 1H, H-5'),

7.58 (t, J = 7.8 Hz, 1H, H-4'), 7.43 (dd, J = 7.8, 3.0 Hz, 1H, H-6'''), 7.12 (dd, J = 9.0,

3.0 Hz, 1H, H-4'''), 7.09 (t, J = 7.8 Hz, 1H, H-5'''), 4.63 (s, 2H, H-2''), 3.84 (s, 3H,

CH3O-3'''), 3.79 (s, 3H, CH3O-2'''); EIMS (m/z): 434 (2%), 432 [M]•+ (5%), 253 (5%),

225 (4%), 212 (11%), 207 (5%), 179 (25%), 153 (23%), 151 (16%), 139 (BP, 100%),

137 (29%), 111 (36%), 51 (26%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl






(t, J = 7.8 Hz, 1H, H-5'), 7.39 (t, J = 8.4 Hz, 1H, H-4'), 6.62 (d, J = 2.4 Hz, 1H, H-

3'''), 6.56 (dd, J = 7.8, 2.4 Hz, 1H, H-5'''), 4.63 (s, 2H, H-2''), 3.81 (s, 3H, CH3O-2'''),

3.81 (s, 3H, CH3O-4'''); EIMS (m/z): 434 (1%), 432 [M]•+ (4%), 253 (6%), 225 (8%),

212 (13%), 207 (7%), 179 (28%), 153 (22%), 151 (14%), 139 (BP, 100%), 137

(28%), 111 (37%), 51 (23%).




Page 60

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl





7.8 Hz, 1H, H-6'), 7.62 (d, J = 7.8 Hz, 1H, H-3'), 7.39 (d, J = 9.0 Hz, 1H, H-4'''), 7.26

(t, J = 7.2 Hz, 1H, H-5'), 7.17 (t, J = 8.4 Hz, 1H, H-4'), 7.05 (d, J = 7.8 Hz, 1H, H-

3'''), 6.97 (d, J = 3.6 Hz, 1H, H-6'''), 4.64 (s, 2H, H-2''), 3.82 (s, 3H, CH3O-5'''), 3.74

(s, 3H, CH3O-2'''); EIMS (m/z): 434 (2%), 432 [M]•+ (7%), 253 (6%), 225 (7%), 212

(14%), 207 (3%), 179 (26%), 153 (24%), 151 (15%), 139 (BP, 100%), 137 (28%),

111 (35%), 51 (24%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl





= 7.8, 1.8 Hz, 1H, H-6'), 7.59 (d, J = 7.8 Hz, 1H, H-3'), 7.44 (t, J = 7.8 Hz, 1H, H-5'),

7.38 (t, J = 7.2 Hz, 1H, H-4'), 7.33 (d, J = 1.8 Hz, 1H, H-2'''), 7.19 (dd, J = 8.4, 1.8

Hz, 1H, H-6'''), 6.99 (d, J = 8.4 Hz, 1H, H-5'''), 4.65 (s, 2H, H-2''), 3.82 (s, 3H, CH3O-

3'''), 3.80 (s, 3H, CH3O-4'''); EIMS (m/z): 434 (1%), 432 [M]•+ (3%), 253 (4%), 225

(6%), 212 (10%), 207 (8%), 179 (32%), 153 (17%), 151 (17%), 139 (BP, 100%), 137

(26%), 111 (32%), 51 (23%).




Page 61


Pale yellow liquid; Yield: 86%; HRMS: [M]•+ 184.0291 (Calcd. for C9H9ClO2;

184.0304).


Dirty white amorphous solid; Yield: 79%; M.P.: 156-158 oC; HRMS: [M]•+ 170.0241












(VIII33)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl





= 7.8, 1.8 Hz, 2H, H-2''' & H-6'''), 7.92 (dd, J = 8.4, 1.2 Hz, 1H, H-6'), 7.71-7.69 (m,

3H, H-3''' to H-5'''), 7.60 (t, J = 7.8 Hz, 1H, H-5'), 7.43 (dd, J = 7.2, 1.8 Hz, 1H, H-

4'), 7.42 (d, J = 1.8 Hz, 1H, H-2'), 4.68 (s, 2H, H-2''); EIMS (m/z): 374 (1%), 372

[M]•+ (5%), 253 (7%), 225 (9%), 212 (15%), 179 (14%), 153 (23%), 147 (16%), 139

(BP, 100%), 137 (22%), 119 (13%), 111 (34%), 91 (23%), 65 (47%), 51 (28%).


hydrazide (VIII34)




Page 62

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl



= 7.8, 1.8 Hz, 1H, H-6'), 7.75 (ddd, J = 9.0, 1.8 Hz, 1H, H-5'''), 7.70 (d, J = 7.8 Hz,

1H, H-6'''), 7.61 (t, J = 8.4 Hz, 1H, H-5'), 7.33 (s, 1H, H-2'), 7.30 (ddd, J = 7.8, 1.2

Hz, 1H, H-4'''), 7.26 (d, J = 7.2 Hz, 1H, H-4'), 7.23 (d, J = 7.2 Hz, 1H, H-3'''), 4.67 (s,

2H, H-2''), 2.42 (s, 3H, CH3-2'''); EIMS (m/z): 388 (2%), 386 [M]•+ (7%), 253 (5%),

225 (7%), 212 (18%), 179 (16%), 161 (13%), 153 (27%), 139 (BP, 100%), 137

(19%), 133 (16%), 111 (32%), 105 (18%), 65 (33%), 51 (26%).


hydrazide (VIII35)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3Cl






(t, J = 7.8 Hz, 1H, H-5'), 7.24 (t, J = 9.0 Hz, 1H, H-5'''), 7.16 (d, J = 9.0 Hz, 1H, H-

4'''), 7.06 (d, J = 2.4 Hz, 1H, H-2'), 6.73 (s, 1H, H-2'''), 4.67 (s, 2H, H-2''), 2.34 (s, 3H,

CH3-3'''); EIMS (m/z): 388 (4%), 386 [M]•+ (10%), 253 (7%), 225 (5%), 212 (23%),

179 (15%), 161 (13%), 153 (21%), 139 (BP, 100%), 137 (13%), 133 (17%), 111

(33%), 105 (14%), 65 (38%), 51 (21%).


hydrazide (VIII36)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl


Page 63





8.4 Hz, 1H, H-6'), 7.70 (d, J = 7.8 Hz, 1H, H-4'), 7.66 (s, 1H, H-2'), 7.63 (d, J = 8.4

Hz, 2H, H-2''' & H-6'''), 7.59 (t, J = 8.4 Hz, 1H, H-5'), 7.20 (d, J = 8.4 Hz, 2H, H-3'''

& H-5'''), 4.66 (s, 2H, H-2''), 2.34 (s, 3H, CH3-4'''); EIMS (m/z): 388 (1%), 386 [M]•+

(4%), 253 (6%), 225 (9%), 212 (23%), 179 (12%), 161 (11%), 153 (25%), 139 (BP,

100%), 137 (19%), 133 (17%), 111 (34%), 105 (16%), 65 (35%), 51 (28%).


ohydrazide (VIII37)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl




Cl); 1H-NMR (600 MHz, DMSO-d6, δ, ppm): 11.71 (s, 1H, CONH), 8.36 (s, 1H, H-

7'''), 7.98 (d, J = 7.8 Hz, 1H, H-6'), 7.93 (d, J = 7.8 Hz, 1H, H-6'''), 7.70 (d, J = 8.4

Hz, 1H, H-4'), 7.64 (s, 1H, H-2'), 7.62 (t, J = 7.8 Hz, 1H, H-5'), 7.57 (dd, J = 7.8, 1.8

Hz, 1H, H-3'''), 7.25 (ddd, J = 7.8, 1.8 Hz, 1H, H-4'''), 6.91 (ddd, J = 7.2, 1.8 Hz, 1H,

H-5'''), 4.68 (s, 2H, H-2''); EIMS (m/z): 390 (3%), 388 [M]•+ (6%), 253 (8%), 225

(9%), 212 (13%), 179 (26%), 163 (18%), 153 (21%), 139 (BP, 100%), 137 (27%),

135 (7%), 111 (39%), 107 (15%), 65 (37%), 51 (34%).


ohydrazide (VIII38)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHCl





Page 64


3'''), 8.14 (s, 1H, H-7'''), 7.94 (dd, J = 9.0, 1.2 Hz, 1H, H-6'), 7.70 (dd, J = 7.8, 1.2 Hz,

1H, H-6'''), 7.61 (t, J = 7.8 Hz, 1H, H-5'), 7.24 (t, J = 7.8 Hz, 1H, H-5'''), 7.13 (s, 1H,

H-2'), 7.09 (d, J = 7.8 Hz, 1H, H-4'), 6.82 (dd, J = 9.6, 1.2 Hz, 1H, H-4'''), 6.78 (s,

1H, H-2'''), 4.67 (s, 2H, H-2''); EIMS (m/z): 390 (2%), 388 [M]•+ (6%), 253 (8%), 225

(6%), 212 (12%), 179 (21%), 163 (13%), 153 (22%), 139 (BP, 100%), 137 (20%),

135 (12%), 111 (43%), 107 (19%), 65 (35%), 51 (32%).


ohydrazide (VIII39)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl





1H, HO-4'''), 8.17 (s, 1H, H-7'''), 7.95 (dd, J = 8.4, 1.2 Hz, 1H, H-6'), 7.60 (t, J = 7.8

Hz, 1H, H-5'), 7.52 (d, J = 9.0 Hz, 2H, H-2''' & H-6'''), 7.14 (d, J = 8.4 Hz, 1H, H-4'),

6.99 (d, J = 3.0 Hz, 1H, H-2'), 6.80 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H, H-

2''); EIMS (m/z): 390 (1%), 388 [M]•+ (5%), 253 (6%), 225 (6%), 212 (19%), 179

(26%), 163 (17%), 153 (28%), 139 (BP, 100%), 137 (25%), 135 (8%), 111 (37%),

107 (17%), 65 (36%), 51 (39%).


drazide (VIII40)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl





8.09 (d, J = 8.4 Hz, 1H, H-6'), 8.02 (d, J = 7.8 Hz, 1H, H-6'''), 7.92 (d, J = 7.8 Hz,


Page 65

1H, H-3'''), 7.76 (t, J = 7.2 Hz, 1H, H-5'), 7.69 (d, J = 7.8 Hz, 1H, H-4'), 7.66 (s, 1H,

H-2'), 7.65-7.59 (m, 2H, H-4''' & H-5'''), 4.66 (s, 2H, H-2''); EIMS (m/z): 419 (2%),

417 [M]•+ (7%), 253 (9%), 225 (7%), 212 (16%), 192 (7%), 179 (11%), 164 (6%),

153 (8%), 139 (BP, 100%), 137 (22%), 136 (14%), 111 (39%), 65 (25%), 51 (31%).


drazide (VIII41)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2Cl





8.35 (s, 1H, H-7'''), 8.21 (d, J = 8.4 Hz, 1H, H-6'''), 8.13 (d, J = 7.8 Hz, 1H, H-6'),

8.08 (d, J = 8.4 Hz, 1H, H-4'''), 7.88 (t, J = 8.4 Hz, 1H, H-5'''), 7.73 (t, J = 7.8 Hz,

1H, H-5'), 7.56 (d, J = 7.8 Hz, 1H, H-4'), 7.51 (s, 1H, H-2'), 4.70 (s, 2H, H-2''); EIMS

(m/z): 419 (2%), 417 [M]•+ (6%), 253 (4%), 225 (6%), 212 (17%), 192 (6%), 179

(12%), 164 (5%), 153 (4%), 139 (BP, 100%), 137 (22%), 136 (10%), 111 (42%), 65

(24%), 51 (29%).


drazide (VIII42)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl





8.4 Hz, 1H, H-6'), 8.25 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.96 (d, J = 8.4 Hz, 2H, H-

3''' & H-5'''), 7.69 (d, J = 7.2 Hz, 1H, H-4'), 7.64 (s, 1H, H-2'), 7.61 (t, J = 7.8 Hz, 1H,

H-5'), 4.71 (s, 2H, H-2''); EIMS (m/z): 419 (1%), 417 [M]•+ (3%), 253 (4%), 225


Page 66

(7%), 212 (16%), 192 (8%), 179 (14%), 164 (9%), 153 (5%), 139 (BP, 100%), 137

(28%), 136 (15%), 111 (38%), 65 (30%), 51 (32%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2

Cl





= 7.8, 3.0 Hz, 1H, H-6'), 7.60 (t, J = 7.8 Hz, 1H, H-5'), 7.47 (d, J = 9.0 Hz, 2H, H-2'''

& H-6'''), 7.14 (d, J = 8.4 Hz, 1H, H-4'), 6.97 (s, 1H, H-2'), 6.69 (d, J = 9.0 Hz, 2H,

H-3''' & H-5'''), 4.61 (s, 2H, H-2''), 3.02 (s, 6H, (CH3)2N-4'''); EIMS (m/z): 417 (2%),

415 [M]•+ (7%), 253 (5%), 225 (8%), 212 (15%), 190 (12%), 179 (13%), 162 (8%),

153 (24%), 139 (BP, 100%), 137 (21%), 133 (15%), 111 (36%), 65 (31%), 51 (38%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2

Cl





8.4 Hz, 1H, H-6'), 7.62 (t, J = 7.8 Hz, 1H, H-5'), 7.45 (d, J = 9.0 Hz, 2H, H-2''' & H-

6'''), 7.15 (d, J = 7.2 Hz, 1H, H-4'), 6.96 (s, 1H, H-2'), 6.65 (d, J = 9.0 Hz, 2H, H-3'''

& H-5'''), 4.62 (s, 2H, H-2''), 3.38 (q, J = 7.2 Hz, 4H, (CH3CH2)2N-4'''), 1.10 (t, J =

7.2 Hz, 6H, (CH3CH2)2N-4'''); EIMS (m/z): 445 (2%), 443 [M]•+ (5%), 253 (8%), 225

(6%), 218 (5%), 212 (15%), 190 (6%), 179 (14%), 162 (12%), 153 (24%), 139 (BP,

100%), 137 (29%), 111 (26%), 65 (41%), 51 (27%).


Page 67



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3Cl





= 9.0, 1.8 Hz, 1H, H-6'), 7.70 (s, 1H, H-2'), 7.68 (d, J = 7.8 Hz, 1H, H-4'), 7.60 (t, J =

7.8 Hz, 1H, H-5'), 7.42 (dd, J = 7.8, 3.0 Hz, 1H, H-6'''), 7.11 (dd, J = 9.0, 3.0 Hz, 1H,

H-4'''), 7.08 (t, J = 7.8 Hz, 1H, H-5'''), 4.65 (s, 2H, H-2''), 3.83 (s, 3H, CH3O-3'''), 3.78

(s, 3H, CH3O-2'''); EIMS (m/z): 434 (1%), 432 [M]•+ (4%), 253 (8%), 225 (9%), 212

(13%), 207 (6%), 179 (27%), 153 (24%), 151 (15%), 139 (BP, 100%), 137 (31%),

111 (33%), 51 (24%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl





7.8 Hz, 1H, H-6'), 7.73 (d, J = 8.4 Hz, 1H, H-6'''), 7.61 (t, J = 7.2 Hz, 1H, H-5'), 7.43

(d, J = 7.8 Hz, 1H, H-4'), 7.37 (s, 1H, H-2'), 6.60 (d, J = 2.4 Hz, 1H, H-3'''), 6.57 (dd,

J = 7.8, 2.4 Hz, 1H, H-5'''), 4.62 (s, 2H, H-2''), 3.83 (s, 3H, CH3O-2'''), 3.80 (s, 3H,

CH3O-4'''); EIMS (m/z): 434 (2%), 432 [M]•+ (7%), 253 (4%), 225 (7%), 212 (9%),

207 (8%), 179 (26%), 153 (28%), 151 (14%), 139 (BP, 100%), 137 (27%), 111

(34%), 51 (21%).




Page 68

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl





7.8 Hz, 1H, H-6'), 7.59 (t, J = 7.8 Hz, 1H, H-5'), 7.34 (d, J = 9.0 Hz, 1H, H-4'''), 7.23

(d, J = 7.2 Hz, 1H, H-4'), 7.19 (s, 1H, H-2'), 7.04 (d, J = 7.8 Hz, 1H, H-3'''), 6.98 (d, J

= 3.6 Hz, 1H, H-6'''), 4.66 (s, 2H, H-2''), 3.80 (s, 3H, CH3O-5'''), 3.73 (s, 3H, CH3O-

2'''); EIMS (m/z): 434 (2%), 432 [M]•+ (6%), 253 (7%), 225 (9%), 212 (16%), 207

(6%), 179 (28%), 153 (22%), 151 (13%), 139 (BP, 100%), 137 (21%), 111 (34%), 51

(27%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3Cl





= 7.8, 1.2 Hz, 1H, H-6'), 7.58 (t, J = 7.8 Hz, 1H, H-5'), 7.43 (d, J = 7.8 Hz, 1H, H-4'),

7.39 (d, J = 1.2 Hz, 1H, H-2'), 7.31 (d, J = 1.8 Hz, 1H, H-2'''), 7.18 (dd, J = 8.4, 1.8

Hz, 1H, H-6'''), 6.98 (d, J = 8.4 Hz, 1H, H-5'''), 4.66 (s, 2H, H-2''), 3.80 (s, 3H, CH3O-

3'''), 3.79 (s, 3H, CH3O-4'''); EIMS (m/z): 434 (1%), 432 [M]•+ (3%), 253 (8%), 225

(5%), 212 (13%), 207 (6%), 179 (21%), 153 (28%), 151 (18%), 139 (BP, 100%), 137

(32%), 111 (34%), 51 (32%).




Page 69


Yellow liquid; Yield: 84%; HRMS: [M]•+ 184.0291 (Calcd. for C9H9ClO2; 184.0304).














(VIII49)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl





8.4 Hz, 2H, H-2' & H-6'), 7.70 (dd, J = 7.2, 1.8 Hz, 2H, H-2''' & H-6'''), 7.65 (d, J =

9.0 Hz, 2H, H-3' & H-5'), 7.47-7.43 (m, 3H, H-3''' to H-5'''), 4.67 (s, 2H, H-2''); EIMS

(m/z): 374 (1%), 372 [M]•+ (4%), 253 (9%), 225 (11%), 212 (18%), 179 (21%), 153

(27%), 147 (17%), 139 (BP, 100%), 137 (24%), 119 (16%), 111 (30%), 91 (22%), 65

(43%), 51 (21%).


hydrazide (VIII50)





Page 70

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl


8.4 Hz, 2H, H-2' & H-6'), 7.75 (dd, J = 9.0, 1.8 Hz, 1H, H-6'''), 7.65 (d, J = 9.0 Hz,

2H, H-3' & H-5'), 7.35-7.30 (m, 2H, H-4''' & H-5'''), 7.26 (d, J = 7.2 Hz, 1H, H-3'''),

4.67 (s, 2H, H-2''), 2.44 (s, 3H, CH3-2'''); EIMS (m/z): 388 (2%), 386 [M]•+ (5%), 253

(7%), 225 (4%), 212 (14%), 179 (17%), 161 (14%), 153 (25%), 139 (BP, 100%), 137

(18%), 133 (15%), 111 (32%), 105 (16%), 65 (36%), 51 (29%).


hydrazide (VIII51)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl





9.0 Hz, 2H, H-2' & H-6'), 7.63 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 7.48 (d, J = 7.2 Hz,

1H, H-6'''), 7.32 (t, J = 7.8 Hz, 1H, H-5'''), 7.26 (s, 1H, H-2'''), 7.23 (d, J = 7.2 Hz,

1H, H-4'''), 4.66 (s, 2H, H-2''), 2.33 (s, 3H, CH3-3'''); EIMS (m/z): 388 (2%), 386

[M]•+ (8%), 253 (6%), 225 (9%), 212 (22%), 179 (16%), 161 (18%), 153 (20%), 139

(BP, 100%), 137 (11%), 133 (15%), 111 (31%), 105 (16%), 65 (35%), 51 (25%).


hydrazide (VIII52)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3Cl




Page 71




2H, H-2''' & H-6'''), 7.24 (d, J = 7.8 Hz, 2H, H-3''' & H-5'''), 4.65 (s, 2H, H-2''), 2.34

(s, 3H, CH3-4'''); EIMS (m/z): 388 (3%), 386 [M]•+ (12%), 253 (6%), 225 (8%), 212

(24%), 179 (19%), 161 (15%), 153 (23%), 139 (BP, 100%), 137 (15%), 133 (12%),

111 (36%), 105 (16%), 65 (34%), 51 (26%).


ohydrazide (VIII53)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl





7'''), 7.97 (d, J = 9.0 Hz, 2H, H-2' & H-6'), 7.71 (dd, J = 7.8, 1.8 Hz, 1H, H-6'''), 7.65

(d, J = 8.4 Hz, 2H, H-3' & H-5'), 7.56 (dd, J = 7.2, 1.2 Hz, 1H, H-3'''), 7.25 (ddd, J =

7.2, 1.8 Hz, 1H, H-4'''), 6.85 (t, J = 7.2 Hz, 1H, H-5'''), 4.66 (s, 2H, H-2''); EIMS

(m/z): 390 (5%), 388 [M]•+ (16%), 253 (8%), 225 (5%), 212 (18%), 179 (23%), 163

(17%), 153 (24%), 139 (BP, 100%), 137 (26%), 135 (9%), 111 (30%), 107 (12%), 65

(35%), 51 (33%).


ohydrazide (VIII54)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl





3'''), 8.12 (s, 1H, H-7'''), 7.97 (d, J = 7.8 Hz, 2H, H-2' & H-6'), 7.65 (d, J = 9.0 Hz,


Page 72

2H, H-3' & H-5'), 7.24 (t, J = 7.8 Hz, 1H, H-5'''), 7.15 (s, 1H, H-2'''), 7.09 (d, J = 7.8

Hz, 1H, H-6'''), 6.83 (dd, J = 7.8, 2.4 Hz, 1H, H-4'''), 4.66 (s, 2H, H-2''); EIMS (m/z):

390 (3%), 388 [M]•+ (10%), 253 (6%), 225 (7%), 212 (14%), 179 (20%), 163 (16%),

153 (21%), 139 (BP, 100%), 137 (19%), 135 (14%), 111 (38%), 107 (16%), 65

(31%), 51 (37%).


ohydrazide (VIII55)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHCl





7'''), 7.96 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.64 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 7.52

(d, J = 9.0 Hz, 2H, H-2''' & H-6'''), 6.80 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.62 (s,

2H, H-2''); EIMS (m/z): 390 (2%), 388 [M]•+ (4%), 253 (7%), 225 (6%), 212 (12%),

179 (28%), 163 (18%), 153 (26%), 139 (BP, 100%), 137 (24%), 135 (9%), 111

(36%), 107 (15%), 65 (34%), 51 (43%).


drazide (VIII56)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl





9.0 Hz, 1H, H-6'''), 8.26 (d, J = 9.0 Hz, 2H, H-2' & H-6'), 7.98 (dd, J = 9.0, 2.4 Hz,

1H, H-3'''), 7.97-7.95 (m, 2H, H-4''' & H-5'''), 7.65 (d, J = 8.4 Hz, 2H, H-3' & H-5'),

4.70 (s, 2H, H-2''); EIMS (m/z): 419 (3%), 417 [M]•+ (6%), 253 (6%), 225 (8%), 212


Page 73

(17%), 192 (9%), 179 (13%), 164 (8%), 153 (9%), 139 (BP, 100%), 137 (26%), 136

(18%), 111 (41%), 65 (21%), 51 (36%).


drazide (VIII57)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl






4'''), 7.96 (d, J = 9.0 Hz, 2H, H-2' & H-6'), 7.74 (t, J = 8.4 Hz, 1H, H-5'''), 7.65 (d, J =

8.4 Hz, 2H, H-3' & H-5'), 4.72 (s, 2H, H-2''); EIMS (m/z): 419 (1%), 417 [M]•+ (3%),

253 (5%), 225 (8%), 212 (11%), 192 (9%), 179 (15%), 164 (8%), 153 (4%), 139 (BP,

100%), 137 (21%), 136 (13%), 111 (39%), 65 (27%), 51 (24%).


drazide (VIII58)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2Cl





7.8 Hz, 2H, H-3''' & H-5'''), 8.05 (d, J = 9.6 Hz, 2H, H-2''' & H-6'''), 7.96 (d, J = 7.8

Hz, 2H, H-2' & H-6'), 7.66 (d, J = 9.0 Hz, 2H, H-3' & H-5'), 4.67 (s, 2H, H-2''); EIMS

(m/z): 419 (1%), 417 [M]•+ (4%), 253 (6%), 225 (9%), 212 (14%), 192 (9%), 179

(16%), 164 (7%), 153 (7%), 139 (BP, 100%), 137 (23%), 136 (13%), 111 (37%), 65

(32%), 51 (30%).




Page 74

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2Cl






2H, H-2''' & H-6'''), 6.69 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.59 (s, 2H, H-2''), 2.96

(s, 6H, (CH3)2N-4'''); EIMS (m/z): 417 (2%), 415 [M]•+ (5%), 253 (6%), 225 (7%),

212 (13%), 190 (11%), 179 (19%), 162 (9%), 153 (21%), 139 (BP, 100%), 137

(27%), 133 (12%), 111 (38%), 65 (39%), 51 (31%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2Cl






2H, H-2''' & H-6'''), 6.64 (d, J = 9.0 Hz, 2H, H-3''' & H-5'''), 4.58 (s, 2H, H-2''), 2.60

(q, J = 7.2 Hz, 4H, (CH3CH2)2N-4'''), 1.09 (t, J = 7.2 Hz, 6H, (CH3CH2)2N-4'''); EIMS

(m/z): 445 (2%), 443 [M]•+ (7%), 253 (9%), 225 (10%), 218 (8%), 212 (17%), 190

(11%), 179 (18%), 162 (13%), 153 (28%), 139 (BP, 100%), 137 (31%), 111 (28%),

65 (43%), 51 (23%).







Page 75

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl



1H, H-6'''), 7.43 (dd, J = 7.8, 1.8 Hz, 1H, H-4'''), 7.11 (t, J = 7.8 Hz, 1H, H-5'''), 4.65

(s, 2H, H-2''), 3.84 (s, 3H, CH3O-3'''), 3.77 (s, 3H, CH3O-2'''); EIMS (m/z): 434 (1%),

432 [M]•+ (4%), 253 (9%), 225 (7%), 212 (14%), 207 (4%), 179 (25%), 153 (29%),

151 (17%), 139 (BP, 100%), 137 (33%), 111 (36%), 51 (27%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3Cl





9.0 Hz, 2H, H-2' & H-6'), 7.73 (d, J = 8.4 Hz, 1H, H-6'''), 7.65 (d, J = 9.0 Hz, 2H, H-

3' & H-5'), 6.62 (d, J = 2.4 Hz, 1H, H-3'''), 6.57 (dd, J = 8.4, 1.8 Hz, 1H, H-5'''), 4.61


432 [M]•+ (6%), 253 (6%), 225 (9%), 212 (8%), 207 (9%), 179 (24%), 153 (27%),

151 (13%), 139 (BP, 100%), 137 (25%), 111 (37%), 51 (28%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl



Page 76





1H, H-6'''), 7.05 (d, J = 7.8 Hz, 1H, H-3'''), 7.01 (dd, J = 9.0, 3.0 Hz, 1H, H-4'''), 4.66


432 [M]•+ (5%), 253 (9%), 225 (10%), 212 (15%), 207 (5%), 179 (24%), 153 (21%),

151 (14%), 139 (BP, 100%), 137 (25%), 111 (37%), 51 (24%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl






1H, H-2'''), 7.18 (dd, J = 8.4, 1.8 Hz, 1H, H-6'''), 6.98 (d, J = 8.4 Hz, 1H, H-5'''), 4.64


432 [M]•+ (5%), 253 (9%), 225 (7%), 212 (16%), 207 (8%), 179 (26%), 153 (29%),

151 (17%), 139 (BP, 100%), 137 (31%), 111 (35%), 51 (39%).


methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VIII65-83)

Ethyl 4-methylbenzoate (II5)

Yellow liquid; Yield: 84%; HRMS: [M]•+ 164.0839 (Calcd. for C10H12O2; 164.0846).

4-Methylbenzohydrazide (III5)


150.0795 (Calcd. for C8H10N2O; 150.0816).

5-(4-Methylphenyl)-1,3,4-oxadiazol-2-thiol (IV5)


(Calcd. for C9H8N2OS; 192.0375).

Ethyl 2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetate (V5)


Page 77


(Calcd. for C13H14N2O3S; 278.0735).

2-{[5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VI5)


(Calcd. for C11H12N4O2S; 264.0693).

N'-Benzylidene-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide

(VIII65)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

H3C




CHCl3-d1, δ, ppm): 10.69 (s, 1H, CONH), 8.19 (s, 1H, H-7'''), 7.90 (d, J = 8.0 Hz, 2H,

H-2' & H-6'), 7.74 (dd, J = 8.0, 1.2 Hz, 2H, H-2''' & H-6'''), 7.41-7.36 (m, 3H, H-3''' to

H-5'''), 7.25 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.62 (s, 2H, H-2''), 2.39 (s, 3H, CH3-4');

EIMS (m/z): 352 [M]•+ (27%), 233 (5%), 192 (15%), 147 (3%), 133 (16%), 119 (BP,

100%), 117 (22%), 91 (46%), 65 (56%), 51 (28%).

N'-(2-Methylbenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}aceto-

hydrazide (VIII66)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

H3C





H-2' & H-6'), 7.71 (dd, J = 8.4, 1.2 Hz, 1H, H-6'''), 7.39-7.36 (m, 2H, H-4''' & H-5'''),

7.31 (d, J = 8.4 Hz, 1H, H-3'''), 7.29 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.61 (s, 2H, H-

2''), 2.40 (s, 3H, CH3-4'), 2.37 (s, 3H, CH3-2'''); EIMS (m/z): 366 [M]•+ (30%), 233

(4%), 192 (18%), 161 (1%), 133 (17%), 119 (BP, 100%), 117 (24%), 105 (11%), 91


Page 78

(57%), 65 (51%), 51 (26%).


hydrazide (VIII67)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

H3C





H-2' & H-6'), 7.47 (d, J = 8.0 Hz, 1H, H-6'''), 7.32 (t, J = 8.4 Hz, 1H, H-5'''), 7.23 (d,

J = 8.4 Hz, 2H, H-3' & H-5'), 7.20 (s, 1H, H-2'''), 7.16 (d, J = 8.0 Hz, 1H, H-4'''), 4.63

(s, 2H, H-2''), 2.41 (s, 3H, CH3-4'), 2.34 (s, 3H, CH3-3'''); EIMS (m/z): 366 [M]•+

(29%), 233 (5%), 192 (19%), 161 (3%), 133 (19%), 119 (BP, 100%), 117 (21%), 105

(13%), 91 (59%), 65 (44%), 51 (31%).


hydrazide (VIII68)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3H3C





H-2' & H-6'), 7.53 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.22 (d, J = 8.4 Hz, 2H, H-3'''

& H-5'''), 7.20 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.63 (s, 2H, H-2''), 2.38 (s, 3H, CH3-

4'), 2.34 (s, 3H, CH3-4'''); EIMS (m/z): 366 [M]•+ (26%), 233 (5%), 192 (17%), 161

(4%), 133 (20%), 119 (BP, 100%), 117 (27%), 105 (10%), 91 (58%), 65 (49%), 51

(35%).

N'-(2-Hydroxybenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}ace-

tohydrazide (VIII69)



Page 79

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

H3C



1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 10.71 (s, 1H, CONH), 8.23 (s, 1H, H-7'''),

7.83 (d, J = 8.8 Hz, 2H, H-2' & H-6'), 7.76 (dd, J = 8.4, 2.0 Hz, 1H, H-6'''), 7.54 (dd,

J = 8.4, 1.6 Hz, 1H, H-3'''), 7.28 (dt, J = 8.4, 2.0 Hz, 1H, H-4'''), 7.23 (d, J = 8.4 Hz,

2H, H-3' & H-5'), 6.86 (t, J = 8.0 Hz, 1H, H-5'''), 4.65 (s, 2H, H-2''), 2.43 (s, 3H, CH3-

4'); EIMS (m/z): 368 [M]•+ (32%), 233 (7%), 192 (20%), 163 (2%), 135 (5%), 133

(9%), 119 (BP, 100%), 117 (26%), 107 (13%), 91 (51%), 65 (46%), 51 (30%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

H3C




(400 MHz, CHCl3-d1, δ, ppm): 10.71 (s, 1H, CONH), 8.13 (s, 1H, H-7'''), 7.89 (d, J =

8.4 Hz, 2H, H-2' & H-6'), 7.29 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 7.26 (t, J = 8.4 Hz,

1H, H-5'''), 7.18 (s, 1H, H-2'''), 7.08 (d, J = 8.4 Hz, 1H, H-6'''), 6.82 (dd, J = 8.4, 2.0

Hz, 1H, H-4'''), 4.64 (s, 2H, H-2''), 2.41 (s, 3H, CH3-4'); EIMS (m/z): 368 [M]•+ (27%),

233 (6%), 192 (15%), 163 (2%), 135 (8%), 133 (2%), 119 (BP, 100%), 117 (28%),

107 (10%), 91 (67%), 65 (43%), 51 (32%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHH3C


Page 80





7.86 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.57 (d, J = 8.0 Hz, 2H, H-2''' & H-6'''), 7.28

(d, J = 8.4 Hz, 2H, H-3' & H-5'), 6.86 (d, J = 8.0 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H,

H-2''), 2.40 (s, 3H, CH3-4'); EIMS (m/z): 368 [M]•+ (26%), 233 (3%), 192 (15%), 163

(3%), 135 (10%), 133 (6%), 119 (BP, 100%), 117 (25%), 107 (8%), 91 (60%), 65

(48%), 51 (30%).

N'-(2-Nitrobenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetoh-

ydrazide (VIII72)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

H3C





8.4 Hz, 1H, H-6'''), 7.97 (dd, J = 8.0, 2.0 Hz, 1H, H-3'''), 7.95-7.92 (m, 2H, H-4''' &

H-5'''), 7.89 (d, J = 8.0 Hz, 2H, H-2' & H-6'), 7.28 (d, J = 8.4 Hz, 2H, H-3' & H-5'),

4.67 (s, 2H, H-2''), 2.42 (s, 3H, CH3-4'); EIMS (m/z): 397 [M]•+ (28%), 233 (5%), 192

(16%), 164 (9%), 136 (4%), 133 (7%), 119 (BP, 100%), 117 (24%), 91 (57%), 65

(51%), 51 (31%).


ydrazide (VIII73)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

H3C





Page 81

CHCl3-d1, δ, ppm): 11.83 (s, 1H, CONH), 8.53 (t, J = 2.0 Hz, 1H, H-2'''), 8.31 (s, 1H,

H-7'''), 8.18 (dd, J = 8.4, 2.0 Hz, 1H, H-6'''), 8.13 (d, J = 8.4 Hz, 1H, H-4'''), 7.90 (d, J

= 8.0 Hz, 2H, H-2' & H-6'), 7.74 (t, J = 8.4 Hz, 1H, H-5'''), 7.28 (d, J = 8.0 Hz, 2H,

H-3' & H-5'), 4.69 (s, 2H, H-2''), 2.43 (s, 3H, CH3-4'); EIMS (m/z): 397 [M]•+ (21%),

233 (6%), 192 (17%), 164 (12%), 136 (10%), 133 (8%), 119 (BP, 100%), 117 (29%),

91 (63%), 65 (45%), 51 (26%).


ydrazide (VIII74)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2H3C





H-3''' & H-5'''), 8.01 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.92 (d, J = 8.8 Hz, 2H, H-2'

& H-6'), 7.26 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.68 (s, 2H, H-2''), 2.42 (s, 3H, CH3-

4'); EIMS (m/z): 397 [M]•+ (31%), 233 (2%), 192 (23%), 164 (14%), 136 (7%), 133

(3%), 119 (BP, 100%), 117 (34%), 91 (62%), 65 (50%), 51 (24%).

N'-[4-(Dimethylamino)benzylidene]-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2H3C





H-2' & H-6'), 7.49 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.22 (d, J = 8.0 Hz, 2H, H-3' &

H-5'), 6.64 (d, J = 8.0 Hz, 2H, H-3''' & H-5'''), 4.64 (s, 2H, H-2''), 2.91 (s, 6H,

(CH3)2N-4'''), 2.37 (s, 3H, CH3-4'); EIMS (m/z): 395 [M]•+ (26%), 233 (5%), 192


Page 82

(17%), 190 (2%), 162 (5%), 134 (11%), 133 (6%), 119 (BP, 100%), 117 (29%), 91

(56%), 65 (49%), 51 (25%).

N'-[4-(Diethylamino)benzylidene]-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]th-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2H3C





8.0 Hz, 2H, H-2' & H-6'), 7.45 (d, J = 8.0 Hz, 2H, H-2''' & H-6'''), 7.25 (d, J = 8.0 Hz,

2H, H-3' & H-5'), 6.69 (d, J = 8.0 Hz, 2H, H-3''' & H-5'''), 4.61 (s, 2H, H-2''), 2.63 (q,

J = 7.2 Hz, 4H, (CH3CH2)2N-4'''), 2.39 (s, 3H, CH3-4'), 1.04 (t, J = 7.2 Hz, 6H,

(CH3CH2)2N-4'''); EIMS (m/z): 423 [M]•+ (21%), 233 (8%), 218 (6%), 192 (16%), 190

(13%), 162 (5%), 133 (9%), 119 (BP, 100%), 117 (23%), 91 (60%), 65 (49%), 51

(26%).

N'-(2,3-Dimethoxybenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thi-

o}acetohydrazide (VIII77)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

H3C





H-2' & H-6'), 7.56 (d, J = 8.4 Hz, 1H, H-6'''), 7.44 (dd, J = 8.4, 1.2 Hz, 1H, H-4'''),

7.22 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 7.14 (t, J = 8.4 Hz, 1H, H-5'''), 4.63 (s, 2H, H-

2''), 3.82 (s, 3H, CH3O-3'''), 3.80 (s, 3H, CH3O-2'''), 2.40 (s, 3H, CH3-4'); EIMS (m/z):

412 [M]•+ (21%), 233 (7%), 207 (4%), 192 (12%), 179 (12%), 151 (4%), 133 (10%),

119 (BP, 100%), 117 (28%), 91 (56%), 65 (50%), 51 (27%).


Page 83



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3H3C





H-2' & H-6'), 7.75 (d, J = 8.0 Hz, 1H, H-6'''), 7.29 (d, J = 8.4 Hz, 2H, H-3' & H-5'),

6.63 (d, J = 2.4 Hz, 1H, H-3'''), 6.54 (dd, J = 8.0, 2.4 Hz, 1H, H-5'''), 4.64 (s, 2H, H-


412 [M]•+ (31%), 233 (5%), 207 (2%), 192 (11%), 179 (14%), 151 (9%), 133 (5%),

119 (BP, 100%), 117 (29%), 91 (62%), 65 (44%), 51 (26%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

H3C








412 [M]•+ (18%), 233 (6%), 207 (4%), 192 (18%), 179 (7%), 151 (11%), 133 (9%),

119 (BP, 100%), 117 (28%), 91 (52%), 65 (46%), 51 (35%).




Page 84

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

H3C








412 [M]•+ (30%), 233 (8%), 207 (3%), 192 (10%), 179 (1%), 151 (15%), 133 (8%),

119 (BP, 100%), 117 (21%), 91 (51%), 65 (48%), 51 (37%).

N'-(4-Methoxybenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}ace-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3H3C





H-2' & H-6'), 7.73 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.28 (d, J = 8.4 Hz, 2H, H-3' &

H-5'), 6.57 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 4.63 (s, 2H, H-2''), 3.81 (s, 3H, CH3O-

4'''), 2.42 (s, 3H, CH3-4'); EIMS (m/z): 382 [M]•+ (25%), 233 (1%), 192 (21%), 177

(2%), 149 (6%), 133 (7%), 121 (14%), 119 (BP, 100%), 117 (24%), 91 (67%), 65

(49%), 51 (23%).

N'-(2,4-Dichlorobenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}a-

cetohydrazide (VIII82)


(Calcd. for C18H14Cl2N4O2S; 420.0224); IR (KBr, υmax, cm-1): 3457 (N-H), 3076 (Ar



Page 85

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

ClH3C


8.4 Hz, 2H, H-2' & H-6'), 7.58 (d, J = 8.0 Hz, 1H, H-6'''), 7.43 (dd, J = 8.0, 1.2 Hz,

1H, H-5'''), 7.34 (d, J = 1.2 Hz, 1H, H-3'''), 7.29 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.63

(s, 2H, H-2''), 2.39 (s, 3H, CH3-4'); EIMS (m/z): 424 (6%), 422 (12%), 420 [M]•+

(23%), 233 (3%), 215 (6%), 192 (21%), 187 (8%), 159 (9%), 133 (2%), 119 (BP,

100%), 117 (34%), 91 (69%), 65 (54%), 51 (27%).

N'-(2,6-Dichlorobenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]thio}a-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

H3C Cl





8.4 Hz, 2H, H-2' & H-6'), 7.54 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 7.42 (t, J = 8.4 Hz,

1H, H-4'''), 7.23 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.64 (s, 2H, H-2''), 2.38 (s, 3H,

CH3-4'); EIMS (m/z): 424 (10%), 422 (15%), 420 [M]•+ (27%), 233 (3%), 215 (1%),

192 (19%), 187 (6%), 159 (12%), 133 (9%), 119 (BP, 100%), 117 (36%), 91 (66%),

65 (52%), 51 (29%).


hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VIII84-102)

Ethyl 4-hydroxybenzoate (II6)


(Calcd. for C9H10O3; 166.0647).

4-Hydroxybenzohydrazide (III6)


(Calcd. for C7H8N2O2; 152.0594).


Page 86

5-(4-Hydroxyphenyl)-1,3,4-oxadiazol-2-thiol (IV6)


(Calcd. for C8H6N2O2S; 194.0179).

Ethyl 2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetate (V6)


(Calcd. for C12H12N2O4S; 280.0527).

2-{[5-(4-Hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VI6)


(Calcd. for C10H10N4O3S; 266.0489).

N'-Benzylidene-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazid-

e (VIII84)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

HO

Cream yellow amorphous solid; Yield: 77%; M.P.: 198-200 oC; HRMS: [M]•+




7.92 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.72 (dd, J = 8.0, 1.6 Hz, 2H, H-2''' & H-6'''),

7.43-7.38 (m, 3H, H-3''' to H-5'''), 6.65 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.65 (s, 2H,

H-2''); EIMS (m/z): 354 [M]•+ (12%), 235 (10%), 194 (17%), 147 (5%), 135 (34%),

121 (BP, 100%), 119 (48%), 93 (49%), 91 (32%), 67 (9%), 65 (59%), 51 (53%).

N'-(2-Methylbenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}ace-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

HO






Page 87

8.4 Hz, 2H, H-2' & H-6'), 7.73 (dd, J = 8.8, 1.6 Hz, 1H, H-6'''), 7.37-7.34 (m, 2H, H-

4''' & H-5'''), 7.27 (d, J = 8.4 Hz, 1H, H-3'''), 6.69 (d, J = 8.0 Hz, 2H, H-3' & H-5'),

4.63 (s, 2H, H-2''), 2.41 (s, 3H, CH3-2'''); EIMS (m/z): 368 [M]•+ (7%), 235 (10%),

194 (19%), 161 (3%), 135 (37%), 133 (5%), 121 (BP, 100%), 119 (26%), 105 (18%),

93 (42%), 67 (17%), 65 (52%), 51 (44%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

HO





8.8 Hz, 2H, H-2' & H-6'), 7.46 (d, J = 8.0 Hz, 1H, H-6'''), 7.34 (t, J = 8.4 Hz, 1H, H-

5'''), 7.21 (s, 1H, H-2'''), 7.18 (d, J = 8.0 Hz, 1H, H-4'''), 6.63 (d, J = 8.4 Hz, 2H, H-3'

& H-5'), 4.65 (s, 2H, H-2''), 2.34 (s, 3H, CH3-3'''); EIMS (m/z): 368 [M]•+ (7%), 235

(2%), 194 (17%), 161 (4%), 135 (35%), 133 (6%), 121 (BP, 100%), 119 (34%), 105

(13%), 93 (48%), 67 (6%), 65 (51%), 51 (48%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3HO






2H, H-3''' & H-5'''), 6.71 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.64 (s, 2H, H-2''), 2.35 (s,

3H, CH3-4'''); EIMS (m/z): 368 [M]•+ (14%), 235 (4%), 194 (15%), 161 (6%), 135

(8%), 133 (36%), 121 (BP, 100%), 119 (39%), 105 (19%), 93 (49%), 67 (5%), 65


Page 88

(55%), 51 (53%).

N'-(2-Hydroxybenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}ac-

etohydrazide (VIII88)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

HO





7.87 (d, J = 8.8 Hz, 2H, H-2' & H-6'), 7.73 (dd, J = 8.8, 2.0 Hz, 1H, H-6'''), 7.53 (dd,

J = 8.4, 1.6 Hz, 1H, H-3'''), 7.27 (dt, J = 8.4, 1.6 Hz, 1H, H-4'''), 6.84 (t, J = 8.0 Hz,

1H, H-5'''), 6.63 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.67 (s, 2H, H-2''); EIMS (m/z): 370

[M]•+ (13%), 235 (7%), 194 (11%), 163 (2%), 135 (49%), 121 (BP, 100%), 119

(42%), 107 (15%), 93 (47%), 67 (13%), 65 (50%), 51 (41%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

HO





8.0 Hz, 2H, H-2' & H-6'), 7.26 (t, J = 8.4 Hz, 1H, H-5'''), 7.17 (s, 1H, H-2'''), 7.05 (d,

J = 8.4 Hz, 1H, H-6'''), 6.85 (dd, J = 8.8, 2.0 Hz, 1H, H-4'''), 6.69 (d, J = 8.4 Hz, 2H,

H-3' & H-5'), 4.63 (s, 2H, H-2''); EIMS (m/z): 370 [M]•+ (15%), 235 (8%), 194 (14%),

163 (2%), 135 (49%), 121 (BP, 100%), 119 (27%), 107 (17%), 93 (31%), 67 (3%), 65

(57%), 51 (50%).




Page 89

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHHO





7.86 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.54 (d, J = 8.0 Hz, 2H, H-2''' & H-6'''), 6.82

(d, J = 8.0 Hz, 2H, H-3''' & H-5'''), 6.64 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.63 (s, 2H,

H-2''); EIMS (m/z): 370 [M]•+ (9%), 235 (5%), 194 (16%), 163 (2%), 135 (43%), 121

(BP, 100%), 119 (32%), 107 (9%), 93 (46%), 67 (8%), 65 (56%), 51 (41%).

N'-(2-Nitrobenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}aceto-

hydrazide (VIII91)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

HO





8.0 Hz, 1H, H-6'''), 7.99 (dd, J = 8.0, 2.4 Hz, 1H, H-3'''), 7.96-7.94 (m, 2H, H-4''' &

H-5'''), 7.91 (d, J = 8.0 Hz, 2H, H-2' & H-6'), 6.88 (d, J = 8.4 Hz, 2H, H-3' & H-5'),

4.69 (s, 2H, H-2''); EIMS (m/z): 399 [M]•+ (11%), 235 (7%), 194 (15%), 192 (3%),

164 (4%), 136 (14%), 135 (36%), 121 (BP, 100%), 119 (34%), 93 (44%), 67 (12%),

65 (55%), 51 (49%).


hydrazide (VIII92)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

HO


Page 90




1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 12.03 (s, 1H, CONH), 8.54 (t, J = 1.6 Hz,

1H, H-2'''), 8.32 (s, 1H, H-7'''), 8.24 (dd, J = 8.0, 1.6 Hz, 1H, H-6'''), 8.15 (d, J = 8.4

Hz, 1H, H-4'''), 7.91 (d, J = 8.0 Hz, 2H, H-2' & H-6'), 7.76 (t, J = 8.4 Hz, 1H, H-5'''),

6.78 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.72 (s, 2H, H-2''); EIMS (m/z): 399 [M]•+

(15%), 235 (9%), 194 (18%), 192 (1%), 164 (9%), 136 (11%), 135 (37%), 121 (BP,

100%), 119 (39%), 93 (52%), 67 (15%), 65 (53%), 51 (53%).


hydrazide (VIII93)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2HO





8.8 Hz, 2H, H-3''' & H-5'''), 8.02 (d, J = 8.8 Hz, 2H, H-2''' & H-6'''), 7.93 (d, J = 8.4

Hz, 2H, H-2' & H-6'), 6.76 (d, J = 8.4 Hz, 2H, H-3' & H-5'), 4.68 (s, 2H, H-2''); EIMS

(m/z): 399 [M]•+ (12%), 235 (9%), 194 (13%), 192 (3%), 164 (8%), 136 (18%), 135

(27%), 121 (BP, 100%), 119 (26%), 93 (45%), 67 (8%), 65 (54%), 51 (43%).

N'-[4-(Dimethylamino)benzylidene]-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-

yl]thio}acetohydrazide (VIII94)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2HO

Light orange amorphous solid; Yield: 79%; M.P.: 212-214 oC; HRMS: [M]•+





Page 91

7.88 (d, J = 8.0 Hz, 2H, H-2' & H-6'), 7.46 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 6.73


H-2''), 2.93 (s, 6H, (CH3)2N-4'''); EIMS (m/z): 397 [M]•+ (11%), 235 (14%), 194

(16%), 190 (3%), 162 (11%), 135 (48%), 134 (33%), 121 (BP, 100%), 119 (41%), 93

(54%), 67 (13%), 65 (57%), 51 (59%).

N'-[4-(Diethylamino)benzylidene]-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2HO

Light orange amorphous solid; Yield: 84%; M.P.: 216-218 oC; HRMS: [M]•+




7.86 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.42 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 6.73


H-2''), 2.61 (q, J = 7.6 Hz, 4H, (CH3CH2)2N-4'''), 1.07 (t, J = 7.6 Hz, 6H,

(CH3CH2)2N-4'''); EIMS (m/z): 425 [M]•+ (13%), 235 (11%), 218 (2%), 194 (23%),

190 (11%), 162 (6%), 135 (28%), 121 (BP, 100%), 119 (37%), 93 (35%), 67 (9%), 65

(52%), 51 (61%).

N'-(2,3-Dimethoxybenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thi-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

HO






1H, H-4'''), 7.13 (t, J = 8.4 Hz, 1H, H-5'''), 6.62 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.65


Page 92

(s, 2H, H-2''), 3.83 (s, 3H, CH3O-3'''), 3.79 (s, 3H, CH3O-2'''); EIMS (m/z): 414 [M]•+

(17%), 235 (9%), 207 (4%), 194 (23%), 179 (7%), 151 (8%), 135 (38%), 121 (BP,

100%), 119 (43%), 93 (31%), 67 (15%), 51 (55%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3HO

Cream amorphous solid; Yield: 84%; M.P.: 238-240 oC; HRMS: [M]•+ 414.0996





3' & H-5'), 6.61 (d, J = 2.0 Hz, 1H, H-3'''), 6.56 (dd, J = 8.4, 1.6 Hz, 1H, H-5'''), 4.63


(10%), 235 (5%), 207 (4%), 194 (19%), 179 (3%), 151 (3%), 135 (41%), 121 (BP,

100%), 119 (26%), 93 (32%), 67 (13%), 51 (45%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

HO






3'''), 7.02 (dd, J = 8.0, 2.0 Hz, 1H, H-4'''), 6.68 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.65


(19%), 235 (7%), 207 (3%), 194 (16%), 179 (2%), 151 (6%), 135 (47%), 121 (BP,


Page 93

100%), 119 (24%), 93 (34%), 67 (12%), 51 (59%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

HO






1H, H-6'''), 6.96 (d, J = 8.4 Hz, 1H, H-5'''), 6.67 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.62


(7%), 235 (14%), 207 (2%), 194 (12%), 179 (5%), 151 (9%), 135 (34%), 121 (BP,

100%), 119 (31%), 93 (32%), 67 (11%), 51 (49%).

N'-(4-Methoxybenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}ac-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3HO






2H, H-3' & H-5'), 6.52 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 4.62 (s, 2H, H-2''), 3.83 (s,

3H, CH3O-4'''); EIMS (m/z): 384 [M]•+ (12%), 235 (8%), 194 (25%), 177 (2%), 149

(6%), 135 (21%), 121 (BP, 100%), 119 (44%), 93 (33%), 67 (11%), 65 (56%), 51

(54%).

N'-(2,4-Dichlorobenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}-



Page 94

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

ClHO


(Calcd. for C17H12Cl2N4O3S; 422.0024); IR (KBr, υmax, cm-1): 3451 (N-H), 3209 (O-


Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 11.61 (s, 1H, CONH), 8.71 (s, 1H, H-

7'''), 7.89 (d, J = 8.0 Hz, 2H, H-2' & H-6'), 7.53 (d, J = 8.4 Hz, 1H, H-6'''), 7.45 (dd, J

= 8.4, 1.6 Hz, 1H, H-5'''), 7.31 (d, J = 1.6 Hz, 1H, H-3'''), 6.69 (d, J = 8.0 Hz, 2H, H-

3' & H-5'), 4.61 (s, 2H, H-2''); EIMS (m/z): 426 (8%), 424 (12%), 422 [M]•+ (18%),

235 (16%), 215 (5%), 194 (27%), 187 (7%), 159 (3%), 135 (38%), 121 (BP, 100%),

119 (23%), 93 (36%), 67 (4%), 51 (43%).

N'-(2,6-Dichlorobenzylidene)-2-{[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]thio}-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

HO Cl





7'''), 7.86 (d, J = 8.4 Hz, 2H, H-2' & H-6'), 7.53 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''),

7.43 (t, J = 8.4 Hz, 1H, H-4'''), 6.73 (d, J = 8.0 Hz, 2H, H-3' & H-5'), 4.61 (s, 2H, H-

2''); EIMS (m/z): 426 (4%), 424 (9%), 422 [M]•+ (12%), 235 (8%), 216 (5%), 194

(24%), 188 (9%), 160 (19%), 135 (47%), 121 (BP, 100%), 119 (32%), 93 (46%), 67

(8%), 51 (49%).

4.0.7 Physical and spectral data of N'-Substituted-2-{[5-(2,4-

dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VIII103-117)

Ethyl 2,4-dichlorobenzoate (II7)

Pale yellow liquid; Yield: 78%; HRMS: [M]•+ 217.9901 (Calcd. for C9H8Cl2O2;

217.9926).


Page 95

2,4-Dichlorobenzohydrazide (III7)


(Calcd. for C7H6Cl2N2O; 203.9868).

5-(2,4-Dichlorophenyl)-1,3,4-oxadiazol-2-thiol (IV7)


(Calcd. for C8H4Cl2N2OS; 245.9437).

Ethyl 2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetate (V7)


(Calcd. for C12H10Cl2N2O3S; 331.9795).

2-{[5-(2,4-Dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VI7)


(Calcd. for C10H8Cl2N4O2S; 317.9762).

N'-Benzylidene-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydraz-

ide (VIII103)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

Cl

Light brown amorphous solid; Yield: 79%; M.P.: 176-178 oC; HRMS: [M]•+ 406.0056




8.0 Hz, 1H, H-6ꞌ), 7.75 (dd, J = 8.0, 1.6 Hz, 2H, H-2''' & H-6'''), 7.51 (d, J = 1.6 Hz,

1H, H-3ꞌ), 7.49-7.43 (m, 3H, H-3''' to H-5'''), 7.35 (dd, J = 8.0, 1.6 Hz, 1H, H-5ꞌ), 4.64

(s, 2H, H-2''); EIMS (m/z): 410 (2%), 408 (11%), 406 [M]•+ (19%), 287 (7%), 246

(26%), 187 (19%), 173 (BP, 100%), 171 (37%), 147 (5%), 145 (28%), 119 (13%), 91

(78%), 65 (52%).

N'-(2-Methylbenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl

Cl

Light green amorphous solid; Yield: 88%; M.P.: 186-188 oC; HRMS: [M]•+ 420.0216


Page 96




8.8 Hz, 1H, H-6ꞌ), 7.76 (dd, J = 8.4, 1.6 Hz, 1H, H-6'''), 7.59 (d, J = 1.2 Hz, 1H, H-3ꞌ),

7.39-7.35 (m, 2H, H-4''' & H-5'''), 7.33 (dd, J = 8.4, 1.6 Hz, 1H, H-5ꞌ), 7.28 (d, J = 8.4

Hz, 1H, H-3'''), 4.63 (s, 2H, H-2''), 2.39 (s, 3H, CH3-2'''); EIMS (m/z): 424 (1%), 422

(10%), 420 [M]•+ (18%), 287 (10%), 246 (25%), 187 (17%), 173 (BP, 100%), 171

(40%), 161 (8%), 145 (28%), 133 (13%), 105 (13%), 65 (61%).

N'-(3-Methylbenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}a-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

Cl

Cl

Green amorphous solid; Yield: 86%; M.P.: 178-180 oC; HRMS: [M]•+ 420.0216




8.4 Hz, 1H, H-6ꞌ), 7.55 (d, J = 1.6 Hz, 1H, H-3ꞌ), 7.41 (d, J = 8.0 Hz, 1H, H-6'''), 7.37

(dd, J = 8.0, 1.6 Hz, 1H, H-5ꞌ), 7.31 (t, J = 8.0 Hz, 1H, H-5'''), 7.20 (s, 1H, H-2'''),

7.16 (d, J = 8.0 Hz, 1H, H-4'''), 4.63 (s, 2H, H-2''), 2.33 (s, 3H, CH3-3'''); EIMS (m/z):

424 (3%), 422 (11%), 420 [M]•+ (19%), 287 (13%), 246 (28%), 187 (17%), 173 (BP,

100%), 171 (34%), 161 (10%), 145 (29%), 133 (14%), 105 (9%), 65 (57%).

N'-(4-Methylbenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}a-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3Cl

Cl





8.0 Hz, 1H, H-6ꞌ), 7.57 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.54 (d, J = 1.2 Hz, 1H, H-


Page 97

3ꞌ), 7.35 (dd, J = 8.0, 1.2 Hz, 1H, H-5ꞌ), 7.21 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 4.63

(s, 2H, H-2''), 2.37 (s, 3H, CH3-4'''); EIMS (m/z): 424 (2%), 422 (8%), 420 [M]•+

(15%), 287 (13%), 246 (27%), 187 (19%), 173 (BP, 100%), 171 (43%), 161 (7%),

145 (31%), 133 (17%), 105 (10%), 65 (55%).

N'-(3-Hydroxybenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

Cl

Cl





7'''), 7.83 (d, J = 8.8 Hz, 1H, H-6ꞌ), 7.56 (d, J = 2.4 Hz, 1H, H-3ꞌ), 7.32 (dd, J = 8.8,

2.0 Hz, 1H, H-5ꞌ), 7.29 (t, J = 8.4 Hz, 1H, H-5'''), 7.19 (s, 1H, H-2'''), 7.07 (d, J = 8.0

Hz, 1H, H-6'''), 6.83 (dd, J = 8.4, 1.6 Hz, 1H, H-4'''), 4.63 (s, 2H, H-2''); EIMS (m/z):

426 (1%), 424 (10%), 422 [M]•+ (18%), 287 (6%), 246 (23%), 187 (13%), 173 (BP,

100%), 171 (38%), 163 (4%), 145 (27%), 135 (16%), 107 (9%), 65 (57%).

N'-(4-Hydroxybenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHCl

Cl





7'''), 7.84 (d, J = 8.4 Hz, 1H, H-6ꞌ), 7.58 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.51 (d, J

= 1.6 Hz, 1H, H-3ꞌ), 7.38 (dd, J = 8.4, 1.2 Hz, 1H, H-5ꞌ), 6.85 (d, J = 8.4 Hz, 2H, H-

3''' & H-5'''), 4.62 (s, 2H, H-2''); EIMS (m/z): 426 (1%), 424 (12%), 422 [M]•+ (19%),

287 (3%), 246 (21%), 187 (17%), 173 (BP, 100%), 171 (42%), 163 (7%), 145 (24%),

135 (13%), 107 (13%), 65 (59%).


Page 98

N'-(2-Nitrobenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}ace-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

Cl

Cl





8.4 Hz, 1H, H-6'''), 7.91 (dd, J = 8.4, 2.0 Hz, 1H, H-3'''), 7.88-7.84 (m, 2H, H-4''' &

H-5'''), 7.81 (d, J = 8.0 Hz, 1H, H-6ꞌ), 7.50 (d, J = 1.2 Hz, 1H, H-3ꞌ), 7.33 (dd, J = 8.0,

1.2 Hz, 1H, H-5ꞌ), 4.69 (s, 2H, H-2''); EIMS (m/z): 455 (3%), 453 (12%), 451 [M]•+

(21%), 287 (7%), 246 (22%), 192 (14%), 187 (19%), 173 (BP, 100%), 171 (45%),

164 (21%), 145 (25%), 136 (17%), 65 (63%).

N'-(4-Nitrobenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}ace-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2Cl

Cl





8.4 Hz, 2H, H-3''' & H-5'''), 8.01 (d, J = 8.4 Hz, 2H, H-2''' & H-6'''), 7.84 (d, J = 8.0

Hz, 1H, H-6ꞌ), 7.52 (d, J = 2.0 Hz, 1H, H-3ꞌ), 7.37 (dd, J = 8.0, 2.0 Hz, 1H, H-5ꞌ), 4.65

(s, 2H, H-2''); EIMS (m/z): 455 (2%), 453 (11%), 451 [M]•+ (19%), 287 (11%), 246

(24%), 192 (10%), 187 (17%), 173 (BP, 100%), 171 (39%), 164 (18%), 145 (29%),

136 (13%), 65 (60%).

N'-[4-(Dimethylamino)benzylidene]-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-




Page 99

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2Cl

Cl




8.0 Hz, 1H, H-6ꞌ), 7.54 (d, J = 1.6 Hz, 1H, H-3ꞌ), 7.47 (d, J = 8.0 Hz, 2H, H-2''' & H-

6'''), 7.39 (dd, J = 8.4, 1.6 Hz, 1H, H-5ꞌ), 6.73 (d, J = 8.0 Hz, 2H, H-3''' & H-5'''), 4.63

(s, 2H, H-2''), 2.97 (s, 6H, (CH3)2N-4'''); EIMS (m/z): 453 (1%), 451 (9%), 449 [M]•+

(16%), 287 (12%), 246 (29%), 190 (7%), 187 (14%), 173 (BP, 100%), 171 (37%),

162 (13%), 145 (37%), 134 (8%), 65 (63%).

N'-(2,3-Dimethoxybenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl

Cl





8.4 Hz, 1H, H-6ꞌ), 7.59 (d, J = 8.0 Hz, 1H, H-6'''), 7.54 (d, J = 2.0 Hz, 1H, H-3ꞌ), 7.43

(dd, J = 8.0, 1.6 Hz, 1H, H-4'''), 7.36 (dd, J = 8.0, 2.4 Hz, 1H, H-5ꞌ), 7.12 (t, J = 8.4

Hz, 1H, H-5'''), 4.63 (s, 2H, H-2''), 3.81 (s, 3H, CH3O-3'''), 3.79 (s, 3H, CH3O-2''');

EIMS (m/z): 470 (4%), 468 (13%), 466 [M]•+ (21%), 287 (12%), 246 (20%), 207

(7%), 187 (18%), 179 (9%), 173 (BP, 100%), 171 (36%), 151 (9%), 145 (21%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3Cl

Cl


Page 100

Dirty green amorphous solid; Yield: 87%; M.P.: 224-226 oC; HRMS: [M]•+ 466.0265




8.0 Hz, 1H, H-6ꞌ), 7.75 (d, J = 8.4 Hz, 1H, H-6'''), 7.57 (d, J = 1.6 Hz, 1H, H-3ꞌ), 7.34

(dd, J = 8.0, 1.6 Hz, 1H, H-5ꞌ), 6.63 (d, J = 2.0 Hz, 1H, H-3'''), 6.52 (dd, J = 8.4, 1.6


EIMS (m/z): 470 (1%), 468 (8%), 466 [M]•+ (17%), 287 (11%), 246 (27%), 207 (5%),

187 (13%), 179 (14%), 173 (BP, 100%), 171 (31%), 151 (6%), 145 (26%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl

Cl





8.4 Hz, 1H, H-6ꞌ), 7.54 (d, J = 1.6 Hz, 1H, H-3ꞌ), 7.39 (dd, J = 8.4, 1.6 Hz, 1H, H-5ꞌ),

7.33 (d, J = 2.0 Hz, 1H, H-6'''), 7.11 (d, J = 8.4 Hz, 1H, H-3'''), 7.03 (dd, J = 8.4, 2.0


EIMS (m/z): 470 (2%), 468 (9%), 466 [M]•+ (19%), 287 (15%), 246 (22%), 207

(16%), 187 (13%), 179 (8%), 173 (BP, 100%), 171 (29%), 151 (5%), 145 (37%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

Cl

Cl




Page 101




7.33 (d, J = 1.2 Hz, 1H, H-2'''), 7.15 (dd, J = 8.4, 1.2 Hz, 1H, H-6'''), 6.94 (d, J = 8.4


EIMS (m/z): 470 (3%), 468 (11%), 466 [M]•+ (17%), 287 (16%), 246 (31%), 207

(6%), 187 (20%), 179 (16%), 173 (BP, 100%), 171 (34%), 151 (15%), 145 (32%).

N'-(2,4-Dichlorobenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thi-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

ClCl

Cl





8.4 Hz, 1H, H-6ꞌ), 7.56 (d, J = 2.0 Hz, 1H, H-3ꞌ), 7.52 (d, J = 8.8 Hz, 1H, H-6'''), 7.48

(dd, J = 8.4, 1.2 Hz, 1H, H-5'''), 7.36 (dd, J = 8.0, 1.2 Hz, 1H, H-5ꞌ), 7.32 (d, J = 1.6

Hz, 1H, H-3'''), 4.62 (s, 2H, H-2''); EIMS (m/z): 482 (1%), 480 (2%), 478 (4%), 476

(13%), 474 [M]•+ (21%), 287 (12%), 246 (34%), 215 (4%), 187 (27%), 173 (BP,

100%), 171 (37%), 159 (19%), 145 (29%).

N'-(2,6-Dichlorobenzylidene)-2-{[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]thi-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

Cl

Cl Cl

Cl







Page 102

7.51 (d, J = 8.8 Hz, 2H, H-3''' & H-5'''), 7.46 (t, J = 8.4, 2.4 Hz, 1H, H-4'''), 4.64 (s,

2H, H-2''); EIMS (m/z): 482 (1%), 480 (2%), 478 (2%), 476 (9%), 474 [M]•+ (19%),

287 (14%), 246 (30%), 215 (12%), 187 (31%), 173 (BP, 100%), 171 (39%), 159

(7%), 145 (28%).

4.0.8 Physical and spectral data of N'-Substituted-2-{[5-(3,4-

methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide

(VIII118-133)

Ethyl 3,4-(methylenedioxy)benzoate (II8)

Yellow liquid; Yield: 91%; HRMS: [M]•+ 194.0579 (Calcd. for C10H10O4; 194.0583).

3,4-(Methylenedioxy)benzohydrazide (III8)


(Calcd. for C8H8N2O3; 180.0553).

5-(3,4-Methylenedioxyphenyl)-1,3,4-oxadiazol-2-thiol (IV8)


(Calcd. for C9H6N2O3S; 222.0112).

Ethyl 2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetate (V8)


(Calcd. for C13H12N2O5S; 308.0479).

2-{[5-(3,4-Methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VI8)


(Calcd. for C11H10N4O4S; 294.0443).

N'-Benzylidene-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]thio}acet-

ohydrazide (VIII118)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

O

O

7'




CHCl3-d1, δ, ppm): 11.76 (s, 1H, CONH), 8.19 (s, 1H, H-7'''), 7.72 (dd, J = 8.0, 1.6

Hz, 2H, H-2''' & H-6'''), 7.52 (dd, J = 8.4, 1.6 Hz, 1H, H-6'), 7.50-7.46 (m, 3H, H-3'''

to H-5'''), 7.38 (d, J = 1.2 Hz, 1H, H-2'), 6.84 (d, J = 8.0 Hz, 1H, H-5'), 6.06 (s, 2H,

H-7'), 4.65 (s, 2H, H-2''); EIMS (m/z): 382 [M]•+ (26%), 263 (12%), 235 (18%), 221


Page 103

(13%), 189 (8%), 163 (9%), 149 (BP, 100%), 147 (28%), 121 (29%), 119 (7%), 91

(74%), 65 (23%), 51 (6%).

N'-(2-Methylbenzylidene)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl-

]thio}acetohydrazide (VIII119)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

O

O

7'





Hz, 1H, H-6'''), 7.57 (dd, J = 8.0, 1.6 Hz, 1H, H-6'), 7.38 (d, J = 1.2 Hz, 1H, H-2'),

7.38-7.34 (m, 2H, H-4''' & H-5'''), 7.26 (d, J = 7.6 Hz, 1H, H-3'''), 6.81 (d, J = 8.0 Hz,

1H, H-5'), 6.02 (s, 2H, H-7'), 4.68 (s, 2H, H-2''), 2.45 (s, 3H, CH3-2'''); EIMS (m/z):

396 [M]•+ (32%), 263 (8%), 235 (27%), 221 (11%), 189 (6%), 163 (15%), 161 (13%),

149 (BP, 100%), 147 (16%), 133 (5%), 121 (35%), 105 (3%), 65 (28%), 51 (12%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3O

O

7'





Hz, 1H, H-6'), 7.47 (d, J = 7.6 Hz, 1H, H-6'''), 7.34 (d, J = 1.6 Hz, 1H, H-2'), 7.31 (t,

J = 7.6 Hz, 1H, H-5'''), 7.22 (s, 1H, H-2'''), 7.20 (d, J = 7.6 Hz, 1H, H-4'''), 6.86 (d, J

= 8.4 Hz, 1H, H-5'), 6.09 (s, 2H, H-7'), 4.64 (s, 2H, H-2''), 2.31 (s, 3H, CH3-3''');

EIMS (m/z): 396 [M]•+ (42%), 263 (11%), 235 (28%), 221 (8%), 189 (6%), 163 (3%),

161 (22%), 149 (BP, 100%), 147 (16%), 133 (12%), 121 (31%), 105 (13%), 65 (9%),

51 (5%).


Page 104



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

CH3

O

O

7'





H-2''' & H-6'''), 7.49 (dd, J = 8.4, 1.6 Hz, 1H, H-6'), 7.31 (d, J = 1.2 Hz, 1H, H-2'),

7.27 (d, J = 7.6 Hz, 2H, H-3''' & H-5'''), 6.83 (d, J = 8.0 Hz, 1H, H-5'), 6.11 (s, 2H, H-

7'), 4.64 (s, 2H, H-2''), 2.31 (s, 3H, CH3-4'''); EIMS (m/z): 396 [M]•+ (37%), 263 (9%),

235 (31%), 221 (7%), 189 (4%), 163 (10%), 161 (17%), 149 (BP, 100%), 147 (13%),

133 (7%), 121 (43%), 105 (4%), 65 (21%), 51 (5%).

N'-(2-Hydroxybenzylidene)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-


O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

O

O

7'





7.72 (dd, J = 7.6, 1.6 Hz, 1H, H-6'''), 7.52 (dd, J = 7.6, 1.2 Hz, 1H, H-3'''), 7.45 (dd, J

= 8.0, 1.2 Hz, 1H, H-6'), 7.33 (d, J = 1.6 Hz, 1H, H-2'), 7.22 (dt, J = 7.6, 1.2 Hz, 1H,

H-4'''), 6.88 (t, J = 7.6 Hz, 1H, H-5'''), 6.81 (d, J = 8.4 Hz, 1H, H-5'), 6.13 (s, 2H, H-

7'), 4.67 (s, 2H, H-2''); EIMS (m/z): 398 [M]•+ (37%), 263 (10%), 235 (28%), 221

(13%), 189 (4%), 163 (22%), 149 (BP, 100%), 147 (7%), 135 (6%), 121 (41%), 107

(5%), 65 (17%), 51 (6%).




Page 105

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OHO

O

7'




(400 MHz, CHCl3-d1, δ, ppm): 11.73 (s, 1H, CONH), 9.61 (s, 1H, HO-3'''), 8.11 (s,

1H, H-7'''), 7.51 (dd, J = 8.0, 1.2 Hz, 1H, H-6'), 7.37 (d, J = 1.2 Hz, 1H, H-2'), 7.21 (t,

J = 7.6 Hz, 1H, H-5'''), 7.17 (s, 1H, H-2'''), 7.07 (d, J = 7.6 Hz, 1H, H-6'''), 6.86 (dd, J

= 7.6, 2.0 Hz, 1H, H-4'''), 6.79 (d, J = 8.4 Hz, 1H, H-5'), 6.18 (s, 2H, H-7'), 4.66 (s,

2H, H-2''); EIMS (m/z): 398 [M]•+ (41%), 263 (6%), 235 (34%), 221 (7%), 189 (1%),

163 (25%), 149 (BP, 100%), 147 (8%), 135 (4%), 121 (36%), 107 (2%), 65 (15%), 51

(4%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OH

O

O

7'





8.4 Hz, 2H, H-2''' & H-6'''), 7.49 (dd, J = 8.0, 1.2 Hz, 1H, H-6'), 7.36 (d, J = 1.6 Hz,

1H, H-2'), 6.82 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 6.75 (d, J = 8.4 Hz, 1H, H-5'), 6.16

(s, 2H, H-7'), 4.63 (s, 2H, H-2''); EIMS (m/z): 398 [M]•+ (36%), 263 (9%), 235 (32%),

221 (9%), 189 (3%), 163 (28%), 149 (BP, 100%), 147 (11%), 135 (12%), 121 (31%),

107 (6%), 65 (18%), 51 (7%).

N'-(2-Nitrobenzylidene)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl]-






Page 106

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

O

O

7'


H-6'''), 7.96 (dd, J = 8.8, 2.0 Hz, 1H, H-3'''), 7.95-7.92 (m, 2H, H-4''' & H-5'''), 7.51

(dd, J = 8.0, 1.6 Hz, 1H, H-6'), 7.32 (d, J = 1.2 Hz, 1H, H-2'), 6.75 (d, J = 8.4 Hz, 1H,

H-5'), 6.15 (s, 2H, H-7'), 4.67 (s, 2H, H-2''); EIMS (m/z): 427 [M]•+ (2%), 263 (1%),

235 (37%), 221 (1%), 192 (1%), 189 (5%), 164 (3%), 163 (15%), 149 (BP, 100%),

147 (33%), 136 (1%), 121 (22%), 65 (11%), 51 (9%).



O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2O

O

7'




(400 MHz, CHCl3-d1, δ, ppm): 12.01 (s, 1H, CONH), 8.51 (t, J = 1.6 Hz, 1H, H-2'''),


4'''), 7.71 (t, J = 8.4 Hz, 1H, H-5'''), 7.50 (dd, J = 8.0, 1.2 Hz, 1H, H-6'), 7.29 (d, J =

1.2 Hz, 1H, H-2'), 6.77 (d, J = 8.4 Hz, 1H, H-5'), 6.17 (s, 2H, H-7'), 4.71 (s, 2H, H-

2''); 13C-NMR (100 MHz, DMSO-d6, δ, ppm): 168.3 (C-1''), 164.9 (C-2), 163.2 (C-

3'''), 162.6 (C-5), 150.3 (C-3'), 148.1 (C-4'), 145.0 (C-7'''), 141.8 (C-6'), 135.8 (C-1'''),

132.9 (C-6'''), 130.3 (C-5'''), 124.1 (C-4'''), 121.6 (C-2'''), 116.6 (C-1'), 109.0 (C-5'),

106.0 (C-2'), 102.0 (C-7'), 34.5 (C-2''); EIMS (m/z): 427 [M]•+ (4%), 263 (2%), 235

(31%), 221 (3%), 192 (2%), 189 (9%), 164 (6%), 163 (12%), 149 (BP, 100%), 147

(28%), 136 (4%), 121 (18%), 65 (15%), 51 (17%).






Page 107

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

NO2

O

O

7'



H-3''' & H-5'''), 8.04 (d, J = 8.0 Hz, 2H, H-2''' & H-6'''), 7.50 (dd, J = 8.4, 1.2 Hz, 1H,

H-6'), 7.31 (d, J = 1.2 Hz, 1H, H-2'), 6.73 (d, J = 8.0 Hz, 1H, H-5'), 6.17 (s, 2H, H-7'),

4.65 (s, 2H, H-2''); EIMS (m/z): 427 [M]•+ (1%), 263 (4%), 235 (43%), 221 (7%), 192

(3%), 189 (2%), 164 (6%), 163 (17%), 149 (BP, 100%), 147 (37%), 136 (6%), 121

(27%), 65 (10%), 51 (16%).

N'-[4-(Dimethylamino)benzylidene]-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxa-

diazol-2-yl]thio}acetohydrazide (VIII128)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH3)2

O

O

7'







7'), 4.51 (s, 2H, H-2''), 2.90 (s, 6H, (CH3)2N-4'''); EIMS (m/z): 425 [M]•+ (27%), 263

(1%), 235 (1%), 221 (1%), 190 (6%), 189 (3%), 163 (5%), 162 (9%), 149 (BP,

100%), 147 (14%), 133 (19%), 121 (24%), 51 (4%).

N'-[4-(Diethylamino)benzylidene]-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadi-

azol-2-yl]thio}acetohydrazide (VIII129)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)2

O

O

7'



Page 108






7'), 4.54 (s, 2H, H-2''), 2.64 (q, J = 7.2 Hz, 4H, (CH3CH2)2N-4'''), 1.11 (t, J = 7.2 Hz,

6H, (CH3CH2)2N-4'''); EIMS (m/z): 453 [M]•+ (35%), 263 (1%), 235 (1%), 221 (1%),

218 (5%), 190 (4%), 189 (3%), 163 (4%), 162 (13%), 149 (BP, 100%), 147 (12%),

121 (19%), 65 (6%), 51 (2%).

N'-(2,3-Dimethoxybenzylide ne)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazo-

l-2-yl]thio}acetohydrazide (VIII130)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3O

O

7'





H-6'''), 7.47 (dd, J = 8.4, 1.2 Hz, 1H, H-6'), 7.41 (dd, J = 7.6, 1.2 Hz, 1H, H-4'''), 7.35

(d, J = 1.2 Hz, 1H, H-2'), 7.13 (t, J = 7.6 Hz, 1H, H-5'''), 6.82 (d, J = 8.0 Hz, 1H, H-

5'), 6.18 (s, 2H, H-7'), 4.67 (s, 2H, H-2''), 3.82 (s, 3H, CH3O-3'''), 3.79 (s, 3H, CH3O-

2'''); EIMS (m/z): 442 [M]•+ (12%), 263 (16%), 235 (4%), 221 (7%), 207 (3%), 189

(13%), 179 (8%), 163 (78%), 151 (11%), 149 (BP, 100%), 147 (43%), 121 (17%), 51

(6%).

N'-(2,4-Dimethoxybenzylidene)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazo-

l-2-yl]thio}acetohydrazide (VIII131)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

O

O

7'




Page 109



8.4 Hz, 1H, H-5'), 7.47 (s, 1H, H-2'), 7.42 (dd, J = 7.2, 1.2 Hz, 1H, H-6'), 6.88 (d, J =

8.0 Hz, 1H, H-6'''), 6.70 (dd, J = 8.8, 1.6 Hz, 1H, H-5'''), 6.36 (d, J = 1.6 Hz, 1H, H-

3'''), 5.99 (s, 2H, H-7'), 4.31 (s, 2H, H-2''), 3.88 (s, 3H, CH3O-2'''), 3.86 (s, 3H, CH3O-

4'''); EIMS (m/z): 442 [M]•+ (5%), 263 (13%), 235 (6%), 221 (4%), 207 (9%), 189

(14%), 179 (6%), 163 (85%), 151 (13%), 149 (BP, 100%), 147 (42%), 121 (26%), 51

(8%).


l-2-y]thio}acetohydrazide (VIII132)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3

O

O

7'




(400 MHz, CHCl3-d1, δ, ppm): 11.74 (s, 1H, CONH), 8.32 (s, 1H, H-7'''), 7.49 (dd, J

= 8.4, 1.2 Hz, 1H, H-6'), 7.38 (d, J = 2.0 Hz, 1H, H-6'''), 7.33 (d, J = 1.2 Hz, 1H, H-

2'), 7.07 (d, J = 7.6 Hz, 1H, H-3'''), 7.02 (dd, J = 8.0, 2.0 Hz, 1H, H-4'''), 6.82 (d, J =

8.0 Hz, 1H, H-5'), 6.22 (s, 2H, H-7'), 4.68 (s, 2H, H-2''), 3.83 (s, 3H, CH3O-5'''), 3.77

(s, 3H, CH3O-2'''); EIMS (m/z): 442 [M]•+ (7%), 263 (10%), 235 (2%), 221 (2%), 207

(7%), 189 (9%), 179 (2%), 163 (91%), 151 (7%), 149 (BP, 100%), 147 (34%), 121

(21%), 51 (4%).


l-2-y]thio}acetohydrazide (VIII133)

O

NN

S

NH

O

N

CH1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''

OCH3

OCH3O

O

7'




Page 110



Hz, 1H, H-6'), 7.36 (d, J = 1.6 Hz, 1H, H-2'''), 7.30 (d, J = 1.2 Hz, 1H, H-2'), 7.14

(dd, J = 8.0, 1.6 Hz, 1H, H-6'''), 6.99 (d, J = 8.0 Hz, 1H, H-5'''), 6.72 (d, J = 8.0 Hz,

1H, H-5'), 6.14 (s, 2H, H-7'), 4.66 (s, 2H, H-2''), 3.81 (s, 3H, CH3O-3'''), 3.78 (s, 3H,

CH3O-4'''); EIMS (m/z): 442 [M]•+ (11%), 263 (9%), 235 (5%), 221 (5%), 207 (3%),

189 (14%), 179 (8%), 163 (89%), 151 (4%), 149 (BP, 100%), 147 (29%), 121 (26%),

51 (8%).

4.0.9 Physical and spectral data of N'-Substituted-2-({5-[(2,4-

dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio)acetohydrazide

(XV1-13)

Ethyl 2-(2,4-dimethylphenoxy)acetate (X)

Light brown liquid; Yield: 86%; HRMS: [M]•+ 208.1096 (Calcd. for C12H16O3;

208.1109).

2-(2,4-Dimethylphenoxy)acetohydrazide (XI)

Pink amorphous solid; Yield: 80%; M.P.: 134-136 oC; HRMS: [M]•+ 194.1056

(Calcd. for C10H14N2O2; 194.1067).

5-[(2,4-Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-thiol (XII)


236.0617 (Calcd. for C11H12N2O2S; 236.0634).

Ethyl 2-({5-[(2,4-Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio)acetate

(XIII)


(Calcd. for C15H18N2O4S; 322.0996).

2-({5-[(2,4-Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio)acetohydrazide

(XIV)


308.0946 (Calcd. for C13H16N4O3S; 308.0962).

N'-Benzylidene-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio)-

acetohydrazide (XV1)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''1'

3'

5'

CH3H3C

O

7'


Page 111

Light grey amorphous solid; Yield: 81%; M.P.: 136-138 oC; HRMS: [M]•+ 396.1253




Hz, 2H, H-2''' & H-6'''), 7.47-7.43 (m, 3H, H-3''' to H-5'''), 6.95 (d, J = 8.0 Hz, 1H, H-

5'), 6.92 (d, J = 1.6 Hz, 1H, H-3'), 6.71 (d, J = 8.4 Hz, 1H, H-6'), 4.91 (s, 2H, H-7'),

4.65 (s, 2H, H-2''), 2.23 (s, 3H, CH3-4'), 2.19 (s, 3H, CH3-2'); EIMS (m/z): 396 [M]•+

(12%), 277 (8%), 249 (15%), 236 (12%), 203 (21%), 177 (23%), 163 (17%), 161

(14%), 147 (11%), 135 (26%), 122 (BP, 100%), 119 (6%), 105 (21%), 93 (34%), 91

(59%), 65 (36%).

N'-(2-Methylbenzylidene)-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazol-

2-yl}thio)acetohydrazide (XV2)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

CH3

1'

3'

5'

CH3H3C

O

7'





Hz, 1H, H-6'''), 7.37-7.33 (m, 2H, H-4''' & H-5'''), 7.26 (d, J = 7.6 Hz, 1H, H-3'''), 6.92

(d, J = 8.4 Hz, 1H, H-5'), 6.92 (d, J = 1.2 Hz, 1H, H-3'), 6.73 (d, J = 8.4 Hz, 1H, H-

6'), 4.94 (s, 2H, H-7'), 4.66 (s, 2H, H-2''), 2.44 (s, 3H, CH3-2'''), 2.23 (s, 3H, CH3-4'),

2.21 (s, 3H, CH3-2'); EIMS (m/z): 410 [M]•+ (13%), 277 (13%), 249 (18%), 236

(22%), 203 (17%), 177 (21%) 163 (13%), 161 (14%), 135 (17%), 133 (6%), 122 (BP,

100%), 105 (51%), 93 (33%), 65 (34%).



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

CH3

1'

3'

5'

CH3H3C

O

7'




Page 112



H-6'''), 7.33 (t, J = 8.0 Hz, 1H, H-5'''), 7.27 (s, 1H, H-2'''), 7.20 (d, J = 8.0 Hz, 1H, H-

4'''), 6.93 (d, J = 8.4 Hz, 1H, H-5'), 6.93 (d, J = 1.2 Hz, 1H, H-3'), 6.72 (d, J = 8.4 Hz,

1H, H-6'), 4.93 (s, 2H, H-7'), 4.67 (s, 2H, H-2''), 2.32 (s, 3H, CH3-3'''), 2.23 (s, 3H,

CH3-4'), 2.21 (s, 3H, CH3-2'); EIMS (m/z): 410 [M]•+ (9%), 277 (10%), 249 (13%),

236 (19%), 203 (18%), 177 (22%) 163 (12%), 161 (11%), 135 (33%), 133 (5%), 122

(BP, 100%), 105 (57%), 93 (31%), 65 (37%).



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

CH3

1'

3'

5'

CH3H3C

O

7'





H-2''' & H-6'''), 7.26 (d, J = 8.4 Hz, 2H, H-3''' & H-5'''), 6.91 (d, J = 8.0 Hz, 1H, H-5'),

6.88 (d, J = 1.6 Hz, 1H, H-3'), 6.72 (d, J = 8.0 Hz, 1H, H-6'), 4.93 (s, 2H, H-7'), 4.64

(s, 2H, H-2''), 2.34 (s, 3H, CH3-4'''), 2.23 (s, 3H, CH3-4'), 2.20 (s, 3H, CH3-2'); EIMS

(m/z): 410 [M]•+ (16%), 277 (14%), 249 (9%), 236 (24%), 203 (19%), 177 (32%) 163

(17%), 161 (14%), 135 (18%), 133 (7%), 122 (BP, 100%), 105 (48%), 93 (38%), 65

(33%).

N'-(2-Hydroxybenzylidene)-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazo-

l-2-yl}thio)acetohydrazide (XV5)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

OH

1'

3'

5'

CH3H3C

O

7'






Page 113

7.72 (dd, J = 8.0, 1.6 Hz, 1H, H-6'''), 7.54 (dd, J = 8.4, 1.2 Hz, 1H, H-3'''), 7.23 (dt, J

= 8.4, 1.6 Hz, 1H, H-4'''), 6.90 (d, J = 8.4 Hz, 1H, H-5'), 6.86 (d, J = 1.6 Hz, 1H, H-

3'), 6.84 (t, J = 8.0 Hz, 1H, H-5'''), 6.74 (d, J = 8.4 Hz, 1H, H-6'), 4.93 (s, 2H, H-7'),

4.65 (s, 2H, H-2''), 2.21 (s, 3H, CH3-4'), 2.19 (s, 3H, CH3-2'); EIMS (m/z): 412 [M]•+

(12%), 277 (18%), 249 (19%), 236 (16%), 203 (11%), 177 (23%), 163 (14%), 161

(7%), 135 (37%), 122 (BP, 100%), 107 (17%), 105 (31%), 93 (35%), 65 (39%).



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

OH

1'

3'

5'

CH3H3C

O

7'




(400 MHz, CHCl3-d1, δ, ppm): 11.79 (s, 1H, CONH), 8.14 (s, 1H, H-7'''), 7.21 (t, J =

8.8 Hz, 1H, H-5'''), 7.16 (s, 1H, H-2'''), 7.09 (d, J = 8.8 Hz, 1H, H-6'''), 6.94 (d, J = 8.4

Hz, 1H, H-5'), 6.90 (d, J = 1.6 Hz, 1H, H-3'), 6.85 (dd, J = 8.4, 2.0 Hz, 1H, H-4'''),

6.73 (d, J = 8.4 Hz, 1H, H-6'), 4.93 (s, 2H, H-7'), 4.64 (s, 2H, H-2''), 2.20 (s, 3H, CH3-

4'), 2.17 (s, 3H, CH3-2'); EIMS (m/z): 412 [M]•+ (10%), 277 (15%), 249 (12%), 236

(21%), 203 (9%), 177 (28%), 163 (16%), 161 (6%), 135 (41%), 122 (BP, 100%), 107

(22%), 105 (30%), 93 (39%), 65 (43%)..



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

OH

1'

3'

5'

CH3H3C

O

7'

Brown crystalline solid; Yield: 81%; M.P.: 166-168 oC; HRMS: [M]•+ 412.1207




8.4 Hz, 2H, H-2''' & H-6'''), 6.92 (d, J = 8.0 Hz, 1H, H-5'), 6.89 (d, J = 1.6 Hz, 1H, H-

3'), 6.81 (d, J = 8.8 Hz, 2H, H-3''' & H-5'''), 6.74 (d, J = 8.0 Hz, 1H, H-6'), 4.94 (s,


Page 114

2H, H-7'), 4.65 (s, 2H, H-2''), 2.24 (s, 3H, CH3-4'), 2.21 (s, 3H, CH3-2'); EIMS (m/z):

412 [M]•+ (15%), 277 (21%), 249 (16%), 236 (24%), 203 (5%), 177 (32%), 163

(10%), 161 (4%), 135 (36%), 122 (BP, 100%), 107 (19%), 105 (35%), 93 (26%), 65

(36%).

N'-(2-Nitrobenzylidene)-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-

yl}thio)acetohydrazide (XV8)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

NO2

1'

3'

5'

CH3H3C

O

7'





H-6'''), 7.95 (dd, J = 8.4, 1.6 Hz, 1H, H-3'''), 7.95-7.93 (m, 2H, H-4''' & H-5'''), 6.91

(d, J = 8.8 Hz, 1H, H-5'), 6.88 (d, J = 2.0 Hz, 1H, H-3'), 6.76 (d, J = 8.8 Hz, 1H, H-

6'), 4.93 (s, 2H, H-7'), 4.65 (s, 2H, H-2''), 2.23 (s, 3H, CH3-4'), 2.21 (s, 3H, CH3-2');

EIMS (m/z): 441 [M]•+ (6%), 277 (22%), 249 (11%), 236 (28%), 203 (16%), 192

(4%), 177 (23%), 164 (34%), 163 (17%), 161 (8%), 136 (18%), 135 (19%), 122 (BP,

100%), 105 (26%), 93 (44%), 65 (31%).



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

NO2

1'

3'

5'

CH3H3C

O

7'




CHCl3-d1, δ, ppm): 12.02 (s, 1H, CONH), 8.44 (t, J = 1.6 Hz, 1H, H-2'''), 8.38 (s, 1H,

H-7'''), 8.21 (dd, J = 8.4, 1.6 Hz, 1H, H-6'''), 8.12 (d, J = 8.8 Hz, 1H, H-4'''), 7.69 (t, J

= 8.4 Hz, 1H, H-5'''), 6.93 (d, J = 8.4 Hz, 1H, H-5'), 6.91 (d, J = 1.2 Hz, 1H, H-3'),

6.71 (d, J = 8.4 Hz, 1H, H-6'), 4.92 (s, 2H, H-7'), 4.65 (s, 2H, H-2''), 2.24 (s, 3H, CH3-


Page 115

4'), 2.22 (s, 3H, CH3-2'); EIMS (m/z): 441 [M]•+ (4%), 277 (20%), 249 (14%), 236

(32%), 203 (8%), 192 (8%), 177 (19%), 164 (31%), 163 (13%), 161 (7%), 136 (16%),

135 (29%), 122 (BP, 100%), 105 (22%), 93 (37%), 65 (37%).



O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

NO2

1'

3'

5'

CH3H3C

O

7'

Brown amorphous solid; Yield: 79%; M.P.: 154-156 oC; HRMS: [M]•+ 441.1106




H-3''' & H-5'''), 8.05 (d, J = 8.0 Hz, 2H, H-2''' & H-6'''), 6.96 (d, J = 8.0 Hz, 1H, H-5'),

6.93 (d, J = 1.6 Hz, 1H, H-3'), 6.72 (d, J = 8.4 Hz, 1H, H-6'), 4.93 (s, 2H, H-7'), 4.62

(s, 2H, H-2''), 2.23 (s, 3H, CH3-4'), 2.21 (s, 3H, CH3-2'); EIMS (m/z): 441 [M]•+ (3%),

277 (13%), 249 (17%), 236 (18%), 203 (10%), 192 (7%), 177 (27%), 164 (38%), 163

(14%), 161 (6%), 136 (15%), 135 (21%), 122 (BP, 100%), 105 (25%), 93 (35%), 65

(34%).

N'-[4-(Dimethylamino)benzylidene]-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-

oxadiazol-2-yl}thio)acetohydrazide (XV11)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

N(CH3)2

1'

3'

5'

CH3H3C

O

7'

Brown crystalline solid; Yield: 77%; M.P.: 178-180 oC; HRMS: [M]•+ 439.1675




H-2''' & H-6'''), 6.97 (d, J = 8.4 Hz, 1H, H-5'), 6.92 (d, J = 1.6 Hz, 1H, H-3'), 6.77 (d,

J = 8.4 Hz, 1H, H-6'), 6.61 (d, J = 8.8 Hz, 2H, H-3''' & H-5'''), 4.94 (s, 2H, H-7'), 4.56

(s, 2H, H-2''), 2.94 (s, 6H, (CH3)2N-4'''), 2.20 (s, 3H, CH3-4'), 2.17 (s, 3H, CH3-2');

EIMS (m/z): 439 [M]•+ (6%), 277 (10%), 249 (19%), 236 (14%), 203 (26%), 190

(4%), 177 (34%), 163 (12%), 162 (5%), 161 (9%), 135 (25%), 134 (27%), 122 (BP,


Page 116

100%), 105 (38%), 93 (46%), 65 (34%).

N'-[4-(Diethylamino)benzylidene]-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-ox-

adiazol-2-yl}thio)acetohydrazide (XV12)

O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

N(CH2CH3)23'

5'

CH3H3C

O

7'1'







(s, 2H, H-2''), 2.63 (q, J = 7.6 Hz, 4H, (CH3CH2)2N-4'''), 2.19 (s, 3H, CH3-4'), 2.17 (s,

3H, CH3-2'), 1.05 (t, J = 7.6 Hz, 6H, (CH3CH2)2N-4'''); EIMS (m/z): 467 [M]•+ (9%),

277 (16%), 249 (12%), 236 (15%), 218 (3%), 203 (17%), 190 (4%), 177 (26%), 163

(11%), 162 (16%), 161 (8%), 135 (31%), 122 (BP, 100%), 105 (33%), 93 (39%), 65

(32%).

N'-(4-Methoxybenzylidene)-2-({5-[(2,4-dimethylphenoxy)methyl]-1,3,4-oxadiazo-


O

NN

S

NH

O

N

CH1

34

1''2''

7'''

1'''

5'''

3'''

OCH3

1'

3'

5'

CH3H3C

O

7'







(s, 2H, H-2''), 3.83 (s, 3H, CH3O-4'''), 2.23 (s, 3H, CH3-4'), 2.20 (s, 3H, CH3-2');

EIMS (m/z): 426 [M]•+ (11%), 277 (10%), 249 (15%), 236 (24%), 203 (13%), 177

(34%), 163 (13%), 161 (11%), 149 (8%), 135 (27%), 122 (BP, 100%), 107 (17%),

105 (33%), 93 (36%), 65 (36%).


Page 117

4.0.10 Physical and spectral data of 7-Alkoxy/aralkoxy-6-

chloro-4-methylbenzo-2-pyrone (XIX1-9)

7-Hydroxy-6-chloro-4-methylbenzo-2-pyrone (XVII)


(Calcd. for C10H7ClO3; 210.0095).

7-Methoxy-6-chloro-4-methylbenzo-2-pyrone (XIX1)

OO

Cl

O

CH3

1

35

7H3C

1'

11


(Calcd. for C11H9ClO3; 224.0257); IR (KBr, υmax, cm-1): 3057 (Ar C-H), 1731 (C=O),

1607 (Ar C=C), 1141 (C-O), 701 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm):

7.56 (s, 1H, H-5), 6.85 (s, 1H, H-8), 6.16 (s, 1H, H-3), 3.95 (s, 3H, CH3-1'), 2.37 (s,

3H, CH3-11); 13C-NMR (125 MHz, CHCl3-d1, δ, ppm): 160.6 (C-2), 157.6 (C-7),

153.6 (C-4), 151.6 (C-9), 125.3 (C-5), 118.9 (C-6), 113.8 (C-10), 112.9 (C-3), 100.4

(C-8), 56.6 (C-1'), 18.6 (C-11); EIMS (m/z): 226 (2%), 224 [M]•+ (7%), 210 (BP,

100%), 182 (71%).

7-(1-Propoxy)-6-chloro-4-methylbenzo-2-pyrone (XIX2)

OO

Cl

O

CH3

1

35

71'

H3C

3'

11




7.55 (s, 1H, H-5), 6.82 (s, 1H, H-8), 6.16 (s, 1H, H-3), 3.99 (t, J = 7.2 Hz, 2H, H-1'),

2.36 (s, 3H, CH3-11), 1.86-1.88 (m, 2H, H-2'), 1.07 (t, J = 6.8 Hz, 3H, CH3-3'); EIMS

(m/z): 254 (3%), 252 [M]•+ (8%), 210 (BP, 100%), 182 (74%), 43 (5%).

7-(1-Butoxy)-6-chloro-4-methylbenzo-2-pyrone (XIX3)





Page 118

OO

Cl

O

CH3

1

35

71'3'

H3C

11


2.36 (s, 3H, CH3-11), 1.84 (qui, J = 6.8 Hz, 2H, H-2'), 1.48-1.51 (m, 2H, H-3'), 0.98

(t, J = 7.2 Hz, 3H, CH3-4'); EIMS (m/z): 268 (2%), 266 [M]•+ (5%), 210 (54%), 182

(79%), 57 (BP, 100%).

7-(2-Butoxy)-6-chloro-4-methylbenzo-2-pyrone (XIX4)

OO

Cl

O

CH3

1

35

7

1'H3C

3'CH34'

11




7.55 (s, 1H, H-5), 6.82 (s, 1H, H-8), 6.13 (s, 1H, H-3), 4.35-4.40 (m, 1H, H-1'), 2.36

(s, 3H, CH3-11), 1.36 (d, J = 6.0 Hz, 3H, CH3-4'), 1.21-1.30 (m, 2H, H-2'), 0.98 (t, J

= 7.2 Hz, 3H, CH3-3'); EIMS (m/z): 268 (1%), 266 [M]•+ (4%), 210 (58%), 182

(76%), 57 (BP, 100%).

7-(1-Pentoxy)-6-chloro-4-methylbenzo-2-pyrone (XIX5)

OO

Cl

O

CH3

1

35

71'3'

H3C

5'

11

Dark brown amorphous solid; Yield: 53%; M.P.: 158-160 oC; HRMS: [M]•+ 280.0869




2.36 (s, 3H, CH3-11), 1.86 (qui, J = 6.8 Hz, 2H, H-2'), 1.38-1.47 (m, 4H, H-3', H-4'),

0.93 (t, J = 7.2 Hz, 3H, CH3-5'); EIMS (m/z): 282 (1%), 280 [M]•+ (4%), 210 (BP,

100%), 182 (74%), 71 (3%).

7-(1-Heptoxy)-6-chloro-4-methylbenzo-2-pyrone (XIX6)


Page 119

OO

Cl

O

CH3

1

35

71'3'5'

H3C

7'

11

Brown amorphous solid; Yield: 62%; M.P.: 172-174 oC; HRMS: [M]•+ 308.1175




2.36 (s, 3H, CH3-11), 1.82-1.86 (m, 4H, H-2', H-3'), 1.29-1.53 (m, 6H, H-4' to H-6'),

0.88 (t, J = 7.2 Hz, 3H, CH3-7'); EIMS (m/z): 310 (3%), 266 [M]•+ (9%), 210 (BP,

100%), 182 (79%), 99 (2%).

7-[(2-Methylbenzyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XIX7)

OO

Cl

O

CH3

1

35

7

1'3'

5'

7'

CH38'

11




7.57 (s, 1H, H-5), 7.28-7.43 (m, 4H, H-3' to H-6'), 6.92 (s, 1H, H-8), 6.15 (s, 1H, H-

3), 5.16 (s, 2H, H-7'), 2.39 (s, 3H, CH3-11), 2.37 (s, 3H, CH3-8'); EIMS (m/z): 316

(<1%), 314 [M]•+ (1%), 210 (3%), 121 (2%), 182 (5%), 105 (BP, 100%), 90 (67%), 65

(5%).

7-[(2-Bromobenzyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XIX8)

OO

Cl

O

CH3

1

35

7

1'3'

5'

7'

Br

11


(Calcd. for C17H12BrClO3; 377.9671); IR (KBr, υmax, cm-1): 3050 (Ar C-H), 1735


Page 120

(C=O), 1606 (Ar C=C), 1156 (C-O), 707 (C-Cl), 632 (C-Br); 1H-NMR (400 MHz,

CHCl3-d1, δ, ppm): 7.60 (s, 1H, H-5), 7.57 (brs, 1H, H-3'), 7.55 (brs, 1H, H-6'), 7.34

(t, J = 7.2 Hz, 1H, H-5'), 7.22 (t, J = 7.2 Hz, 1H, H-4'), 6.90 (s, 1H, H-8), 6.16 (s, 1H,

H-3), 5.24 (s, 2H, H-7'), 2.37 (s, 3H, CH3-11); EIMS (m/z): 382 (<1%), 380 (4%), 378

[M]•+ (3%), 210 (2%), 187 (2%), 185 (2%), 182 (4%), 169 (99%), 171 (BP, 100%), 65

(7%).

7-[(3-Bromobenzyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XIX9)

OO

Cl

O

CH3

1

35

7

1'3'

5'

7'

11

Br

Dark pink amorphous solid; Yield: 56%; M.P.: 124-126 oC; HRMS: [M]•+ 377.9659


(C=O), 1606 (Ar C=C), 1144 (C-O), 707 (C-Cl), 637 (C-Br); 1H-NMR (400 MHz,

CHCl3-d1, δ, ppm): 7.60 (s, 1H, H-5), 7.58 (s, 1H, H-2'), 7.46 (d, J = 7.6 Hz, 1H, H-

6'), 7.37 (d, J = 7.6 Hz, 1H, H-4'), 7.27 (t, J = 8.0 Hz, 1H, H-5'), 6.85 (s, 1H, H-8),

6.16 (s, 1H, H-3), 5.16 (s, 2H, H-7'), 2.37 (s, 3H, CH3-11); EIMS (m/z): 382 (<1%),

380 (3%), 378 [M]•+ (2%), 210 (2%), 187 (2%), 185 (1%), 182 (3%), 169 (99%), 171

(BP, 100%), 65 (4%).

4.0.11 Physical and spectral data of 7-Acyloxy-6-chloro-4-

methylbenzo-2-pyrone (XXI1-8)

7-[(Ethanoyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI1)

OO

Cl

O

CH3

1

35

71'

H3C

11

O

12




7.64 (s, 1H, H-5), 7.15 (s, 1H, H-8), 6.29 (s, 1H, H-3), 2.40 (s, 3H, CH3-11), 2.37 (s,

3H, CH3-1'); 13C-NMR (125 MHz, CHCl3-d1, δ, ppm): 163.8 (C-12), 160.3 (C-2),


Page 121

157.3 (C-4), 153.4 (C-7), 151.8 (C-9), 125.1 (C-5), 118.7 (C-6), 113.5 (C-10), 112.2

(C-3), 100.3 (C-8), 23.0 (C-1'), 18.4 (C-11); EIMS (m/z): 254 (1%), 252 [M]•+ (3%),

237 (13%), 210 (BP, 100%), 182 (71%).

7-[(2-Bromoethanoyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI2)

OO

Cl

O

CH3

1

35

71'Br

11

O

12



(C=O), 1601 (Ar C=C), 1161 (C-O), 704 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ,

ppm): 7.52 (s, 1H, H-5), 6.98 (s, 1H, H-8), 6.13 (s, 1H, H-3), 2.30 (s, 3H, CH3-11),

3.68 (s, 2H, H-1'); EIMS (m/z): 334 (<1%), 332 (2%), 330 [M]•+ (5%), 237 (17%), 210

(BP, 100%), 182 (77%).

7-[(Phenoxycarbonyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI3)

OO

Cl

O

CH3

1

35

71'

O

11

O

12

3'

5'

Dark brown amorphous solid; Yield: 81%; M.P.: 246-248 oC; HRMS: [M]•+ 330.0292



7.59 (s, 1H, H-5), 7.44 (t, J = 7.2 Hz, 2H, H-3' & H-5'), 7.37 (d, J = 7.2 Hz, 2H, H-2'

& H-6'), 7.23-7.19 (m, 1H, H-4'), 6.98 (s, 1H, H-8), 6.13 (s, 1H, H-3), 2.30 (s, 3H,

CH3-11); EIMS (m/z): 332 (2%), 330 [M]•+ (7%), 237 (18%), 210 (86%), 182 (79%),

121 (15%), 93 (9%), 77 (BP, 100%), 51 (37%).

7-[(Benzoyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI4)

OO

Cl

O

CH3

1

35

7

1'3'

5'

12

11

O


Page 122




7.52 (s, 1H, H-5), 7.46 (dd, J = 7.6, 2.0 Hz, 2H, H-2' & H-6'), 7.39-7.37 (m, 3H, H-3'

to H-5'), 6.98 (s, 1H, H-8), 6.13 (s, 1H, H-3), 2.30 (s, 3H, CH3-11); EIMS (m/z): 316

(2%), 314 [M]•+ (5%), 237 (13%), 210 (81%), 182 (72%), 105 (25%), 77 (BP, 100%),

51 (31%).

7-[(2-Chlorobenzoyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI5)

OO

Cl

O

CH3

1

35

7

1'3'

5'

12

Cl

11

O


347.9959 (Calcd. for C17H10Cl2O4; 347.9974); IR (KBr, υmax, cm-1): 3059 (Ar C-H),

1737 (C=O), 1601 (Ar C=C), 1162 (C-O), 701 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1,

δ, ppm): 7.73 (dd, J = 7.6, 1.6 Hz, 1H, H-3'), 7.59 (s, 1H, H-5), 7.51 (t, J = 7.6 Hz,

1H, H-4'), 7.47 (dd, J = 7.6, 1.6 Hz, 1H, H-6'), 7.40 (t, J = 7.6 Hz, 1H, H-5'), 6.93 (s,

1H, H-8), 6.14 (s, 1H, H-3), 2.36 (s, 3H, CH3-11); EIMS (m/z): 352 (1%), 350 (2%),

348 [M]•+ (3%), 237 (11%), 210 (83%), 182 (76%), 139 (21%), 111 (BP, 100%), 51

(33%).

7-[(2,4-Dichlorobenzoyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI6)

OO

Cl

O

CH3

1

35

7

1'3'

5'

12

Cl

11

O

Cl


(Calcd. for C17H9Cl3O4; 381.9577); IR (KBr, υmax, cm-1): 3063 (Ar C-H), 1734 (C=O),


7.87 (d, J = 1.6 Hz, 1H, H-3'), 7.63 (s, 1H, H-5), 7.47 (d, J = 7.2 Hz, 1H, H-6'), 7.41

(dd, J = 7.2, 1.6 Hz, 1H, H-5'), 6.91 (s, 1H, H-8), 6.17 (s, 1H, H-3), 2.33 (s, 3H, CH3-


Page 123

11); EIMS (m/z): 388 (<1%), 386 (1%), 384 (3%), 382 [M]•+ (7%), 237 (16%), 210

(87%), 182 (78%), 174 (27%), 111 (BP, 100%).

7-[(Thiophen-2-carbonyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI7)

OO

Cl

O

CH3

1

35

7

1'

3'5'

12

11

O

S


(Calcd. for C15H9ClO4S; 319.9932); IR (KBr, υmax, cm-1): 3062 (Ar C-H), 1735


ppm): 7.69 (dd, J =7.2, 1.2 Hz, 1H, H-5'), 7.59 (s, 1H, H-5), 7.47 (t, J = 7.6 Hz, 1H,

H-4'), 7.35 (dd, J = 7.2, 1.2 Hz, 1H, H-3'), 6.98 (s, 1H, H-8), 6.17 (s, 1H, H-3), 2.38

(s, 3H, CH3-11); EIMS (m/z): 322 (3%), 320 [M]•+ (9%), 237 (16%), 210 (84%), 182

(67%), 111 (27%), 83 (BP, 100%).

7-[(Morpholin-4-carbonyl)oxy]-6-chloro-4-methylbenzo-2-pyrone (XXI8)

OO

Cl

O

CH3

1

35

7

N 12

11

O

1'

3'

5'

O

Grey amorphous solid; Yield: 84%; M.P.: 232-234 oC; HRMS: [M]•+ 323.0563

(Calcd. for C15H14ClNO5; 323.0576); IR (KBr, υmax, cm-1): 3056 (Ar C-H), 1739


ppm): 7.54 (s, 1H, H-5), 6.93 (s, 1H, H-8), 6.15 (s, 1H, H-3), 3.96 (t, J = 4.8 Hz, 4H,

H-2' & H-6'), 2.96 (t, J = 4.8 Hz, 4H, H-3' & H-5'), 2.33 (s, 3H, CH3-11); EIMS (m/z):

325 (2%), 323 [M]•+ (7%), 237 (13%), 210 (85%), 182 (71%), 114 (33%), 86 (BP,

100%).

4.0.12 Physical and spectral data of N-Substituted-2-[(6-chloro-

4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1-26)

N-Cyclohexyl-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1)


349.1083 (Calcd. for C18H20ClNO4; 349.1104); IR (KBr, υmax, cm-1): 3426 (N-H),


Page 124

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

3067 (Ar C-H), 1737 (ester C=O), 1673 (amide C=O), 1590 (Ar C=C), 1154 (C-O),

699 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 9.31 (s, 1H, CON-H), 7.66 (s,

1H, H-5), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 3.75-3.73 (m, 1H,

H-1''), 2.41 (s, 3H, CH3-11), 1.86-1.83 (m, 2H, Heq-2'' & Heq-6''), 1.66-1.53 (m, 4H,

H-3'' & H-5''), 1.34-1.28 (m, 2H, Hax-2'' & Hax-6''), 1.20-1.14 (m, 2H, H-4''); EIMS

(m/z): 351 (5%), 349 [M]•+ (15%), 314 (BP, 100%), 224 (12%), 210 (4%), 196 (5%),

193 (8%), 182 (6%), 165 (4%), 149 (3%), 126 (8%), 98 (3%).

N-Benzyl-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV2)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

5'' 1''

3''

7''





1H, H-5), 7.28-7.21 (m, 5H, H-2'' to H-6''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.67

(s, 2H, H-2'), 4.39 (s, 2H, H-7''), 2.40 (s, 3H, CH3-11); EIMS (m/z): 359 (5%), 357

[M]•+ (16%), 322 (BP, 100%), 224 (13%), 210 (4%), 196 (6%), 193 (12%), 182 (6%),

165 (3%), 149 (1%), 106 (2%).

N-(2-Phenylethyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV3)





1H, H-5), 7.14-7.09 (m, 5H, H-2'' to H-6''), 6.90 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.68


Page 125

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

7''

5''

1''3'' 8''

(s, 2H, H-2'), 3.41 (t, J = 7.6 Hz, 2H, H-8''), 2.40 (s, 3H, CH3-11), 2.72 (t, J = 7.6 Hz,

2H, H-7''); EIMS (m/z): 373 (4%), 371 [M]•+ (14%), 336 (BP, 100%), 224 (9%), 210

(4%), 196 (6%), 193 (7%), 182 (6%), 165 (5%), 149 (3%), 148 (7%), 120 (3%).

N-Phenyl-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV4)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''


(Calcd. for C18H14ClNO4; 343.0628); IR (KBr, υmax, cm-1): 3424 (N-H), 3036 (Ar C-

H), 1739 (ester C=O), 1661 (amide C=O), 1587 (Ar C=C), 1127 (C-O), 705 (C-Cl);

1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.49 (s, 1H, CON-H), 7.65 (s, 1H, H-5), 7.59

(d, J = 7.6 Hz, 2H, H-2'' & H-6''), 7.36 (t, J = 7.6 Hz, 2H, H-3'' & H-5''), 7.16 (t, J =

7.6 Hz, 1H, H-4''), 6.90 (s, 1H, H-8), 6.23 (s, 1H, H-3), 4.69 (s, 2H, H-2'), 2.40 (s, 3H,

CH3-11); EIMS (m/z): 345 (6%), 343 [M]•+ (17%), 308 (BP, 100%), 224 (13%), 210

(5%), 196 (4%), 193 (11%), 182 (6%), 165 (4%), 149 (3%), 120 (6%), 92 (2%).

N-(2-Methylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV5)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

CH3

1''

3''

5''

7''




Page 126


1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 9.73 (s, 1H, CON-H), 7.71 (d, J = 8.0 Hz,

1H, H-6''), 7.63 (s, 1H, H-5), 7.18 (d, J = 8.0 Hz, 1H, H-3''), 7.13 (t, J = 8.0 Hz, 1H,

H-5''), 7.06 (t, J = 8.0 Hz, 1H, H-4''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.68 (s, 2H,

H-2'), 2.40 (s, 3H, CH3-11), 2.27 (s, 3H, CH3-7''); EIMS (m/z): 359 (7%), 357 [M]•+

(19%), 322 (BP, 100%), 224 (9%), 210 (2%), 196 (5%), 193 (7%), 182 (3%), 165

(4%), 149 (3%), 106 (2%).


(XXIV6)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

H3C7''





(d, J = 7.6 Hz, 1H, H-6''), 7.37 (s, 1H, H-2''), 7.19 (t, J = 7.6 Hz, 1H, H-5''), 7.03 (d, J

= 7.6 Hz, 1H, H-4''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.39 (s,

3H, CH3-11), 2.34 (s, 3H, CH3-7''); EIMS (m/z): 359 (5%), 357 [M]•+ (16%), 322 (BP,

100%), 224 (8%), 210 (1%), 196 (3%), 193 (4%), 182 (5%), 165 (3%), 149 (2%), 106

(3%).


(XXIV7)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

7''

H3C




Page 127



(d, J = 8.0 Hz, 2H, H-2'' & H-6''), 7.17 (d, J = 8.4 Hz, 2H, H-3'' & H-5''), 6.89 (s, 1H,

H-8), 6.23 (s, 1H, H-3), 4.68 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11), 2.27 (s, 3H, CH3-7'');

EIMS (m/z): 359 (4%), 357 [M]•+ (15%), 322 (BP, 100%), 224 (4%), 210 (6%), 196

(4%), 193 (6%), 182 (2%), 165 (3%), 149 (5%), 106 (3%).

N-(2-Ethylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV8)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

CH2CH3

7'' 8''





(dd, J = 8.4, 2.4 Hz, 1H, H-6''), 7.13 (dt, J = 8.4, 2.4 Hz, 1H, H-5''), 7.05 (dt, J = 8.0,

2.4 Hz, 1H, H-4''), 6.97 (dd, J = 8.4, 2.4 Hz, 1H, H-3''), 6.90 (s, 1H, H-8), 6.23 (s, 1H,

H-3), 4.69 (s, 2H, H-2'), 2.47 (q, J = 7.2 Hz, 2H, H-7''), 2.40 (s, 3H, CH3-11), 1.03 (t,

J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z): 373 (5%), 371 [M]•+ (16%), 336 (BP, 100%),

224 (8%), 210 (4%), 196 (3%), 193 (9%), 182 (5%), 165 (4%), 149 (4%), 148 (6%),

120 (3%).

N-(4-Ethylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV9)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

7''

H3CH2C

8''

Yellowish white amorphous solid; Yield: 82%; M.P.: 154-156 oC; HRMS: [M]•+



Page 128



1H, H-5), 7.07 (d, J = 8.0 Hz, 2H, H-2'' & H-6''), 6.95 (d, J = 8.0 Hz, 2H, H-3'' & H-

5''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.56 (q, J = 7.2 Hz, 2H,

H-7''), 2.40 (s, 3H, CH3-11), 1.12 (t, J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z): 373 (5%),

371 [M]•+ (14%), 336 (BP, 100%), 224 (6%), 210 (1%), 196 (2%), 193 (7%), 182

(4%), 165 (5%), 149 (2%), 148 (4%), 120 (4%).

N-(2-Methoxyphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV10)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

OCH3

7''





1H, H-6''), 7.66 (s, 1H, H-5), 7.03 (t, J = 7.6 Hz, 1H, H-5''), 6.94 (t, J = 7.6 Hz, 1H,

H-4''), 6.90 (s, 1H, H-8), 6.83 (d, J = 8.0 Hz, 1H, H-3''), 6.22 (s, 1H, H-3), 4.68 (s, 2H,

H-2'), 3.83 (s, 3H, CH3-7''), 2.40 (s, 3H, CH3-11); EIMS (m/z): 375 (7%), 373 [M]•+

(20%), 338 (BP, 100%), 224 (7%), 210 (2%), 196 (5%), 193 (8%), 182 (3%), 165

(3%), 150 (6%), 149 (3%), 122 (2%).

N-(2-Ethoxyphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV11)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

OCH2CH3

7'' 8''




Page 129



(dd, J = 8.4, 2.4 Hz, 1H, H-6''), 7.13 (dt, J = 8.4, 2.0 Hz, 1H, H-4''), 6.91 (s, 1H, H-8),

6.85 (dt, J = 8.8, 2.4 Hz, 1H, H-5''), 6.76 (dd, J = 8.0, 2.0 Hz, 1H, H-3''), 6.24 (s, 1H,

H-3), 4.68 (s, 2H, H-2'), 3.75 (q, J = 7.2 Hz, 2H, H-7''), 2.40 (s, 3H, CH3-11), 1.15 (t,


224 (8%), 210 (2%), 196 (5%), 193 (9%), 182 (4%), 165 (3%), 164 (4%), 149 (3%),

136 (2%).

N-(4-Ethoxyphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV12)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

7''

H3CH2CO

8''





(d, J = 8.4 Hz, 2H, H-2'' & H-6''), 6.90 (s, 1H, H-8), 6.74 (d, J = 8.8 Hz, 2H, H-3'' &

H-5''), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 3.91 (q, J = 7.2 Hz, 2H, H-7''), 2.39 (s,

3H, CH3-11), 1.29 (t, J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z): 389 (6%), 387 [M]•+

(19%), 352 (BP, 100%), 224 (7%), 210 (3%), 196 (4%), 193 (8%), 182 (5%), 165

(2%), 164 (5%), 149 (4%), 136 (3%).

N-(2-Methoxycarbonylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]ace-

tamide (XXIV13)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

COOCH3

7'' 8''



Page 130



704 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 11.21 (s, 1H, CON-H), 8.72 (d, J

= 8.4 Hz, 1H, H-6''), 8.11 (d, J = 7.6 Hz, 1H, H-3''), 7.64 (s, 1H, H-5), 7.51 (t, J = 7.6

Hz, 1H, H-5''), 7.16 (t, J = 7.6 Hz, 1H, H-4''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3),

4.68 (s, 2H, H-2'), 3.89 (s, 3H, CH3-8''), 2.40 (s, 3H, CH3-11); EIMS (m/z): 403 (6%),

401 [M]•+ (19%), 366 (BP, 100%), 224 (10%), 210 (3%), 196 (4%), 193 (10%), 182

(4%), 178 (7%), 165 (2%), 150 (1%), 149 (2%).

N-(4-Bromophenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV14)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

Br


(Calcd. for C18H13BrClNO4; 420.9727); IR (KBr, υmax, cm-1): 3419 (N-H), 3059 (Ar

C-H), 1736 (ester C=O), 1665 (amide C=O), 1595 (Ar C=C), 1141 (C-O), 701 (C-Cl),

636 (C-Br); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 9.27 (s, 1H, CON-H), 7.64 (s,

1H, H-5), 7.44 (d, J = 8.4 Hz, 2H, H-2'' & H-6''), 7.40 (d, J = 8.4 Hz, 2H, H-3'' & H-

5''), 6.92 (s, 1H, H-8), 6.24 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11);

EIMS (m/z): 425 (6%), 423 (14%), 421 [M]•+ (18%), 387 (BP, 100%), 224 (8%), 210

(2%), 198 (7%), 196 (3%), 193 (9%), 182 (6%), 170 (2%), 165 (3%), 149 (4%), 134

(2%).

N-(4-Nitrophenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV15)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

O2N

Dark yellow amorphous solid; Yield: 79%; M.P.: 172-174 oC; HRMS: [M]•+ 388.0464


Page 131

(Calcd. for C18H13ClN2O6; 388.0481); IR (KBr, υmax, cm-1): 3428 (N-H), 3043 (Ar C-



2H, H-3'' & H-5''), 8.05 (d, J = 8.0 Hz, 2H, H-2'' & H-6''), 7.64 (s, 1H, H-5), 6.91 (s,

1H, H-8), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11); EIMS (m/z): 390

(4%), 388 [M]•+ (14%), 353 (BP, 100%), 224 (9%), 210 (4%), 196 (7%), 193 (8%),

182 (6%), 165 (6%), 149 (3%), 137 (2%).

N-(2,3-Dimethylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide

(XXIV16)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

H3C

7''

8''

CH3





(d, J = 8.0 Hz, 1H, H-6''), 7.13 (t, J = 8.0 Hz, 1H, H-5''), 7.04 (d, J = 8.0 Hz, 1H, H-

4''), 6.92 (s, 1H, H-8), 6.21 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.39 (s, 3H, CH3-11), 2.35

(s, 3H, CH3-7''), 2.13 (s, 3H, CH3-8''); EIMS (m/z): 373 (7%), 371 [M]•+ (22%), 336

(BP, 100%), 224 (12%), 210 (6%), 196 (7%), 193 (13%), 182 (6%), 165 (5%), 149

(4%), 148 (8%), 120 (2%).


(XXIV17)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

H3C

CH3

7''

8''




Page 132



1H, H-6''), 7.66 (s, 1H, H-5), 7.05 (d, J = 8.0 Hz, 1H, H-5''), 6.95 (s, 1H, H-3''), 6.91

(s, 1H, H-8), 6.22 (s, 1H, H-3), 4.68 (s, 2H, H-2'), 2.39 (s, 3H, CH3-11), 2.29 (s, 3H,

CH3-7''), 2.23 (s, 3H, CH3-8''); EIMS (m/z): 373 (6%), 371 [M]•+ (17%), 336 (BP,

100%), 224 (11%), 210 (5%), 196 (9%), 193 (11%), 182 (7%), 165 (4%), 149 (6%),

148 (9%), 120 (3%).


(XXIV18)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

CH3

7''

8'' CH3





(s, 1H, H-6''), 7.05 (d, J = 7.6 Hz, 1H, H-3''), 6.94 (d, J = 7.6 Hz, 1H, H-4''), 6.92 (s,

1H, H-8), 6.22 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11), 2.33 (s, 3H,


100%), 224 (10%), 210 (4%), 196 (9%), 193 (11%), 182 (7%), 165 (8%), 149 (3%),

148 (9%), 120 (5%).


(XXIV19)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

CH3

7''

8''

CH3

Pinkish white amorphous solid; Yield: 75%; M.P.: 182-184 oC; HRMS: [M]•+


Page 133




1H, H-5), 7.13-7.06 (m, 3H, H-3'' to H-5''), 6.91 (s, 1H, H-8), 6.22 (s, 1H, H-3), 4.68

(s, 2H, H-2'), 2.40 (s, 3H, CH3-11), 2.25 (s, 6H, CH3-7'' & CH3-8''); EIMS (m/z): 373

(8%), 371 [M]•+ (23%), 336 (BP, 100%), 224 (11%), 210 (5%), 196 (4%), 193 (9%),

182 (4%), 165 (7%), 149 (8%), 148 (6%), 120 (3%).


(XXIV20)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

H3C

7''

8''

H3C





(d, J = 8.0 Hz, 1H, H-6''), 7.29 (s, 1H, H-2''), 7.08 (d, J = 8.0 Hz, 1H, H-5''), 6.91 (s,

1H, H-8), 6.24 (s, 1H, H-3), 4.68 (s, 2H, H-2'), 2.39 (s, 3H, CH3-11), 2.25 (s, 3H,


100%), 224 (9%), 210 (3%), 196 (6%), 193 (14%), 182 (5%), 165 (3%), 149 (6%),

148 (6%), 120 (3%).


(XXIV21)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

7''

8''

H3C

H3C



Page 134




(s, 2H, H-2'' & H-6''), 6.96 (s, 1H, H-4''), 6.90 (s, 1H, H-8), 6.23 (s, 1H, H-3), 4.69 (s,

2H, H-2'), 2.40 (s, 3H, CH3-11), 2.27 (s, 6H, CH3-7'' & CH3-8''); EIMS (m/z): 373

(6%), 371 [M]•+ (19%), 336 (BP, 100%), 224 (13%), 210 (7%), 196 (3%), 193 (8%),

182 (2%), 165 (4%), 149 (5%), 148 (6%), 120 (1%).

N-(2-Ethyl-6-methylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]aceta-

mide (XXIV22)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

CH2CH3

7'' 8''

CH39''




1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 9.32 (s, 1H, CON-H), 7.66 (s, 1H, H-5),

7.15-7.02 (m, 3H, H-3'' to H-5''), 6.90 (s, 1H, H-8), 6.23 (s, 1H, H-3), 4.68 (s, 2H, H-

2'), 2.43 (q, J = 7.2 Hz, 2H, H-7''), 2.40 (s, 3H, CH3-11), 1.94 (s, 3H, CH3-9''), 1.01 (t,


224 (8%), 210 (4%), 196 (5%), 193 (8%), 182 (3%), 165 (3%), 162 (9%), 149 (3%).

N-(4-Bromo-2-methylphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acet-

amide (XXIV23)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

Br

CH3

7''


(Calcd. for C19H15BrClNO4; 434.9889); IR (KBr, υmax, cm-1): 3425 (N-H), 3047 (Ar

C-H), 1736 (ester C=O), 1674 (amide C=O), 1593 (Ar C=C), 1151 (C-O), 708 (C-Cl),


Page 135

635 (C-Br); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 9.67 (s, 1H, CON-H), 7.74 (d, J

= 7.6 Hz, 1H, H-6''), 7.64 (s, 1H, H-5), 7.21 (d, J = 7.6 Hz, 1H, H-5''), 7.11 (s, 1H, H-

3''), 6.92 (s, 1H, H-8), 6.24 (s, 1H, H-3), 4.69 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11), 2.26

(s, 3H, CH3-7''); EIMS (m/z): 439 (5%), 437 (14%), 435 [M]•+ (16%), 400 (BP,

100%), 224 (7%), 212 (4%), 210 (4%), 196 (6%), 193 (9%), 184 (3%), 182 (5%), 165

(4%), 149 (5%).

N-(2-Methyl-4-nitrophenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]aceta-

mide (XXIV24)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

O2N

CH3

7''


(Calcd. for C19H15ClN2O6; 402.0625); IR (KBr, υmax, cm-1): 3427 (N-H), 3039 (Ar C-



1H, H-6''), 7.65 (s, 1H, H-5), 7.56 (d, J = 7.6 Hz, 1H, H-5''), 7.39 (s, 1H, H-3''), 6.93

(s, 1H, H-8), 6.23 (s, 1H, H-3), 4.67 (s, 2H, H-2'), 2.40 (s, 3H, CH3-11), 2.29 (s, 3H,

CH3-7''); EIMS (m/z): 404 (5%), 402 [M]•+ (16%), 367 (BP, 100%), 224 (7%), 210

(4%), 196 (6%), 193 (8%), 182 (7%), 179 (5%), 165 (4%), 151 (3%), 149 (5%).

N-(2-Methyl-6-nitrophenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]aceta-

mide (XXIV25)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

CH3

7''

NO2

Yellowish white amorphous solid; Yield: 87%; M.P.: 174-176 oC; HRMS: [M]•+

402.0617 (Calcd. for C19H15ClN2O6; 402.0625); IR (KBr, υmax, cm-1): 3438 (N-H),


696 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.79 (s, 1H, CON-H), 7.95 (d, J


Page 136

= 8.4 Hz, 1H, H-5''), 7.65 (s, 1H, H-5), 7.31 (d, J = 8.8 Hz, 1H, H-3''), 6.90 (s, 1H, H-

8), 6.59 (t, J = 8.8 Hz, 1H, H-4''), 6.23 (s, 1H, H-3), 4.69 (s, 2H, H-2'), 2.40 (s, 3H,

CH3-11), 2.24 (s, 3H, CH3-7''); EIMS (m/z): 404 (5%), 402 [M]•+ (15%), 367 (BP,

100%), 224 (8%), 210 (7%), 196 (4%), 193 (9%), 182 (5%), 179 (6%), 165 (3%), 151

(6%), 149 (4%).

N-(5-Chloro-2-methoxyphenyl)-2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]ac-

etamide (XXIV26)

OO

Cl

O

CH3

1

35

7HN

O

1' 2'

11

1''

5''

3''

OCH3

7''

Cl


(Calcd. for C19H15Cl2NO5; 407.0336); IR (KBr, υmax, cm-1): 3418 (N-H), 3054 (Ar C-



1H, H-6''), 7.64 (s, 1H, H-5), 7.04 (dd, J = 8.8, 2.4 Hz, 1H, H-4''), 6.88 (s, 1H, H-8),

6.81 (d, J = 8.4 Hz, 1H, H-3''), 6.22 (s, 1H, H-3), 4.68 (s, 2H, H-2'), 3.89 (s, 3H, CH3-

7''), 2.40 (s, 3H, CH3-11); EIMS (m/z): 409 (5%), 407 [M]•+ (17%), 372 (BP, 100%),

224 (7%), 210 (3%), 196 (5%), 193 (7%), 184 (6%), 182 (5%), 165 (4%), 156 (3%),

149 (3%).

4.0.13 Physical and spectral data of N-substituted-2-[(benzo-2-

pyron-4-yl)oxy]acetamide (XXVI1-18)

N-(2-Phenylethyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI1)

1

35

7

1'2'

O O

O

NH

O

1''8''

7''

5''

3''


323.1154 (Calcd. for C19H17NO4; 323.1243); IR (KBr, υmax, cm-1): 3448 (N-H), 3077


Page 137

(Ar C-H), 1736 (ester C=O), 1665 (amide C=O), 1601 (Ar C=C), 1173 (C-O); 1H-

NMR (400 MHz, CHCl3-d1, δ, ppm): 8.83 (s, 1H, CON-H), 7.93 (d, J = 8.4 Hz, 1H,

H-5), 7.63 (t, J = 8.4 Hz, 1H, H-7), 7.39 (d, J = 8.0 Hz, 1H, H-8), 7.34 (t, J = 8.0 Hz,

1H, H-6), 7.17-7.11 (m, 5H, H-2'' to H-6''), 5.78 (s, 1H, H-3), 4.79 (s, 2H, H-2'), 3.42

(t, J = 7.2 Hz, 2H, H-8''), 2.69 (t, J = 7.2 Hz, 2H, H-7''); EIMS (m/z): 323 [M]•+

(51%), 176 (38%), 162 (40%), 148 (56%), 146 (BP, 100%), 145 (9%), 134 (52%),

132 (59%), 120 (76%), 118 (83%), 117 (38%), 101 (41%).

N-Phenyl-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI2)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''


(Calcd. For C17H13NO4; 295.0913); IR (KBr, υmax, cm-1): 3447 (N-H), 3052 (Ar C-H),

1734 (ester C=O), 1678 (amide C=O), 1604 (Ar C=C), 1139 (C-O); 1H-NMR (400

MHz, CHCl3-d1, δ, ppm): 8.89 (s, 1H, CON-H), 7.93 (d, J = 8.4 Hz, 1H, H-5), 7.64 (t,

J = 8.0 Hz, 1H, H-7), 7.56 (d, J = 8.4 Hz, 2H, H-2'' & H-6''), 7.39 (d, J = 8.0 Hz, 1H,

H-8), 7.35 (t, J = 8.4 Hz, 2H, H-3'' & H-5''), 7.32 (t, J = 8.4 Hz, 1H, H-6), 7.18 (t, J =

8.0 Hz, 1H, H-4''), 5.77 (s, 1H, H-3), 4.76 (s, 2H, H-2'); EIMS (m/z): 295 [M]•+

(55%), 176 (37%), 162 (41%), 148 (39%), 146 (BP, 100%), 145 (5%), 134 (59%),

132 (57%), 120 (24%), 118 (80%), 117 (36%), 101 (44%), 92 (73%).

N-(2-Methylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI3)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3C

7''


(Calcd. for C18H15NO4; 309.1043); IR (KBr, υmax, cm-1): 3429 (N-H), 3053 (Ar C-H),


MHz, CHCl3-d1, δ, ppm): 8.75 (s, 1H, CON-H), 7.93 (d, J = 8.0 Hz, 1H, H-5), 7.72

(d, J = 8.4 Hz, 1H, H-6''), 7.64 (t, J = 8.0 Hz, 1H, H-7), 7.39 (d, J = 8.0 Hz, 1H, H-8),


Page 138

7.36 (t, J = 8.0 Hz, 1H, H-6), 7.16 (d, J = 8.4 Hz, 1H, H-3''), 7.11 (t, J = 8.0 Hz, 1H,

H-5''), 7.08 (t, J = 8.0 Hz, 1H, H-4''), 5.73 (s, 1H, H-3), 4.76 (s, 2H, H-2'), 2.26 (s, 3H,

CH3-7''); EIMS (m/z): 309 [M]•+ (58%), 176 (36%), 162 (48%), 148 (32%), 146 (BP,

100%), 145 (6%), 134 (78%), 132 (58%), 118 (89%), 117 (36%), 106 (74%), 101

(45%).

N-(4-Methylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI4)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''CH3





J = 8.0 Hz, 1H, H-7), 7.39 (d, J = 8.0 Hz, 1H, H-8), 7.36 (t, J = 8.0 Hz, 1H, H-6), 7.34


H-3), 4.77 (s, 2H, H-2'), 2.27 (s, 3H, CH3-7''); EIMS (m/z): 309 [M]•+ (56%), 176

(37%), 162 (49%), 148 (36%), 146 (BP, 100%), 145 (8%), 134 (75%), 132 (59%),

118 (85%), 117 (31%), 106 (77%), 101 (44%).

N-(2-Ethylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI5)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3CH2C

7''8''




MHz, CHCl3-d1, δ, ppm): 8.91 (s, 1H, CON-H), 7.94 (d, J = 8.0 Hz, 1H, H-6''), 7.83

(d, J = 8.0 Hz, 1H, H-5), 7.62 (t, J = 8.0 Hz, 1H, H-7), 7.38 (d, J = 8.0 Hz, 1H, H-8),

7.34 (t, J = 8.0 Hz, 1H, H-6), 7.29-7.22 (m, 2H, H-4'' & H-5''), 7.18 (d, J = 7.6 Hz,

1H, H-3''), 5.80 (s, 1H, H-3), 4.81 (s, 2H, H-2'), 2.63 (q, J = 7.6 Hz, 2H, H-7''), 1.22


Page 139

(t, J = 7.6 Hz, 3H, CH3-8''); EIMS (m/z): 323 [M]•+ (54%), 176 (37%), 162 (39%),

148 (60%), 146 (BP, 100%), 145 (5%), 134 (60%), 132 (57%), 120 (77%), 118

(84%), 117 (36%), 101 (41%).

N-(4-Ethylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI6)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7'' 8''

CH2CH3







H-3), 4.79 (s, 2H, H-2'), 2.57 (q, J = 7.6 Hz, 2H, H-7''), 1.11 (t, J = 7.6 Hz, 3H, CH3-

8''); EIMS (m/z): 323 [M]•+ (58%), 176 (39%), 162 (34%), 148 (66%), 146 (BP,

100%), 145 (8%), 134 (64%), 132 (56%), 120 (76%), 118 (83%), 117 (32%), 101

(46%).

N-(2-Methoxyphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI7)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3CO

7''





H-6''), 7.92 (d, J = 8.4 Hz, 1H, H-5), 7.64 (t, J = 8.4 Hz, 1H, H-7), 7.38 (d, J = 8.4 Hz,

1H, H-8), 7.36 (t, J = 8.4 Hz, 1H, H-6), 7.08 (t, J = 8.0 Hz, 1H, H-5''), 6.93 (t, J = 8.4

Hz, 1H, H-4''), 6.84 (d, J = 8.4 Hz, 1H, H-3''), 5.76 (s, 1H, H-3), 4.77 (s, 2H, H-2'),

3.86 (s, 3H, CH3-7''); EIMS (m/z): 325 [M]•+ (52%), 176 (37%), 162 (45%), 150

(26%), 148 (34%), 146 (BP, 100%), 145 (6%), 134 (54%), 132 (55%), 122 (69%),


Page 140

118 (84%), 117 (35%), 101 (46%).

N-(2-Ethoxyphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI8)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3CH2CO

7''8''





J = 8.0 Hz, 1H, H-7), 7.43 (dd, J = 8.0, 2.0 Hz, 1H, H-6''), 7.39 (d, J = 8.0 Hz, 1H, H-

8), 7.34 (t, J = 8.4 Hz, 1H, H-6), 7.11 (dt, J = 8.0, 2.0 Hz, 1H, H-4''), 6.83 (dt, J = 8.0,

2.4 Hz, 1H, H-5''), 6.74 (dd, J = 8.0, 2.4 Hz, 1H, H-3''), 5.76 (s, 1H, H-3), 4.79 (s, 2H,

H-2'), 3.79 (q, J = 7.6 Hz, 2H, H-7''), 1.19 (t, J = 7.6 Hz, 3H, CH3-8''); EIMS (m/z):

339 [M]•+ (53%), 176 (34%), 164 (26%), 162 (44%), 148 (37%), 146 (BP, 100%),

145 (8%), 136 (73%), 134 (52%), 132 (55%), 118 (81%), 117 (37%), 101 (43%).

N-(4-Ethoxyphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI9)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7'' 8''

OCH2CH3







H-3), 4.74 (s, 2H, H-2'), 3.92 (q, J = 7.6 Hz, 2H, H-7''), 1.27 (t, J = 7.6 Hz, 3H, CH3-

8''); EIMS (m/z): 339 [M]•+ (51%), 176 (36%), 164 (28%), 162 (48%), 148 (34%), 146

(BP, 100%), 145 (7%), 136 (76%), 134 (58%), 132 (59%), 118 (88%), 117 (36%),

101 (47%).

N-(2-Methoxycarbonylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI10)


Page 141

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3COOC

7''8''




MHz, CHCl3-d1, δ, ppm): 8.91 (s, 1H, CON-H), 8.64 (d, J = 8.0 Hz, 1H, H-6''), 8.06

(d, J = 8.0 Hz, 1H, H-3''), 7.91 (d, J = 8.4 Hz, 1H, H-5), 7.63 (t, J = 8.4 Hz, 1H, H-7),

7.53 (t, J = 8.0 Hz, 1H, H-5''), 7.43 (d, J = 8.0 Hz, 1H, H-8), 7.35 (t, J = 8.0 Hz, 1H,

H-6), 7.15 (t, J = 8.0 Hz, 1H, H-4''), 5.74 (s, 1H, H-3), 4.75 (s, 2H, H-2'), 3.87 (s, 3H,

CH3-8''); EIMS (m/z): 353 [M]•+ (54%), 178 (22%), 176 (35%), 162 (40%), 150

(71%), 148 (32%), 146 (BP, 100%), 145 (8%), 134 (50%), 132 (56%), 118 (82%),

117 (31%), 101 (47%).

N-(2,3-Dimethylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI11)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''H3C

7''

8'' CH3





J = 8.0 Hz, 1H, H-7), 7.53 (d, J = 8.4 Hz, 1H, H-6''), 7.37 (d, J = 8.0 Hz, 1H, H-8),

7.33 (t, J = 8.4 Hz, 1H, H-6), 7.17 (t, J = 8.4 Hz, 1H, H-5''), 7.07 (d, J = 8.4 Hz, 1H,

H-4''), 5.74 (s, 1H, H-3), 4.77 (s, 2H, H-2'), 2.34 (s, 3H, CH3-7''), 2.12 (s, 3H, CH3-

8''); EIMS (m/z): 323 [M]•+ (51%), 176 (35%), 162 (47%), 148 (64%), 146 (BP,

100%), 145 (8%), 134 (53%), 132 (51%), 120 (75%), 118 (82%), 117 (36%), 101

(49%).





Page 142

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''CH3

8''

H3C



H-5), 7.74 (d, J = 8.0 Hz, 1H, H-6''), 7.61 (t, J = 8.0 Hz, 1H, H-7), 7.39 (d, J = 8.0 Hz,

1H, H-8), 7.36 (t, J = 8.0 Hz, 1H, H-6), 7.09 (d, J = 8.0 Hz, 1H, H-5''), 6.94 (s, 1H, H-

3''), 5.79 (s, 1H, H-3), 4.78 (s, 2H, H-2'), 2.27 (s, 3H, CH3-7''), 2.22 (s, 3H, CH3-8'');

EIMS (m/z): 323 [M]•+ (54%), 176 (36%), 162 (41%), 148 (63%), 146 (BP, 100%),

145 (6%), 134 (57%), 132 (59%), 120 (71%), 118 (84%), 117 (38%), 101 (41%).


1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''

8''

H3C

CH3






(s, 1H, H-6''), 7.06 (d, J = 8.0 Hz, 1H, H-3''), 6.92 (d, J = 8.0 Hz, 1H, H-4''), 5.77 (s,

1H, H-3), 4.74 (s, 2H, H-2'), 2.34 (s, 3H, CH3-7''), 2.14 (s, 3H, CH3-8''); EIMS (m/z):

323 [M]•+ (53%), 176 (36%), 162 (42%), 148 (61%), 146 (BP, 100%), 145 (5%), 134

(54%), 132 (53%), 120 (71%), 118 (87%), 117 (33%), 101 (42%).






J = 8.4 Hz, 1H, H-7), 7.39 (d, J = 8.0 Hz, 1H, H-8), 7.34 (t, J = 8.0 Hz, 1H, H-6),

7.15-7.08 (m, 3H, H-3'' to H-5''), 5.73 (s, 1H, H-3), 4.78 (s, 2H, H-2'), 2.23 (s, 6H,


Page 143

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''

8''

H3C

CH3

CH3-7'' & CH3-8''); EIMS (m/z): 323 [M]•+ (57%), 176 (38%), 162 (43%), 148 (66%),

146 (BP, 100%), 145 (9%), 134 (54%), 132 (53%), 120 (76%), 118 (85%), 117

(39%), 101 (43%).


1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''

8''

CH3

CH3






(s, 2H, H-2'' & H-6''), 6.93 (s, 1H, H-4''), 5.76 (s, 1H, H-3), 4.77 (s, 2H, H-2'), 2.26 (s,

6H, CH3-7'' & CH3-8''); EIMS (m/z): 323 [M]•+ (50%), 176 (32%), 162 (49%), 148

(68%), 146 (BP, 100%), 145 (9%), 134 (54%), 132 (56%), 120 (79%), 118 (83%),

117 (37%), 101 (45%).

N-(2-Ethyl-6-methylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI16)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''8''

H3CH2C

CH39''





Page 144


J = 8.0 Hz, 1H, H-7), 7.37 (d, J = 8.4 Hz, 1H, H-8), 7.34 (t, J = 8.0 Hz, 1H, H-6),

7.18-7.09 (m, 3H, H-3'' to H-5''), 5.77 (s, 1H, H-3), 4.73 (s, 2H, H-2'), 2.44 (q, J = 7.6

Hz, 2H, H-7''), 1.98 (s, 3H, CH3-9''), 1.03 (t, J = 7.6 Hz, 3H, CH3-8''); EIMS (m/z):

337 [M]•+ (56%), 176 (36%), 162 (69%), 148 (32%), 146 (BP, 100%), 145 (6%), 134

(96%), 132 (55%), 118 (83%), 117 (36%), 101 (44%).

N-(2-Methyl-6-nitrophenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI17)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''H3C

NO2


354.0859 (Calcd. for C18H14N2O6; 354.0878); IR (KBr, υmax, cm-1): 3449 (N-H), 3055




1H, H-8), 7.35 (t, J = 8.0 Hz, 1H, H-6), 7.32 (d, J = 8.4 Hz, 1H, H-3''), 6.56 (t, J = 8.4

Hz, 1H, H-4''), 5.73 (s, 1H, H-3), 4.79 (s, 2H, H-2'), 2.25 (s, 3H, CH3-7''); EIMS

(m/z): 354 [M]•+ (56%), 179 (23%), 176 (35%), 162 (47%), 151 (73%), 148 (37%),

146 (BP, 100%), 145 (5%), 134 (58%), 132 (54%), 118 (87%), 117 (38%), 101

(43%).

N-(5-Chloro-2-methoxyphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide (XXVI18)

1

35

7

1'2'

O O

O

NH

O

1''5''

3''

7''H3CO

Cl



H), 1731 (ester C=O), 1679 (amide C=O), 1593 (Ar C=C), 1168 (C-O), 703 ; 1H-




Page 145

1H, H-8), 7.35 (t, J = 7.6 Hz, 1H, H-6), 7.03 (dd, J = 8.8, 2.4 Hz, 1H, H-4''), 6.79 (d, J

= 8.8 Hz, 1H, H-3''), 5.75 (s, 1H, H-3), 4.75 (s, 2H, H-2'), 3.90 (s, 3H, CH3-7''); EIMS

(m/z): 359 [M]•+ (57%), 184 (27%), 176 (33%), 162 (43%), 156 (71%), 148 (36%),

146 (BP, 100%), 145 (7%), 134 (56%), 132 (53%), 118 (86%), 117 (32%), 101

(48%).

4.0.14 Physical and spectral data of N-Substituted-2-[(5-{[(6-

chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-

yl)thio]acetamide (XXX1-27)

Ethyl 2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetate (XXVII)


296.0457 (Calcd. for C14H13ClO5; 296.0474).

2-[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetohydrazide (XXVIII)


282.0405 (Calcd. for C12H11ClN2O4; 282.0426).

5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-thiol

(XXIX)



N-Cyclohexyl-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-

oxadiazol-2-yl)thio]acetamide (XXX1)

O

NN

S

NH

O

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''



C-H), 1739 (ester C=O), 1676 (amide C=O), 1684 (C=N), 1596 (Ar C=C), 1159 (C-

O), 697 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.71 (s, 1H, CON-H), 7.57

(s, 1H, H-5'), 7.04 (s, 1H, H-8'), 6.23 (s, 1H, H-3'), 5.33 (s, 2H, H-12'), 4.05 (s, 2H, H-

2'''), 3.76-3.73 (m, 1H, H-1''), 2.38 (s, 3H, CH3-11'), 1.85-1.82 (m, 2H, Heq-2'' & Heq-

6''), 1.67-1.56 (m, 4H, H-3'' & H-5''), 1.35-1.32 (m, 2H, Hax-2'' & Hax-6''), 1.22-1.16

(m, 2H, H-4''); EIMS (m/z): 465 (9%), 463 [M]•+ (20%), 428 (16%), 251 (4%), 249


Page 146

(8%), 230 (4%), 214 (13%), 210 (90%), 193 (17%), 182 (BP, 100%), 165 (4%), 126

(28%), 98 (34%).

N-Benzyl-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadi-

azol-2-yl)thio]acetamide (XXX2)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'

1''

3''

5''

7''



3053 (Ar C-H), 1736 (ester C=O), 1672 (amide C=O), 1689 (C=N), 1609 (Ar C=C),

1156 (C-O), 704 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.64 (s, 1H, CON-

H), 7.61 (s, 1H, H-5'), 7.25-7.19 (m, 5H, H-2'' to H-6''), 7.06 (s, 1H, H-8'), 6.23 (s,

1H, H-3'), 5.37 (s, 2H, H-12'), 4.37 (s, 2H, H-7''), 4.06 (s, 2H, H-2'''), 2.34 (s, 3H,

CH3-11'); EIMS (m/z): 473 (8%), 471 [M]•+ (24%), 436 (13%), 251 (5%), 249 (9%),

230 (3%), 214 (8%), 210 (84%), 193 (11%), 182 (BP, 100%), 165 (7%), 106 (35%).

N-(2-Phenylethyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-

1,3,4-oxadiazol-2-yl)thio]acetamide (XXX3)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'

7''

1'' 3''

5''

8''





(s, 1H, H-5'), 7.15-7.10 (m, 5H, H-2'' to H-6''), 7.05 (s, 1H, H-8'), 6.21 (s, 1H, H-3'),

5.34 (s, 2H, H-12'), 4.07 (s, 2H, H-2'''), 3.43 (t, J = 7.6 Hz, 2H, H-8''), 2.73 (t, J = 7.6

Hz, 2H, H-7''), 2.38 (s, 3H, CH3-11'); EIMS (m/z): 487 (6%), 485 [M]•+ (17%), 450

(13%), 251 (4%), 249 (8%), 230 (1%), 214 (9%), 210 (88%), 193 (15%), 182 (BP,

100%), 165 (7%), 148 (31%), 120 (34%).


Page 147

N-Phenyl-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadi-

azol-2-yl)thio]acetamide (XXX4)

O

NN

S

NH

O

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'1'' 3''

5''





(s, 1H, H-5'), 7.57 (d, J = 7.6 Hz, 2H, H-2'' & H-6''), 7.34 (t, J = 7.6 Hz, 2H, H-3'' &

H-5''), 7.17 (t, J = 7.6 Hz, 1H, H-4''), 7.05 (s, 1H, H-8'), 6.20 (s, 1H, H-3'), 5.36 (s,

2H, H-12'), 4.07 (s, 2H, H-2'''), 2.39 (s, 3H, CH3-11'); EIMS (m/z): 459 (6%), 457

[M]•+ (21%), 422 (18%), 251 (6%), 249 (10%), 230 (4%), 214 (12%), 210 (87%), 193

(15%), 182 (BP, 100%), 165 (7%), 120 (37%), 92 (29%).

N-(2-Methylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7'' CH3





(d, J = 8.0 Hz, 1H, H-6''), 7.63 (s, 1H, H-5'), 7.21 (d, J = 8.0 Hz, 1H, H-3''), 7.15 (t, J

= 8.0 Hz, 1H, H-5''), 7.07 (t, J = 8.0 Hz, 1H, H-4''), 7.02 (s, 1H, H-8'), 6.22 (s, 1H, H-

3'), 5.34 (s, 2H, H-12'), 4.06 (s, 2H, H-2'''), 2.38 (s, 3H, CH3-11'), 2.28 (s, 3H, CH3-

7''); EIMS (m/z): 473 (7%), 471 [M]•+ (24%), 436 (12%), 251 (4%), 249 (7%), 230

(5%), 214 (16%), 210 (81%), 193 (13%), 182 (BP, 100%), 165 (8%), 106 (32%).


Page 148



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7''CH3

Yellowish grey amorphous solid; Yield: 83%; M.P.: 88-90 oC; HRMS: [M]•+




H), 7.59 (s, 1H, H-5'), 7.33 (s, 1H, H-2''), 7.30 (d, J = 7.6 Hz, 1H, H-6''), 7.17 (t, J =

8.0 Hz, 1H, H-5''), 7.04 (s, 1H, H-8'), 6.91 (d, J = 7.6 Hz, 1H, H-4''), 6.21 (s, 1H, H-

3'), 5.34 (s, 2H, H-12'), 3.98 (s, 2H, H-2'''), 2.37 (s, 3H, CH3-11'), 2.30 (s, 3H, CH3-

7''); EIMS (m/z): 473 (5%), 471 [M]•+ (19%), 436 (13%), 251 (7%), 249 (8%), 230

(2%), 214 (15%), 210 (83%), 193 (14%), 182 (BP, 100%), 165 (9%), 106 (28%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5'' 7''

CH3





(s, 1H, H-5'), 7.36 (d, J = 8.4 Hz, 2H, H-2'' & H-6''), 7.17 (d, J = 8.4 Hz, 2H, H-3'' &

H-5''), 7.05 (s, 1H, H-8'), 6.21 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.06 (s, 2H, H-2'''),

2.36 (s, 3H, CH3-11'), 2.26 (s, 3H, CH3-7''); EIMS (m/z): 473 (8%), 471 [M]•+ (23%),

436 (15%), 251 (7%), 249 (9%), 230 (3%), 214 (15%), 210 (87%), 193 (14%), 182

(BP, 100%), 165 (9%), 106 (31%).


Page 149

N-(2-Ethylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7''CH2CH3

8''





(s, 1H, H-5'), 7.16 (d, J = 8.0 Hz, 1H, H-6''), 7.11 (t, J = 8.0 Hz, 1H, H-5''), 7.07 (t, J

= 8.0 Hz, 1H, H-4''), 7.04 (s, 1H, H-8'), 6.98 (d, J = 8.0 Hz, 1H, H-3''), 6.21 (s, 1H, H-

3'), 5.35 (s, 2H, H-12'), 4.09 (s, 2H, H-2'''), 2.46 (q, J = 7.2 Hz, 2H, H-7''), 2.36 (s, 3H,

CH3-11'), 1.03 (t, J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z): 487 (6%), 485 [M]•+ (17%),

450 (13%), 251 (4%), 249 (5%), 230 (2%), 214 (13%), 210 (88%), 193 (14%), 182

(BP, 100%), 165 (6%), 148 (33%), 120 (32%).

N-(4-Ethylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5'' 7'' 8''

CH2CH3





H), 7.61 (s, 1H, H-5'), 7.09 (d, J = 8.0 Hz, 2H, H-2'' & H-6''), 7.04 (s, 1H, H-8'), 6.96

(d, J = 8.0 Hz, 2H, H-3'' & H-5''), 6.21 (s, 1H, H-3'), 5.36 (s, 2H, H-12'), 4.08 (s, 2H,

H-2'''), 2.54 (q, J = 7.2 Hz, 2H, H-7''), 2.36 (s, 3H, CH3-11'), 1.13 (t, J = 7.2 Hz, 3H,

CH3-8''); EIMS (m/z): 487 (8%), 485 [M]•+ (17%), 450 (15%), 251 (4%), 249 (7%),

230 (5%), 214 (9%), 210 (92%), 193 (17%), 182 (BP, 100%), 165 (7%), 148 (35%),


Page 150

120 (38%).

N-(2-Methoxyphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl-

}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX10)

O

NN

S

NH

O

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7''

OCH3





H), 8.22 (d, J = 8.0 Hz, 1H, H-6''), 7.62 (s, 1H, H-5'), 7.05 (s, 1H, H-8'), 7.01 (t, J =

7.6 Hz, 1H, H-5''), 6.92 (t, J = 7.6 Hz, 1H, H-4''), 6.81 (d, J = 8.0 Hz, 1H, H-3''), 6.21

(s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.06 (s, 2H, H-2'''), 3.82 (s, 3H, CH3-7''), 2.37 (s,

3H, CH3-11'); EIMS (m/z): 489 (5%), 487 [M]•+ (17%), 452 (16%), 251 (4%), 249

(6%), 230 (2%), 214 (13%), 210 (86%), 193 (12%), 182 (BP, 100%), 165 (4%), 150

(31%), 122 (39%).

N-(2-Ethoxyphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7''OCH2CH3

8''





(s, 1H, H-5'), 7.43 (d, J = 8.4 Hz, 1H, H-6''), 7.17 (t, J = 8.4 Hz, 1H, H-4''), 7.03 (s,

1H, H-8'), 6.84 (t, J = 8.4 Hz, 1H, H-5''), 6.75 (d, J = 8.0 Hz, 1H, H-3''), 6.20 (s, 1H,

H-3'), 5.35 (s, 2H, H-12'), 4.04 (s, 2H, H-2'''), 3.74 (q, J = 7.2 Hz, 2H, H-7''), 2.37 (s,

3H, CH3-11'), 1.11 (t, J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z): 503 (8%), 501 [M]•+


Page 151

(22%), 466 (11%), 251 (4%), 249 (7%), 230 (2%), 214 (14%), 210 (85%), 193 (18%),

182 (BP, 100%), 165 (8%), 164 (30%), 136 (28%).

N-(4-Ethoxyphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5'' 7'' 8''

OCH2CH3

Reddish purple amorphous solid; Yield: 74%; M.P.: 108-110 oC; HRMS: [M]•+




H), 7.59 (s, 1H, H-5'), 7.39 (d, J = 8.0 Hz, 2H, H-2'' & H-6''), 7.03 (s, 1H, H-8'), 6.81

(d, J = 8.4 Hz, 2H, H-3'' & H-5''), 6.20 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 3.98 (s, 2H,

H-2'''), 3.97 (q, J = 6.8 Hz, 2H, H-7''), 2.37 (s, 3H, CH3-11'), 0.86 (t, J = 6.8 Hz, 3H,

CH3-8''); EIMS (m/z): 503 (9%), 501 [M]•+ (21%), 466 (13%), 251 (6%), 249 (8%),

230 (3%), 214 (15%), 210 (81%), 193 (19%), 182 (BP, 100%), 165 (9%), 164 (32%),

136 (25%).

N-(2-Methoxycarbonylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)ox-

y]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX13)

O

NN

S

NH

O

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'1'' 3''

5''

COOCH3

7'' 8''





(d, J = 8.4 Hz, 1H, H-6''), 8.10 (d, J = 7.6 Hz, 1H, H-3''), 7.62 (s, 1H, H-5'), 7.51 (t, J

= 7.6 Hz, 1H, H-5''), 7.18 (t, J = 7.6 Hz, 1H, H-4''), 7.05 (s, 1H, H-8'), 6.21 (s, 1H, H-


Page 152

3'), 5.36 (s, 2H, H-12'), 4.07 (s, 2H, H-2'''), 3.81 (s, 3H, CH3-8''), 2.37 (s, 3H, CH3-

11'); EIMS (m/z): 517 (9%), 515 [M]•+ (19%), 480 (13%), 251 (6%), 249 (9%), 230

(2%), 214 (14%), 210 (92%), 193 (17%), 182 (BP, 100%), 178 (37%), 165 (6%), 150

(33%).

N-(4-Bromophenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''Br


(Calcd. for C21H15BrClN3O5S; 534.9623); IR (KBr, υmax, cm-1): 3422 (N-H), 3056 (Ar


O), 702 (C-Cl), 639 (C-Br); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.28 (s, 1H,

CON-H), 7.62 (s, 1H, H-5'), 7.47 (d, J = 8.4 Hz, 2H, H-2'' & H-6''), 7.41 (d, J = 8.4

Hz, 2H, H-3'' & H-5''), 7.05 (s, 1H, H-8'), 6.22 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.08

(s, 2H, H-2'''), 2.36 (s, 3H, CH3-11'); EIMS (m/z): 539 (7%), 537 (18%), 535 [M]•+

(20%), 500 (14%), 251 (6%), 249 (8%), 230 (4%), 214 (13%), 210 (92%), 198 (33%),

193 (13%), 182 (BP, 100%), 170 (31%), 165 (6%).

N-(4-Nitrophenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''NO2





H), 8.41 (d, J = 8.0 Hz, 2H, H-3'' & H-5''), 8.06 (d, J = 8.0 Hz, 2H, H-2'' & H-6''),

7.62 (s, 1H, H-5'), 7.05 (s, 1H, H-8'), 6.22 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.07 (s,


Page 153

2H, H-2'''), 2.36 (s, 3H, CH3-11'); EIMS (m/z): 504 (5%), 502 [M]•+ (17%), 467

(18%), 251 (8%), 249 (7%), 230 (5%), 214 (11%), 210 (91%), 193 (18%), 182 (BP,

100%), 165 (42%), 137 (32%).

N-(2,3-Dimethylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]meth-

yl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX16)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

8''CH3

CH37''



C-H), 1733 (ester C=O), 1673 (amide C=O), 1687 (C=N), 1687 (C=N), 1597 (Ar

C=C), 1149 (C-O), 708 (C-Cl); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.58 (s, 1H,

CON-H), 7.59 (s, 1H, H-5'), 7.54 (d, J = 8.0 Hz, 1H, H-6''), 7.06 (t, J = 8.4 Hz, 1H, H-

5''), 7.03 (s, 1H, H-8'), 6.98 (d, J = 7.6 Hz, 1H, H-4''), 6.20 (s, 1H, H-3'), 5.35 (s, 2H,

H-12'), 4.04 (s, 2H, H-2'''), 2.37 (s, 3H, CH3-11'), 2.25 (s, 3H, CH3-7''), 2.10 (s, 3H,

CH3-8''); EIMS (m/z): 487 (9%), 485 [M]•+ (20%), 450 (16%), 251 (3%), 249 (6%),

230 (3%), 214 (8%), 210 (94%), 193 (16%), 182 (BP, 100%), 165 (5%), 148 (32%),

120 (36%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5'' 8''

CH37''

CH3





(d, J = 8.4 Hz, 1H, H-6''), 7.59 (s, 1H, H-5'), 7.08 (d, J = 8.4 Hz, 1H, H-5''), 7.03 (s,

1H, H-8'), 6.94 (s, 1H, H-3''), 6.21 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.08 (s, 2H, H-


Page 154

2'''), 2.36 (s, 3H, CH3-11'), 2.28 (s, 3H, CH3-7''), 2.24 (s, 3H, CH3-8''); EIMS (m/z):

487 (7%), 485 [M]•+ (19%), 450 (14%), 251 (7%), 249 (8%), 230 (4%), 214 (13%),

210 (92%), 193 (13%), 182 (BP, 100%), 165 (7%), 148 (39%), 120 (29%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

8''

CH37''

CH3





(s, 1H, H-5'), 7.19 (s, 1H, H-6''), 7.06 (d, J = 8.0 Hz, 1H, H-3''), 7.02 (s, 1H, H-8'),

6.93 (d, J = 8.0 Hz, 1H, H-4''), 6.22 (s, 1H, H-3'), 5.35 (s, 2H, H-12'), 4.07 (s, 2H, H-


487 (8%), 485 [M]•+ (22%), 450 (15%), 251 (6%), 249 (8%), 230 (2%), 214 (13%),

210 (95%), 193 (17%), 182 (BP, 100%), 165 (7%), 148 (33%), 120 (34%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''8''

CH37''

H3C





(s, 1H, H-5'), 7.17-7.12 (m, 3H, H-3'' to H-5''), 7.06 (s, 1H, H-8'), 6.23 (s, 1H, H-3'),

5.36 (s, 2H, H-12'), 4.06 (s, 2H, H-2'''), 2.38 (s, 3H, CH3-11'), 2.26 (s, 6H, CH3-7'' &

CH3-8''); EIMS (m/z): 487 (6%), 485 [M]•+ (19%), 450 (15%), 251 (8%), 249 (9%),


Page 155

230 (2%), 214 (14%), 210 (90%), 193 (17%), 182 (BP, 100%), 165 (6%), 148 (35%),

120 (36%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5'' 8''

7''

CH3

CH3





(d, J = 8.0 Hz, 1H, H-6''), 7.59 (s, 1H, H-5'), 7.27 (s, 1H, H-2''), 7.09 (d, J = 8.0 Hz,

1H, H-5''), 7.03 (s, 1H, H-8'), 6.21 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.07 (s, 2H, H-


487 (6%), 485 [M]•+ (22%), 450 (15%), 251 (4%), 249 (5%), 230 (4%), 214 (13%),

210 (89%), 193 (15%), 182 (BP, 100%), 165 (7%), 148 (29%), 120 (35%).



O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

8''

7''

CH3

CH3





(s, 1H, H-5'), 7.18 (s, 2H, H-2'' & H-6''), 7.04 (s, 1H, H-8'), 6.94 (s, 1H, H-4''), 6.23 (s,

1H, H-3'), 5.37 (s, 2H, H-12'), 4.09 (s, 2H, H-2'''), 2.37 (s, 3H, CH3-11'), 2.26 (s, 6H,

CH3-7'' & CH3-8''); EIMS (m/z): 487 (8%), 485 [M]•+ (25%), 450 (17%), 251 (4%),

249 (7%), 230 (3%), 214 (12%), 210 (84%), 193 (19%), 182 (BP, 100%), 165 (7%),


Page 156

148 (34%), 120 (38%).

N-(2-Ethyl-6-methylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]-

methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX22)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

7''CH2CH3

8''

H3C

9''

Grayish white amorphous solid; Yield: 79%; M.P.: 104-106 oC; HRMS: [M]•+




H), 7.61 (s, 1H, H-5'), 7.16-7.09 (m, 3H, H-3'' to H-5''), 7.04 (s, 1H, H-8'), 6.21 (s,

1H, H-3'), 5.36 (s, 2H, H-12'), 4.05 (s, 2H, H-2'''), 2.44 (q, J = 7.2 Hz, 2H, H-7''), 2.37

(s, 3H, CH3-11'), 1.95 (s, 3H, CH3-9''), 1.02 (t, J = 7.2 Hz, 3H, CH3-8''); EIMS (m/z):

501 (8%), 499 [M]•+ (23%), 464 (15%), 251 (4%), 249 (7%), 230 (4%), 214 (12%),

210 (93%), 193 (14%), 182 (BP, 100%), 165 (6%), 162 (33%).

N-(4-Bromo-2-methylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

CH37''

Br


(Calcd. for C22H17BrClN3O5S; 548.9785); IR (KBr, υmax, cm-1): 3427 (N-H), 3042 (Ar


O), 703 (C-Cl), 636 (C-Br); 1H-NMR (400 MHz, CHCl3-d1, δ, ppm): 8.67 (s, 1H,

CON-H), 7.76 (d, J = 7.6 Hz, 1H, H-6''), 7.59 (s, 1H, H-5'), 7.19 (d, J = 7.6 Hz, 1H,

H-5''), 7.13 (s, 1H, H-3''), 7.04 (s, 1H, H-8'), 6.21 (s, 1H, H-3'), 5.34 (s, 2H, H-12'),

4.08 (s, 2H, H-2'''), 2.36 (s, 3H, CH3-11'), 2.25 (s, 3H, CH3-7''); EIMS (m/z): 551

(9%), 549 [M]•+ (25%), 514 (15%), 251 (7%), 249 (8%), 230 (5%), 214 (12%), 212

(31%), 210 (90%), 193 (17%), 184 (37%), 182 (BP, 100%), 165 (6%).


Page 157

N-(2-Methyl-4-nitrophenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]-


O

NN

S

NH

O

Cl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'1'' 3''

5''

CH3

7''

NO2






1H, H-3''), 7.07 (s, 1H, H-8'), 6.22 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.08 (s, 2H, H-

2'''), 2.38 (s, 3H, CH3-11'), 2.28 (s, 3H, CH3-7''); EIMS (m/z): 518 (6%), 516 [M]•+

(21%), 481 (19%), 251 (7%), 249 (8%), 230 (3%), 214 (12%), 210 (88%), 193 (14%),

182 (BP, 100%), 179 (28%), 165 (7%), 151 (37%).

N-(2-Methyl-6-nitrophenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]-


O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

CH37''

O2N






1H, H-8'), 6.58 (t, J = 8.8 Hz, 1H, H-4''), 6.21 (s, 1H, H-3'), 5.34 (s, 2H, H-12'), 4.08

(s, 2H, H-2'''), 2.38 (s, 3H, CH3-11'), 2.25 (s, 3H, CH3-7''); EIMS (m/z): 518 (7%), 516

[M]•+ (24%), 481 (16%), 251 (8%), 249 (9%), 230 (4%), 214 (11%), 210 (89%), 193

(15%), 182 (BP, 100%), 179 (29%), 165 (8%), 151 (36%).


Page 158

N-(5-Chloro-2-methoxyphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)ox-

y]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX26)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12' 1'' 3''

5''

OCH3

7''

Cl

Purple amorphous solid; Yield: 78%; M.P.: 116-118 oC; HRMS: [M]•+ 521.0214




(d, J = 2.0 Hz, 1H, H-6''), 7.61 (s, 1H, H-5'), 7.06 (dd, J = 8.4, 2.0 Hz, 1H, H-4''), 7.01

(s, 1H, H-8'), 6.81 (d, J = 8.0 Hz, 1H, H-3''), 6.21 (s, 1H, H-3'), 5.35 (s, 2H, H-12'),

4.07 (s, 2H, H-2'''), 3.87 (s, 3H, CH3-7''), 2.37 (s, 3H, CH3-11'); EIMS (m/z): 525

(6%), 523 (13%), 521 [M]•+ (22%), 486 (15%), 251 (7%), 249 (9%), 230 (2%), 214

(10%), 210 (94%), 193 (16%), 184 (30%), 182 (BP, 100%), 165 (6%), 156 (31%).

N-(4-Methylpyridin-2-yl)-2-[(5-{[(6-chloro-4-methylbenzo-2-pyron-7-yl)oxy]met-

hyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX27)

O

NN

S

NH

OCl

O 1

34

1'

3'5'

1'''2'''

11'

OO

CH3

7' 12'

N1''

3''

5''

7''

CH3





(d, J = 7.6 Hz, 1H, H-6''), 7.61 (s, 1H, H-5'), 7.14 (s, 1H, H-3''), 7.09 (d, J = 7.6 Hz,

1H, H-5''), 7.02 (s, 1H, H-8'), 6.21 (s, 1H, H-3'), 5.35 (s, 2H, H-12'), 4.05 (s, 2H, H-

2'''), 2.41 (s, 3H, CH3-7''), 2.37 (s, 3H, CH3-11'); EIMS (m/z): 474 (5%), 472 [M]•+

(17%), 437 (17%), 251 (8%), 249 (10%), 230 (5%), 214 (12%), 210 (88%), 193

(14%), 182 (BP, 100%), 165 (8%), 135 (26%), 107 (27%).


Page 159

4.1 Results of biological activities (in vitro)

This part of the running chapter includes the data obtained for biological activities

including antibacterial and lipoxygenase enzyme (LOX) inhibition for all the

synthesized molecules. The inactive compounds against all strains and LOX are not

listed.

4.1.1 Antibacterial and enzyme inhibition data of N'-Substituted-2-[(5-

substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide (VIII1-133, XV1-13)

Table-4.1: The MIC values of antibacterial activity for VIII1-32

Compound

MIC (µM)

Gram negative bacteria Gram positive bacteria

S. typhi E. coli P. aeruginosa B. subtilis S. aureus

VIII1 10.67±2.50 10.39±1.93 14.83±4.08 13.38±5.00 14.10±0.63

VIII2 10.24±3.00 10.21±2.07 14.94±0.38 19.62±5.00 17.30±2.81 VIII3 14.62±3.50 14.44±2.67 - 10.56±1.82 15.05±5.00

VIII4 10.94±1.83 17.26±4.93 - 15.41±3.75 16.97±5.00 VIII5 10.34±2.76 10.56±2.98 10.37±2.90 10.25±1.93 12.53±1.09 VIII6 14.65±2.77 12.97±1.98 13.99±2.09 14.04±2.31 13.35±5.00

VIII7 11.82±3.09 13.77±1.85 13.74±3.38 11.87±1.98 12.04±5.00 VIII8 13.89±2.19 14.90±4.53 17.83±5.00 12.81±1.12 12.58±5.00

VIII9 13.95±1.80 16.77±1.79 - 12.99±2.25 14.24±2.65 VIII10 14.43±1.66 18.53±4.60 - - - VIII11 14.39±4.13 - - 13.70±4.81 15.59±4.31

VIII12 12.78±1.23 14.13±0.40 - - 13.61±3.88 VIII13 14.46±3.00 - 19.36±0.65 - -

VIII14 13.47±2.00 16.86±3.00 - 17.75±1.00 - VIII15 13.56±1.66 19.58±0.45 - 15.21±2.87 - VIII16 15.13±1.00 16.37±2.43 - - -

VIII17 12.41±2.32 16.88±4.64 15.10±1.83 - 12.43±5.00

VIII18 17.04±1.76 15.26±5.00 17.58±1.25 - - VIII19 14.71±2.04 13.02±1.34 16.80±1.25 18.13±2.04 -

VIII20 - 18.57±2.08 - - - VIII21 10.65±1.31 11.51±5.00 15.08±3.50 12.78±1.65 17.03±1.76 VIII22 12.73±1.95 15.38±1.87 - 18.28±4.37 -

VIII23 13.47±2.37 - - 17.03±2.76 - VIII24 13.68±1.00 15.11±5.00 - - 13.32±2.00

VIII25 17.32±0.98 14.09±2.65 14.93±1.17 17.53±1.88 - VIII26 - - - 17.65±1.65 - VIII28 18.57±0.55 18.91±1.64 - 19.08±3.87 14.52±2.50

VIII29 18.19±1.82 - - 16.60±2.12 - VIII30 10.23±2.43 11.04±1.17 17.20±1.25 - -

VIII31 14.87±1.72 12.82±2.12 - 12.29±1.65 - VIII32 17.55±0.54 15.41±5.00 19.93±1.08 18.05±0.87 19.11±0.44

Ciprofloxacin 9.13±2.00 8.90±1.65 9.01±0.13 8.02±0.33 8.41±1.04


Page 160


Compound

MIC (µM)



VIII33 14.60±5.00 10.56±2.18 17.93±1.85 15.46±4.25 12.11±3.69 VIII34 16.80±2.17 10.86±1.44 15.70±4.69 11.06±2.44 13.17±1.56 VIII35 15.63±4.86 14.44±4.87 18.48±4.52 11.41±1.66 15.27±1.94

VIII36 16.70±1.00 12.58±5.00 - 19.40±2.13 13.15±2.75 VIII37 13.15±3.72 10.69±1.67 13.45±1.07 - 11.75±2.38

VIII38 12.21±1.58 11.39±2.00 14.86±3.16 12.95±1.14 15.49±4.71 VIII39 10.62±2.67 10.28±1.07 14.25±1.77 10.47±2.01 18.08±4.88 VIII40 10.85±3.25 17.07±1.87 15.20±2.77 - 16.97±5.00

VIII42 13.54±5.00 13.16±2.00 15.96±5.00 19.32±3.44 11.25±1.19 VIII43 15.45±5.00 14.45±1.33 18.02±3.00 14.48±1.69 14.75±5.00

VIII44 - 17.85±2.93 19.06±1.31 18.97±2.50 17.44±2.72 VIII45 13.74±0.25 10.27±1.87 18.35±0.23 11.82±5.00 15.59±2.50 VIII46 - 19.47±2.00 - - -

VIII47 - - - - 13.54±2.00 VIII48 12.89±3.67 10.45±1.49 15.04±2.38 11.11±5.00 11.96±2.60

VIII49 10.37±2.13 13.46±2.50 - 17.54±1.50 -

VIII50 - - - - 16.51±2.50 VIII51 18.21±4.83 - - - - VIII52 14.29±3.67 16.58±5.00 - 13.59±1.94 16.40±1.15

VIII53 12.03±4.92 9.45±1.00 10.53±2.97 11.94±5.00 10.65±3.43 VIII54 10.32±1.42 11.21±1.60 18.52±3.46 14.67±0.55 19.09±1.38

VIII55 12.93±3.00 13.18±4.07 15.47±1.23 15.44±5.00 13.37±5.00 VIII56 19.08±5.00 19.66±4.00 19.02±4.08 19.69±1.38 - VIII57 17.64±5.00 16.32±1.20 - 15.45±4.37 12.13±5.00

VIII58 14.26±5.00 12.03±4.13 12.42±1.85 14.68±2.16 10.98±2.64 VIII59 14.15±0.42 15.36±2.67 18.13±1.12 14.40±3.81 14.15±4.63

VIII60 17.00±1.87 14.02±5.00 17.68±4.62 16.73±4.75 16.03±3.38 VIII61 11.41±1.25 12.02±1.87 18.44±3.11 14.41±2.31 15.18±2.38 VIII62 10.92±1.67 12.76±1.33 15.43±1.46 12.71±4.13 14.31±3.00

VIII63 12.10±1.00 13.44±4.67 14.91±3.00 11.01±3.94 16.01±5.00 VIII64 10.04±1.25 11.90±4.20 - 18.10±2.00 17.90±4.00

VIII65 15.25±1.67 15.94±1.01 13.77±1.00 - 9.67±0.03

VIII66 17.90±1.02 13.49±0.32 14.45±1.55 - 8.42±1.01 VIII67 - 17.82±0.33 18.79±0.34 - 18.40±0.54 VIII68 13.28±0.34 16.77±0.78 17.21±0.91 - 14.03±0.95

VIII69 - 14.19±1.04 11.28±1.05 - 14.69±0.58 VIII70 19.51±0.22 17.90±0.00 15.94±1.04 - 11.36±0.92

VIII71 9.65±0.21 13.56±0.98 13.02 0.67 13.45±1.10 9.46±0.59

VIII72 - 16.68±0.40 17.35±0.89 - 16.68±1.22 VIII73 12.50±0.13 17.77±0.87 15.95±1.02 - 14.23±0.51 VIII74 - 10.21±1.20 15.48±0.87 16.43±0.76 10.06±0.86

VIII75 - - - - 12.33±0.89 VIII76 - - 19.90±1.11 - 11.17±0.14

VIII77 17.43±1.56 18.32±1.31 19.65±0.65 - - VIII78 19.46+0.00 16.84±1.20 12.55±0.79 - 10.29±0.44

Ciprofloxacin 9.13±2.00 8.90±1.65 9.01±0.13 8.02±0.33 8.41±1.04


Page 161


Compound

MIC (µM)



VIII79 14.27±0.22 14.27±0.30 11.89±0.44 - 10.26±1.00 VIII80 - 16.22±1.00 19.43±0.64 - 10.63±1.41 VIII81 15.26±0.44 15.26±1.40 10.90±0.78 - 12.17±0.49

VIII82 - - - 15.90±0.98 19.76±0.98 VIII83 - 15.36±0.65 18.21±0.67 - 17.57±1.54

VIII84 13.84±0.21 16.33±0.98 13.43 0.67 13.45±1.90 13.91±0.96

VIII85 19.18±0.22 19.05±0.00 13.66±0.87 17.63±1.20 17.63±0.92

VIII87 - - - 19.09±0.90 - VIII88 - - 14.82±0.89 - 15.09±0.32 VIII89 11.84±0.92 10.04±0.65 12.19±0.67 13.91±0.65 15.09±0.54

VIII90 12.57±0.54 10.43±0.20 11.40±0.87 16.43±0.76 15.17±0.86 VIII91 11.44±1.00 16.84±0.32 14.45±1.55 13.56±0.91 13.56±0.09

VIII92 - - - 16.97±0.05 - VIII93 - - 17.48±0.09 15.90±0.98 10.82±0.98 VIII94 17.58±0.34 - 18.99±0.91 15.17±0.50 13.91±0.95

VIII96 - - - - 18.10±0.54 VIII97 15.54±0.44 16.90±0.82 13.08±0.44 13.46±0.50 13.46±0.41

VIII98 11.54±0.95 10.47±0.44 15.43±0.24 19.18±0.30 15.40±0.96 VIII99 10.09±0.90 12.39±0.40 13.55±0.89 14.05±0.09 - VIII100 - - - - 18.31±0.22

VIII101 15.44±0.14 18.26±0.91 17.14±0.97 13.97±0.05 19.18±0.24 VIII102 - 17.15±0.90 - 17.04±0.67 -

VIII104 18.38±0.89 19.37±0.45 - - 10.64±0.19

VIII106 - - - - 17.65±0.90 VIII107 - - 10.67±0.76 - 16.09±0.98 VIII108 - - - - 12.54±0.62

VIII109 - 19.64±0.61 - - - VIII110 13.94±0.44 16.72±0.98 - - -

VIII112 - 18.78±0.29 - - - VIII113 17.49±0.92 10.48±0.10 18.07±0.78 - 13.09±1.00 VIII114 15.27±0.22 11.74±0.60 - - 14.04±0.54

VIII115 - 18.93±0.92 - - - VIII116 - 19.70±0.20 14.07±0.11 - 9.38±0.51

VIII118 12.93±2.50 11.18±4.75 13.27±1.42 - 11.74±4.00

VIII119 - 12.13±3.00 13.58±2.83 - 17.86±5.00 VIII120 12.21±3.51 12.96±3.21 12.99±4.83 14.29±2.13 10.47±2.87 VIII121 18.23±4.66 18.55±3.12 12.43±5.00 18.84±1.73 11.10±1.13

VIII122 - 14.24±2.98 10.77±3.21 - 14.28±1.73 VIII123 17.55±3.21 13.15±2.00 11.15±2.08 - 19.24±1.50

VIII124 11.08±5.00 10.46±3.56 10.48±4.25 12.37±3.07 12.05±5.00 VIII125 14.09±5.00 14.33±1.98 13.26±1.33 13.90±1.40 11.44±1.60 VIII126 - 14.04±3.12 18.04±4.25 - 15.81±5.00

VIII127 17.43±3.45 12.24±4.10 13.79±2.33 - 15.51±5.00 VIII128 - 15.02±3.24 16.56±2.00 - 17.69±5.00

VIII129 - 16.82±4.00 11.49±4.25 18.39±5.00 14.35±4.00

Ciprofloxacin 9.13±2.00 8.90±1.65 9.01±0.13 8.02±0.33 8.41±1.04


Page 162

Table-4.4: The MIC values of antibacterial activity for VIII130-133, XV1-13

Table-4.5: The IC50 values of enzyme inhibition activity for VIII1-102

Compound Lipoxygenase (LOX)

Conc. (mM) IC50 ( µM )

VIII1 0.5 336.2±1.12 VIII2 0.5 438.9±2.67 VIII4 0.5 205.51±0.87

VIII17 0.5 242.3±0.13 VIII22 0.5 351.7±0.45

VIII36 0.5 367.7±0.98 VIII47 0.5 212.20±1.55

VIII59 0.5 268.9±1.37

VIII61 0.5 450.21±0.76 VIII63 0.5 173.71±1.23

VIII65 0.5 272.5±1.46

VIII66 0.5 61.11±0.31 VIII68 0.5 301.2±0.26

VIII71 0.125 36.12±0.39 VIII73 0.25 168.41±0.83 VIII76 0.5 288.72±1.54

VIII81 0.5 132.81±0.79 VIII83 0.5 290.32±1.26

VIII88 0.25 80.8±0.16

VIII90 0.5 23.14±0.15 VIII91 0.5 103.1±0.57 VIII101 0.5 269.6±0.73

Baicalein 0.5 22.4±1.3

Compound

MIC (µM)



VIII130 18.90±2.01 14.11±5.00 12.31±2.42 17.63±5.00 14.59±2.93 VIII131 - 8.49±4.87 11.32±5.00 - 10.09±3.87 VIII132 - 14.89±2.00 14.08±3.58 14.30±5.00 13.32±2.53

VIII133 - 15.11±2.98 12.42±2.58 16.64±5.00 11.16±3.98

XV1 12.62±0.11 13.32±0.68 12.83±1.11 10.20±0.05 12.85±0.51 XV2 13.26±0.90 15.01±0.10 14.43±0.78 10.01±0.55 13.59±1.03

XV3 14.53±1.21 16.19±1.30 16.63±1.44 10.51±0.82 13.78±0.19 XV4 14.66±0.44 17.34±0.80 16.68±0.11 11.37±0.40 14.69±1.05 XV5 17.02±1.22 16.04±0.45 19.13±1.00 - 14.05±0.62

XV6 17.42±0.22 16.33±0.60 18.26±0.67 - 13.43±0.54 XV7 - 10.78±1.21 13.02±0.45 16.44±1.65 13.87±2.34

XV8 13.30±1.33 14.33±0.80 12.88±1.33 10.87±0.09 12.70±1.68 XV9 13.25±1.67 14.42±0.46 13.18±1.29 10.54±1.54 12.98±2.08 XV10 13.22±0.48 14.57±0.07 14.42±0.76 10.08±0.91 12.55±0.05

XV11 - 15.49±0.70 17.87±1.67 - 14.13±0.92 XV12 - 15.98±1.10 18.42±0.88 - 13.21±0.98

XV13 9.48±0.00 7.37±0.23 13.69±1.66 - 10.88±1.21

Ciprofloxacin 9.13±2.00 8.90±1.65 9.01±0.13 8.02±0.33 8.41±1.04


Page 163

Table-4.6: The IC50 values of enzyme inhibition activity for VIII103-133, XV1-13



VIII104 0.5 284.7±1.68

VIII105 0.25 96.7±0.42 VIII106 0.5 133.2±0.89

VIII107 0.5 292.1±1.59 VIII109 0.5 92.2±0.14 VIII111 0.5 329.6±1.68

VIII113 0.5 78.2±0.42 VIII114 0.25 38.12±0.15

VIII117 0.125 79.8±0.64

VIII118 0.25 175.4±0.24 VIII122 0.5 364.2±0.96 VIII131 0.5 196.4±1.37

XV2 0.5 259.9±1.79 XV3 0.5 231.5±1.83 XV6 0.5 395.3±1.56

XV8 0.5 54.8±0.32 XV9 0.0625 5.21±0.011


4.1.2 Antibacterial data of 7-Alkoxy/aralkoxy/acyloxy-6-chloro-4-methylbenzo-

2-pyrone (XIX1-9, XXI1-8)

Here the 7-acyloxy series is not listed because it was inactive against all the bacterial

strains taken into account. Only the active compounds among XIX1-9 are listed in the

given table.

Table-4.7: The MIC values of antibacterial activity for XIX1-9

4.1.3 Antibacterial and enzyme inhibition data of N-Substituted-2-[(6-chloro-4-

methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV1-26)

Compound

MIC (µM)



XIX1 11.01±0.22 7.52±0.14 13.06±0.12 8.43±0.42 19.14±0.17

XIX2 15.03±0.27 11.05±0.10 14.18 ±0.34 8.88±0.24 7.42±0.16 XIX4 15.18±0.17 17.91±0.11 14.42 ± 0.05 10.00±0.41 11.03±0.09

XIX8 14.17±0.26 9.61±0.08 14.27 ±0.06 7.78±0.11 6.50±0.29 XIX9 11.19±0.31 8.84±0.41 15.30 ±0.17 8.40±0.18 6.57±0.12

Ciprofloxacin 8.19 ± 0.01 8.22 ± 0.12 10.03 ± 0.1 8.96 ± 0.02 8.12 ± 0.21


Page 164

Table-4.8: The MIC values of antibacterial activity for XXIV1-26

Compound

MIC (µM)



XXIV1 11.18±3.32 11.30±2.72 11.50±5.00 - 13.87±0.65

XXIV2 10.49±4.05 10.50±1.30 10.70±3.32 - 18.38±3.40 XXIV3 14.37±1.16 - - - 18.79±1.32

XXIV4 11.82±1.72 11.44±5.00 9.54±5.00 16.66±2.54 14.39±5.00 XXIV5 18.25±3.25 - - - - XXIV6 15.04±1.05 15.67±2.08 11.53±1.25 - -

XXIV8 18.81±0.32 - 15.30±5.00 - - XXIV9 - 17.31±3.61 19.87±1.47 19.26±0.41 18.99±2.21

XXIV10 18.98±4.53 - - - - XXIV11 10.49±1.26 10.96±1.39 12.62±4.18 - 18.86±1.25 XXIV13 16.87±2.79 - - - -

XXIV14 15.57±1.19 - - - 16.77±4.35 XXIV15 10.90±1.34 13.31±2.62 9.20±5.00 13.78±0.82 12.61±1.50

XXIV16 13.92±1.62 16.43±1.96 12.85±1.52 - 10.96±1.45 XXIV17 13.96±2.94 13.10±3.66 12.53±1.03 - 14.31±1.70 XXIV18 17.32±1.75 - - - -

XXIV19 15.79±5.00 - 16.45±3.80 - - XXIV20 14.40±2.63 19.33±2.08 - - -

XXIV22 15.01±1.63 17.45±1.14 17.87±2.15 - - XXIV23 8.82±1.42 9.06±1.84 8.42±1.03 8.60±1.10 9.10±1.05 XXIV24 19.27±1.84 - - - -

XXIV25 11.70±1.58 - 16.30±1.36 - - XXIV26 10.07±3.11 9.75±1.20 11.91±4.57 11.05±4.08 9.91±2.90

Ciprofloxacin 8.00±2.54 7.96±1.14 8.05±1.60 8.32±1.00 7.43±0.45

Table-4.9: The IC50 values of enzyme inhibition activity for XXIV1-26



XXIV1 0.5 415±0.42

XXIV2 0.5 396.7±0.34 XXIV3 0.5 104.9±1.43

XXIV4 0.5 261.70±0.49 XXIV6 0.5 409.17±0.87 XXIV12 0.5 386.9±1.65

XXIV23 0.5 181.71±0.47 XXIV24 0.5 300.12±0.52


4.1.4 Antibacterial data of N-substituted-2-[(benzo-2-pyron-4-yl)oxy]acetamide

(XXVI1-18)


Page 165

Table-4.10: The MIC values for antibacterial activity for XXVI1-18

Compound

MIC (µM)



XXVI1 9.10±0.76 8.97±0.60 10.48±0.33 8.76±0.50 9.83±0.90

XXVI2 9.23±0.67 9.20±0.56 13.86±0.16 9.43±0.35 9.89±0.56 XXVI3 9.29±0.70 9.38±0.17 16.96±0.47 10.11±0.73 10.13±0.64

XXVI4 19.56±0.33 - - 14.31±0.49 - XXVI5 8.78±0.49 8.78±0.50 12.74±0.11 9.46±0.49 10.42±0.50 XXVI6 9.45±0.10 9.27±0.15 16.24±0.90 10.44±0.21 10.57±0.38

XXVI7 9.80±0.11 9.34±0.07 - 16.37±0.15 - XXVI8 9.60±0.01 10.05±0.11 17.52±0.95 10.71±0.19 10.63±0.10

XXVI9 9.27±0.51 9.11±0.57 15.39±0.67 9.24±0.33 10.36±0.12 XXVI10 9.92±0.41 9.63±0.31 14.75±0.72 10.58±0.11 9.75±0.19 XXVI11 9.11±0.34 8.34±0.10 10.89±0.16 8.87±0.13 10.14±0.90

XXVI12 9.78±0.50 10.22±0.64 15.36±0.66 9.78±0.67 19.80±0.13 XXVI13 9.57±0.84 9.12±0.72 17.85±0.23 10.65±0.54 16.78±0.44

XXVI14 10.98±0.16 8.86±0.50 16.55±0.49 10.23±0.76 13.69±0.58 XXVI15 9.89±0.80 12.96±0.30 14.74±0.12 10.42±0.18 14.80±0.33 XXVI16 8.66±0.57 8.76±0.58 9.86±0.12 9.25±0.78 10.26±0.44

XXVI17 8.13±0.45 8.90±0.12 9.52±0.51 9.65±0.04 9.78±0.47 XXVI18 10.02±0.51 9.49±0.12 16.89±0.38 10.86±0.27 12.36±0.12

Ciprofloxacin 7.45±0.58 7.16±0.58 7.14±0.18 7.29±0.90 7.80±0.19

4.1.5 Antibacterial and enzyme inhibition data of N-substituted-2-[(5-{[(6-

chloro-4-methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]aceta-

mide (XXX1-27)

Table-4.11: The MIC values of antibacterial activity for XXX1-16

Compound

MIC (µM)



XXX1 12.59±4.60 12.98±1.56 11.30±2.25 19.58±1.08 17.86±0.65

XXX2 - 13.41±5.00 - 14.47±5.00 13.35±2.25 XXX3 14.46±1.10 11.07±1.94 11.42±3.17 13.19±1.83 10.91±2.87 XXX4 - 19.93±1.81 15.40±5.00 16.51±1.98 -

XXX5 10.61±5.00 10.39±1.62 10.22±3.33 12.86±3.85 8.90±2.08 XXX6 9.50±1.30 10.15±4.12 10.43±4.65 15.94±3.06 13.18±2.17

XXX7 17.19±3.70 14.86±5.00 19.50±2.67 12.12±4.00 19.53±1.65 XXX8 9.16±2.20 11.28±1.06 11.52±3.42 15.32±5.00 12.95±3.15 XXX9 19.07±0.40 14.24±1.25 19.97±3.50 14.87±2.71 -

XXX10 8.87±1.20 10.41±1.44 10.54±0.80 14.58±1.87 11.14±2.22 XXX11 8.84±2.00 10.94±1.25 12.00±1.33 12.96±1.82 12.14±1.48

XXX12 12.75±4.50 12.07±5.00 15.61±5.00 15.75±3.35 11.35±2.00 XXX13 9.01±1.40 10.86±1.19 11.04±4.17 14.18±4.35 18.62±1.00 XXX14 17.64±5.00 15.97±5.00 17.56±2.00 11.95±4.71 -

XXX15 19.92±3.21 - - - 18.32±1.11 XXX16 12.05±2.60 11.19±2.94 12.48±1.00 11.61±4.14 13.24±1.80

Ciprofloxacin 8.00±2.54 7.96±1.14 8.05±1.60 8.32±1.00 7.43±0.45


Page 166

Table-4.12: The MIC values of antibacterial activity for XXX17-27

Compound

MIC (µM)



XXX17 13.75±1.70 10.91±3.44 12.26±0.83 10.94±2.29 10.88±3.13

XXX18 16.12±4..80 11.71±2.31 14.55±4.50 11.88±2.76 12.17±2.00 XXX19 - 17.78±4.56 - 14.17±2.29 -

XXX20 15.32±2.98 16.48±1.56 15.46±2.75 11.47±1.06 13.06±2.54 XXX21 18.35±3.00 14.93±2.81 18.55±1.42 16.61±2.18 12.73±1.35 XXX22 9.78±2.80 11.40±1.80 11.71±0.83 16.90±2.87 18.96±1.02

XXX23 19.21±0.45 10.83±1.81 17.40±3.00 14.13±2.06 - XXX24 19.11±2.53 - - - 17.87±3.65

XXX25 18.55±1.02 - - - 15.16±2.89 XXX26 19.77±4.40 10.24±3.69 - 11.04±5.00 - XXX27 - 12.84±5.00 - 17.00±2.97 19.50±0.14

Ciprofloxacin 8.00±2.54 7.96±1.14 8.05±1.60 8.32±1.00 7.43±0.45

Table-4.13: The IC50 values of enzyme inhibition activity for XXX1-27



XXX6 0.5 353.9±1.59 XXX8 0.5 225.6±1.57 XXX9 0.5 387.7±1.47

XXX10 0.5 310.9±0.73 XXX11 0.5 327.1±0.61

XXX13 0.5 193.9±0.38 XXX17 0.25 217±0.68 XXX27 0.5 375±0.59


4.2 Discussion of chemistry of organic synthesis

This section of the running chapter is about the discussion of chemistry of synthetic

methods, the mechanisms of the reactions and the spectral corroboration of the

synthesized molecules including 13C-NMR, 1H-NMR and EIMS.

4.2.1 N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide

(VIII1-133, XV1-13)

This section is including two of the synthetic schemes, that is, Scheme-1 (page-11)

and Scheme-2 (page-14). In Scheme-1, a series of eight carboxylic acids (I1-8) were

converted to corresponding esters, II1-8, through nucleophilic condensation reaction

with EtOH on reflux. This step is catalysed by conc. H2SO4 because of weak

electrophilic nature of carbonyl carbon in carboxylic acids. This weak electrophilic

nature may be attributed to the resonance of lone pairs present on hydroxyl oxygen in

carboxylic acids. The reaction is set to reflux to attain the activation energy but


Page 167

simultaneously conc. H2SO4 is hydrolyzing the ester back to the reactants. The

reaction is reversible. To shift the equilibrium to product side, EtOH is added in

excess to act as reactant and solvent. The suggested mechanism of this step is given

below in Figure-4.1.

C

R

H2SO4H+ HSO4

-1

OH

O

H+C

R

O

OH

H

HOC2H5

C

R

O

O

H

H

OH

C2H5

C

R

O

O

H

O

C2H5

H

HH2O

C

R

OC2H5

O

H2O H3O+

H2SO4HSO4-1

H3O+ H2O

Figure-4.1: General mechanism for ester formation

The synthesized esters, II1-8, were separated from the mixture of unreacted carboxylic

acids, H2SO4 and EtOH by solvent extraction after neutralizing the mixture. The

neutralization of mixture was performed through the addition of aq. Na2CO3 solution.

The unreacted carboxylic acids and H2SO4 were transferred to aq. layer because of

salt formation. The solvent ethanol was also shifted to aq. layer because of strong

hydrogen bonding with water molecules. Thus the esters were collected after

distillation of solvent used for extraction. The solid phase esters were simply filtered

out from the medium after addition of excess water and washed out by distilled water.

The solid esters were recrystallized from MeOH.

The second step comprised of carbohydrazide, III1-8, formation from

corresponding ethyl esters. This step is carried out by the nucleophilic attack of

nitrogen of monohydrated hydrazine on the electrophilic carbon of ethyl ester in

methanol followed by the removal of EtOH group from ethyl ester. Normally this step


Page 168

is accomplished on simple stirring but refluxing can be applied. The refluxing is often

required because of decrease in electrophilic character of carbonyl carbon due to

electron donating species. The electron withdrawing species increase the rate of

reaction. The suggested mechanism of this step is is given below in Figure-4.2.

C2H5OH

C

R

NHNH2

O

NH2NH2

C

R

OC2H5

O

C

R

OC2H5

N

O

H2N H

H

C

R

O

O

HN

NH2

H

C2H5

Figure-4.2: General mechanism for carbohydrazide formation

Excess of solvent was evaporated on heating and the precipitates of products were

yielded upon addition of excess cold distilled water. Before the addition of cold water

to the whole mixture, a small amount was taken from reaction mixture and same

procedure was performed to check out precipitation. Sometimes there was no

precipitation after addition of water then in that case, the who le solvent was

evaporated and the obtained precipitates were filtered and washed with n-hexane.

The third step is the intermolecular cyclization of carbohydrazides, III1-8, to 5-

substituted-1,3,4-oxadiazol-2-thiol, IV1-8, by CS2 aided by KOH on reflux. The

suggested mechanism of this step is is given in Figure-4.3. The mole ratio of

carbohydrazide, CS2 and KOH was 1:2:1. The ratio of CS2 is taken double because of

its high volatility. KOH is used to balance the negative charge resonating and also to

extract proton at some instances during the process of cyclization. The resulting

compounds, IV1-8, have acidic proton in the form of mercapto or thiol group. So after

addition of excess cold distilled water, a homogeneous solution was obtained and no

precipitation because of potassium thioxide formation. Before the addition of cold

water, excess of solvent can be distilled off or evaporated to proceed further. The

clear solution was due to dissolution of formed salt in water. Dil. HCl was added to

reverse this salt back into acidic form at low acidic pH (ranging 5-6) and hence

precipitation. Excess of acid or conc. acid is strictly obviated because of further salt


Page 169

formation as hydrothioxonium chloride and thus again the dissolution of precipitates

will occur. That is, too low pH decrements the yield.

OH

C

R

NHNH2

O

RO

NN

S

C SS

RO

NHN

S

HH

S

RO

NHN

SHS

H

H2OR

O

NN

H

S

SH

H2S

RO

NN

SHH+

Figure-4.3: General mechanism for 1,3,4-oxadiazole formation

In the fourth step, the acidic proton of mercapto group in compounds IV1-8 was

replaced by the ethoxycarbonylmethyl group of EBE in a polar aprotic solvent, DMF,

in the presence of LiH. The suggested mechanism of this step is given in Figure-4.4.

The aprotic polar solvent like DMF (or CH3CN may be applied) was used to avoid the

reconversion into acidic form. LiH is an activator which was applied to activate the

nucleophilic attack of conjugate base (R-S-) on the weak electrophilic carbon attached

to halogen (bromine in this case). The solid precipitates were acquired on gentle

shaking after addition of ice cold distilled water and were filtered out.

RO

NN

S

H

Li H+ -

-

+

H2

RO

NN

S

Li

RO

NN

S

Li

R1 X+ -

-

+

LiX

RO

NN

S

R1

R1 = C2H5OOC-CH2- X = Br

Figure-4.4: General mechanism for S-substitution


Page 170

In the fifth step, the formed ethyl esters, V1-8, were again converted into

corresponding hydrazides, VI1-8. The same procedure and mechanism was followed as

that in second step (Figure-4.2). The minute difference in this step is that it is strictly

carried out at room temperature and on stirring. Heating or refluxing is avoided so

that the molecule may not decompose. As the size of molecule increases, the chances

for fracturing of molecule on strong heating or refluxing become prominent.

In the sixth and last step of this Scheme, the formed carbohydrazides, VI1-8,

were simply stirred with different aryl carboxaldehydes (VII1-19) in methanol. A few

drops of Glac. AcOH were also used as catalyst. The suggested mechanism of this

step is given in Figure-4.5. Weak acid and also a few drops of it were used to avoid

the deactivation of nucleophilic character of amine by protonation. Strong acid or

excess of weak acid can also hydrolyze the azomethine linkage back into its reactants.

The products were acquired through filtration and washed by distilled water.

RO

NN

S

NHNH2

O

RO

NN

S

NH

O

N

CH

R1

R1

H

O

H+

R1

H

O

H

R1

H

O

H

OH

H

H

RO

NN

S

NH

O

N

CH

R1

OH2

H

RO

NN

S

NH

O

N

CH

R1

-OAc

-AcOH

-H2O

Figure-4.5: General mechanism for azomethine formation

Scheme-2 is also the synthesis of azomethine derivatives starting from a disubstituted

phenol. All the steps and mechanisms were just similar to that of Scheme-1 except the


Page 171

first one. In the first step, 2,4-dimethylphenol was O-substituted by EBE. The reaction

was made to proceed in a protic solvent, EtOH, in the presence of a strong base,

KOH. But if it is carried out in a polar aprotic solvent then the time for completion

will surely be minimized because of fewer chances for reprotonation. The suggested

mechanism of this step is given in Figure-4.6.

O

CH3H3C

-+

R1 X+ -

R1 = C2H5OOC-CH2- X = Br

H -OH

H2O

O

CH3H3C

O

CH3H3C

O

CH3H3C

R1

X-

Figure-4.6: Mechanism for O-substitution

One of the azomethine compounds, N'-(2,5-Dimethoxybenzylidene)-2-{[5-(4-

methylphenyl)-1,3,4-oxadiazol-2-yl]thio}acetohydrazide (VIII79) is structurally

elaborated with respect to its PNMR. The aliphatic region of its PNMR spectra is

given in Figure-4.7 and aromatic region in Figure-4.8.

Figure-4.7: Aliphatic region of PNMR spectrum of VIII79

O

NN

S

NH

O

N

CH

OCH3

OCH3

H3C

1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''


Page 172

Figure-4.8: Aromatic region of PNMR spectrum of VIII79

The aliphatic region of this compound presented four singlets. The most downfield

signal, at δ 4.59 ppm, in this region was owned by two protons attached to acetamoyl

linkage because of high deshielding effect of carbonyl and sulfur along with

oxadiazole ring. The two singlets at δ 3.87 and 3.78 ppm, with six proton integration

collectively, were assigned to two methoxy groups. The most upfield singlet at δ 2.40

ppm was allocated to three protons of methyl group.

In the aromatic region, there appeared six signals overall. The methine proton

of azomethine carbon is highly deshielded as resonated at δ 8.18 ppm as singlet. The

amidic proton i.e. CONH resonated in more deshielded region at δ 10.42 ppm. This

signal is not shown in the given figures but was present in the complete spectrum of

this compound. The complete spectrum is not shown because of unexpanded signals

which were difficult to observe for their splitting. The two protons in the vicinity of

oxadiazole ring resonated at δ 7.86 ppm as ortho-coupled doublet and were more

deshielded than that in the vicinity of methyl group which resonated at δ 7.28 ppm as

doublet. The number of protons for each signal was found to be two as nominated by

their integration in the spectrum. The CHCl3-d1 was used as solvent and its peak also

appeared at δ 7.24 ppm in aromatic section, such downfield singlet of this aliphatic

proton might be because of three electonegative chloro groups attached to the same

carbon bearing the proton.

O

NN

S

NH

O

N

CH

OCH3

OCH3

H3C

1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''


Page 173

The three protons of dimethoxy ring presented two ortho-coupled doublets and one

doublet of doublet. The doublet of doublet was assigned to 4th position proton. This

proton ortho-coupled with 3rd position proton and meta-coupled with 6th position one.

One of the two doublets appeared at δ 7.31 ppm but with small coupling constant

value (meta-coupled) which confirmed this signal for 6th position proton. The second

doublet resonated at δ 6.92 ppm as ortho-coupled. All this discussion corroborated the

structure regarding the positions and numbers of protons in the molecule.

N'-(3-Nitrobenzylidene)-2-{[5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-

yl]thio}acetohydrazide (VIII126), another molecule of the same series of compounds,

is also discussed with respect to its CNMR.

CNMR has been recorded in BB (Broad Band) and DEPT (Distorsionless

Enhancement by Polarization Transfer) for 90o & 135o. Two methylene carbons

(carbons bearing two hydrogens) were observed in DEPT135 spectrum (Figure-4.9) at

δ 102.0 and 34.5 ppm for methylenedioxy and acetamidic respectively. DEPT135

spectrum presents all the hydrogen bonded carbons but the odd and even ones are in

inverse phase. The methyl and methine carbons are observed with upward directed

signals and methylene carbons are observed from downwards directed signals. Thus

the methylene carbons are easily distinguished from others. DMSO-d6 was employed

as solvent and hence solvent peaks also resonated in spectrum at about δ 39-40 ppm.

Figure-4.9: DEPT135 of CNMR spectrum of VIII126

O

NN

S

NH

O

N

CH NO2O

O

1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''7'


Page 174

DEPT90 spectrum of this molecule is given in Figure-4.10. This spectrum presents

signals for all the methine carbons (carbons bearing one hydrogen) only. DEPT90

presented eight methine carbons; three for trisubstituted 3,4-methylenedioxyphenyl

ring at δ 141.8, 109.0 and 106.0 ppm; four for disubstituted 3-nitrophenyl ring at δ

132.9, 130.3, 124.1 and 121.6 ppm; and one for methine carbon of azomethine

functionality at δ 145.0 ppm.

Figure-4.10: DEPT90 of CNMR spectrum of VIII126

The BB spectrum of CNMR, given in Figure-4.11 (a & b), shows the resonance of all

type of carbons including quaternary ones. First, we found all methylene carbons from

DEPT135 spectrum and second, all methine carbons from DEPT90 spectrum. Now

the only left quaternary carbons were nominated from BB spectrum by neglecting the

signals for all the methylene and methine carbons.

Thus eight quaternary carbons including two of 1,3,4-oxadiazole ring

resonating at δ 164.9 and 162.6 ppm were observed. The other six signals included

three for trisubstituted 3,4-methylenedioxyphenyl ring at δ 150.3, 148.1 and 116.6

ppm; two for disubstituted 3-nitrophenyl ring at δ 163.2 and 135.8 ppm; and one for

carbonyl carbon of acetamoyl functionality at δ 168.3 ppm. These quaternary signals

fully justified the whole structure including 1,3,4-oxadiazole formation.

O

NN

S

NH

O

N

CH NO2O

O

1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''7'


Page 175

Figure-4.11(a): BB of CNMR spectrum of VIII126

Figure-4.11(b): BB of CNMR spectrum of VIII126

One of synthesized compounds among the series of azomethine derivatives has also

been considered for EIMS discussion. The original EIMS spectrum of the selected

compound, N'-(4-Hydroxybenzylidene)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-

yl]thio}acetohydrazide (VIII71) is given in Figure-4.12 and its suggested mass

fragmentation pattern in Figure-4.13. The EIMS spectrum presented a number of

signals for different fragments of molecule. The molecular ion peak was observed at

O

NN

S

NH

O

N

CH NO2O

O

1

34

1'3'

5'

1''2''

7'''

1'''

5'''

3'''7'


Page 176

m/z 368 (26%) which was further fragmented. The formation of molecule was also

confirmed by fragments appearing at m/z 233 (3%) for 2-{[5-(4-methylphenyl)-1,3,4-

oxadiazol-2-yl]thio}acetyl cation and m/z 163 (3%) for 4-

hydroxybenzylidenehydrazin carbonyl cation.

The 5-substituted group of 1,3,4-oxadiazole appeared as 5-(4-methylphenyl)-

1,3,4-oxadiazol-2-thiol radical cation at m/z 192 (15%). This radical cation was

further fragmented into three peaks including 4-cyanotoluene radical cation, 4-(1,2-

oxaziren-3-yl)toluene radical cation and base peak at m/z 119 (100%) for 4-

methylphenyl carbonyl cation. The base peak was fragmented, after the removal of

CO, to phenylcarbonyl cation at m/z 91 (60%) which further lost propyne molecule to

give a peak at m/z 51 (30%) for 1,3-cyclobutadiene cation.

The fragment at m/z 163 (3%) lost CO to give 4-hydroxybenzylidenehydrazin

cation [m/z 135 (10%)] which further lost N2 to give hydroxy substituted tropyllium

cation [m/z 107 (8%)]. The formed tropyllium cation lost ethynylol molecule and

formed 1,3-cyclopentadiene cation at m/z 65 (48%).

Mainly the two fragments at m/z 233 and m/z 163 confirmed the whole

structure of molecule. The former fragment confirmed the S-substitution and latter

one confirmed the hydrazide and benzylidene formations.

By combining all these fragments collectively, the whole molecular structure

of the compound was confirmed along with different sites of attachments in the

molecule at various positions.

Figure-4.12: EIMS spectrum of VIII71

O

NN

S

NH

O

N

CH

OHH3C


Page 177

C9H8N2O2

CHNS

CO

[M] + m/z = 368 (26%)

m/z = 163 (3%)m/z = 192 (15%)

m/z = 135 (10%)

m/z = 107 (8%)

m/z = 65 (48%)

N2

C2H2O

C7H7N2O

m/z = 91 (60%)

m/z = 119 (BP, 100%)

C10H9N2OS

m/z = 133 (6%)

H3C

m/z = 51 (30%)

m/z = 117 (25%)

CHNOSCHN2S

CO

C3H4

HO

m/z = 233 (3%)

O

NN

SNH

O

NCH

OHH3C

O

NN

S

OH3C

O

NN

SH

H3C

NH

O

NCH

OH

O

H3C

N

H3C

O

N

H3C

NHN

CH

OH

Figure-4.13: Mass fragmentation pattern of VIII71

The PNMR of one of intermediate molecules from Scheme-2, 5-[(2,4-

Dimethylphenoxy)methyl]-1,3,4-oxadiazol-2-thiol (XII) is also provided in Figure-

4.14 (a & b). In the aromatic region of spectrum, two ortho-coupled doublets and one

meta-coupled doublet resonated for trisubstituted benzene ring at δ 6.95, 6.75 and

6.92 ppm respectively. The two substituted methyl groups appeared as singlets in the

aliphatic region at δ 2.24 and 2.19 ppm. The O-substitution and certainly molecular

structure were well supported by singlet at δ 4.99 ppm for two methylene protons.

This methylene carbon was attaching site to phenol and hence the further structure.


Page 178

Figure-4.14(a): PNMR spectrum of XII

Figure-4.14(b): PNMR spectrum of XII

4.2.2 7-Substituted-6-chloro-4-methylbenzo-2-pyrone (XIX1-9, XXI1-8)

In this section, the synthesis of benzo-2-pyrone and its different alkyl/aralkyl and acyl

derivatives have been discussed; see Scheme-3 (page-16). In the first step, 4-Chloro-

O

NN

SH

CH3H3C

O 1

34

1'

3'

5'7'


Page 179

1,3-dihydroxybenzene (XVI) was treated with equimolar EEE in the presence of

conc. H2SO4 to yield the benzo-2-pyrone ring. Here conc. H2SO4 acts as a catalyst in

the reaction medium. The suggested mechanism of this reaction is given in Figure-

4.15.

O

H

-H2O

H2SO4H+ HSO4

-1

-OSO3H

OC2H5

O

H+

H3C

O

OC2H5

O

H3C

O

H

HO

ClOC2H5

O

H3C

O

HOHO

Cl

H

HO

CH3

OC2H5

O

OHO

ClO

CH3

OC2H5

O

H

H

-H2SO4

-C2H5OH

OHO

ClO

CH3

O

HO

Cl

O O

HO CH3

HO

Cl

O O

HO CH3

H+

HO

Cl

O O

H2O CH3

H

H

-OSO3H

-H2SO4

HO

Cl

O O

H3C

Figure-4.15: Mechanism for benzo-2-pyrone ring formation

After a stay for half day, cold dist. water was added to quench the precipitates. The

precipitates were filtered out and excessive washing was performed to get pure


Page 180

compound by washing out the excess acid. Then recrystallization was performed in

MeOH.

The synthesized compound, 6-Chloro-4-methylbenzo-2-pyrone (XVII), was

simultaneously subjected to O-alkylation by different alkyl/aralkyl halides in DMF in

the presence of LiH and O-acylation by different acyl halides in water in the presence

of NaOH, both on stirring. The alkylation step followed same mechanism suggested

in Figure-4.4 and the acylation step that one suggested in Figure-4.6. In alkylation,

LiH and in acylation, NaOH act as an activator. The alkylation can be activated by

NaOH but in aprotic polar solvent and likewise acylation by LiH in aprotic polar

solvent and not in water. LiH reacts with water to produce some side products.

7-Methoxy-6-chloro-4-methylbenzo-2-pyrone (XIX1) was synthesized by

alkylation of XVII. Its PNMR spectrum is given in Figure-4.16. Five singlets were

observed in the whole spectrum; two for aromatic proton, one for olefinic proton and

two for two methyl groups present in varying vicinities. The methyl attached to

oxygen appeared relatively downfield at δ 3.95 ppm but the second methyl group

resonated at δ 2.37 ppm, each with three protons integration.

Figure-4.16: PNMR spectrum of XIX1

OO

Cl

O

CH3

H3C 1

35

71'

11


Page 181

The DEPT135 CNMR spectrum of this compound is given in Figure-4.17. Two

methyl carbons resonated at δ 56.6 ppm (attached to oxygen) and 18.6 ppm (attached

to olefinic carbon). The CHCl3-d1, solvent peak appeared at δ 76-77 ppm.

Figure-4.17: DEPT135 of CNMR spectrum of XIX1

Figure-4.18: DEPT90 of CNMR spectrum of XIX1

OO

Cl

O

CH3

H3C 1

35

71'

11


Page 182

Figure-4.19: BB of CNMR spectrum of XIX1

The three methine carbons of the molecule were nominated from DEPT90 CNMR

spectrum, given in Figure-4.18. The six quaternary carbons in the molecule were

identified from the BB CNMR spectrum given in Figure-4.19.

The EIMS spectrum of 7-[(3-Bromobenzyl)oxy]-6-chloro-4-methylbenzo-2-

pyrone (XIX9) is given in Figure-4.20 and its suggested mass fragmentation pattern in

Figure-4.21.

Figure-4.20: EIMS spectrum of XIX9

OO

Cl

O

CH3

Br

OO

Cl

O

CH3

H3C 1

35

71'

11


Page 183

The spectrum demonstrated the molecular ion and two isotopic peaks for the

molecule. The isotopic peaks were observed because of isotopes of chlorine (Cl35 and

Cl37) and that of bromine (Br79 and Br81). The molecular ion peak was for Cl35 and

Br79. M+2 was for Cl37 or Br81 but M+4 for Cl37 and Br81. The O-substituted part

presented two cations at m/z 169 (99%) and 171 (100%), the latter one was base peak.

The peaks at m/z 185 and 187 confirmed the O-substitution of benzo-2-pyrone. The

benzo-2-pyrone part of molecule demonstrated two peaks at m/z 210 (2%) for benzo-

2-pyrone complete moiety and then after removal of CO, at m/z 182 (3%). The

isotopic peaks for chlorine are not mentioned in fragmentation pattern and also in

EIMS data in results section.

O O

CH3

HO

Cl

Br

C2HBr

O

CH3

HO

Cl

CO

m/z = 380 [M + 2] + (3%)

m/z = 65 (4%)

m/z = 210 (2%)

m/z = 182 (3%)

m/z = 378 [M] + (2%)

m/z = 169 (99%)

m/z = 171 (BP, 100%)

m/z = 185 (2%)

m/z = 187 (2 %)

m/z = 382 [M + 4] + (<1%)

C10H6ClO3C7H5Br

C10H6ClO2

OO

Cl

O

CH3

Br

OBr

Figure-4.21: Mass fragmentation pattern of XIX9

The first compound of O-acylated series was 7-[(Ethanoyl)oxy]-6-chloro-4-

methylbenzo-2-pyrone (XXI1) and its PNMR spectrum is given in Figure-4.22. The

benzo-2-pyrone moiety signals remained just about the same as that for compound

XIX1, shown in Figure-4.16. The three protons of methyl group of ethanoyl moiety

resonated as a singlet at δ 2.37 ppm. This methyl group resonated somewhat upfield

as compared to that of XIX1 where it was attached directly to electronegative oxygen

atom.


Page 184

Figure-4.22: PNMR spectrum of XXI1


This section is comprised of three schemes. Scheme-4 (page-18) is about the synthesis

of different electrophiles as N-Substituted-2-bromoacetamide (XXIII1-27). This step

involves the nucleophilic substitution reaction of different alkyl/aralkyl/aryl amines

(XXII1-27) with BEB in water on stirring in the presence of Na2CO3. The basic

conditions are necessary to achieve complete conversion of amines into corresponding

electrophiles because HBr, the by product, deactivates the amines by protonation. The

suggested mechanism if this step is similar as mentioned in Figure-4.2. Although BEB

has two bromo groups and hence two electrophilic carbons but the nitrogen of amine

attacks carbonyl carbon owing to its more electrophilic character.

Scheme-5 (page-18) is about reaction of above synthesized electrophiles with

benzo-2-pyrone nucleus in DMF in the presence of LiH on stirring. The suggested

mechanism of this step was similar to that of Figure-4.4. The synthesized compounds

were acquired through filtration after addition of excess dist. water.

One molecule of this series is explained for its PNMR spectrum and one for its

EIMS spectrum. The PNMR spectrum of N-(5-Chloro-2-methoxyphenyl)-2-[(6-

chloro-4-methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV26) is given in Figure-4.23

(a & b). The aliphatic and aromatic regions confirmed the protons of benzo-2-pyrone

moiety as discussed earlier. The signals for varying moiety has been discussed in

detail here.

OO

Cl

O

CH3

H3C

O

1

35

71'

11

12


Page 185

Figure-4.23(a): PNMR spectrum of XXIV26

Figure-4.23(b): PNMR spectrum of XXIV26

OO

Cl

O

CH3

HN

O

OCH3

Cl

1

35

71' 2'

11

1''

5''

3''

7''


Page 186

The varying moiety showed one singlet with two protons integration for acetamidic

group at δ 4.68 ppm. The most deshielded singlet in the spectrum owed to heteroatom

proton, that is, proton attached to nitrogen of acetamoyl group. For 5-Chloro-2-

methoxyphenyl group, one signal resonated in aliphatic region and three in aromatic

one. The methoxy protons appeared at δ 3.89 ppm as singlet. Three signals for

aromatic protons included one ortho-coupled doublet (assigned to one proton in

vicinity of methoxy and upfield because of electron donating effect of methoxy

group), one meta-coupled doublet (assigned to one proton in between chloro and

amino groups) and one both ortho- & meta-coupled doublet of doublet (assigned to

one proton in vicinity of chloro groups). Their respective chemical shift values along

with coupling constant values are given in results section but signals are nominated in

the given figure.

The EIMS spectrum of N-(2-Methoxycarbonylphenyl)-2-[(6-chloro-4-

methylbenzo-2-pyron-7-yl)oxy]acetamide (XXIV13) is given in Figure-4.24 and its

mass fragmentation pattern in Figure-4.25.

Figure-4.24: EIMS spectrum of XXIV13

The fragments at m/z 366 (100%) supported the whole molecule and is formed from

molecular radical cation after removal of chlorine radical. The peak observed at m/z

224 (10%) confirmed the O-substitution and also the acetamoyl moiety attachment.

The acetamoyl part of molecule was observed at m/z 178 (7%) which after removal of

OO

Cl

O

CH3

HN

O

COOCH3


Page 187

CO produced a fragment at m/z 150 (1%). Thus these main fragments and the

remaining ones confirmed the moleculer structure and also the different attachments

performed during synthesis of this molecule.

O O

CH3

O

Cl

O O

CH3

H3CO

Cl

O

CH3

H3CO

Cl

CO

m/z = 403 [M+2] + (6%)

m/z = 224 (10%)

m/z = 401 [M] + (19%)

CO2CH3

HN

O

O O

CH3

O

CO2CH3

HN

O

m/z = 366 (BP, 100%)

Cl

C9H7NO3

m/z = 196 (4%)

O O

CH3

HO

Cl

O

CH3

HO

Cl

CO

m/z = 210 (3%)

C10H10NO3

m/z = 182 (4%)

CO2CH3

HN

O

CO

m/z = 178 (7%)

CO2CH3

HN

m/z = 150 (1%)

C11H8ClO3

O O

CH3

Cl

m/z = 193 (10%)

C10H10NO4

O

CH3

Cl

m/z = 165 (2%) m/z = 149 (2%)

CO2

Cl CH3

CO

Figure-4.25: Mass fragmentation pattern of XXIV13

Scheme-6 (page-18) is also about the reaction of previously used electrophiles with

another analogue of benzo-2-pyrone by same method and mechanism. This analogue

was not synthesized in laboratory and was purchased through local suppliers.

The compound, N-(5-Chloro-2-methoxyphenyl)-2-[(benzo-2-pyron-4-

yl)oxy]acetamide (XXVI18), is justified for its PNMR spectrum given in Figure-4.26

(a, b & c). The N-substituted part presented same pattern as discussed in the last

spectrum in Figure-4.23 (a & b). The benzo-2-pyron-4-yl group possessing five

protons presented five signals including two ortho-coupled doublets & two ortho-

coupled triplets and one singlet. The four aromatic protons resonated in aromatic

region from δ 7.33-7.92 ppm and singlet appeared at δ 5.75 ppm. Thus molecule was

confirmed to be pure with all type of protons in its spectrum.


Page 188

Figure-4.26(a): PNMR spectrum of XXVI18

Figure-4.26(b): PNMR spectrum of XXVI18

The EIMS spectrum of N-(2-Ethylphenyl)-2-[(benzo-2-pyron-4-yl)oxy]acetamide

(XXVI5), one of the compound from above series, is given in Figure-4.27 and its

mass fragmentation pattern in Figure-4.28. The different fragments given below also

confirmed the molecular structure of such type of molecules.

O O

O

NH

O

H3CO

Cl

1

35

7

1'2'

1''5''

3''

7''


Page 189

Figure-4.26(c): PNMR spectrum of XXVI18

Figure-4.27: EIMS spectrum of XXVI5

Among all the fragments, m/z 148 (60%) and 176 (37%) were the important ones. The

former one confirmed the amide formation step of e lectrophile along with attachment

with oxygen of benzo-2-pyrone moiety and later one the O-substitution step

performed during the synthesis of molecule, respectively. Base peak appeared at m/z

146 and fragmented from molecular radical cation as part of benzo-2-pyrone moiety.

Thus the whole molecular structure was confirmed.

O O

O

NH

O

H3CO

Cl

1

35

7

1'2'

1''5''

3''

7''

O O

O

NH

O

H3CH2C


Page 190

O O

O

O O

OCH3

O

OCH3

CO

m/z = 176 (37%)

m/z = 323 [M]+ (54%)

O O

m/z = 146 (BP, 100%)

C10H11NO2

C9H9NO

m/z = 148 (60%)

C10H10NO3

C2H5

HN

O CO

m/z = 148 (60%) C2H5

HN

m/z = 120 (77%)

C10H7O3

m/z = 132 (57%)

CO2

OCH3

O O

OH

O

OH

CO

m/z = 162 (39%)

m/z = 134 (60%)

CO2

m/z = 118 (84%)

OH

O O

m/z = 145 (5%) O

m/z = 117 (36%)m/z = 101 (41%)

C2H5

O

NH

C10H12NO2

COCO2

Figure-4.28: Mass fragmentation pattern of XXVI5

Figure-4.29(a): PNMR spectrum of XXX6

O

NN

S

NH

O

Cl

OOO

CH3

CH31

34

1'

3'5'

1'''2'''

11'

7' 12' 1'' 3''

5''

7''


Page 191

Figure-4.29(b): PNMR spectrum of XXX6

Scheme-7 (page-19) demonstrates the O-substitution of benzo-2-pyrone moiety with

EBE, hydrazide formation, conversion to 1,3,4-oxadiazole and finally S-substitution

by the previously used acetamoyl electrophiles using previously discussed methods

and mechanisms.

Figure-4.30: EIMS spectrum of XXX16

O

NN

S

NH

O

Cl

OOO

CH3

CH31

34

1'

3'5'

1'''2'''

11'

7' 12' 1'' 3''

5''

7''

O

NN

S

NH

O

Cl

OOO

CH3

CH3

CH3


Page 192

The PNMR spectrum of compound, N-(3-Methylphenyl)-2-[(5-{[(6-chloro-4-

methylbenzo-2-pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX6),

from this series was given in Figure-4.29 (a & b). The benzo-2-pyrone part of

molecule demonstrated the same pattern as discussed earlier.

The 3-Methylphenyl group of molecule depicted four signals as two doublets, one

triplet and one singlet in the aromatic region as shown by the numbered structure and

spectrum. The methyl group of this part resonated as singlet at δ 2.30 ppm. The four

protons of two methylene carbons resonated as two singlets, each with two proton

integration and thus confirming the different attachments.

O O

CH3

O

Cl

m/z = 487 [M+2] + (9%)

m/z = 485 [M] + (20%)

m/z = 450 (16%)

Cl

C13H14N3O3S

O O

CH3

HO

Cl

O

CH3

HO

Cl

CO

m/z = 210 (94%)

C13H13N3O2S

m/z = 182 (BP, 100%)

m/z = 148 (32%)

C14H10ClN2O4S

O O

CH3

Cl

m/z = 193 (16%)

O

CH3

Cl

m/z = 165 (5%)

CO

HN

O

NN

OS

CH3

H3C

HN

O

CH3

H3CO O

CH3

OHN

O

NN

OS

CH3

H3C

m/z = 251 (3%)

m/z = 249 (6%)

O O

CH3

O

C11H12N3OS

C11H12N2O2S

CO

m/z = 120 (36%)

HN

H3C

H3CO O

CH3

O

N

m/z = 214 (8%)

Cl

C11H12N2O2S

m/z = 230 (3%)

O O

CH3

O

N

O

C11H12N2OS

N

O O

CH3

O

ClO

Figure-4.31: Mass fragmentation pattern of XXX16

EIMS spectrum of N-(2,3-Dimethylphenyl)-2-[(5-{[(6-chloro-4-methylbenzo-2-

pyron-7-yl)oxy]methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (XXX16), another


Page 193

compound of this series, was given in Figure-4.30 and its mass fragmentation pattern

in Figure-4.31. The spectrum showed a peak at m/z 450 (16%) after removal of

chlorine radical from molecular radical cation. This fragment completely describes

molecular structure. The other notable fragments were m/z 251 (3%), 249 (6%) and

148 (32%).

4.3 Discussion of biological activities (in vitro)

This section of the running chapter is about the discussion of structure activity

relationship (SAR) of the synthesized molecules for their inhibition of certain

bacterial strains and LOX enzyme. All the compounds were screened against two

Gram-positive and three Gram-negative bacteria to evaluate their antibacterial

potential with reference of Ciprofloxacin, the reference drug. Along with antibacterial

potential, these were also evaluated for their LOX inhibition potential with reference

of Baicalein. Hence to evaluate their pharmacological behavior regarding drug

designing program or drug discovery pathway, in the results section, MIC values were

given and here the comparative study of those synthesized compounds has been

performed.

4.3.1 N'-Substituted-2-[(5-substituted-1,3,4-oxadiazol-2-yl)thio]acetohydrazide

(VIII1-133, XV1-13)

The in vitro screening of 1,3,4-oxadiazole bearing azomethine compounds has been

discussed in this section. The MIC values of all these compounds have been listed in

Table-4.1 to Table-4.4 (page-159 to page-162) for antibacterial potential. Forty seven

(47) compounds among this series remained active against all of five bacterial strains

and eight (8) remained inactive at all.

The compounds, VIII1-16, remained efficient against almost all the bacterial

strains except P. aeruginosa. S. typhi was inhibited by all the molecules but the other

bacterial strains were not completely inhibited by all the molecules. Against S. typhi,

VIII1,2,4,5, were the most active ones, with MIC values (µM) of 10.67±2.50,

10.24±3.00, 10.94±1.83 and 10.34±2.76 respectively, relative to that of reference,

9.13±2.00. E. coli was also inhibited by all the molecules except VIII11,13. Among the

active molecules, VIII1,2,5 executed prominent inhibition with MIC (µM) of

10.39±1.93, 10.21±2.07 and 10.56±2.98 respectively, relative to 8.90±1.65. Against

P. aeruginosa half of the series remained inactive at all and the most active one was

VIII5 with MIC (µM) of 10.37±2.90 in comparison to that of reference, 9.01±0.13. B.

subtilis was also inhibited by the most of compounds except VIII10,12,13,16. The


Page 194

compounds, VIII3,5 were the most active ones with MIC (µM) of 10.56±1.82 and

10.25±1.93 respectively, relative to 8.02±0.33. Likewise, S. aureus, was not inhibited

by VIII10,13-16. The compound, VIII7 remained the most active against this strain with

MIC of 12.04±5.00 µg/mL with respect to 8.41±1.04 µg/mL. The molecule VIII5 was

found to be the best one among all the synthesized molecules and the most credibly of

2-hydroxybezylidene moiety present in this molecule. Against LOX enzyme, only

three molecules, VIII1,2,4, remained weakly moderate active against this enzyme.

The compounds, VIII17-32, have shown moderately better activity against the

bacterial strains of Gram-bacteria. The compound, VIII21,30 demonstrated better

activity as predicted by its low MIC value against S. typhi as 10.65±1.31 and

10.23±2.43 respectively relative to that of reference, 9.13±2.00. The molecule, VIII20

showed no activity at all. Against E. coli, again VIII21,23 was found to possess low

MIC values as 11.51±5.00 and relative to 8.90±1.65 for reference and so good

inhibitory potential. A few compounds remained moderate and mostly inactive

against P. aeruginosa and B. subtilis. Against S. aureus, VIII17,21 showed moderate

activity and the remaining ones were inactive. Against LOX enzyme, the molecules

exhibited the least. The only two molecules, VIII17,22 presented the very moderate

activity with somewhat high IC50 values.

The compounds, VIII33-48, the molecule VIII41 was inactive for all the

bacterial strains and VIII46,47 exhibited somewhat activity only against E. coli & S.

aureus, respectively. Against S. typhi, VIII39,40 depicted almost the round about

activity to reference and VIII34,36, 50% activity of reference but VIII41,44,46,47

exhibited no activity at all. The molecules, VIII35,40,43,44,46 also demonstrated half

activity potential as compared to reference against E. coli but others remained

moderate inhibitors. All the compounds presented against P. aeruginosa an activity of

50% relative to ciprofloxacin. The molecules showed very moderate activity against

the both Gram-positive bacteria. Against LOX, only two compounds, VIII36,47,

showed some weak activity.

Among the compounds, VIII49-64, the three mono-substituted

methylbenzylidene (VIII50-52) and nitrobenzylidene (VIII56-58) showed the least

activity except for the p-substituted ones. Overall VIII49-52,56,57,64 executed the low

activity and remained inactive against some of the bacterial strains. The molecule,

VIII50, was only active against S. aureus and VIII51 against S. typhi. Among Gram-

negative bacterial strains, VIII64 was the most active against S. typhi with MIC value

of 10.04±1.25 µM relative to the reference standard, ciprofloxacin with MIC value of


Page 195

9.13±2.00 µM and VIII53 against E. coli with MIC value of 9.45±1.00 µM relative to

8.90±1.65 µM. The most of the active molecules showed 50% inhibition activity

relative to the reference against P. aeroginosa, B. subtilis and S. aureus. Against

LOX, again only three compounds, VIII59,61,63, were active and that were also with

too low activity.

Among the compounds, VIII65-83, VIII71 was the most efficient against all the

bacterial strains. Half of the molecules remained inactive against S. typhi, VIII71 was

the best one bearing 4-hydroxyphenyl ring with MIC (µM) of 9.65 ± 0.21 with respect

to 9.13±2.00, the MIC of ciprofloxacin. The bacterial strains, E. coli, P. aeruginosa

and S. aureus were inhibited by all the compounds. P. aeruginosa was best inhibited

by VIII69,79,81 with MIC (µM) of 11.28±1.05, 11.89±0.44 and 10.90±0.78 in

comparison of 9.01±0.13. B. subtilis was less efficiently inhibited but S. aureus was

efficiently inhibited by VIII65,66,71,76,78-80. The anti- lipoxygenase enzyme activity was

too low and only VIII66,71,76,81,83 presented some values of IC50.

Among the compounds, VIII84-102, VIII84,85,89-91,97,98 were found to be better

inhibitors of all the strains. Half of the molecules remained inactive against S. typhi

but VIII99, bearing disubstitued 3,4-dimethoxybenzylidene moiety, presented low

MIC (µM) of 10.09±0.90 relative to 9.13±2.00, that of reference. The bacterial

strains, E. coli, P. aeruginosa and S. aureus were less efficiently inhibited. Against E.

coli, VIII89,98 was best with MIC (µM) of 10.04±0.65 and 10.47±0.44 respectively,

relative to 8.90±1.65. The least activity was presented against B. subtilis. S. aureus

was efficiently inhibited by VIII93 with considerably low value of MIC as compared

to ciprofloxacin. The anti- lipoxygenase enzyme activity was also too low and only

VIII88,90,101 presented the notably significant activities. The most active compound,

VIII90, presented IC50 of 23.14 ± 0.15 µM relative to 22.4 ± 1.3 µM.

Among the compounds, VIII103-117, the series remained less efficient against

the bacterial strains taken into account. The S. typhi was inhibited by only four

compounds, VIII104,110,113,114, and P. aeruginosa by only three compounds

VIII107,113,116 but with too much moderate or low activity relative to reference. None

of the compounds inhibited B. Subtilis. The two bacterial strains, E. coli and S. aureus

were inhibited by most of the molecules and also with relatively low MIC values. The

molecules, VIII113 (2,4-dimethoxybenzylidene) and VIII114 (2,5-

dimethoxybenzylidene) presented best inhibition against E. coli with MIC values of

10.48±0.10 µM and 11.74±0.60 µM relative to 8.90±1.65 µM, the MIC of reference.

The compounds, VIII104 (2-methylbenzylidene) and VIII116 (2,4-


Page 196

dichlorobenzylidene) remained efficient against S. aureus with low MIC values of

10.64±0.19 µM and 9.38±0.51 µM relative to that of reference, 8.41±1.04 µM. The

compounds, VIII103,105,111,117 remained inactive at all against all the strains. The

compounds, VIII106,108 remained active only against S. aureus; and VIII109,112,115 only

against E. coli. The compounds might be tested for the diseases caused by E. coli and

S. aureus bacterial strains. Against LOX enzyme, the most of the synthesized

molecules remained efficient with notably low IC50 values. The compounds,

VIII108,110 showed no activity at all against this enzyme. Four compounds

(VIII103,112,115,116) among the whole series remained the least active and four

compounds (VIII104,106,107,111) moderate because of their relatively low IC50 values.

The compound, VIII114, rendered the best inhibition potential with IC50 value of

38.12±0.15 µM relative to 22.4±1.3 µM, credibly because of 2,5-dimethoxyphenyl

group attached to the molecule. The compounds VIII113,117 presented almost the same

activity with IC50 values of 78.2±0.42 µM and 79.8±0.64 µM, both bearing 2,4-

dimethoxyphenyl and 2,6-dichlorophenyl groups respectively. The molecules,

VIII105,109 also showed reasonable IC50 values of 96.7±0.42 µM and 92.2±0.14 µM

relative to the reference standard. The ortho-substituted molecules presented better

activities as compared to others and especially ortho-disubstituted molecules. These

molecules might be further evaluated for in vivo activity and thus as new drug

candidates.

Among the compounds, VIII118-133, all the molecules more efficiently

inhibited E. coli, P. aeruginosa and S. aureus; but less efficiently S. typhi and B.

subtilis. All the molecules remained active against the former strains but half of series

against the later ones. Against E. coli, the MIC values of all the molecules were

reasonably low except a few. The molecule VIII131 was the most efficient and also

better than the reference. Its MIC value was 8.49±4.87 µM relative to 8.90±1.65 µM,

the MIC of reference. The other active compounds were included to be VIII118,124. P.

aeruginosa was best inhibited by VIII122-124,129,131. The most active compound against

this strain was VIII124 with MIC of 10.48±4.25 µM relative to that of reference,

9.01±0.13 µM. The compound VIII131 also remained most active against S. aureus

with MIC of 10.09±3.87 µM in comparison of 8.41±1.04 µM. The other most active

molecules against this strain were VIII118,120,121,125,133. The five compounds,

VIII120,121,124,125,130 remained active against all the bacterial strains taken into account.

Against LOX enzyme, only three compounds, VIII118,122,131, were active but with high

IC50 values.


Page 197

Among the compounds, XV1-13, the whole series exhibited moderate

antibacterial behavior with 50% inhibition potential as compared to ciprofloxacin, the

reference drug. The bacterial strains, E. coli, P. aeruginosa and S. aureus were

inhibited by all the synthesized compounds but some remained inactive against S.

typhi and B. subtilis. Half of the series remained moderately active against all the

bacterial strains. The compound XV13 demonstrated the prominent activity against all

the strains except B. subtilis and the most probably because of para methoxy

substitutent on benzylidene. The prominent MIC values shown by XV13 were

9.48±0.00 (S. typhi), 7.37±0.23 (E. coli), 13.69±1.66 (P. aeruginosa) and 10.88±1.21

(S. aureus) relative to MIC of ciprofloxacin, 9.13±2.00, 8.90±1.65, 9.01±0.13 and

8.41±1.04 respectively. E. coli was best inhibited by XV7 also, bearing para hydroxy

benzylidene, with MIC of 10.78±1.21 µM relative to 8.90±1.65 µM. Against LOX,

more than half of the synthesized molecules remained inactive at all and only five

compounds showed inhibition potential varying from excellent to moderate. The

compounds XV2,3,6,8,9 were the only active molecules. The molecule, XV9, bearing 3-

nitrobenzylidene moiety executed the best inhibition potential with IC50 value of

5.21±0.011 µM with respect to that of baicalein, 22.4±1.3 µM, the reference standard.

Against B. subtilis, seventeen (17) compounds, VIII3,5,7,34,35,39,45,48,53,63 & XV1-

4,8-10, showed notable inhibition potential and about sixty (60) compounds remained

inactive. The most active compounds can be shown as graph, given in Figure-4.32.

Figure-4.32: Inhibition potential against B. subtilis for VIII1-133, XV1-13

The most of 5-phenyl-1,3,4-oxadiazol-2-yl compounds (VIII1-16) were active. The

results of 5-(3- or 4-chlorophenyl)-1,3,4-oxadiazol-2-yl compounds (VIII33-64)

presented more better activity as compared to 5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl

compounds (VIII17-32). The 5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl compounds

(VIII84-102) also presented valuable inhibition potential. A few compounds were active


Page 198

among 5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl compounds (VIII65-83) and none

among 5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl compounds (VIII103-117).

Against S. aureus, twenty four (24) compounds executed notable inhibition

potential. Among these compounds; VIII65 bearing 5-(4-methylphenyl)-1,3,4-

oxadiazol-2-yl along with benzylidene, VIII71 bearing 5-(4-methylphenyl)-1,3,4-

oxadiazol-2-yl along with 4-hydroxybenzylidene and VIII116 bearing 5-(2,4-

dichlorophenyl)-1,3,4-oxadiazol-2-yl along with 2,4-dichlorobenzylidene exhibited

the best MIC values of 9.67±0.03, 9.46±0.59 and 9.38±0.51 µM, respectively, relative

to reference with MIC value of 8.41±1.04 µM. The compound VIII66 executed the

highest activity against this strain with MIC value of 8.42±1.01 µM relative to the

reference and also comparable to it. The most of compounds were moderate to

excellent active against this strain and a few were inactive. Compounds bearing 5-(4-

methyl/4-hydroxy/3,4-methylenedioxy/2,4-dimethylphenoxymethyl)-1,3,4-oxadiazol-

2-yl moieties were active. Again the results of 5-(3- or 4-chlorophenyl)-1,3,4-

oxadiazol-2-yl compounds (VIII33-64) were better than 5-(2-chlorophenyl)-1,3,4-

oxadiazol-2-yl compounds (VIII17-32). The most active compounds can be shown as

graph in comparison to the reference, see Figure-4.33 below.

Figure-4.33: Inhibition potential against S. aureus for VIII1-133, XV1-13

Against S. typhi, twenty one (21) active compounds were found to be valuable with

notable inhibition potential. These twenty one (21) most active compounds can be

compared to reference as graph, see Figure-4.34. Furthermore, out of these twenty one

(21) compounds, two compounds were the most active ones. These two compounds,

VIII71 bearing 5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl along with 4-

hydroxybenzylidene and XV13 bearing 5-(2,4-dimethylphenoxymethyl)-1,3,4-

oxadiazol-2-yl along with 4-methoxybenzylidene demonstrated the lowest MIC

values of 9.65±0.21 and 9.48±0.00 µM, respectively, relative to 9.13±2.00 µM, the


Page 199

MIC of reference. The compounds VIII1-64 were the most active against this strain on

the whole in comparison of others and these active ones bear 5-(phenyl or 2/3/4-

chlorophenyl)-1,3,4-oxadiazol-2-yl moieties.

Figure-4.34: Inhibition potential against S. typhi for VIII1-133, XV1-13

Against E. coli, the most active compounds were twenty six (26). Among these ones,

VIII53 bearing 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl with 2-hydroxybenzylidene,

VIII131 bearing 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl with 2,4-

dimethoxybenzylidene and XV13 bearing 5-(2,4-dimethylphenoxymethyl)-1,3,4-

oxadiazol-2-yl along with 4-methoxybenzylidene depicted the lowest MIC values as

9.45±1.00, 8.49±4.87 and 7.37±0.23 µM, respectively, relative to 8.90±1.65 µM for

reference. Here both VIII131 and XV13 were even better than the reference,

Ciprofloxacin. The compounds VIII118-133 & XV1-13 were all the active ones against

this strain. The former series bear 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl

and latter one 5-(2,4-dimethylphenoxymethyl)-1,3,4-oxadiazol-2-yl moiety. The most

active compounds can be studied by the graph given in Figure-4.35.

Figure-4.35: Inhibition potential against E. coli for VIII1-133, XV1-13


Page 200

P. aeruginosa was less efficiently inhibited by all the compounds with a few

exceptions. The compounds VIII118-133 & XV1-13 were all the active ones against this

strain. The former series bear 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl and

latter one 5-(2,4-dimethylphenoxymethyl)-1,3,4-oxadiazol-2-yl moiety. Among the

compounds bearing 5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl moiety, only a few were

inactive. The most active compounds against this strain were twelve (12) and can be

studied from graph in Figure-4.36.

Figure-4.36: Inhibition potential against P. aeruginosa for VIII1-133, XV1-13

Among the whole series of compounds, VIII5,7,48,53 & XV1,8-10, were the most active

against both of the Gram-positive bacterial strains and the compounds, VIII5,53,90,124,

were the most active against all the three Gram-negative bacterial strains. Also against

all of the five bacterial strains, VIII5,53, were the best inhibitors.

The IC50 values are given in Table-4.5 and Table-4.6 (page-162 and page-163)

for LOX inhibition. The low efficiency might be attributed to less interaction with

active site of enzyme. Despite of it, eleven (11) compounds (Figure-4.37) were the

most active ones with comparable IC50 values to Baicalein.

Figure-4.37: Inhibition potential against LOX for VIII1-133, XV1-13


Page 201

Out of these eleven (11) compounds, five (5) belong to 5-(2,4-dichlorophenyl)-1,3,4-

oxadiazol-2-yl series and their better activity might be because of 2,4-dichlorophenyl

group showing some special interactions with amino acids present in active binding

site of enzyme. The compound, XV9 bearing 5-(2,4-dimethylphenoxymethyl)-1,3,4-

oxadiazol-2-yl and 3-nitrobenzylidene, was even better inhibitor than Baicalein, as

evident from its four times low IC50 value.

4.3.2 7-Substituted-6-chloro-4-methylbenzo-2-pyrone (XIX1-9, XXI1-8)

The alkylated and acylated compounds of benzo-2-pyrone moiety have been

discussed in this section. The MIC values of all these compounds have been listed in

Table-4.7 (page-163).

The compounds obtained after alkylation were relatively more efficient

against the bacterial strains taken into account than the acylated ones. The only active

alkylated compounds were XIX1,2,4,8,9, five (5) out of nine (9). The compound, XIX4

bearing branched but small aliphatic chain, rendered moderate activity against all the

strains. Also all the compounds remained less efficient against P. aeruginosa. Against

B. subtilis, S. aureus and E. coli, four (4) compounds out of five (5) demonstrated

better inhibition potential even than that of reference. The too low MIC values of

these compounds might be because of small aliphatic chain or bromo-substituted

aralkyl groups linked to benzo-2-pyrone through oxygen. Against S. typhi, only two

compounds were much efficient as compared to others but lesser than the reference.


The section is about the relative studies of acetamoyl compounds of benzo-2-pyrone

moiety synthesized in three different schemes.

The antibacterial potential of XXIV1-26 has been listed as their MIC values in

Table-4.8 (page-164). The compounds, XXIV4,15,23,26, were found to be efficiently

active against all the bacterial strains taken into account. On the other hand,

XXIV7,12,21 demonstrated no activity at all. B. subtilis was inhibited by only five (5)

compounds; moderately by XXIV4,9,15 and efficiently by XXIV23,26. The efficiency of

these two compounds might be associated to halo groups along with small

alkyl/alkoxy groups attached to nitrogen of acetamoyl moiety. S. aureus was also less

efficiently inhibited and three (3) compounds remained efficient up to some extent but

nine (9) moderate inhibitors. Among these three, two were same as for B. subtilis and

third one, XXIV16, bearing 2,3-dimethylphenyl as varying group. All the compounds

remained active against S. typhi except XXIV7,9,12,21. Among the active ones, the low

MIC values were depicted by XXIV2,11,23,26 as 10.49±4.05, 10.49±1.26, 8.82±1.42 and


Page 202

10.07±3.11 µM respectively, with respect to 8.00±2.54 µM, MIC of reference. The

compounds XXIV2,11 bear aromatic ring linked to nitrogen through one carbon and

ortho ethoxyphenyl group, respectively. E. coli was also inhibited by half of series

and actively by XXIV2,23,26, with MIC values of 10.50±1.30, 9.06±1.84 and 9.75±1.20

µM respectively, in comparison of 7.96±1.14 µM. Low number of compounds were

also active against P. aeruginosa. The compounds XXIV4,15,23,26 with MIC values of

9.54±5.00, 9.20±5.00, 8.42±1.03 and 11.91±4.57 µM, respectively, relative to

8.05±1.60 µM were the most active ones. The Gram-negative bacterial strains were

efficiently inhibited by five (5) compounds, XXIV1,2,4,11,15 and the Gram-positive ones

were less efficiently inhibited. Overall the compounds, XXIV4,15,23,26 presented

notably valuable inhibitory potential for all the bacterial strains. Their better activity

might be because of un-substituted phenyl, 4-nitrophenyl, 4-bromo-2-methylphenyl

and 5-chloro-2-methoxyphenyl groups respectively, bonded to acetamoyl nitrogen.

The LOX inhibition potential is expressed as IC50 values in Table-4.9 (page-164). All

the compounds depicted too much low potential as LOX inhibitors, as evident from

their high IC50 values.

The antibacterial potential of XXVI1-18 has been listed as their MIC values in

Table-4.10 (page-165). All the compounds demonstrated low MIC values against all

the strains except XXVI4,7 which showed no activity for some of the strains. All the

compounds inhibited B. subtilis and S. typhi. S. aureus was also inhibited by all the

compounds efficiently except a few. The compounds XXVI12-15,18 inhibit the strain

moderately and XXVI4,7 not at all. Against S. typhi, only XXVI4 was moderate

inhibitor. Likewise, E. coli was efficiently inhibited by all, moderately by XXVI15 and

not at all by XXVI4. P. aeruginosa was moderately inhibited by all ones excluding

XXVI4,7. It was best inhibited by only XXVI16,17 with MIC of 9.86±0.12 and

9.52±0.51 µM, respectively, in comparison of reference, 7.14±0.18 µM. The

compounds, XXVI16,17, were the most efficient ones, credibly because of di ortho-

alkyl/nitro phenyl group in the vicinity of acetamoyl group. Overall all the

compounds were notably active against all the strains.

The antibacterial potential of XXX1-27 has been listed as their MIC values in

Table-4.11 and Table-4.12 (page-165 and page-166). B. subtilis was moderately

inhibited by all the molecules except XXX15,24,25 and efficiently by XXX17 with MIC

of 10.94±2.29 µM in comparison of 8.32±1.00 µM, might be because of 2,4-

dimethylphenyl group. The compounds against S. aureus were moderate to excellent

inhibitors including XXX3,5,10,12,17 as better ones and XXX4,9,14,19,23,26 as inactive ones.


Page 203

The compound XXX5, bearing 2-methylphenyl group, was the most efficient with

MIC of 8.90±2.08 µM relative to 7.43±0.45 µM. The Gram-negative strain, S. typhi

was not inhibited by XXX2,4,19,27. It was the most efficiently inhibited by

XXX5,6,8,10,11,13,22. The best activity against it was observed for XXX10,11 with MIC

values of 8.87±1.20 and 8.84±2.00 µM with respect to that of reference as 8.00±2.54

µM. Both of molecules bear 2-methoxy/ethoxy phenyl groups. Only XXX15,24,25 were

inactive against E. coli and remaining moderate to good with the efficient ones as

XXX5,6,10,11,13,17,23,26. The most active ones were XXX6,26 with MIC of 10.15±4.12 and

10.24±3.69 µM relative to 7.96±1.14 µM, owing to the presence of 3-methylphenyl

and 5-chloro-2-methoxyphenyl groups respectively. Against P. aeruginosa,

XXX2,15,19,24-27 were inactive and remaining weakly moderate. The efficient ones

against this strain were XXX1,3,5,6,8,10,13,22. It was the most actively inhibited by XXX5

presenting MIC of 10.22±3.33 µM as compared to 8.05±1.60 µM. Overall the gram

negative strains were efficiently inhibited by the synthesized molecules relative to

gram positive ones. The best activity was presented by XXX5,6,10,22 and their activity

might be owned to the presence of ortho mono/di alkyl substituted phenyl rings

generally and one meta substituted one, attached to nitrogen of acetamoyl linkage.

The alkyl substitution resulted in moderate to good activity against all the strains.

Among aralkyl groups, the long aliphatic chain containing was moderate to good

against all the strains. The molecules bearing ortho substituted phenyl rings remained

active against all the strains, also good to excellent and more efficient against the

Gram negative strains. The meta substituted were also good against negative strain.

The para substituted phenyl rings presented varying activities but moderate ones. The

LOX inhibition potential is expressed as IC50 values in Table-4.13 (page-166). The

most of compounds remained inactive and the active ones depicted too much low

potential as LOX inhibitors, as evident from their high IC50 values.

4.4 Conclusion

The great use of organic synthesis, now-a-days, is in the field of pharmacy. The

different bioactive functionalities have been synthesized and further variations have

been attempted in their structures to get more bioactive compounds. Because of the

valuable bioactivity data for 1,3,4-oxadiazole, azomethine and benzo-2-pyrone

moieties (as referenced in introduction and literature review sections), an attempt was

made to synthesize some new molecules bearing multiple functionalities. In this

regard, therefore, 1,3,4-oxadiazole with azomethine and benzo-2-pyrone with


Page 204

acetamide have been synthesized. Furthermore, all the molecules were evaluated for

their antibacterial and enzyme inhibition potential to find out new drug candidates.

The whole research work was divided into different seven (7) schemes

(Chapter-1) and new two hundred thirty four (234) compounds have been listed. The

precursors might be available in literature but the target molecules were unknown

before it. All compounds were structurally corroborated through spectral data of IR,

PNMR and EIMS. Some compounds were also supported by CNMR spectral data.

The biological activity of all the compounds was listed after screening for two Gram-

positive and three Gram-negative bacteria relative to Ciprofloxacin as reference and

for LOX inhibition relative to Baicalein as reference.

Many compounds have been found to be bioactive with notably valuable

results for anti-bacterial potential and a few for enzyme inhibition potential. Among

the molecules bearing 1,3,4-oxadiazole and azomethine moieties, VIII5,7,48,53 & XV1,8-

10, were efficient for Gram-positive bacterial strains, VIII5,53,90,124, for Gram-negative

bacterial strains and VIII5,53, for all the five bacterial strains, taken into account. For

LOX inhibition, XV9 was four times more active than Baicalein. Among the

molecules bearing only benzo-2-pyrone ring, XIX1,2,8,9, were active antibacterial

agents. Among the molecules bearing benzo-2-pyrone and acetamide moieties, The

compounds, XXIV4,15,23,26, XXVI16,17 and XXX5,6,10,22 presented notably valuable

inhibitory potential for all the bacterial strains. The LOX inhibition potential was too

much low for all of these compounds.

The discussed synthetic work has emphasized the synthesis of multiple

functionality molecules with more biological activity potential. Analogues of such

type of molecules with minor structural modifications or even molecules bearing

some other functionality can be synthesized to get new more bioactive molecules as

new drug candidates.

The MIC results for antibacterial potential demonstrated the fact that the

subtle changes in the molecular structure, regarding number, position and nature of

substitutents, has greatly affected their bioactivity potential. It is also demonstrated in

SAR study of synthesized compounds. The most active compounds might be

subjected to in vivo bioactivity analysis along with cytotoxicity to check out their

application in the field of pharmacy as new drug candidates. Hence these molecules

might have their future in the drug discovery program.

1,3,4-Oxadiazol-2-yl Azomethine and Benzo-2-pyrone References

Page 205

CHAPTER FIVE

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Page 217

CHAPTER SIX

Appendices


Page 218

6.0 APPENDIX-I

List of Carboxylic Acids

Name Company MW (g/mol)

2,4-Dichlorobenzoic acid Alfa Aesar 191.01 2-Chlorobenzoic acid Merck 156.67 3-Chlorobenzoic acid Merck 156.67

4-Chlorobenzoic acid Merck 156.67 4-Hydroxybenzoic acid Aldrich 138.12

4-Methylbenzoic acid Sigma 136.2 Benzoic acid Merck 122.04

Piperonylic acid Alfa Aesar 166.13

6.1 APPENDIX-II

List of Alkyl Halides

Name Company MW (g/mol) Density (g/mL)

1-Bromoheptane Alfa Aesar 179.11 1.139 1-Bromopentane Alfa Aesar 151.05 1.215

1-Bromopropane Alfa Aesar 123.00 1.353 1-Iodobutane Aldrich 184.02 1.617

2-Bromobenzyl chloride Alfa Aesar 249.94 1.850

2-Bromobutane Alfa Aesar 137.03 1.260 2-Methylbenzyl chloride Alfa Aesar 140.67 1.081

3-Bromobenzyl chloride Alfa Aesar 249.94 1.560 Iodomethane Merck 141.93 2.28

6.2 APPENDIX-III

List of Acyl Halides


2,4-Dichlorobenzoyl chloride Aldrich 209.4 1.494

2-Bromoethanoyl bromide Alfa Aesar 201.86 2.324 2-Chlorobenzoyl chloride Alfa Aesar 175.01 1.379

Benzoyl chloride Aldrich 140.57 1.21

Ethanoyl chloride Merck 78.50 1.10 Morpholine-4-carbonyl chloride Aldrich 149.5 1.28

Phenoxymethanoyl chloride Merck 156.57 1.240 Thiophene-2-carbonyl chloride Alfa Aesar 146.60 1.372


Page 219

6.3 APPENDIX-IV

List of Aldehydes


2,3-Dimethoxybenzaldehyde Alfa Aesar 166.18 - 2,4-Dichlorobenzaldehyde Aldrich 175.01 -

2,4-Dimethoxybenzaldehyde Alfa Aesar 166.18 -

2,5-Dimethoxybenzaldehyde Alfa Aesar 166.18 - 2,6-Dichlorobenzaldehyde Aldrich 175.01 -

2-Hydroxybenzaldehyde Alfa Aesar 122.12 1.168 2-Methylbenzaldehyde Alfa Aesar 120.15 1.037 2-Nitrobenzaldehyde Alfa Aesar 151.12 -

3,4-Dimethoxybenzaldehyde Alfa Aesar 166.18 - 3-Hydroxybenzaldehyde Alfa Aesar 122.12 -

3-Methylbenzaldehyde Alfa Aesar 120.15 1.020 3-Nitrobenzaldehyde Alfa Aesar 151.12 -

4-Diethylaminobenzaldehyde Alfa Aesar 177.25 -

4-Dimethylaminobenzaldehyde Alfa Aesar 149.19 - 4-Hydroxybenzaldehyde Alfa Aesar 122.12 -

4-Methoxybenzaldehyde Scharlau 136.15 1.12 4-Methylbenzaldehyde Alfa Aesar 120.15 1.018 4-Nitrobenzaldehyde Alfa Aesar 151.12 -

Benzaldehyde Merck 106.13 1.05

6.4 APPENDIX-V

List of Miscellaneous Chemicals


2,4-Dimethylphenol Fluka 122.17 1.018

4-Chlororesorcinol Merck 144.56 - 4-Hydroxycoumarin Merck 162.03 -

Carbon disulfide Reidel-de Haen 76.13 1.266

Conc. sulfuric acid Reidel-de Haen 98.08 1.84 Ethanol (99.8%) Merck 46.07 0.79

Ethyl 2-bromoacetate Merck 167.00 1.500 Ethyl acetoacetate Fluka 130.41 1.029

Hydrazine monohydrate (80%) Dae Jung 50.06 0.80

Lithium hydride Fluka 7.95 - Methanol (99.9%) Reidel-de Haen 32.04 0.791

N,N-Dimethylformamide (99%) Riedel-de Haen 73.09 0.949 Potassium Hydroxide Merck 56.11 -


Page 220

6.5 APPENDIX-VI

List of Amines


2,3-Dimethylaniline Aldrich 121.18 0.993 2,4-Dimethylaniline Aldrich 121.18 0.98 2,5-Dimethylaniline Aldrich 121.18 0.973

2,6-Dimethylaniline Aldrich 121.18 0.984 2-Ethoxyaniline Acros 137.08 1.051

2-Ethyl-6-methylaniline Alfa Aesar 135.21 0.969 2-Ethylaniline Alfa Aesar 121.18 0.983

2-Methoxyaniline Merck 123.07 1.092

2-Methyl-6-nitroaniline Merck 152.06 - 2-Methylaniline Merck 107.07 0.998

2-Phenylethylamine Alfa Aesar 121.18 0.964 3,4-Dimethylaniline Aldrich 121.18 1.076 3,5-Dimethylaniline Aldrich 121.18 0.972

3-Methylaniline Merck 107.07 0.988 4-Chloro-o-anisidinium sulfate Fluka 255.00 -

4-Ethoxyaniline Aldrich 137.08 1.065 4-Ethylaniline Alfa Aesar 121.18 0.975

4-Methylaniline Alfa Aesar 107.07 -

4-Methylpyridin-2-amine Alfa Aesar 108.07 - Aniline Riedel-de Haen 93.13 1.02

Benzylamine Acros 107.15 0.98 Cyclohexylamine Aldrich 99.17 0.8647

Methyl anthranilate Aldrich 151.17 1.168


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6.6 APPENDIX-VII

Sr. # List of Publications

1 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Samreen Gul, Khalid Mohammad Khan, Irshad Ahmad, Saira Afzal, Sidra Hassan and Syeda Abida Ejaz. Antibacterial and enzyme inhibition study of

heterocyclic hydrazone derivatives of benzoic acid. Acta Chemica Solvanica, (Submitted).

2 Aziz-ur-Rehman, Samreen Gul, Muhammad Athar Abbasi, Shahid

Rasool, Khalid Mohammad Khan, Muhammad Nadeem Akhtar, Irshad Ahmad and Saira Afzal. Synthesis, characterization and biological

activity of some new S-substituted derivatives of 5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-thiol. Journal of Chemical Society of Pakistan,

(Submitted). 3 Aziz-ur-Rehman, Samreen Gul, Muhammad Athar Abbasi, Shahid

Rasool, Khalid Mohammad Khan, Muhammad Nadeem Akhtar, Irshad

Ahmad, Saira Afzal and Syeda Abida Ejaz. Antibacterial and enzyme inhibition screening of some new acetamide and azomethine derivatives.

Journal of Chillian Chemical Society, (Submitted). 4 Shahid Rasool, Aziz-ur-Rehman, Muhammad Athar Abbasi, Khadija

Nafeesa, Muhammad Nadeem Akhtar, Irshad Ahmad and Saira Afzal.

Synthesis, spectral analysis and antibacterial evaluation of N'-substituted-2-(5-(3-chlorophenyl)-1,3,4-Oxadiazol-2-ylthio)acetohydrazide

derivatives. Pakistan Journal of Pharmaceutical Sciences, (Submitted). 5 Shahid Rasool, Aziz-ur-Rehman, Muhammad Athar Abbasi, Khadija

Nafeesa, Muhammad Nadeem Akhtar, Irshad Ahmad and Saira Afzal.

Synthesis, spectral analysis and antibacterial evaluation of Synthesis of N'-substituted-2-(5-(4-chlorophenyl)-1,3,4-Oxadiazol-2-

ylthio)acetohydrazide derivatives as suitable antibacterial agents. Tropical Journal of Pharmaceutical Research, 14(6), 1081-1088, 2015.

6 Shahid Rasool, Aziz-ur-Rehman, Muhammad Athar Abbasi, Irshad

Ahmad and Rabia Malik. Synthesis, characterization and biological evaluation of N'-substituted-2-(5-(4-substitutedphenyl)-1,3,4-Oxadiazol-

2-ylthio)acetohydrazide derivatives. Journal of Chemical Society of Pakistan, (Accepted).

7 Shahid Rasool, Aziz-ur-Rehman, Muhammad Athar Abbasi, Sabahat

Zahra Siddiqui, Asma Salah-ud-din Gondal, Haris Ahmad Noor, Shanza Sheral and Irshad Ahmad. Antibacterial and enzyme inhibition study of

hydrazone derivatives bearing 1,3,4-Oxadiazole. Pakistan Journal of Chemistry, 5(1), 14-22, 2015.

8 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Samreen

Gul, Khalid Mohammad Khan, Irshad Ahmad, Rabia Malik and Sidra Hassan. Synthesis, characterization and biological evaluation of

hydrazone derivatives of 2-mercapto-(5-(2,4-dichlorophenyl)-1,3,4-oxadiazole. Letters in Drug Design & Discovery, (Submitted).

9 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Samreen

Gul, Khalid Mohammad Khan, Irshad Ahmad, Saira Afzal, Sidra Hassan and Syeda Abida Ejaz. Pharmacological evaluation of some new

hydrazone derivatives bearing 1,3,4-oxadiazole and benzodioxole heterocycles. Bulgarian Chemical Communications, (Submitted).

10 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid


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Muhmmad Khan, Irshad Ahmad, Rabia Malik and Sidra Hassan. Synthesis, spectral analysis and pharmacological study of N'-substituted-

2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)aceto hydrazides. Brazillian Journal of Pharmaceutical Research,

(Submitted). 11 Shahid Rasool, Aziz-ur-Rehman, Muhammad Athar Abbasi, Khadija

Nafeesa, Asia Siddiqa, Ghulam Hussain, Irshad Ahmad and Shafia

Arshad. Synthesis, characterization and antibacterial study of 7-O-substituted derivatives of chlorinated coumarin. Asian Journal of

Chemistry, 26(3), 690-696, 2014. 12 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid

Mohammad Khan, Irshad Ahmad and Saira Afzal. Synthesis and

antibacterial activity analysis of N-(alkyl/aralkyl/aryl)substituted acetamide derivatives of 6-chloro-7-hydroxy-4-methyl-2-oxo-2H-

chromene. Journal of Chemical Society of Pakistan, (Submitted). 13 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid

Mohammad Khan, Irshad Ahmad and Saira Afzal. Synthesis,

characterization and antibacterial evaluation of N-arylsubstituted acetamides from 6-chloro-7-hydroxy-4-methyl-2-oxo-2H-chromene.

Pakistan Journal of Pharmaceutical Sciences, (Submitted). 14 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid

Mohammad Khan, Irshad Ahmad and Rabia Malik. Synthesis and

antibacterial activity study of N-substituted acetamide derivatives of 4-hydroxy-2-oxo-2H-chromene. Pakistan Journal of Chemistry,

(Accepted). 15 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid

Mohammad Khan, Irshad Ahmad, Saira Afzal and Syeda Abida Ejaz.

Synthesis, structural elucidation and antibacterial evaluation of some new molecules derived from coumarin, 1,3,4-oxadiazole and acetamide.

Phosphorus, Sulfur, and Silicon and the Related Elements, (Submitted). 16 Aziz-ur-Rehman, Shahid Rasool, Muhammad Athar Abbasi, Khalid

Mohammad Khan, Irshad Ahmad, Saira Afzal and Syeda Abida Ejaz.

Synthesis and antibacterial evaluation of some acetamide derivatives of 5-{[(6-chloro-4-methyl-2-oxo-2H-chromen-7-yl)oxy]methyl}-1,3,4-

oxadiazol-2-thiol. Journal of Saudi Chemical Society, (Submitted).

Documents

prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/7563/1/... · IV DECLARATION I, Shahid Rasool, Reg. No. 2012-GCU-PHD-CHEM-09, student of PhD in the subject of Chemistry, Session