chapter i introduction to azolesshodhganga.inflibnet.ac.in/bitstream/10603/37384/7/07_chapter...
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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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Chapter I
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12
Chapter /
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