Chapter I

1

1.0. Introduction

From the earlier days of development of organic chemistry, heterocyclic chemistry

has held center stage in the development of molecules to enhance quality of human

life. For example, more than seventy percent of drugs used today are heterocyclic

compounds. They are widely distributed in nature and are key intermediates in many

biological processes. Generally, heterocyclic compounds isolated from natural sources

act as lead compounds for the development of new molecules of biological interest. In

addition, most of the heterocyclic drugs are synthesized from readily available fine

chemicals. In this aspect, synthesis and characterization of new molecular entities

incorporating heterocyclic structures is of high significance. There are multiple

benefits exploring this type of research in organic chemistry. Firstly, it will help in

unraveling intrinsic chemical behavior of small molecules which still remains

mysterious. Secondly, it will immensely help in the development of new methods for

synthesis. Thirdly, characterization of a set of compounds by spectral methods would

create benchmarks for characterization of similar molecules. Finally, biological

evaluation of the synthesized compounds may explore lead compounds for further

structural fine tuning. Among organic compounds, those incorporating one or more

sulphur or nitrogen atoms are of high significance because of their unique properties

imparted by these elements.

Heterocyclic chemistry includes a large class of compounds, azoles being one among

them. Azoles are five-membered heterocyclic compounds containing nitrogen atom

and at least one other non-carbon atom of either nitrogen, sulphur, or oxygen [1]. It

includes the following heterocyclic rings.

ON

N

ON

N

NO

NO

NN

1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole

N

N

HN

HN

N

N

1,2,4-triazole 1,2,3-triazole

N

O

Isoxazole

O

N

Oxazole

Chapter I

2

NH

N

pyrazole

S

N

thiazole

N

HN

imidazole

S

N

isothiazole

S

NN S

NN

1,3,4-thiadiazole1,2,3-thiadiazole

NH

NN

N

tetrazole

NH

pyrrole

1 nitrogen (only includes one nitrogen and no other heteroatom)

o pyrrole

1 nitrogen atom and 1 oxygen atom

o oxazole

o isoxazole

1 nitrogen atom and 1 sulfur atom

o thiazole

o isothiazole

2 or more nitrogen atoms

o pyrazole

o imidazole, included in histidine

o triazole, included in Ribavirin

o tetrazole

o pentazole

Being main ingredients in many drugs, azoles are known for their broad spectrum of

biological activities including antimicrobial, anti-inflammatory, analgesic, antimitotic,

anticonvulsive, diuretic and many other uses [2-8]. They play an important role

against skin diseases and secondary symptoms of AIDS. They are also used in the

protection of plants and in industry (leather, wool, fibers). The rapid development in

this field affords a comprehensive handbook about their uses and applications.

Chapter I

3

1.1. Reported activities of azoles

1.1.1. Azole drugs showing antifungal activity

The first report of antifungal activity of an azole compound, benzimidazole, was

described in 1944 [9], it was however only after the introduction of topical

chlormidazole in 1958 that researchers became interested in the antifungal activity of

azole compounds [9]. In the late 1960s, three new topical compounds were introduced

[10] clotrimazole, developed by Bayer Ag, Germany [11], miconazole and econazole,

both developed by Janssen Pharmaceutica, Belgium [12].

Miconazole, a phenethyl imidazole synthesized in 1969, was the first azole available

for parenteral administration. Like other azoles, it interferes with the biosynthesis of

fungal ergosterol, but at high concentrations. Miconazole may also cause direct

membrane damage that result in leakage of cell constituents. It has been recently

withdrawn from the markets because of toxicity. In 1981, Food and Drug

Administration (FDA) approved the systemic use of ketoconazole, an imidazole

derivative synthesized and developed by Janssen Pharmaceutica, Belgium [13].

NN

Cl

Clotrimazole

O

NN

Cl

Cl

Cl

Cl

Miconazole

N

N

Cl

Cl

O

O O N N

CH3

O

Ketoconazole

N

NN

HO

NN

F

F

F CH3

Voriconazole

F

N

NN

HO

N

NN

F

Fluconazole

However, the poor response rates and frequent recurrences of major fungal infections,

as well as the toxicity associated with ketoconazole therapy, led to the search for a

second chemical group of azole derivatives, namely the triazoles. In general the

triazoles demonstrate a broader spectrum of antifungal activity with reduced toxicity

Chapter I

4

in comparison to imidazole antifungals. The serum half-life allows once-daily dosing

of triazole based antifungals agents viz. fluconazole. In contrast to ketoconazole,

renal clearance is the major route of elimination of fluconazole, with 70-80% of

unchanged drug excreted in the urine [14].

Mechanism of action of azoles against fungal infection

Azoles inhibit the enzyme lanosterol 14 α-demethylase which is necessary to convert

lanosterol to ergosterol. Diminution of ergosterol in fungal membrane disrupts the

structure and many functions of fungal membrane leading to inhibition of fungal

growth [15]. Moreover, a number of secondary effects such as inhibition of the

morphogenetic transformation of yeasts to the mycelia form, decreased fungal

adherence and direct toxic effects on membrane phospholipids, have also been

reported [16].

1.1.2. Azoles as antibacterial agents

The azole pharmacophore is still considered a viable lead structure for the synthesis of

more efficacious and broad spectrum antimicrobial agents. Potential antibacterial

Chapter I

5

activities have been encountered with some azoles. Some of the potent azoles as

antibacterial agents are as follows.

N

S

OO

O

H

NN

N

OHO

Tazobactum

S

N

H3C NH

O

NS

H3CO

O

HO

Meloxicam

NO

N

O

NO

O

O

Muscoride A

1.1.3. Azoles as Non-steroidal anti-inflammatory drugs (NSAIDs)

Azoles are one of the important class of compounds used as NSAIDs viz. Celecoxib

etc. NSAIDs are non-narcotic drugs [17] that produce relief of pain and lower

elevated body temperature. As these drugs do not have steroidal nucleus and also

produce anti-inflammatory effect, they are known as non-steroidal anti-inflammatory

drugs (NSAIDs). NSAIDs are better in use than steroidal drugs. As a group, NSAIDs

tend to cause gastric irritation and considerable effort has gone into preventing this

complication or reducing its severity [18]. Furthermore, there are number of non azole

NSAIDs present in the market to heal the inflammation but majority of them cause

adverse side effects like gastric ulcer [19] and kidney damage [20] while some of the

NSAIDs cause hepatotoxicity [21].

1.1.3.1. Properties of NSAIDs

Mildly analgesic

Antipyretic

Anti-inflammatory

Act on sub-cortical sites such as thalamus and hypothalamus

No affinity for morphine receptors

In addition, tolerance and drug dependence do not develop to these

drugs in patients

Chapter I

6

1.1.3.2. Classification of NSAIDs

The NSAIDs are classified into different groups on the basis of their basic moieties

and are listed in the table given below.

Class Structures IUPAC Name Generic name

Pyrazole

derivatives

O

S N

N

F

F

F

H3C

H2N

O

4-[5-(4-methylphenyl)-3-

(trifluoromethyl)pyrazolo-1-

yl]benzenesulfonamide

Celecoxib

Oxicams

derivatives

S

N

OO

OH

CH3

NH

O

N

4-hydroxy-2-methyl-N-2-

pyridinyl-2H-1, 2-

benzothiazine-3-carboxamide 1,

1- dioxide

Piroxicam

Indole acetic

acid derivatives

N

O Cl

CH3

OH

OO

CH3

1-(4-chlorobenzoyl)-5-

methoxy-2-methyl-3-

indoleacetic acid

Indomethacin

Indole acetic

acid derivatives

N

O Cl

CH3

OH

OO

CH3

1-(4-chlorobenzoyl)-5-

methoxy-2-methyl-3-

indoleacetic acid

Indomethacin

Pyrrole

Alkanoic acid

N

H3C O

CH3

OH

O

[1-methyl-5-(4-methylbenzoyl)-

1H-pyrrol-2-yl]acetic acid

Tolmetin

Salicylates

O

OHO

O

CH3

2-Acetoxybenzoic acid

Aspirin

p-aminophenol

derivatives

O

NHHO

CH3

N-(4-hydroxyphenyl) acetamide

Paracetamol

Chapter I

7

Propionic acid

derivatives

H3C

CH3

H3C

O

HO

2-[4-(2-methylpropyl)

phenyl]propanoic acid

Ibuprofen

Anthranilic acid

derivatives

HN

CH3

CH3

O OH

2-[(2,3-dimethylphenyl)amino]

benzoic acid

Mefenamic acid

Phenyl acetic

acid derivatives

HN

ClO ONa

Cl

2-[2-(2,6-

dichloroanilino)phenyl]

acetic acid

Diclofenac

sodium

Difluorophenyl

derivatives

O

OH

OHF

F

2',4'-difluoro-4-

hydroxybiphenyl-3-carboxylic

acid

Diflunisal

Naphthyl acetic

acid derivatives

CH3

O

OH3C

4-(6-methoxy-2-naphthyl)-2-

butanone

Nabumetone

Mechanism of action of anti-inflammatory agents

The anti-inflammatory drugs inhibit inflammation by inhibiting the biosynthesis of

prostaglandin [22]. Synthesis of prostaglandin is mediated by an enzyme called

cyclooxygenase (COX or PGH2 synthase). It exists in two isofonns, COX-1 and

COX-2. COX-1 is constitutive whereas COX-2 is inducible. COX-1 protects

gastrointestinal mucosa and also maintains homeostasis, whereas COX-2 is

responsible for inflammation, pain and fever. Most of the NSAIDs inhibit both

isoforms of COX, which lead to other side effects (gastric ulcer and renal toxcicity

due to inhibition of COX-1).

Selective COX-2 inhibitors are better anti-inflammatory agents, because COX-2 is

usually specific to inflamed tissue. Further, there is much less gastric irritation

associated with COX-2 inhibitors, with a decreased risk of peptic ulceration.

Selectivity for COX-2 is the main feature of azole based drugs such as celecoxib,

rofecoxib, and other members of this class.

Chapter I

8

1.1.4. Azoles as antiviral and analgesic agents.

During the past few years several marine natural products with 2,4-disubstituted

azoles have been isolated and synthesized [23]. Hennoxazole is an azole based potent

antiherpes virus agent and peripheral analgesic containing a bioxazole unit [24].

N

O

O

N

OH

MeO

H

O RHCH3

X

CH3

H

Hennoxazoles

1.1.4. Azoles as anticancer agents.

Azoles are known selective COX-2 inhibitors and also show anticancer properties

[25]. COX-2 derived prostaglandin may accelerate the development of cancer by

different mechanisms [26-28]. COX-2 inhibitors have been shown to reduce the

occurrence of cancers and pre-cancerous growths [29]. One of the azoles with

anticancer properties is carboxyamidotriazole [30].

Chapter I

9

N

NN

H2N

H2N

O

Cl

Cl

O

ClCarboxyamidotriazole

RAF265 (CHIR-265; Novartis Pharmaceuticals, Basel, Switzerland), an orally

bioavailable small molecule, under clinical trial phase-I, is a potent inhibitor of RAF

(proto-oncogene) with a highly selective profile and is a derivative of benz azoles

(Chiron, a subsidiary of Novartis) [31].

O

NNH

F

FF

N

H3C

HN

F

F F

RAF265

AZD6244 is an imidazole based anticancer agent under clinical trial Phase II

(Astrazeneca), active against recurrent low grade ovarian cancer [32].

NN

H3C

HN O

HN

NBr

OHO

AZD6244

1.5. Conclusion

The usage of most antimicrobial agents is limited, not only by the rapidly developing

drug resistance, but also by the unsatisfactory status of present treatments of bacterial

and fungal infections and drug side effects [33-36]. Therefore, the development of

new and different antimicrobial drugs is a very important objective and much of the

research program efforts are directed towards the design of new agents. Further

several non steroidal anti-inflammatory drugs (NSAIDs) have been developed so far

Chapter I

10

to heal the inflammation. The use of these NSAIDs has also been limited owing to

their adverse effects like ulceration, hepatotoxicity, renal toxicity etc. [37-38].

Due to drug resistance and adverse side effects of the antimicrobial and

anti-inflammatory agents present in the markets, there is need for undertaking

research in this area for the development of new lead molecules. Since azole

derivatives show numerous activities like anti-inflammatory and antimicrobial agents

and are reported both from natural as well as synthetic sources, our main emphasis

was on the development of azole based small molecule high affinity ligands (SHALs)

with potent anti-inflammatory, analgesic and antimicrobial activities.

Chapter I

11

1.4. References

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[19] Alsarra, A. I., Ahmed, O. M., Alanazi, K. F., Tahir, H. E., Alsheikh, M. A. and

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