Review of literature Chapter-II - Information and Library ...shodhganga.inflibnet.ac.in/bitstream/10603/21288/11/11...Chapter – II Review of Literature 35 O CH 3 O 1H, Benzimidzole

Chapter – II Review of Literature

30

2.0 REVIEW OF LITERATURE

2.1 Computer Aided Drug Design

Kadam RU et al., 2007 reported the computational techniques for identifying

drug-like molecules, ranging from simple counting schemes to sophisticated machine

learning techniques such as neural networks, along with their application and challenges.

Bakht et al., 2010 reported the octanol/water partition coefficients, solubilities,

absorption, molecular volumes and polar surface areas, rotatable single bonds, hydrogen

bond donors acceptors and lipophilicities for a set of 28 oxadiazoles and reported

synthesis, antibacterial, antifungal activity.

Dwivedi PB et al., 2009 reported drug likeliness of N-(furan-2-ylmethyl) -2-(1H-

tetrazol-5-yl) acetamide and its 14 hypothetical analogs based on toxicity, lipophilicity,

solubility and molecular weight. Properties were calculated by Osiaris molecular property

explorer. Lipophilicity of N-(furan-2-ylmethyl)-2-(1H-tetrazol-5-yl) acetamide is low.

Drug likeness was predicted based on atomfragment based contribution. Overall drug

score combines all other into one grand total. Heat of formation and lipophilicity of all

analogs is also calculated.. In early stages of designing antiinflammatory and analgesic

drug based on N-(furan-2-ylmethyl) -2-(1H-tetrazol-5-yl) acetamide, it is beneficial to do

this in-silico study before synthesis work is under-taken with the aim of avoiding the

synthesis of compounds.

Wager et al., 2010 reported properties for 119 marketed CNS drugs and a set of

108 Pfizer CNS candidates in understanding the relationships between physicochemical

properties, in vitro ADME attributes, primary pharmacological binding efficiencies and

in vitro safety data for these two sets of compounds.


31

Ursu et al., 2010 reported drug-likeness filter (DLF), starting from molecular

fragments and molecular weight a key property relevant in drug design. The molecular

fragments were selected from extended connectivity atom environments based on their

occurrence ratio in our collection of drugs and "nondrugs".

Huang et al., 2010 reported a new pharmacophore-based de novo design method

of drug-like molecules. The method first generates a set of new molecules that

completely conform to the requirements of a given pharmacophore model, followed by a

series of assessments to the generated molecules, including assessments of drug-likeness,

bioactivity and synthetic accessibility.

Jihane F et al., 2011 reported the design and molecular properties of some

aldazines derivatives on the basis of hypothetical antibacterial pharmacophore sire , to

interact with gram positive and negative bacteria. Lipinski rule of five, drug likeness and

physic-chemical properties of drugs are described.

Aliasghar J et al., 2012 reported the design and molecular properties often azo

Shiff bases on the basis of hypothetical antibacterial pharmacophore sire , to interact

with Gram positive and Gram negative bacteria. The antibacterial activity of the azo

Schiff bases was discussed on the basis of the theoretical calculations by using Petra,

Osiris, molinspiration.

Taibi Ben Hadda et al., 2012 reported the rational design of bioactive

pharmacophore sites as antiviral candidates based on X-ray structures of drugs and

reported the correlation between the theoretical predictions of bioavailability using Petra,

Osiris, molinspiration.


32

Mohammed Afroz Bakht et al., 2010 reported the synthesis and antimicrobial

activity of some newer 1,3,4- oxadiazole analogies based on molecular properties

prediction and reported drug-likeness by Molinspiration and Molsoft softwares.

Lipophilicity and solubility parameters using ALOGPS 2.1 program.

Peter E et al., 2000 reported the new approach for the calculation of the Polar

surface area belonging to polar atoms to correlate well with positive molecular transport

through membranes and reported this new methodology may used for fast bioavailability

screening of virtual libraries having millions of molecules.

Ahmed M Alafeefy et al., 2011 reported the molecular docking to understand he

structural features responsible for anti-inflammatory activity of quinazoline derivatives.

Aliasghar J et al., 2012 reported the development of a computational model for

the rational design of bioactive pharmacophore sites as an antibacterial , antifungal and

antiviral candidates based on available X-ray structures of bis-Schiff bases.

Mohammed Jawed Ahsan et al., 2011 reported the synthesis antimicrobial and

antitubercular activity of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl) methyl]

amino} -1,2-dihydro-3H-pyrazol-3-one based based on molecular properties prediction,

and reported drug-likeness by Molinspiration and Molsoft softwares. Lipophilicity and

solubility parameters using ALOGPS 2.1 program.

Ravi G et al., 1996 reported the structural basis for selective inhibition of

cyclooxygenase-2 by anti-inflammatory agents.


33

Vittorio Limongell et al., 2010 reported molecular basis of cyclooxygenase

enzymes selective inhibition using advanced computational technique and dissociation

process of the a highly potent and selective inhibitor , sc-558 in both COX-1 and COX-2.

Parvesh Singh et al., 2011 reported the synthesis of thiophene compounds,

additionally the binding conformations of these compounds and anti-inflammatory drugs

were determined by their docking in the active site of the COX-2 enzyme.

Arumgam M et al., 2012 reported the cyclooxygenase inhibitory activity of

flavonoids using Auto Dock 4.2, in silico docking studies. Three important parameters

like binding energy, inhibition constant and intermolecular energy were determined.

2.2 Chemistry and Pharmacology

It is seen from the literature that such efforts have led to the development of a

number of potent molecules synthetic methods and activities derived from

benzimidazoles, thiadiazoles, triazoles, oxadiazoles and Schiff base derivatives.

Benzimidazoles

Vinodkumar R et al., 2007 reported synthesis of a series of novel and functioned

benzimidazole derivatives 6 by the condensation of o-phenylenediamine with 4-Bromo

benzoic acid and subsequent reactions of the product obtained with phenyl acetylene and

6-ethynyl-4,4-dimethylthiochroman utilizing Sonogashira coupling. The Sonogashira

coupling products were then alkylated at the benzimidazole –NH with different

electrophilic reagents leading to functionalized derivatives. All the compounds


34

synthesized were screened for their potential anti-bacterial, anti-asthmatic and anti-

diabetic properties, which exhibited moderate activities in screening studies in vitro.

NH

N

Br

NH

N

ArAlkylating Agent

Aryl Acetylene

6

Kam RV et al., 2007 reported the synthesis of a series of novel class of N-

substituted-2-9 benzo[d] isooxazol-3-ylmethyl)-1H benzimidazoles 7 by the condensation

of o-phenyl enediamine with benzo[d] isooxazol-3-yl aceticacid and subsequent reaction

with different types of electrophiles. These compounds were screened for antibacterial,

antiasthmatic and antidiabetic activity. Compound with CH2C6H5-Br substitution on

ortho position of the benzimidazole ring showed good antibacterial activity.

NH2

NH2

+ N

N

NO

reflux / 6 h

R-X or Ar-X

Base

N

N

NO

R

R = CH3, CO=CH3, CO-CH2-CH2CH3, CH2-C6H4-Br

4N HCl

HO

N

CH2COOH

7

Guven OO et al., 2007 reported the synthesis of some novel furyl and

benzimidazole substituted benzyl ethers 8. These compounds were screened for

antibacterial activity. Compounds substituted with phenyl ring having two chlorine atoms

at different positions showed good activity.


35

O

CH3

O 1H, Benzimidzole

NNO

NNO

NNO

OAr

Ar =

Cl

Cl Cl

Cl

F Cl

Cl

Br

NaBH4

NaH

ArCH2X

Br2

8

Duhiya R et al., 2007 reported the synthesis of substituted benzimidazolyl-

benzoic/ salicylic acids by interaction of 5,6-dimethyl-6-nitrobenzimidazole with

diazotized substituted and unsubstiruted aminobenzoicacids in the presence of cupric

chloride. The coupling of these compounds with different amino acid ester

hydrochlorides, dipeptides, tripeptides methyl esters afforded novel benzimidazolo-

peptide derivatives 9, 10. These compounds were screened for antimicrobial, cytotoxic

and anthelmintic activity. All the compounds were found to have good activity.

H3C

H3C NH

N R1

CO-X-OH

R29

R3

R4 NH

N

OH

CO-X-OH

10

R1 = R2 = H; R3 = H, CH3; R4 = NO2, CH3

X = Aminoacids, dipeptides, tripeptides, tetrapeptides.


36

Thiadiazoles

Nizamuddin et al., 1992

reported the synthesis of several 3-substituted-6-

arylamino-1,2,4-triazolo (3,4-b) -1,3,4 thiadiazoles 11, 12. Synthesis of 1,3,4-thiadiazoles

was carried out in following way. Refluxing of 2-arylamino-5-mercapto-1,3,4-

thiadiazoles with hydrazine hydrate in methanol yielded 2-arylamino-5-hydrazino-1,3,4-

thiadiazole which on treatment with formic acid, aryloxyacetic acid, methyl

chloroformate and carbondisulphide yielded required compounds. These compounds

were screened for antifungal activity. Among all the active compounds methoxy

substituted compound showed good activity.

NH

N

S

N

NN

CH2O

R'

R

11

NH

N

S

N

NN

R

H

12

R = 4-OCH3, 4-CH3, H, 4-Cl R’ = 4-OCH3, 4-Cl, H, 4-CH3

Nizamuddin et al., 1988 reported the synthesis of several 1-(5’substituted-phenyl-

1’,3,4’- thiadiazol-2’-yl) -3-chloro-4-substituted-2-azitidinone 13 by the annulations of

acid chlorides on anils using Et3N and were screened for antifungal activity. All the

compounds were found to have good activity.

NH

N

S

N

N H

HHO

R1

R

13

R = 2Cl, 2, 4-(CH2)2. R1= C6H6, C6H4.Cl-ρ.


37

Dogan HN et al., 2002

reported the synthesized 2,5-disubstituted-1,3,4-

thiadiazole 14 by following way. First 1,3,4-thiadiazoles were formed by the dihydrative

cyclization of thiosemicarbazides acidic media, which on acetylating with acetic

anhydride yielded acetylated thiadiazole derivatives. These compounds were screened for

anticonvulsant and antimicrobial activity. Compounds with p-fluorophenyl and m-

trifluoromethylphenyl substitution at R position showed good antibacterial activity.

Compounds with phenyl ethyl and p-methoxy phenyl substitution at R position showed

good anticonvulsant activity.

S

NN

NCOCH3

R

OCOCH3

14

R= Phenylethyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, m-trifluoromethyl

phenyl.

Rollas S et al., 2004 reported the synthesis of 2,5, disubstituted-1,3,4,

thiadiazoles 15. For the synthesis of these compounds first 4-substituted benzoic acid

hydrazides were refluxed with arylisothiocyanates in ethanol, this afforded

thiosemicarbazides, which were cyclized into thiadiazoles. The compounds were

screened for antitubercular activity. Compound with 4-fluorophenyl substitution at

thiadiazole moiety was found to be more active.


38

R COCl + HO R COO

NH2NH2

CH3OH

R CONHNH2HN R1CHNHNCAr

O S

NH2NH2

CH3OH

N

S

N

Ar NH

R1

NaOH

NaOH

15

Ar = C6H5, 4-Br-C6H4, 4-Cl-C6H4, C6H5

R1 = C6H5, 4-Br-C6H4, 4-Cl-C6H4, C6H5

Mohan J et al., 2002 reported the synthesis of 2,6 diarylimidazo (2,1-b) -1,3,4-

thiadiazole by the reaction of α haloketones with 2-amino-5-(3,5-dinitrophenyl) -1,3,4-

thiadiazole. Bromination of which furnished 5-bromo-2, 6, -diarylimidazo (2, 1-b) -1,3,4-

thiadiazole 16. These compounds were screened for antimicrobial activity.

O2N

NO2

S

NN

NH

Br

R16

R= Cl, H

Schenone S et al., 2008 reported the synthesis of new 1,3,4-thiadiazole 17

derivatives by cyclizing the acyl thiosemicarbazides with phosgene in anhydrous THF.

The corresponding alkyl thiosemicarbazides were obtained by treating the benzene

sulphonyl hydrazides with different alkyl isothiocyanates in anhydrous THF. The


39

compounds were screened for analgesic and anti-inflammatory activities. Compound with

p-fluoro phenyl substitution at R’ position was found to be more active.

R S NH NH2

O

O

+ S C N C R

OTHF anhyd.

rt, 3daysR S NH NH

O

O

C NH C R'

S O

CH3COONa anhyd.

phosgene

R SO2N

S

N

NHO C R1

O

17

R = H, CH3, R1

= Phenyl, 4-Methoxychlorophenyl, 4-Chlorophenyl, 4-fluorophenyl,

4-Trifluoro methyl phenyl.

Andanappa K et al., 2008 reported the synthesis of a series of 2-trifluoro methyl

sulfonamide -5,6-diarylsubstituted imidazo [2,1-b] -1,3,4-thiadiazole derivatives 18 by

the reaction of 2-amino-5-trifluoromethyl/sulfonamide-1,3,4-thiadiazoles and

appropriately substituted α-bromo-1,2-(p-substituted) diaryl-1-ethanones. The selected

compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory

activity against COX-2 and COX-1.

O

Br

R1

R

EtOH, P2OH5

N

S NH2R2R1

N

NN

SR2

18

R = H, OCH3; R1 = H, F, CH3, OCH3; R

2 = CF3, SO2NH2


40

Triazoles:

Georeg T et al., 1970 reported the synthesis a series of 5-alkyl-4-amino-5-

triazole-3-thiols 19 and screened for analgesic and anti-inflammatory activity.

N N

R SH

NH2

19

R= CH3, (CH2)2CH3, (CH2)3CH3, (CH2)-4CH3, CH2CH (CH3)2, C2H5.

Milcent R et al., 1984 reported the synthesis of 2-substituted-4-amino-5-alkyl-or

aryl-2,4-dihydro-1,2,4-triazol-3-ones 20 and 2-substituted-5-alkyl or aryl-4-(5 nitro-2-

furfuraldehyde) amino-2,4-dihydro-1,2,4 triazol-3-ones 21, and screened for their

antibacterial activities.

N N

NR' O

CH2CH2SH

NH2

20

N N

NR1 O

R2

N CHO NO2

HH.2CH3 COOH

21

R’ = aryl or alkyl R

1 = aryl or alkyl

R2=CH2OCOC2H5, CH2OCOCH3

Reiler J et al., 1990 reported the synthesis of 1,5-diaryl-3-alkylthio-1H-1,2,4

triazoles 22 and corresponding sulfoxides and sulfones (23) by reaction of

phenylhydrazines with potassium thiocyanate in refluxing ethanol produced the

phenylthiosemicarbozide. Acylation of phenylthiosemicarbozide followed by cyclization

afforded an intermediate which on alkylation gave expected alkyl thioester. These


41

compounds were evaluated for antiarthritic activity. Among all the compounds the p-

halogen compounds were found to be more active as antiarthritic agents.

N N

NR2 SOnR3

R1

22

N

N

N

R1

R2SOnR3

23

R1

= R2= substituted phenyl R

1 = H, 4F, 4Cl, 4-NO2

R3 = Alkyl R

2 = H, 4F, 4Cl, 4-NO2

n = 0-2 R3 = CH3, CH2CHF2; n = 0

Andotra GS et al., 1998 reported the synthesis of substituted aryl-6-ρ-chloro

phenyl 5-thione (1H)-1,2,4-triazole (1,5-a) s- triazines-7-ones 24 from 2-substituted-

1,2,4-triazole derivatives and screened for various antibacterial and antifungal activities.

N

NH

N N Cl

OR2R1O

R

S

S

24

R = C2H5, n- C3H7, n-C4H9; R1= CH3, C2H5; R

2 = CH3, C2H5

Shivaram Holla B et al., 1991 reported the synthesis of 5-mercapto-s-triazolo (3,

4,6) -as- triazino (5,6-b) indoles 25 and their mannich bases 26 by the reaction of as

triazino (5,6-b) indol-3-ylhydrazines with carbon disulfide in the presence of methanolic

potassium hydroxide, which gave the title compound through angular cyclization. On

subjecting the title compound to mannich reaction, the NH of the triazole ring underwent

dimethylation reaction.


42

N

R O

O K2CO3/H2O N N

NN

SH

N2H4.H2O

N N

NN

NHNH2

R1

CS2/KOH

N N

NN

R1 N

N

HS

N N

NN

R1 N

N

CH2S N

R2

R3

25

26

RI

NHR2

R3

HCHO

NH2NHCSNH2

MeOH

R1

R = H, Cl, Me, R1 = H, Et, Me, R

2,R

3 = morphine, piperedine.

Udupi RH et al., 2000 reported the synthesis of 3-pyridyl -4-[N-substituted

phenyl carboxamido] -5-mercapto-1,2,4-triazoles 27 by heating the potassium dithio

carbonate and acid hydrazides. Potassium dithiocarbazinate was prepared by condensing

the isonicotinic acid hydrazide with carbon disulphide in ethanolic potassium hydroxide.

The compounds were evaluated for antibacterial, antifungal and antitubercular activity.

Compounds with 4-chlorophenyl, 2-methylphenoxymethyl, 4-bromophenoxy methyl, 2-

chlorophenoxymethyl, 4-chlorophenoxymethyl substitution at Ar position were found to

have good antibacterial activity.


43

N CONH NH2

alcoholic KOHN CONH NH C S K

NN

NN

SH

HN C Ar

CS2

ArCONHNH2

O

27

O

Ar=Phenyl, 4-Chlorophenyl, Benzyl, 2-Methylphenoxyphenyl,4-Bromophenoxy methyl,

2-chlorophenoxymethyl, 4-chlorophenoxymethyl.

Oxadiazoles:

Omar FA et al., 1996 synthesized substituted 1,3,4-oxadiazole derivatives 28.

The target compounds were obtained by cyclodisulfurization of thiosemicarbazides, using

dicyclohexylcarbodiimide. Thiosemicarbazides are readily accessible through conversion

of the carboxylic acids to the reactive hydrazides followed by treatment with appropriate

isothiocyanate derivatives. These compounds were screened for anti-inflammatory

activity. All compounds were found to have good activity.

N

O

N

R NHR1

28

R =

N N

R1 = CH2CH3,


44

Sarvaman J et al., 1998 synthesized 2-substituted amino (2-methyl oxadiazol-5-

yl) -4,5,6,7-tetrahydro benzo (b) thiophenes 29. The target compounds were obtained by

displacement reactions with nucleophiles of 3-(2-methyl oxadiazolol-5-yl) -2-(w-chloro

acetamido)-4,5,6,7 tetrahydro benzo (b) thiophene, which was obtained by treatment of

2-amino-3-(2-methyl oxadiazol-5-yl) -4,5,6,7-tetrahydrobenzo (b) thiophene with chloro

acetyl chloride. These 4,5,6,7-tetrahydrobenzo (b) thiophene with chloroacetyl chlorides.

These compounds were screened for antimicrobial activity. Compound with chlorine

substitution at X position was found to have good antibacterial activity.

S NH

O

NN

CH3

C CH2

O

29

X

X= Cl, -OAc, Marphelinyl, NHNH2

Zarghi A et al., 2005 reported the synthesis of new 2-substituted-5-(2-

benzyloxyphenyl) -1,3,4 oxadiazoles 30. The designed compounds were synthesized in

the following way. The reaction of methylsalicylate with appropriate benzyl chloride in

alkaline hydromethanolic solution afforded corresponding 2-benzyloxy benzoic acid

methyl ester which on treatment with hydrazine hydrate in methanol gave 2-benzyloxy

benzoic acid hydrazides. The hydrazides were converted to 2-amino-5-(2-

benzyloxyphenyl)-1,3,4-oxadiazoles using cyanogen bromide in methanol. 5-(2-

benzyloxyphenyl) -2-mercapto-1,3,4-oxadiazole was prepared by reaction of hydrazides

with carbon disulphide under basic condition which on sonication in the presence of

suitable alkali halide in alkaline media afforded 2-alkylthio-5-(2-benzyloxyphenyl) 1,3,4-

oxadiazoles.


45

O

O

NN

R2

CH2

R1

30

R1 = H, F, Cl

R2 = NH2, SH, SCH3, SC2H5

Tan TMC et al., 2000 reported the synthesis of 2-benzenesulfonyl alkyl-5-

substituted-sulfonyl-(1,3,4)-oxadiazoles 31 and evaluated for antihepatitis-B virus

activity. All compounds were found to have good activity.

SO2

R1

O

NHNH2

SO2

R1

O

OR

SO2NaR1

O

OR

Br

SO2

R1 O

NHN

S

SO2

R1 O

NN

S R2

THF

KI, DMF

NH2NH2

CH3OH

R2X, K2CO3

rt, 24h

X = Br, I

rt, 24 h

31

R1 = CH2CH3, CH3, H; R

2 = (CH2)4CH3, CH2-CO-CH3,


46

Schiff Base:

Zhang L et al., 2007 reported the synthesis of novel 4-(arylmethylidene) amino-5-

(2-ethoxyphenyl) -3-mercapto-4H-1,2,4-triazoles 32 by means of the reaction of 3-(2-

ethoxyphenyl) -3-mercapto-4H-1,2,4-triazole with various aromatic aldehydes.

OC2H5

N

NHN

S

NH2

OC2H5

N

NHN

S

NCH

R

EtOH+ RCHO

Reflux

32

R = 2-HOC6H5, C6H5, 4-CH3C6H4, 4-ClC6H4

Kulig K et al., 2001 reported stereocontrolled synthesis of the enantiomers of 1-

[2-hydroxy-3-(4-phenyl-1-piperazinyl) -propyl] -pyrrolidin-2-one (37).

N

O

NHO N

37

Preliminary biological studies showed that compound 37 prevented or

ameliorated the adrenaline, barium chloride induced arrhythmia and statistically

diminished arrhythmias associated with coronary artery occlusion and reperfusion in the

isolated rat heart. Compound 37 demonstrates potent local anesthetic properties and

depressed the depolarization phase of the action potential of cardiac cells. According to

Williams classification compound 37 is in a class of antiarrhythmic drugs (Vaughan

Williams, 1981). Compound 37 also showed hypertensive effects and displayed α1 and α2

adrenergic blocking activities.


47

According to K. Kulig procedure, the required non-racemic epoxies were obtained

via the Shar- Pless AD and epoxidation. As the starting material for their synthesis, 1-

allylpyrrolidin-2-one was used. The compound was obtained by reaction between

tetrahydrofuran-2-one and allylamine. Oxidation of Compound by standard procedures

with commercially available admix α or β provided the dose (S) -(+) -33 or (R) -(-) -34 in

70-80% yield. AD-mix α or β is a mixture of potassium osmate, K3 [Fe (CN) 6], K2CO3

and (DHQ) 2-PHAL (AD-mix α) and (DHQD) 2-PHAL (AD-mix β), resp- ectively. The

diols (S) -(+) -33 and (R) -(-) -34 were easily converted to the epoxides (S) -(+) -35 and

(R) -(-) -36 using the process based on the acetoxonium ion-mediated formation of

acetate esters of halohydrins.

O

O

1-AllylamineN

O

N

O

OHOH

N

O

OHOH

N

O

N

O

O O

N

O

NHO N

(S)-(+)-37or (R)-(-)-37

(R)-(-)-33 (S)-(+)-34

t-BuOH/H2O, O oC

(S)-(+)-36(R)-(-)-35


48

Subsequently, base-mediated ester saponification and cyclization give the

enantiomeric epoxides (S) -(+) -35 and (R) -(-) -36. Finally the aminolysis of compounds

(S) -(+) and (R) -(-) with 1-phenylpiperizine gave the enantiomers of compound (S) -(+) -

37 and (R) -(-) -37.

Later Barbara Filipek et al., 1997 reported the synthesis of 1-[2-hydroxy-3-(4-

phenyl-1-piperazinyl) -propyl] -pyrrolidine (38) by the reduction of 1-[2-hydroxy-3-(4-

phenyl-1-piperazinyl) -propyl] -pyrrolidin-2-one (37) with lithium aluminum hydride

(LAH), which was isolated as free base and water-soluble dihydrochloride salt (39).

N

O

NHO N

37

N

NHO N

38

LAH

N

NHO N

39

HCl

.2HCl

Later Lingaiah Nagarapu et al., 2011 reported the synthesis of some 3-phenyl-N-

[3-(4-phenylpiperazine-1yl) propyl] -1H-pyrazole-5-carboxamide (42) derivatives by the

reaction of 3-aryl-1H-pyrazole-5- carboxylic acids (40) with 3-(4-phenylpiperzine-1-yl)

Propan-1-amine (41) in the presence of peptide coupling reagents EDC. HCl and HO Bt

to excellent yields.


49

NHNCOOH

+

H2N NN

EDC.HCl

HOBt, DIPEA

CH2Cl2,rt,12h

NHN

O

HN N

N

40 41

42

Derivatives of benzimidazole have been described for biological importance.

Compounds of oxadiazole have shown biological activity against the bacterium triazole

nucleus are having antibacterial and fungicidal properties

Mazzone G et al., 1992 reported the synthesis and biological evaluation of 5-

aryl-2-amino-oxadiazoles (43) and 2-(methylamino) -5-[3,4-methylene dioxy phenyl] -

1,3,4-oxadiazoles (44) and reported high degree of anti inflammatory activity.

N

O

N

R NHR1

43

N

O

N

NHMe

O

O 44

Rao AD et al., 1986 described the synthesis and biological activity of 3-[5-aryl-

1,3,4-oxadiazol-2-yl-methyl] -2-methyl-4-(3H) -aquinazolinones of general structure (45)

and some of the compounds exhibited good analgesic and anti-inflammatory in the rat

paw edema test.


50

Several 2, 5-disubstituted 1,3,4-oxadiazoles were tested for anti-convulsant

activity and maximum protection was observed with 2-[4-bromophenyl amino-5-(4-

tertiary butyl-2-bromophenoxy methyl)] -1,3,4-oxadiazole (46).

Bhat AR et al., 1984

reported 3-[1,3,4-oxadiazole-2-yl]-2-aryl-4-thiazo-

lidinones (47) useful as anti-convulsant and anti-inflammatory agents.

Shah MH et al., 1969 reported a series of 4H-1,2,4-triazoloderivatives were

synthesized and tested for uretic activity. Amongst the compound tested the following

two compounds (48a) and (48b) exhibited potent diuretic activity.

N

N N

C H 2 C H 2

S H

R

48a , R = H

H

48b , R = Cl

N N

O R N

S O

R 2

R 1

47

O

B r

H

N O

N N

B r (C H 3 ) 2 C

46

N N

O

C H 2

N

N

C H 3

O

R

R 2

R 1

R = R 1 = H, Br R 2 = ph, CH 2 Ph, Substituted Ph

45


51

Cazin JC et al., 1974 reported a series of 1-(2-dialkylaminoethyl) -1,2,4-

triazoles (49) were prepared and tested in vivo for their action on CNS and

cardiovascular system.

Wade PC et al., 1982 reported With a view to develop an effective non acidic

anti-inflammatory agent possessing an enhanced therapeutic ratio in comparison with

currently marketed acidic agents a series of 1-acyltriazoles were synthesized and

reaction as a test system. Compounds represented by general formula (50) were

evaluated in (MAA) reaction.

Cavalitto CJ et al., 1973 Triazolo [3,4-b] isoquinalines (51) have been claimed

by mallinkrodt chemicals works USA to posses anti-inflammatory action of various

forms of arthritis edema in man and mammals.

N

N N

R

51

R = H or CF 3

N

N

N C

R 1

R 2

50

R = H, CH 3 , Cl or CF 3 R = CH 3 , or C 2 H 5 R 2 = CH 3 , C 2 H 5 or C 6 H 5

N N

N

C H 2 C H 2 N R R 1

49

R = H, CH 3 , C 2 H 5 cyclic amine

R 1 = H, CH 3 or C 2 H 5


52

Srivastava SK et al., 1999 reported Synthesis of new carbazolyl- thiadiazol-2-

azetidines as antimicrobial, anticonvulsant and anti-inflammatory agents

Baruah J.N et al., 1984 reported Synthesis and antibacterial activity of 1-(2,4-

dichlorobenzoyl) -4-substituted thiosemicarbazides, 1,2,4-triazoles.

Mary Mader et al., 2008 reported the synthesis of benzimidazole derivatives

(52) which have exhibited anti inflammatory activity.

N

N

NH2NH

NR1

R2

R3 (52)

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Review of literature Chapter-II - Information and Library ...shodhganga.inflibnet.ac.in/bitstream/10603/21288/11/11...Chapter – II Review of Literature 35 O CH 3 O 1H, Benzimidzole