Chapter I

Introduction to Azoles

Chapter I

1,0. Introdiictioii

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

has held center stage in the development of molecules to enhance quality o f 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 o f biological interest, In

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

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

incorporating heterocyclic structures is o f high significance. There are multiple

benefits exploring this type o f 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 o f new methods for

synthesis. Thirdly, characterization of a set o f 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 o f their unique properties

imparted by these elements.

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

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

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

includes the following heterocyclic rings.

aO'

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

N -N

V1,2,5-oxadiazole 1,3,4-oxadiazole

H. N .

N 'n'^N

1,2,4-triazole

N

1,2,3-triazole

O

Isoxazole

/r-N

Oxazole

Chapter I

iso th iazo le

N H

pyrazole

aN

thiazole

HN~^V n

im id a zo le

-S\

N

1,2,3-thiadiazole

n - n ^ N HN. -.N

N

N H

1,3,4-thiadiazole tetrazole 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 pjo-azole

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,

anti convulsive, 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

1,L Reported activities of azoks

1.1.1, Azole drugs showing antlfwngal activity

The first report of antifuiigal activity o f an azole compound, benzimidazole, was

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

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

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

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

both developed by Janssen Phannaceutica, 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].

o-~yo

N=?\N '

Clotrimazole

/ —\N N -4 ^ O

Ketoconazole

However, the poor response rates and frequent recurrences o f 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 o f antifungal activity with reduced toxicity

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

o f triazole based antifiingals agents viz. fluconazole. In contrast to ketoconazole,

renal clearance is the major route o f elimination o f 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 a-demethylase which is necessary to convert

lanosterol to ergosterol. Diminution o f ergosterol in fungal membrane disrupts the

structure and many functions o f fungal membrane leading to inhibition o f fungal

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

morphogenetic transformation of yeasts to the mycelia form, decreased fiingal

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

reported [16].

Chapter I

F-ungal cell Fungal cell membrane and cell wall

p - Proteins

\ \

■4^5” - r Terbinafine

Squalene epoxide

Azoles ]

Lanosterol

|5-giucans

Chitin

CeB membrane bilayer

^̂ -glucansynthase

1.1.2. Azoles as antibacterial agents

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

more efficacious and broad spectrum antimicrobial agents. Potential antibacterial

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

antibacterial agents are as follows.

Chapter I

w V °■s;-N

O

Tazobactum

HHjC ^/ %

M e l o x i c a m

1,1.3. Azoles as Non-steroMal anti-m flam m atory drags (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 o f 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 o f 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 [2 0 ] while some o f the

NSAIDs cause hepatotoxicity [21].

1.1.3.1. Properties of NSAIDs

Mildly analgesic

4s Antipyretic

Anti-inflammatory

i Act on sub-cortical sites such as thalamus and hypothalamus

^ No affinity for morphine receptors

4k In addition, tolerance and drug dependence do not develop to these

drugs in patients

Chapter I

1.1.3.2. Classification of NSAIDs

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

and are listed in the table given below.

C lass Structures lU P A C N am e G eneric nam e

Pyrazole

derivativeso Y '

oH,C

4-[5-(4"m ethylphenyl)-3-

(trifluoromethyl)pyrazolo - 1 -

yljbenzenesulfonam ide

C elecoxib

Oxicaras

derivatives

O il 0

L a , N . "

0 o

4-hydroxy-2-m ethyl-N -2-

pyridinyl-2H -l, 2-

benzothiazine-3-carboxam ide 1,

1 - dioxide

Piroxicam

Indole acetic

acid derivatives v O - ^

CH., ^O H

1 -(4-chIorobenzoyl)-5-

m ethoxy-2-m ethyI-3-

indoleacetic acid

Indomethacin

Indole acetic

acid derivatives

O H

1 -(4-chlorobenzoyl)-5-

methoxy-2-m ethyI-3-

indoleacetic acid

Indoniethacin

Pyrrole

Alkanoic acid

^ P H

H3 C 0

[l-m ethyl-5-(4-m ethylbenzoyl)-

1 /?-pyrrol-2 -yl]acetic acid

Tolm etin

Salicylates H O ^ O

0

2-A cetoxybenzoic acid Aspirin

/ 3-aminophenol

derivativesH O — < f ' ^ N H

I - C H 30

N -(4-hydroxyphenyl) acetamide Paracetamol

Propionic acid

derivatives

H,C

HO' ' ^ H3C

0CH3

2-[4-(2-m ethylpropyl)

phenyl]propanoic acid

Chapter /

Ibuprofen

Anthranilic acid

derivatives

0* ^ 0 H 2-[(2,3-dim ethylphenyl)am ino]

benzoic acid

M efenam ic acid

Phenyi acetic

acid derivatives

O^ONa 2-[2-(2,6-dichloroanilino)phenyl]

acetic acid

D iclofenac

sodium

C l'

Difluorophenyl

derivatives

2',4'-difluoro-4-

hydroxybiphenyl-3-carboxylic

acid

Diflunisa!

Naphthyl acetic

acid derivatives

4-(6-m ethoxy-2-naphthyl)-2-

butanone

Nabumetone

M echanism of action of anti-inflam m atory 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 sjmthase), 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 o f 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 o f peptic ulceration.

Selectivity for COX-2 is the main feature o f azole based drugs such as celecoxib and

other members o f this class.

7

1.1.4. Azoies as antiviral and analgesic agents.

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

azoies have been isolated and synthesized [23]. Hermoxazole is an azole based potent

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

1.1.4. Azoies as anticancer agents.

Azoies 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 azoies with

anticancer properties is carboxyamidotriazole [30].

8

Chapter /

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

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

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

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

H,CRAF265

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

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

H.N .

H 3 C - N Br\ ^ N

A Z D 6 2 4 4

1.5, Condiisioii

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 o f bacterial

and fungal infections and drug side effects [33-36], Therefore, the development o f

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

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

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

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 o f 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

10

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12

Chapter /

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13