CHAPTER - 1

A GENERAL INTRODUCTION TO HETEROCYCLIC CHEMISTRY

1

1.1 Introduction

Literature survey revealed that the history of heterocyclic chemistry began in the

1800's, in step with the development of organic chemistry. Heterocyclic compounds offer

a high degree of structural diversity and have proven to be broadly and economically

useful as therapeutic agents. Heterocyclic compounds are cyclic compounds containing

at least one atom of carbon and at least one element other than carbon.1 A ring with only

heteroatom is called homocyclic compound and heterocycles are the counterparts of

monocyclic compounds. Thus incorporation of oxygen, nitrogen, sulphur or an atom of a

related element into an organic ring structure in place of a carbon atom gives rise to a

heterocyclic compounds.2

In the recent years, the incidence of fungal and bacterial infections has increased

dramatically. The widespread use of antifungal and antibacterial drugs in resistance to

drug therapy against fungal and antibacterial infections which led to serious health

hazards.3

It is well-known that heterocyclic compounds having azole nucleus are important

pharmacophore that appear extensively in various types of pharmaceutical agents, widely

implicated in biochemical processes and display diversity of pharmacological activities.

These heterocyclic compounds form a major part of organic chemistry; they are widely

distributed in nature and play a vital role in metabolism of living cells.4 Their practical

applications range from extensive clinical use to fields as diverse as medicine,

agriculture, photochemistry, biocidal formulation and polymer science. By virtue of their

therapeutic properties, they could be employed in the treatment of infectious diseases.

Many heterocyclic compounds synthesized in laboratories have been successfully used as

clinical agents. In the medicinal world, the chemistry of heterocycles has played a vital

role in combating many deadly diseases. A large number of heterocyclic compounds are

2

essential to our life and their functions are often of fundamental importance for living

systems.

A large number of heterocyclic compounds occur naturally. Many heterocyclic

compounds are found as key components in biological processes. Essential diet

ingredients such as Thiamin (Vitamin B1), Riboflavin (Vitamin B2), Nicotinamide

(Vitamin B3), Pyridoxal (Vitamin B6) and Ascorbic acid (Vitamin C) are heterocyclic

compounds. Two of the essential amino acids tryptofan and histidine are also

heterocycles. Nucleic acids, haemoglobin, chlorophyll and many enzymes are also

containing important heterocyclic nucleus.

Amongst the heterocyclic compounds Triazoles, thiadiazoles, pyrazoles,

oxadiazoles, attracted a tremendous attention, as they are full of many ramifications

especially in the biological and industrial applications. In this chapter we have given a

short introduction of these compounds. In view of the general observation that the

biological activities are invariably associated with a large variety of heterocyclic systems

such as 1,2,4-Traizoes, Pyrazoles, 1,3,4-Thaidaizole and 1,3,4-Oxadiazoles etc a large

number of their new derivatives have been synthesized and extensively studied for

various pharmacological properties.

1.2 Biological importance of heterocyclic compounds

1.2.1 Biological importance of 1,3,4-Oxadiazoles

Oxadiazole derivatives have been extensively studied in the past few decades. It is

five membered heterocyclic ring that exist in four isomeric forms. Out of its four isomers

1,3,4-Oxadiazole exhibited a wide range of biological activities. 1,3,4-Oxadiazoles are an

important type of oxygen and nitrogen containing aromatic heterocyclic compounds,

possess desirable electronic and charge-transport properties and the various functional

groups are easily introduced into the structurally rigid oxadiazole ring. These oxadiazole

3

are thermally stable and neutral Heteroaromatic molecules. These characteristics resulted

in the extensive potential applications of oxadiazole based derivatives in the field of

medicinal chemistry.

1,3,4-Oxadiazole moiety is of great importance to chemist as well as biologist

since it is one of the key building blocks for many of the naturally occurring compounds.

Among the numerous heterocyclic moieties of biological and pharmacological interest,

1,3,4-oxadiazoles ring is endowed with various activities, such as anti-inflammatory,

antimicrobial, antifungal, anticonvulsant etc. The fast growing literature on heterocycles

in recent years demonstrates their increasing significance in the pharmaceutical filed.

Keeping in view of the medical importance of different oxadiazole, a number of 1,3,4-

Oxadiazole derivatives containing biologically active functional groups at various

positions of it were synthesized and their in detail medicinal activities were explored.

The ability of 1,3,4-oxadiazole heterocyclic compounds to undergo various

chemical reactions have made them important for molecule planning because of their

privileged structure, which has enormous biological potential. Two examples of

compounds containing the 1,3,4-oxadiazole unit currently used in clinical medicine are:

Raltegravir (1)5, an antiretroviral drug and Zibotentan (2) an anticancer agent

6 (Fig. 1.1).

N

O

NHN

O

N

N

O

OH

NH

O

F

1

N

O

N

N

SNHO

O

N

N

O

2

Fig. 1.1: Structures of Raltegravir and Zibotentan, drugs that are in late stage clinical

development.

The 1,3,4,-oxadiazole have shown significant antimicrobial activity against a wide

variety of microorganisms like fungi, Gram +ve and Gram –ve bacteria. Keeping this in

4

mind the special emphasis is given on recently reported oxadiazoles possessing

antimicrobial activity. A detailed synthetic approach and literature survey on medicinal

properties of 1,3,4-oxadiazole has been dealt in Chapter-2. Based on these exploration

and literature survey, here we have presented some of the example containing 1,3,4-

oxadiazole derivatives in the field of medicinal chemistry.

It has been found that Song Cao et al, (2002)7 prepared and evaluated a series of

2-(5-trifluromethyl) pyridyloxy methyl-containing 1,3,4-oxadiazole derivatives (3) (Fig.

1.2). Among the group of compounds evaluated, especially those having fluorine on the

benzene ring exhibited a significant insecticidal activity on army worm, Leucania

separate Walker at 500 μg/mL.

NF3C

OO

NN

3

F

Fig. 1.2: 2-(5-Trifluoromethyl) pyridyloxy methyl-containing-1,3,4-oxadiazole

Almasirad and co-workers (2004)8 synthesized a series of 2-fluoro phenoxy

substituted 1,3,4-oxadiazoles (Scheme-1.1). The key intermediated (4) was converted in

to different cyclised 1,3,4-oxadiazole derivatives using different condition. All the

compounds (5-8) were screened for their anticonvulsant activity both in PTZ and MES

models. Some of the compound showed very good anticonvulsant activity against the

tested microorganism.

5

NHNH2

O

O

F

O

NNNH2

O

F

O

NHNS

O

F

O

NHN

O

O

F

O

NN

S

O

F4

56

78

CDI, THF

BrCN, NaHCO3CS2, KOH

I) CS2, KOH

2)MeI, NaOH

Scheme-1.1: Synthesis of 2-substituted-5- [2-(2-fluorophenoxy) phenyl]-1,3,4-

oxadiazoles

A series of pyrimidine substituted 1,3,4-oxadiazole derivatives (Fig. 1.3) (9) were

synthesized by Burbuliene et al, (2004).9 Most of the synthesized compounds showed

significant anti-inflammatory activities.

N

O

N

S

CN

SN

N

R

9

Fig. 1.3: 5-[(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-

oxadiazole-2-thiones

Synthesis of some 3-Acetyl-2-substituted phenyl -5-(3,4,5-trimethoxy phenyl) 1,

3,4-oxadiazoles (10) (Fig. 1.4) were synthesized by Jin et al, (2006),10

the synthesized

compounds were evaluated for their antiproliferative activities against some cancer cells

in vitro by MTT method. Some of selected compounds showed moderate activities

against Bcap37 and BGC823 cells.

NH N

HN

O

where R=

6

O

O

O

O

NNR

CH3

O

10

Where R=2-F, 3-F, 4-F, 2-CF3, 4-CF3, 3,4-2Cl, 2,5-2OMe2, 3,4,5-3OMe3, 4-Cl-3-NO2,

3,5-2Cl, 2,6-2Cl, 2,3-2OMe2

Fig. 1.4: 3-Acetyl-2-substituted phenyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1,3,4-

oxadiazole derivatives

Li et al, (2006)11

synthesized various 1,3,4-oxadiazoles containing different

aromatic substitution (Fig. 1.5) (11) and tested for their fungicidal activities activity

against R. solani.

NO

O

OMe

SO

NN

R

11

Fig. 1.5:(E)-α-(Methoxyimino)-benzene acetate derivatives containing 1,3,4-oxadiazole

Synthesis of some new 1,3,4-oxadiazole derivatives containing 3,4,5-trimethoxy

phenyl moiety (Fig. 1.6) was reported by Ch en and Song et al, (2007). 12

The compounds

have been shown to be fungicidally active. The compound (12) and (13) exhibit mycelia

growth by approximately 50% (EC50) AT 2.9-93.3 μg/mL in vitro against 10 different

kinds of fungi.

a: R = H,

b: R = 4-OMe,

c: R = 4-C6H5-CH2O,

d: R = 3-Cl,

e: R = 2,3-Cl2,

f: R = 2,4-Cl2,

g: R = 2,5-Cl2,

7

O

O

O

O

NN

SO

O

O

O

O

O

NN

S

O

O

C2H5

12 13

Fig. 1.6: 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives

It has been well established that fluorinated substituted heterocycles have got a

significant place in medicinal chemistry. Karthikeyan et al, (2008)13

synthesized a series

of 1,3,4-oxadiazole derivatives containing 2,4-dichloro-5-fluoro-phenyl moiety (Fig. 1.7)

(14). Some of the synthesized compounds were found to possess good bactericidal and

fungicidal activities.

N

O

NO

N

Cl

ClF

R

14Where: R=-2-Cl, 4-Cl, 2, 4-dichloro

Fig. 1.7: 2, 4-Dichloro-5-fluorophenyl containing oxadiazoles

Bhandari and co-workers, (2008)14

was developed new chemical entities as

potential anti-inflammatory agents with no GI toxicity (Fig. 1.8). Some of the compounds

(15) were found to have significant anti-inflammatory activity in the carrageenan induced

rat paw oedema model, with significant analgesic activity in the acetic acid induced

writhing model with no ulcerogenicity.

O

NN

SO

O

HNCl Cl

15

8

Fig. 1.8: S-Substituted phenacyl-1,3,4-oxadiazole derivative

Farshori et.al, (2010) 15

synthesised 5-alkenyl/hydroxyalkenyl-2-phenylamine-

1,3,4-oxadiazoles (Fig. 1.9), compound (16) shows very good in vitro antimicrobial

activities by disc diffusion method.

N

O

N

R NH 16

Fig. 1.9: 5-Alkenyl- 1,3,4-oxadiazole derivatives

Kumar et al, (2010)16

synthesised some novel 2-substituted-5-[isopropylthiazole]

clubbed 1,3,4-oxadiazoles (Fig. 1.10) and tested for antimicrobial activity by broth micro

dilution method. Among the various synthesised compounds (17) and (18) showed

improved antibacterial activity against tested Gram-positive bacteria.

N

O

N

N

SCl

17

N

O

N

RN

S

O

CH3

CH3

18

Fig. 1.10: 2-substituted-5-[isopropylthiazole] 1,3,4-oxadiazole

Recently Rashid et al, (2012)17

synthesized a series of benzimidazole bearing

oxadiazole nucleus (22) (Schme-1.2) by microwave irradiation. Initial screening of

compounds showed significant to good in vitro anticancer activity.

Where R= 4-ClC6H5,4-OCH3C6H5

Where R=

9

NH2

NH2

+ HO

O

O

O

OHN

N

O

O

OH

N

N

O

O

NN

R

R-CO2H, MW

(i)C2H5OH, H2SO4

(ii)N2H4

(iii)

22

1920

21

Where R= -CH2Cl

NH

NNH2

Cl

Scheme-1.2: 1-(1H-benzo[d]imidazol-2-yl)-3-(1,3,4-oxadiazol-5-substituted derivatives-

2-yl)propan-1-ones

Lai et al, (2013)18

synthesized a series of 1, 2-Benzisothiazol-3(2H)-ones and

1,3,4-oxadiazoles and screened against Dengue and West Nile virus proteases. Most of

the compounds showed greater than 50% inhibition against DENV2 and WNV proteases

([I] = 10 μM). The IC50 values of compound (23) (Fig. 1.11) against DENV2 and WNV

NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively.

S

N

O

NN

O

O23

Fig. 1.11: Novel 1, 2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives

Recently Debnath et al, (2013)19

synthesized a biologically important 5-aryl-3H-

[1,3,4] oxadiazol-2-ones (28) by heating the easily synthesized N-(chloro-aryl-

methylene)-tert-butylcarbazates (27) on basic alumina surface under solvent-free

condition (Scheme-1. 3).

10

Ar OH

O

+

Ar N

HN O

O

H

Ar N

Cl HN O

O

N

O

NH

OAr

Dry DMF, NCS, RT Basic alumina/ 85 0C

H2N

HN O

O24 2526

27 28

Scheme-1. 3: Synthesis of 5-aryl-3H-[1,3,4] oxadiazol-2-ones from N′-(chloro-aryl-

methylene)-tert-butylcarbazates using basic alumina

1.2.2 Biological importance of Pyrazoles

The pyrazole ring system consists of a doubly unsaturated five member ring

containing two adjacent nitrogen atoms. The procedures for its synthesis have been

extensively studied and such studies have been stimulated by various promising

applications, especially in the case of highly substituted pyrazole derivatives. In fact,

certain substituted pyrazoles are used as antimicrobial,20

anticancer,21

anti-

inflammatory,22

antidepressant,23

anticonvulsant,24

antihyperglycemic,25

antipyretic,26

antibacterial,27

antifungal activities,28

fungicidal,29

anti-arthritic 30

activities.

The knowledge of such applications has pointed out that trisubstituted pyrazole

are important target to be prepared to our interest on synthesis and molecular structure

determination of some types of pyrazole. A detailed synthetic approach and literature

survey on medicinal properties of pyrazole derivatives has been dealt in Chapter-3.

Some of the pyrazole derivatives that are having wide variety of activities are listed in the

below table.

11

Table-1.1: Pyrazole containing drugs.

Name of the Drug

IUPAC Name

Structure

Celecoxib

(Anti-inflammatory

drug)

4-[5-(4-Methylphenyl)-3-

(trifluoromethyl) pyrazol-1-

yl]benzenesulfonamide

NN

F

FF

SO ONH2 29

Lonazolac (Anti-inflammatory

drug)

[3-(4-chlorophenyl)-1-phenyl-

1H-pyrazol-4-yl]acetic acid

NN

OH

O

Cl

30

Crizotinib

(Non-small cell lung

carcinoma)

3-[(1R)-1-(2,6-Dichloro-3-

fluorophenyl) ethoxy]-5-(1-

piperidin-4-ylpyrazol-4-

yl)pyridin-2-amine

NN

NH

N

NH2

O

Cl

Cl

F

31

Tepoxalin

(Nonsteroidal anti-

inflammatory drug

approved for

veterinary use)

3-[5-(4-Chlorophenyl)-1-(4-

methoxy phenyl)pyrazol-3-

yl]-N-hydroxyl-N-

methylpropanamide

NN

O

O

N

HO

Cl

32

12

Deracoxib

(Anti-inflammatory

drug)

4-[3-(Difluoromethyl)-5-(3-

fluoro-4-methoxyphenyl)- 1H-

pyrazole-1-yl]

benzenesulfonamide

NN

S OO

NH2

F

O

F

F

33

Rimonabant

(Anti-obesity drug)

5-(4-Chlorophenyl)-1-(2,4-

dichloro-phenyl)-4-methyl- N-

(piperidin-1-yl)-1H-pyrazole-

3-carboxamide

NN

Cl

Cl

Cl

O

NH

N

34

Watson et al, (1994) 31

synthesized N- alkyl biaryl tetrazoles containing pyrazole

nucleus (Fig. 1.12), among the synthesized compound, (35) was found to be highly potent

antagonists of angiotensin II.

N NN

N

NN

Br

O

O

35

Fig. 1.12: C-linked pyrazole biaryl tetrazoles

1, 4-Diaryl pyrazole derivative (36) was synthesized by Kiyoshi et a l, (1997)32

this compound was tested for anti-inflammatory and analgesic activities to develop anti

inflammatory agents with fewer side effects than existing non-steroidal anti-inflammatory

drugs. The structure activity relationship was extensively studied (Fig. 1.13).

13

NN

C

F

SO

ON

36

Fig. 1.13: 1, 5-Diarylpyrazoles

Huang and co-workers (2000)33

synthesized 4-alkyl-1, 3, 5-triarylpyrazoles (Fig.

1.14 ) (37) which are useful as estrogen receptor.

R2

NN

Et

R1

37

R1=H, OH, OMe

R2=H, OH, OMe

Fig. 1.14: 1,3,5-Triaryl-4-alkylpyrazoles

The synthesis of novel series of structurally related 1H-pyrazolyl derivatives (38)

were described by the Bekhit and Abdel-Aziem (2004).34

All the newly synthesized

compounds were tested for their anti-inflammatory and antimicrobial activities. COX-1

and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were also

determined.

14

NN

N

N

H3C

S

Br

R

38

R=H, C6H5CO, C6H5NHCS, CH3CO

CHO, CH3SO2, 4-CH3C6H4SO2

Fig. 1.15: Thiophene containing diarylpyrazoles

Park et al, (2005)35

synthesized a series of Pyrazole oxime ether derivatives (43)

and examined its cytotoxicity activities. Among those, 5-phenoxypyrazole exhibited very

potent cytotoxicity comparable to Doxorubicin (Scheme-1.4).

Where R1= Me, Ph, 2-Py

R2= Me, Pri

R3= H, Cl,

R4=CH2Ph-3-OMe, CH2Ph-4-CF3

CH2Ph-4-NO2, CH2Ph-2-Me-3-Ph

CH2Ph-4-CO2Et

NN

R1

R2

ONN

Cl

R1

R2

O

H

NN O

R1

R2

O

H

R3

NN

O

R1

R2

N

H

R3

OH

NN

O

R1

R2

N

H

R3

O R4

POCl3/DMFHOPh-R3 NH2OH, NaOH, MeOH

R4-Cl or Br/KOH/DMSO

39 40 41 42

43

Scheme-1.4: pyrazole oxime ethers derivatives

A series of pyrazole derivatives (44) via 1,3-dipolar addition of sydnone and nitro

furan acetylenic ketones (Fig. 1.16) were reported by Rai et al, 36

(2006).

15

O

NN

R2

R1O

NO2

44

Fig. 1.16: 1-Aryl-3-(5-nitro-2-furyl)-4-aroylpyrazoles

Sanjay and his co-workers (2006)37

synthesized a series of 1,5-diaryl and 1,3-

diaryl substituted pyrazoles (Fig. 1.17) and evaluated for their ability to inhibit enoyl-

ACP reductase of Plasmodium falciparum. The inhibitory activity of these synthesized

compounds was evaluated in a continuous spectrophotometric assay. Of all the analyzed

compounds (45) and (46) inhibited the enzyme with IC50 values of 30μM and 50μM,

respectively.

NN

CHO

H3C

N N

F3C 45

NN

CF3

O2N

46

Fig. 1.17: 1, 5-diaryl and 1, 3-diaryl substituted pyrazoles

Jorand-Lebrun et al, (2007)38

synthesized pyrazoles (Fig. 1.18) (47) as low

molecular weight luteinizing hormone receptor agonists.

R1= H, Me, Cl;

R2= H, Me, OCH3

16

NN

NH

O

OH

ONH2

N

47

Fig. 1.18: Pyridine substituted pyrazoles

Farag et al, (2008)39

reported N-pyrazole derivatives (Fig. 1.19) used as

antimicrobial. Among the compounds tested for antimicrobial, compound (48) shown

very good activity against pathogenic mould (Aspergillus).

NN

HN

O Br

48

Fig. 1.19: Novel N-phenyl pyrazole derivatives

Zhao et al, (2008)40

Synthesized and discovered a novel pyrazole derivative (49)

as an inhibitor of apoptosis through modulating integrin β4, ROS, and p53 levels in

vascular endothelial cells (Fig. 1.20).

NN

O

O

Cl

49

Fig. 1.20: N-phenyl -3-2-chlorophenyl substitituted pyrazole derivatives

17

Menozzi et al, (2008)41

synthesized a set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles

and evaluated in vitro for their affinity on human CB1 and CB2 receptors (Fig. 1.21).

Among the synthesized compounds (50) was the closest rimonabant analogue and showed

competitive binding of 79% and 37% against CB1 and CB2 receptor respectively.

NN

ONH

Cl

Cl

Cl

N

50

Fig. 1.21: N-dichloro phenyl-pyrazole derivatives

Isloor and co-workers (2009)42

reported the synthesis and anticancer activity of

new 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (Fig. 1.22) containing

pyrazole moiety (51).

N

N

N

N

S

NH

N

R2

R1

51

Fig. 1.22: 1,2,4-Triazolo [3, 4-b]-1,3,4-thiadiazoles containing Pyrazole derivatives

Rai et al, (2009)43

synthesized a series of 1,3,4-oxadiazole containing pyrazole

derivatives and studied its antibacterial activities. Among the synthesized compounds, 2-

[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-

oxadiazole (Fig. 1.23) (52) was found to exhibit significant antibacterial activity.

18

NN

OH3C

Cl

O

NN

F

52

Fig. 1.23: 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-

phenyl)-[1,3,4] oxadiazoles

Ragavan et al, (2010)44

synthesized a series of 1,5-diary pyrazole derivatives

(Scheme-1.5) (56) and screened for their antibacterial activity against Escherichia coli,

Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumonia. Similarly

all these compounds were screened for their antifungal activity against Aspergillus flavus,

Aspergillus fumigates, Penicillium marneffei and Trichophyton mentagrophytes. Some of

the synthesized compounds exhibited good antibacterial and antifungal activity.

NN

Cl

F

R

O

O

Cl

O

Cl

LiHMDS

Diethyl oxalate

O

OEt

ON N

Cl

F

EtO

O

NHNH2

F

EtOH

i) LiOH/THF/water

iii) R-NH2/TEA

ii) (COCl2)/DCM

Where R=N Cl

N

O

56

53 54

55

Scheme-1.5: Synthesis of novel 1, 5-diaryl pyrazoles

Thumar et al, (2011)45

synthesized a series of 4-pyrazolyl-N-arylquinoline-2,5-

dione derivatives (57) (Fig. 1.24) and are screened, against some of the bacterial

19

pathogens using broth micro dilution MIC (minimum inhibitory concentration) method.

Some of the compounds were found to be equipotent or more potent than commercial

drugs.

N N

CH3

N

OCl

R2

R1

O

R2

R

57

Where R=3-Cl, 4-Me

R1=H, Me

R2=F, OMe,

Fig. 1.24: Carbostyril derivatives of 1H-pyrazole

Faidallah et al, (2011)46

synthesized fluorinated pyrazoles (60) (Scheme-1.6); it

has been observed that Preliminary biological screening of the prepared compounds

revealed significant antidiabetic and antibacterial activities.

NHNH2HCl

SO2NH2

R CF3

OO

NN

SO2NH2

CF3

R Br/CCl4NN

R

CF3Br

SO2NH2

6058

59

Scheme-1.6: 3-Trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives

Recently Isloor et al, (2011)47

synthesized a series of novel imidazole derivatives

containing substituted pyrazole moiety (Fig. 1.25). Among the synthesized compounds,

compound (61) was found to be potent antimicrobial agent. The acute oral toxicity study

Where R=CH3, Furyl

20

for the compound (61) was carried out and the experimental studies revealed that

compound is safe up to 3000 mg/kg and no death of animals were recorded.

NNH

S

N

N

N

S

O

61

Fig. 1.25: New pyrazole incorporated imidazole derivatives

A series of pyrazole-sulfonamide derivatives (62) and (63) were synthesized (Fig.

1.26), characterized, and the inhibition effects of the derivatives on human carbonic

anhydrases (hCA I and hCA II) were investigated as in vitro by Balseven et al, (2013)48

.

Almost all of the compounds have good inhibition effects on the CA I and CA II

isoenzymes.

NN

CN

NH

O

SO2NH2

O

HO

NN

N

NH

O

SO2NH2

O

HO

N

OH62 63

Fig. 1.26: Synthesis of novel pyrazole-sulfonamides

A concise ‘one-pot’ synthesis of a variety of 4-substituted 1,5-diaryl-1H-pyrazole-

3-carboxylates has been developed in moderate to good yields (Scheme-1.7) with

excellent regioselectivity by Jian et al, (2013).49

21

O

R1

R2

Diethyl oxalate

t-BuOLi, THF

OLi

R1

O

O

OEt

R2

O O

R1

OEt

OR2

R3

NHNH2

NN

CO2EtR1

R2

R3

AcOH, reflux

6667

6465

Scheme-1.7: Synthesis of 4-substituted 1, 5-diaryl-1H-pyrazole-3-carboxylates via

lithium tert-butoxide medium

1.2.3 Biological importance of 1,2,4-Triazole

The search for new drug molecule is one of the most challenging tasks to the

medicinal chemist. The synthesis of high nitrogen containing heterocyclic systems has

been attracting increasing interest over the past decade because of their utility in various

applications, such as propellants, explosives, pyrotechnics and especially chemotherapy.

In recent years, the chemistry of Triazoles and their fused heterocyclic derivatives has

received considerable attention owing to their synthetic and effective biological

importance. The derivatization of Triazole is considered to be based on the phenomenon

of bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen

atom yields triazole analogue.

1,2,4-Traizole moiety is of great importance to chemists as well as biologist as it

is chemically useful molecules having diverse biological activities. Triazole, a

heterocyclic nucleus has attracted a wide attention of the medicinal chemist in search for

the new therapeutic molecules. Out of its two possible isomers, 1,2,4- triazole is which

posses almost all types of biological activities. Some of the drugs which are having

22

Triazole as core molecule are given below (Fig. 1.27), several 1,2,4-Traizole containing

compounds are used as drugs for instance Fluconazole (72) is used as an antimicrobial

drug, while Vorozole (68), Letrozole and Anastrozole (70) are used as non steroidal

drugs used for the treatment of cancer. Loreclezole (69) is used as an antifungal agent.

Cl Cl

O

O

N

NN

O

NN

N NN

O

Itraconazole

F

F

NN

N

OH

N

N

N

Fluconazole

Cl

N

NN

N

N

N

Vorazole

Cl

Cl

Cl

NN

N

Loreclezole

NN

N

NC

CN

Anastrozole

6968 70

71

72

Fig. 1.27: 1,2,4-traizole containing drugs

Zamani and his co-workers (2003)50

synthesized a series of l, 5-(isomeric

pyridyl)-4-aryl-1,2,4-triazole-3-thiol, -thioethyl, thiomethyl, thiobenzyl derivatives from

pyridine carboxylic acid hydrazide (73) (Fig. 1.28).

N

N

NN

SR

73 Where R= CH3, C2H5, CH2Ph,

CH2COOH

Fig. 1.28: New Pyridine substituted 1,2,4-triazole

23

Series of 3-benzylsulfanyl derivatives of 1,2,4-triazole were synthesized by

alkylation of starting triazole-3-thiol with appropriately substituted benzyl halide (Fig.

1.29) (74) by Klimesova et al, (2006).51

All members of the set were evaluated for in

vitro antimycobacterial activity. The compounds exhibited only a moderate or slight

antimycobacterial activity. Minimum inhibitory concentrations fall into a range of 32-

>1000 μmol/l. The most active substances bear two nitro groups or a thioamide group on

the benzyl moiety.

N

NH

N

S

N

NN

HN

74

Fig. 1.29: 3-Benzylsulfanyl derivatives of 1,2,4-triazole

Karthikeyan et al, (2006)52

reported the synthesis of some new Schiff bases

bearing 2,4-dichloro-5-fluorophenyl moiety (Fig. 1.30) (75) by condensing triazole with

aromatic aldehydes. Newly synthesized compounds were tested for their antimicrobial

activity.

N

N

N

S

N OCl

Cl

F

N

R

75

Fig. 1.30: Schiff and Mannich bases bearing 2, 4-dichloro-5-fluorophenyl moiety

24

Shridhar et al, (2007)53

studied anticonvulsant activity Thiazolidinone-triazole

derivatives (76). By the treatment of (2-chloroacetyl)-2-arylimino-5-[(Z)-

arylmethylidene]-1,3-thiazolan-4-ones with 5-(1-phenoxyethyl)-4H-1,2,4-triazole-3-thiol

in identical conditions provided a set of bulkier derivatives which have also shown the

anticonvulsant potential (Fig. 1.31).

CH3

N

NNS

N

O

SN

Ar

Ar'

O

76

Fig. 1.31: Thiazolidinone substituted triazole derivatives

Havaldar et al, 54

synthesized 3-[4-(4-substituted phenyl-5-thioxo-4, 5-dihydro-

1H-1,2,4 triazol-3-ylmethoxy)-phenyl]-2-phenyl-3H-quinazolin-4-one (Fig. 1.32) (77).

The synthesized compounds were evaluated in vitro for their antibacterial activity against

Staphylococcus aureus, Escherichia coli and Bacillus subtilis by the ditch-plate technique

using concentrations of 50 μg/mL. The compounds synthesized were screened for their

antifungal activity against. Aspergillus niger, Candida albicans and Cryptococcus

neoformans by paper-disc diffusion method at concentrations of 50 μg/mL.

N

N

O ON

NHN

R1

R2

S

77

Fig. 1.32: 3-[4-(4-substituted phenyl-5-thioxo-4, 5-dihydro-1H-1,2,4 triazol-3-

ylmethoxy)-phenyl]-2-phenyl-3H-quinazolin-4-one

25

Shalini et al, (2009)55

synthesized some substituted diphenyl-1,2,4-triazole-3-ones

by the condensation of substituted benzoyl chlorides and substituted phenyl

semicarbazides. The anticonvulsant activities of these compounds were screened by using

different animal models. Results show that compound (Fig. 1.33) (78) exhibited

anticonvulsant activity in all the four animal models of seizure.

HN

N

N

O

CH3

H3C 78

Fig. 1.33: Diphenyl-1,2,4-triazole-3-ones

Xue Qin et al, (2009) 56

presented a series of N-(5-((1H-1,2,4-triazol-1-yl)

methyl)-4-tertbutylthiazol-2-yl)-4-carboxamide derivatives from 3, 3-dimethyl butan-2-

one. The studies suggested that the presence of fluorine atom at position 2, 3, 4 of phenyl

ring are crucial for exhibited plant-growth regulatory activities and the substitution with

chlorine atom at both 2nd

position and 4th

position of benzene ring caused a decrease of

the activity while the presence of a strong electron-withdrawing group such as nitro-

group led to decrease in activity. Compound (79) having fluorine atom at 4th

position

connected to the phenyl ring produced excellent plant-growth regulatory activity.

(Fig1.34)

N

N

NS

N

NH

O

F

79

Fig. 1.34: N-(5-((1H-1,2,4-triazol-1-yl) methyl)-4-tertbutylthiazol-2-yl)-4-carboxamide

derivatives

26

1,2,4-triazoles incorporated diphenyl sulfone was synthesized by Barbuceanu et

al, (2009).57

The synthesized compounds were tested for its antibacterial activity (Fig.

1.35). The compounds were tested for their in vitro growth inhibitory activity against the

following Gram-negative bacteria and Gram-positive bacteria using the paper disk

diffusion method. Among these compound (80) showed more active against the tested

strains.

SN

NN

O

O

Br

SO

80

Fig. 1.35: S-alkylated 1,2,4-triazoles incorporating biphenyl sulfone moiety

Bayrak et al, (2009)58

synthesized some new 1,2,4-triazoles and their Schiff and

Mannich bases (Scheme-1.8) (83-85) and screened for their antimicrobial activities.

Some of the screened compounds showed good activity.

N

N

N

S

N

NHNH2

O

N

N

N

SN

OEt

O

N

N

NS

N

HN

O

N R

N

N

NS

N

O

NN

SH

N

N

N

SN O

NN

S

NH NO

CS2, KOH

R-NH2, HCHO

RCHO

82

83

84

85

81

Scheme-1.8: 1,2,4-Triazoles, their Schiff and Mannich bases

27

Eswaran et al, (2009)59

synthesized a new class of quinoline derivatives

containing 1,2,4-triazole moiety (Fig. 1.36) (86). The compounds were evaluated for their

in vitro antibacterial and antifungal activities against four strains each. Preliminary results

indicated that most of the compounds demonstrated very good antimicrobial activity,

comparable to the first line standard drugs. The most effective compounds have exhibited

activity at MIC of 6.25 μg/mL.

N

FF

F

R2NN

NHS

R1

86

H2NH2N H2N O

NH

Ph,-CH2PH, -CH2-CH2OMeWhere R1=

R2=

Fig. 1.36: Quinoline derivatives carrying 1,2,4-triazole moiety

Ilango et al, (2010),60

synthesized a new series of 3, 6-disubstituted-1,2,4-triazolo-

[3,4-b]-1,3,4- thiadiazoles. The compounds (Fig. 1.37) (87) were screened for antifungal

activity against Candida albicans and Aspergillus Niger using Ketoconazole as standard

and antioxidant activity by DPPH and Nitric oxide methods using Ascorbic acid standard.

HN

N

NN

N

S

Ar

Cl

Cl 87

Fig. 1.37: 3, 6-disubstituted-1,2,4-triazolo-[3, 4-b]-1,3,4- thiadiazoles

Jubie et al, (2010)61

have synthesized some novel Ciprofloxacin analogues (88) as

antimicrobial agents. Ciprofloxacin have been incorporated to the new series of Schiff

28

and Mannich reaction (Fig. 1.38). The new compounds have been evaluated in vitro for

their antimicrobial activity against B. subtilis, K. pneumoniae, and P. aeruginosa at

10μg/mL concentration. All the compounds showed in vitro gram positive and gram

negative activity generally comparable or superior to that of reference ciprofloxacin.

N

N

NS

NN

N

O

OH

OF

CHR

88

Where R=

Cl Cl OH

OOH

N O

Fig. 1.38: Some novel ciprofloxacin containing 1,2,4-traizole analogues

Patil et al, (2010)62

synthesized a series of sulfone containing 1,2,4- triazole

derivatives (Fig. 1.39). The newly synthesized compounds were screened for their

antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Staphylococcus

epidermidis, Escherichia coli and Pseudomonas aeruginosa. The antifungal activity was

tested against Rhizopus oryzae, Aspergillus Niger, Aspergillus flavus, Candida

albicans and Saccharomyces cerevisiae. Among all the compounds synthesized,

compound (89) exhibited significant antibacterial activity.

N

NN

O

S

O

O

O

R

89

Where R=2-F, 3-F, 4-F, 4-Br, 3-CF3, H

Fig. 1.39: 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2, 4-dihydro-[1,2,4]

triazolo-3-ones

29

Recently Sugane et al, (2011)63

synthesised and evaluated a new series of glycine

transporter 1 inhibitors derived from a high-throughput screening hit (Fig. 1.40). A

pharmacokinetic study was showed that compound (90) showed very good oral

bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.

N

N

N

F

90

Fig. 1.40: 3-Biphenyl-4-yl-4-phenyl-4H-1,2,4-triazoles

Recently a series of novel isoindoline-1,3-diones containing 1,2,4-triazole moiety

were synthesized via a one-pot reaction by Zhao et al. (2012) 64

(Scheme-1.9). Antifungal

and cytotoxic activities of these compounds were evaluated. Antifungal studies of the

novel compounds showed promising activity (94). Some compounds displayed much

stronger antitumor activity than Fluorouracil.

NN

N

NH2

SHR1 + O

O

O

O

O

O

NN

N

R1

HS

O

O

O

NN

N

R1

S

R2

TEA, ZnBr2, Toulene

RT

R2-Br

93

94

91 92

Scheme-1.9: Novel isoindoline-1,3-dione derivatives bearing 1,2,4-triazole derivatives

Recently Sarnpitak et al. (2013)65

developed a new two-step synthesis of medicinally

important 1,2,4-triazoles from isocyanides and thiosemicarbazones (Scheme-1.10). The

30

method is based on the recently discovered TMSCl-promoted reaction of isocyanides that

yields rare N1, N

3-disubstututed formamidrazones (98).

H2NNH

NH2

S

R1 N

HN NH2

SR1 N

N N

H

R2

N

N

N

R2

R1

R1-CHO R2NC

Pd/C

95 96 97

98

Scheme-1.10: Syntheisis of novel 1,2,4-triazoles from isocyanides and

thiosemicarbazones Isloor et al, (2013)

66 synthesized series of new 1,2,4-triazole derivatives. All the

synthesized compounds were screened for their analgesic activity by the tail flick method

(Fig. 1.41). The antimicrobial activity of the new derivatives was also performed by MIC

by the serial dilution method. The results revealed that the compound having 2,5-

dichlorothiophene substituent on pyrazole moiety and a triazole ring (99) showed

significant analgesic and antimicrobial activity.

NNH

Ar1

N

NN

SH

Ar

99

Fig. 1.41: pyrazole containing 1,2,4-triazoles

31

1.2.4 Biological importance 1,3,4-Thaidiazoles

Heterocyclic compounds occupy a central position among those molecules that

makes life possible. The chemistry of heterocyclic compounds has been an interesting

field of study for a long time. Heterocyclic nucleus 1,3,4-thiadiazole constitutes an

important class of compounds for new drug development. The synthesis of novel

Thiadiazole derivatives and investigation of their chemical and biological behaviour have

gained more importance in recent decades. During the recent years there has been intense

investigation of different classes of thiadiazole compounds, many of which possess

extensive pharmacological activities.

Thiadiazole is a heterocyclic compound featuring both two nitrogen atom and one

sulphur atom as part of the aromatic five-membered ring. Thiadiazole and related

compounds are called 1,3,4-thiadiazole (two nitrogen and one other heteroatom in a five-

membered ring). They occur in nature in four isomeric forms as. 1,2,3-thiadiazole; 1,2,5-

thiadiazole; 1,2,4-thiadiazole and 1,3,4-thiadiazole. 1,3,4-thiadiazole are important

because of their versatile biological actions. In particular, compounds bearing the 1,3,4-

thiadiazole nucleus is known to have unique antibacterial and anti-inflammatory

activities. Differently substituted thiadiazole moieties have also been found to have other

interesting activities such as analgesic, antimicrobial, antitubercular, anticonvulsant and

anti-hepatitis B viral activities. In this review article different compounds having

heterocyclic nucleus have been shown to possess different activity. It was found that

among the important pharmacophore responsible for various activities.

Han Song Chen and associates (1999)67

concentrated on the synthesis of new

fungicidally active Pyrazolyl-Substituted 1,3,4-thiadiazole compounds (Fig. 1.42), The

preliminary bioassay tests indicated that compounds (100) and (101) have fungicidal

activity.

32

NN

S

NHN

S

H3C

CH3

Cl

NN

S

NN

S

H3C

CH3

Cl

R

100 101

Where R=Methyl, propyl, Allyl, Amyl

Fig. 1.42: New fungicidally active pyrazolyl-substituted 1,3,4-thiadiazoles

Gadad et al, (2004)68

synthesised a series of 2-sulfonamido/trifluoromethyl-6-

substituted imidazo [2,1-b]-1,3,4-thiadiazole derivatives (102) (Fig. 1.43). The selected

compounds were evaluated for their preliminary in vitro anti-tuberculosis activity

against Mycobacterium tuberculosis. Some of the compounds exhibited moderate to good

anti-tubercular activity.

N

S

N

R1

N

R3R2

102

R1= -SO2NH2, -(CH3)2N-C=N-SO2-CH3, CF3

R2= CH3, Cl, OMe, Trimethoxy, NO2

R3= H, -SCN, -C=N-NH-C=NH-NH2

Fig. 1.43: 2-sulfonamido/trifluoromethyl-6-substituted imidazo [2, 1-b] [1,3,4]

thiadiazole derivatives

Foroumadi et al. (2005)69

synthesized and studied their antibacterial activity of N-

(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl)

piperazinyl quinolone derivatives (103) against Gram-positive and Gram-negative

microorganisms (Fig. 1.44). Some of these derivatives exhibit high activity against Gram

positive bacteria Staphylococcus aureus and Staphylococcus epidermidis, comparable or

more potent than their parent N-piperazinyl quinolones norfloxacin and Ciprofloxacin as

reference drugs.

33

N

S

NN

S

N

N

O

CO2H

R

F

R1

(O)n

Where R= ethyl, cyclopropyl

R1= H, NO2

n=0,2

103

Fig. 1.44: N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-

thiadiazol-2-yl) piperazinyl quinolone derivatives

Rzeski et al, (2007)70

synthesized a set of N-substituted 2-amino5-(2,4-

dihydroxyphenyl)-1,3,4-thaidaizole derivatives (Fig. 1.45). Among these compound

(104) showed a very good anticancer and neuroprotective activity.

N

S

N

NH

F

OHHO

104

Fig. 1.45: 2-Amino-substituted-1,3,4-thiadiazole

A new series of selective cox-2 inhibitors with 2-amino-5-sulfanyl-1,3,4-

thiadiazole derivatives (105) (Fig. 1.46) were synthesized by Sharma et al, (2008)71

these

compounds were selective inhibitiors of COX-2 and potentiated the activity of COX-1

enzyme. The presence of sulphonamide group is a required pharmacophore for selective

inhibition of COX-2 enzyme.

34

NH S

NN

S

R1

R2105

R1= F, CH3, CF3, SO2NH2

R2= SO2NH2,

Fig. 1.46: 2-Amino-5-sulfanyl-1,3,4-thiadiazoles

Pattan et al, (2009)72

have been introduced the synthesis of various compounds

and evaluated for antidiabetic activity (Fig. 1.47). Among of these compounds (106) have

shown significant antidiabetic activity.

S

NN

NH N

O

O2N106

Fig. 1.47:1,3,4-Thaidiazole-piperidine carboxamide derivatives

Moise et al, (2009)73

were showed the 1,3,4-thiadiazole, that containing a

phenylalanine moiety were synthesized by intramolecular cyclization of 1,4-

thiosmicrbazides (107) (Fig. 1.48), in acid and alkaline media and the synthesized

compounds was evaluated by anti-inflammatory activity.

NH

S

NNNH

R

O

O2N107

Fig. 1.48: 1,3,4-Thiadiazole containing a Phenylalanine Moiety

35

Padmavathi et al, (2009)74

have found that 2-(arylmethanesulfonylmethyl)-5-aryl-

1,3,4-thiadiazoles (108) (Fig. 1.49) exhibited high activity on both Gram (+ve) and Gram

(-ve) bacteria.

SS

NN

R2

R1

O O

( )n

108

Fig. 1.49: 2-Phenyl-5-phenylmethanesulfonylmethy-substituted-[1,3,4] thiadiazole

Hilfiker et al, (2009)75

have carried out the investigation to identify new selective

antagonists, and they found that aminothiadiazole (Fig. 1.50) that is compound (109) was

identified from a high throughput screen as having good antagonist activity for human

EP3.

N

S

NNH

O

O

O

109

Fig. 1.50: 2, 3-Dihydro-benzo [1, 4] dioxine-6-carboxylic acid [5-(1-ethyl-propyl)-[1,3,4]

thiadiazol-2-yl]-amide

Mohammad Asif1 and Chhavi Asthana have (2010)76

prepared derivatives of 2,4-

Substituted diphenyl-5-imino-Δ-2-1,3,4-thiadiazole (110) and evaluated their

antimicrobial properties (Fig. 1.51). The newly synthesized compounds exhibited

promising antimicrobial activity.

36

NN

SHN

R3

R4

R2

R1

110

Fig. 1.51: 3, 5-Diphenyl-substituted-3H-[1,3,4] thiadiazol-2-ylideneamine

Salimon et al, (2010)77

synthesized a series of 1,3,4-thaidaizoles, the newly

synthesized compounds were screened for their in vitro antibacterial activity (Fig. 1.52).

All the newly synthesized compounds (111) were initially screened for their in vitro

antibacterial activities against the Gram-positive (S. aureus, S. cerevisiae and C.

diphtheriae) and the Gram negative (E.coli and P. aeruginosa) bacteria by agar cup-plate

method not disc diffusion method.

NS

N

S S

NN

S S

NN

NH2

111

Fig. 1.52: 5-[5-(5-Methyl-[1,3,4] thiadiazol-2-ylmethylsulfanyl)-[1,3,4] thiadiazol-2-

ylsulfanylmethyl]-[1,3,4] thiadiazol-2-ylamine

A series of 2-amino-5-aryl-thiazolo [1,3,4]-Thiadiazole derivatives were prepared

by Asif et al, (2011)78

. Some of the synthesized compounds showed very good anti-

tubercular activity (Scheme-1.11).

R1 R2 R3 R4

H H H H

H H NO2 NO2

Cl H H H

Cl H NO2 NO2

H Cl H H

H Cl NO2 NO2

H NH2 H H

H NH2 NO2 NO2

37

R H

OSH

OH

O

S

R OH

O

OHNH2

HN NH2

S

S

O

OH

RNH

NH

NH2

S

S

NH

O

NHR

NH2

S

S

N

NR

NH2

SH

S

N

S

NRNH2

-H2O

-H2OH2SO4

-H2O

117

113 114

115 116

112

Where R= Ph, 4-MeC6H4,4-OHC6H4, -NO2C6H4, 4Me2NC6H4, 2ClC6H4,

4-ClC6H4, 2,4-Cl2C6H3, 2OMeC6H4, 3-OMeC6H4

Scheme-1.11: One pot synthesis of 2-Amino-5-aryl-5H-Thiazaolo-[4,3-b]-1,3,4-

thiadiazoles

Alagawadi et al, (2011)79

together proved that new 2,4-Thiazolidinediones

bearing Imidazo[2,1-b][1,3,4]Thiadiazole derivatives (121) (Scheme-1.12) show very

good antimicrobial activity.

N

S

N

S

H2N

O

O

NH2

BrO

N

S

NN

SH2N O

O

R

N

S

NN

S

O

ONN

N

S

NN

S

O

ONN

HN

SO

O

HO

EtOH

POCl3/DMF S

HN

O

O

Piperidine/AcOH,

Toulene

R R

R

118119

120 121

Scheme-1.12: 2, 4-Thiazolidinediones bearing imidazo [2,1-b][1,3,4] thiadiazole

derivatives

R= H, 4-Br, 4-Cl, 2, 5-(OMe) 2, 4-

CH3, 4-OMe, 4-NO2

38

Bhat et al, (2011)80

synthesized series of 3-(1,3,4-Thiadiazole-2-yl) quinoline

derivatives (122) (Fig. 1.53) from chloroquinone with an aim to explore their effect on in

vitro growth of microorganisms causing microbial infection.

N Cl

X

S

NN

N

O

O

R

122

X= H, Cl, CH3

R=H, Cyclohexyl, O-tolyl,

4-nitrophenyl, cyclopentyl,

2,5-difluoro phenyl,

Fig. 1.53: 3-(1,3,4-Thiadiazole-2-yl) quinoline derivatives

Kamal et al, (2011)81

synthesized 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl) imidazo

[2,1-b]-1,3,4- thiadiazoles (123) (Fig. 1.54). Some of these compounds were found to

possess slight to moderate activity against the microorganisms Staphylococcus aureus,

Candida albicans, Pseudomonas aeruginosa, and Escherichia coli.

N

N N S

NN

N

I

R2

R1

123

Fig. 1.54: Imidazo [2,1-b]-1,3,4-thiadiazoles

Cancer is a class of disease in which cell, or a group of cells display uncontrolled

growth, invasion, and sometimes metastasis. It affects people at all ages with the risk of

most types increasing with age. It caused about 13% of all human death in 2007.

Recently M. N. Noolvi et al, (2012)82

synthesized a series of 2-cyclopropyl Imidazo [2,1-

b] [1,3,4]-Thiadiazole derivatives (Scheme-1.13). Among the compounds tested,

compound (128) found to be the most active candidate of the series at five dose level

screening with degree of selectivity towards Leukemic cancer cell line.

39

O

Cl

+ H2N

HN NH2

SN

S

NN

RBrN

S

N

NH2

N

S

N

N

ClBr

Where R=H, 4-Cl, 4-Br, 4-F, 2,4-Di-Cl, 2,4-di-OH, 3-NH2, 4-NH2, 3-NO2, 4-NO2,

126 127

128

124 125

Scheme-1.13:2, 6-Disubstituted imidazo [2, 1-b] [1,3,4] thiadiazoles

Recently Alegaon et al, (2012)83

synthesized a series of novel Imidazo [2, 1-b]

[1,3,4]-thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents

(129) (Fig. 1.55). Among synthesized compounds, some of the compounds showed very

good vitro antitubercular activity against M. tuberculosis.

N

S

N

N

F

F

F

N

S

S

O

O

R

129 Where R = H, Cl, Br, F, CH3, OCH3, NO2

Fig. 1.55: Novel imidazo [2,1-b] [1,3,4] thiadiazole carrying rhodanine-3-acetic acid

A regioselective, reagent-based method for the cyclization reaction of 2-Amino-

1,3,4-thiadiazole core skeletons (133) is described by Yang et al, (2013).84

The

thiosemicarbazide intermediate was reacted with EDC·HCl in DMSO or p-TsCl,

triethylamine in N-methyl-2-pyrrolidone to give the corresponding 2-amino-1,3,4-

40

oxadiazoles 4 and 2-amino-1,3,4-thiadiazoles through regioselective cyclization processes

(Scheme- 1.14).

R1 N C S R1NH

NH

SHN R2

O

N

S

N

R2NH

R1

N

S

N

R2N

R1

R3

131 132

133

130

Where R1=Bn, 4-MeO-Bn, 4-CF3-Bn, Ethyl, Ph, 4-F-Ph, 4-NO2-Ph

R2= Ph, 4-MeO-Ph, 4-F-Ph, 4-NO2-Ph, Ph.

Reaction condn: (i)Treithyl amine, THF, RT, (ii) EDC.HCl, DMSO, 60 oC,

(iii) p-TsCl, TEA, NMP, RT (iv) Electrophiles, NaH, NMP, RT

Scheme-1.14: 2-Amino-Substituted 1,3,4-Thiadiazole derivatives

Recently Botros et al, (2013)85

synthesized phenytoin derivatives and studied its

anticonvulsant activity (Scheme-1.15). Among the synthesized compounds, only phenyl

substituted (136) showed promising anticonvulsant activity.

HN

N

O

O

NHO

NH2

HN

N

O

O

NHOHN

HN

S

R

HNN

O

OS

NN

NH

R

(i)(ii)

(i) RNCS, abs EtOH (ii) Conc. H2SO4

134135 136

Where R= C2H5, C6H5, 4-CH3C6H4, 4-OMe-C6H4, 4-Cl-C6H4

Scheme-1.15: Phenytoin derivatives

41

Scope and Objectives of the present work

At present, only a limited number of antimicrobials are available to treat

multidrug resistant strains of infectious bacteria and resistance to even the latest antibiotic

are appearing. Increasing antibiotic resistance in microbial populations has necessitated

the search for new antimicrobial agents. Moreover, some of the currently available drugs

have been shown to exhibit unfavourable side effects and toxicity. It is well established

that small modifications in the structure of the targets are altering their biological

character as well as their physiochemical properties. Both steric and electronic factors are

claimed to be prime determinants in the variation of biological activity. Generally, factors

such as presence of hydrophobic and hydrophilic groups, binding site and solubility of the

molecules are desirable features to exhibit medicinal activity to a great extent.

Stereochemistry of the molecule also plays an important function in their biological

activity.

Generally, a rational drug design process for a new antimicrobial agent could be

achieved in many ways. One of the strategies is the identification of new targets through

better understanding of molecular mechanisms of infections. Another way is to modify

the structure of already existing drugs by improving the binding affinity to the receptor.

Also, the correlation between structure activities of the new compounds would impart

valuable information to assist the development of new types of drugs in new millennium.

Furthermore, the results of research may be useful in understanding the mechanism of

drug action.

The main objectives of the present research work are as follows:

Synthesis some new substituted 1, 2,4-Triazole, Pyrazole, 1,3,4-Oxadiazole and 1,3,4-

Thiadiazole derivatives.

Development of synthetic routes for the newly prepared compounds.

42

Characterization of new compounds by IR, 1H NMR,

13C NMR, Mass spectral studies

and also by X-Ray crystallography and elemental analysis

Evaluation of biological activities of new compounds, such as antibacterial,

antifungal activity.

The thesis comprises of six chapters.

Chapter 1: This is an introductory chapter, which deals with a brief account of synthesis,

reactions and biological activities of some 1,3,4-oxadiazole derivatives based on the

publications appearing in the chemical literature up to Feb-2013. Main objectives of the

present research work were also explained here.

Chapter 2: This chapter describes synthesis, characterization and biological studies of

some new some new 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety.

Structures of newly synthesized compounds were characterized by spectral studies. New

compounds were screened for antifungal and antibacterial activities. The results and

discussion of such studies are presented in this chapter.

Chapter 3: This chapter includes, two series of pyrazole ester derivatives synthesised by

the condensation of Ethyl-3-(dimethylamino)-2-[(phenyl) carbonyl] prop-2-enoate with

different aromatic/aliphatic hydrazines. Further this pyrazole ester was converted in to its

carboxamide derivatives. The newly synthesized compounds were characterized by IR,

1H NMR,

13C NMR, mass spectral analyses. New compounds were screened for their

antibacterial studies. Molecular structure of some compounds was also confirmed by

single crystal X-ray analysis.

Chapter 4: This chapter explained about the synthetic approach and biology studies of

some new 3 (2,6-difluoro-benzyl sulfanyl)-4-(substituted)-5-(3,4,5-trimethoxy phenyl)-

4H-[1,2,4]triazole derivatives. A series of 1,2,4-Triazole derivatives were synthesized

from the commercially available 3,4,5-trimethoxyphenyl benzoic acid through

43

esterification, and hydrazidation. Further this acid hydrazide was then treated with

different aliphatic and aromatic isothiocayante to afford different substituted

carbothioamide derivatives. Cyclization of this intermediate with sodium hydroxide under

reflux condition afford different substituted 1,2,4-triazole derivatives. The newly

synthesized compounds were characterized by IR, 1H NMR,

13C NMR, mass spectral

analyses. New compounds were screened for their antibacterial studies. Molecular

structure of some compounds was also confirmed by single crystal X-ray analysis.

Chapter 5: This chapter focused on the synthesis some new substituted 1,3,4-

Thiadiazole and Imidazo [1,3,4]-Thiadiazole derivatives. Two series of 1,3,4-thiadiazole

derivatives were synthesized by cyclising 4-Fluoro-3-nitrobenzoic acid with Phosphorous

oxychloride and Thiosemicarbazide. The newly synthesized compounds were

characterized by IR, 1H NMR,

13C NMR, mass spectral analyses. New compounds were

screened for their antibacterial studies.

Chapter 6: The summary and conclusions of present research work have been discussed

in this chapter.

In conclusion, the present research work, involving design, synthesis, and

characterization of new, 1,2,4-Triazole, Pyrazole, 1,3,4-Oxadiazole and 1,3,4-Thiadiazole

derivatives and evaluation of their preliminary antibacterial, antifungal activities, has

been aimed at development of new active antimicrobials, which may have future

commercial applications. Further, the optimized synthetic methods and purification

techniques developed these derivatives would be highly useful for future researchers. The

research study is expected to add some more data to the chemistry of new heterocyclic

compounds. The utility of above new heterocyclic compounds may be explored in other

area of applications also.

44

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