INTRODUCTION AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR BIOLOGICAL SIGNIFICANCE
INTRODUCTION
AN OVERVIEW OF HETEROCYCLIC
COMPOUNDS AND THEIR
BIOLOGICAL SIGNIFICANCE
Chapter - 1
1
1.0. INTRODUCTION
1.1. OVERVIEW ON HETEROCYCLIC COMPOUNDS
Two hundred years ago, the chemical science was an undivided field; around 1900
a division into inorganic, organic and physical chemistry became necessary. The increase
of factual material enforced a progressive segmentation into sub disciplines. A map
shows countries and regions neatly separated; similarly, the uninformed observer may
regard chemistry as a side-by-side of numerous disciplines and specialties. The
comparison is fallacious, however, because broad overlap is thwarting clear divisions.
Chemistry has a lot of fascinating facts, one such is hitherto cyclic compounds. Every
first step of life starts with hetero-cyclic compounds.1-3 Heterocycles form by far the
largest of classical divisions of organic chemistry and are of immense importance
biologically and industrially About one half of over six million compounds recorded in
chemical abstracts are heterocyclic.4,5 Heterocyclic chemistry is one of the most complex
and intriguing branch of organic chemistry and heterocyclic compounds constitute the
largest and most varied family of organic compounds. Many broader aspects of
heterocyclic chemistry are recognized as disciplines of general significance that impinge
on almost all aspects of modern organic chemistry, medicinal chemistry and
biochemistry.6 Heterocyclic compounds offer a high degree of structural diversity and
have proven to be broadly and economically useful as therapeutic agents.7,8 The majority
of pharmaceuticals and biologically active agrochemicals are heterocyclic while countless
additives and modifiers used in industrial applications ranging from cosmetics,
reprography, information storage and plastics are heterocyclic in nature.9-11 One striking
structural feature inherent to heterocycles, which continue to be exploited to great
advantage by the drug industry, lies in their ability to manifest substituents around a core
scaffold in defined three dimensional representations.12,13 For more than a century,
Chapter - 1
2
heterocycles have constituted one the largest areas of research in organic chemistry. They
have contributed to the development of society from a biological and industrial point of
view as well as to the understanding of life processes and to the efforts to improve the
quality of life. Among the approximately 20 million chemical compounds identified by
the end of the second millennium, more than two-thirds are fully or partially aromatic and
approximately half are heterocyclic.14,15 The presence of heterocycles in all kinds of
organic compounds of interest in electronics, biology, optics, pharmacology, material
sciences and so on is very well known.16 Between them, sulfur and nitrogen-containing
heterocyclic compounds have maintained the interest of researchers through decades of
historical development of organic synthesis.3 However, heterocycles with other
heteroatoms such as oxygen,17 phosphorus18 and selenium19 also appears.
1.2. IMPORTANCE OF HETEROCYCLIC COMPOUNDS IN LIFE
The nature also prefers to utilize heterocycles during physiological processes
occurring in the human body. This is because heterocycles are associated with unique
properties to get involved in a wide variety of chemical reactions. Many heterocyclic
compounds are biosynthesized by plants and animals and are biologically active.20 Over
millions of years, these organisms have been under intense evolutionary pressure, and
their metabolites may be used to advantage; for example, as toxins to ward off predators,
or as colouring agents to attract mates or pollinating insects.21
Some heterocycles are fundamental to life, such as haem derivatives (1) in blood
and the chlorophylls (2) essential for photosynthesis. Similarly, the paired bases found in
DNA and RNA are heterocycles (Fig. 1.1), as are the sugars that in combination with
phosphates provide the backbones and determine the topology of these nucleic acids.
Dyestuffs of plant origin include indigo blue, used to dye jeans. A poison of detective
novel fame is strychnine, obtained from the plant resin curare The biological properties of
Chapter - 1
3
heterocycles in general make them one of the prime interest of the pharmaceutical and
biotechnology industries.22-24
N N
N N
H2C=HC
H3C
CH3
CH=CH2
CH3
CH2CH2COOHCH2CH2COOH
H3C
Fe Cl
1 2
N N
N N
H3C
R
CH3
H2C
H2C=HC
C2H5
Mg
H3C
H
H2C
OH
H
COOCH3
COOC20H39
R= CH3 it is chlorophyll-aR= CHO it is chlorophyll-b
Fig. 1.1: DNA and RNA
Chapter - 1
4
Besides, they play a vital role in the metabolism of all living cells as
carbohydrate, proteins and enzyme. In recent years, the marine environment has
been recognized as a rich source of novel heterocyclic structures, some of which
have valuable biological properties.25,26
The plant kingdom has an abundance of nitrogen compounds, most being
heterocyclic, with some of great complexity. Because they are weakly basic and form
salts with mineral acids, the compounds from plants became known long ago as
alkaloids.27 They were among the first natural organic compounds to be isolated and
studied and it has been stated that more than 8000 alkaloids are known and that more than
100 are discovered annually in current research, many of which have been structurally
characterized. They occur in all parts of plants and they usually have some form of
biological activity, which can range from high mammalian toxicity to valuable
therapeutic properties of many different kinds.28
Fig. 1.2 Opium
HO
O
HO
N
3
Alkaloid-containing plants have been used by humans since ancient times for
therapeutic and recreational purposes. For example, opium ( Fig. 1.2 ) containing drug
Chapter - 1
5
which contains approximately 12% morphine (3) is believed to be a gift for bringing
oblivion. Extracts from plants containing toxic alkaloids, such as aconitine (4)
and tubocurarine (5), were used since antiquity for poisoning arrows.29
4
5
A significant contribution to the chemistry of alkaloids in the early years of its
development was made by the French researchers, who discovered quinine and
dstrychnine. Several other alkaloids were discovered around that time,
including xanthine, atropine, caffeine, coniine, nicotine, colchicine, sparteine and
cocaine.30
The reason for the utilization of heterocycles by nature is based on the fact that
heterocyles are able to get involved in an extraordinarily wide range of reaction types.31,32
Depending on the pH of the medium, they may behave as acids or bases, forming anions
or cations. Some interact readily with electrophilic reagents, others with nucleophiles, yet
others with both. Some are easily oxidized, but resist reduction, while others can be
readily hydrogenated but are stable toward the action of oxidizing agents.33 Certain
amphoteric heterocyclic systems simultaneously demonstrate all of the above-mentioned
properties. The ability of many heterocycles to produce stable complexes with metal ions
has great biochemical significance.34 The presence of different heteroatoms makes
tautomerism ubiquitous in the heterocyclic series. Such versatile reactivity is linked to the
electronic distributions in heterocyclic molecules.35 Furthermore, the reason for the
Chapter - 1
6
widespread use of heterocyclic compounds is that their structures can be subtly
manipulated to achieve a required modification in function. The water solubility and the
transport of the fungicide through the plants are improved by replacing a benzene ring by
the more polar heterocycle. Another important feature of the structure of many
heterocyclic compounds is that it is possible to incorporate functional groups either as
substituents or as part of the ring system itself. For example, basic nitrogen atoms can be
incorporated both as amino substituent and as part of a ring. This means that the
structures are particularly versatile as a means of providing, or of mimicking, a functional
group.36
OH
N
NOH
QUININE
Anti-malarial
NH
N
ELLIPTICINE
Anti-tumour agent
O
N
O
NH2
PROCAINE
Local anesthetic
N
H3CO
H3CO
OCH3
H3CO
PAPAVERINE
Smooth muscle relaxant
H3CO
O
HO
N
CODEINE
Anti-depressant
N
H3CO
H3CO
HN
OCH3
OCH3 EMETINE Anti-protozoal
N
N N
HN
O
O
THEOPHYLLINE
Reduces asthma
O
O
N
O
O
SANGULNARINE
Antibacterial and a
ntiplaque agent
Fig. 1.3: Natural heterocycles
Chapter - 1
7
Based on the above information, many natural drugs such as codeine,
ellipticine, emetine, papaverine, procaine, quinine, sangulnarine and theophylline (Fig.
1.3) were discovered which are also heterocycles. Natural products have pharmacological
activity that can be of therapeutic benefit in treating diseases. As such, natural products
are the active components of many traditional medicines.37 In fact, natural products are
the inspiration for approximately one half of food and drug administration-approved
drugs. Natural products may be extracted from tissues of terrestrial fermentation broths,
lants, marine organisms or microorganism. A crude extract from any one of these sources
typically contains a novel, structurally diverse chemical compounds, which the natural
environment is a rich source of. Chemical diversity in nature is based on biological and
geographical diversity, so researchers travel around the world obtaining samples to
analyze and evaluate in drug discovery screens or bioassays.38
1.3. HETEROCYCLIC COMPOUNDS IN DRUG DISCOVERY
Research in the field of pharmaceutical has its most important task in the
development of new and better drugs and their successful introduction into clinical
practice.39 The word 'drug' is derived from the French word 'drogue' which means a dry
herb. In a general way, a drug may be defined as a substance used in the prevention,
diagnosis, treatment or cure of disease in human or animals. 40 Most pharmaceuticals are
based on heterocycles. An inspection of the structures of the top-selling brand-name
drugs reveals that 8 of the top 10 and 71 of the top 100 drugs contain heterocycles.
Heterocycles have dominated medicinal chemistry from the beginning. Consistent with
their importance, many patents by pharmaceutical companies involve heterocyclic
compounds. There is every reason to expect this trend to continue. All the major
pharmaceutical companies have significant research efforts involving heterocycles.41
Chapter - 1
8
The basis of understanding the medicinal chemistry lies in awareness of the
relationships between the chemistry of a particular compound or group of compounds and
their interactions with the body, which is known as structure activity relationship, and the
mechanism by which the compound influences the biological system, which is known as
its mode of action.42 We must always continue to search for drugs which exhibit clear
advantages over the already existing respective drugs. Such advantages may be: (i) A
qualitative or quantitative improvement in activity, (ii) a partial or total absence of
undesirable side effects, (iii) a lower toxicity, (iv) more nutritive value, (v) improved
stability and (vi) a decrease in production cost. Any drug must ideally have a broad
spectrum of activity, with a rapid action. During the period of 1940 to 1960 a large
number of important drugs have been introduced and this period is regarded as "Golden
Period" of new drug discovery.43,44 Heterocycles play in modern drug design, they can
serve as useful tools to manipulate lipophilicity, polarity and hydrogen bonding capacity
of molecules, which may lead to improved pharmacological pharmacokinetics,
toxicological and physicochemical properties of drug candidates and ultimately drugs.45-48
7
N
NO
6
The first synthetic heterocyclic pharmaceutical seems to be antipyrine (6). It is a
pyrazole analgesic and an antipyretic, like aspirin. More recently, antipyrine has been
Chapter - 1
9
used in a solution with benzocaine to relieve ear pain and swelling caused by middle ear
infections. Several anticancer drugs contain the pyrimidine ring.49 An early drug, still in
use today is methotrexate (7), which acts by inhibiting the formation of folic acid.
Methotrexate is also used to treat rheumatoid arthritis. For the synthetic chemist,
methotrexate is particularly interesting because it can be prepared in a one-step “shotgun”
reaction.50 Almost all the compounds we know as synthetic drugs such as azidothymidine,
barbituric acid, captopril, chloroquinine, chlorpromazine, diazepam, fluconazole,
isoniazid and metronidazole (Figure – 1.4) are also heterocycles. 51-53
S
NCl
CHLORPROMAZINE
Anti-psychotic
DIAZEPAM
To treat muscle spasms
N
N
O
Cl
N
HN
ISONIAZID
To treat tuberculosis
ONH2
NCl
HNNEt2
CHLOROQUININE
Antimalarial
NH
HN
BARBITURIC ACID
Analgesic
OO
O
N
NH
O
O
AZIDOTHYMIDINE
Antiretroviral
OHO
NN
N +
CAPTOPRIL
Angiotensin converting
agent
N
O
OH
OHS
N
N
N
METRONIDAZOLE
Antibiotic agent
HO
N
O
O
+
_
NN
N
N
OHF
N
N
F
FLUCONAZOLE
antifungal
Figure - 1.4: Synthetic heterocycles
Chapter - 1
10
Heterocyclic compounds hold a unique place among pharmaceutical significant
natural products and synthetic compounds. The remarkable ability of heterocyclic nuclei
to serve both as biomimetics and reactive pharmacophores has largely contributed to their
unique value as traditional key elements of drugs The introduction of heterocyclic group
in the drug molecule enhances their bioactivity.54 This is exemplified by
p-aminobenzenesulphonamide moiety, a well-known drug molecule, but the introduction
of heterocylic groups into the original nucleus markedly enhanced their biological
activity. The important drugs are sulphathiazole, sulphadiazine, sulphadimethoxine etc.,
which are highly effective towards several bacterial strains. There is every reason to
believe that most newly discovered pharmaceutically active compounds will continue to
be based on heterocycles. 55-56
1.4. HETEROCYCLIC COMPOUNDS IN COMMERCIAL FIELDS
Heterocyclic compounds are of great importance in many different fields of
commerce. They represent specialized, well-developed areas of technology and an
extremely important application of heterocyclic compounds is in the field of dyes and
pigments.57 Extended conjugation is an important ingredient for a compound to be
colored, and heterocyclic systems, usually multicyclic, in great numbers have been
constructed around this principle. An extremely important application of heterocyclic
compounds is in the field of dyes and pigments.58
8
9
Chapter - 1
11
Industrial organic chemistry can trace its beginnings back to the (accidental)
discovery of mauveine (8) in 1856. It was the first organic compound to be prepared
synthetically at the industrial scale. Another heterocyclic compound, indigo (9), was
derived from natural sources and was used for centuries before it was synthesized in 1883
and later made commercially. These two early compounds display the extended
conjugation so important in the development of new dye and pigment chemicals. 59
Technology in the area of photography is highly developed, making use of
heterocyclic compounds in various ways in the several steps of the process. Heterocyclic
compounds can participate in polymer technology in several ways.60 They can be
pendants on a polymer chain, as might be formed from the polymerization of vinyl
monomers with heterocyclic substituents.61 There are processes where the polymer is
formed by closing heterocyclic rings. Finally, heterocyclic groups can be added to
previously formed polymers. Hindered heterocyclic amines are used as light stabilizers in
plastic and coating formulations, protecting against degradation by ultraviolet radiation.62
These agents are known as hindered amine light stabilizers (HALS) and are commonly
derivatives of 2,2,6,6-tetramethylpiperidine, an example of a HALS agent is tinuvin (10).
10
P
SS S
11
A thriving and highly important field is the construction of coordination
complexes from metallic species and heterocycles.63 These complexes can be useful as
reaction catalysts and have other uses as well. To illustrate the catalyst area (which is
Chapter - 1
12
large), the zirconium complex formed from the anion of indenylindoyl anion, and
zirconium chloride is offered as an example. The complex is an excellent catalyst for the
polymerization of olefins.64 Also, heterocycles with chirality can form complexes that are
useful catalysts for asymmetric synthesis.65 This is a field of great contemporary interest.
A relatively new and still developing field is the use of heterocyclic compounds in
electro-optical applications, which includes light-emitting diodes (LED), thin-film
transistors, and photovoltaic cells. To possess these properties, molecules must have
extended conjugated unsaturation. This lowers the highest occupied molecular orbital-
lowest unoccupied molecular orbital energy gap and causes light absorption at long
wavelengths. One type of useful structure has several heterocyclic rings such as pyrrole or
thiophene joined in a linear fashion. The phosphole ring system is a new participant in
this type of array. This is illustrated by compound (11) in which two thiophene rings are
attached to a central phosphole ring (as the sulfide). This compound has LED properties;
when deposited as a thin film between a player cathode and anode, the yellow light was
emitted by the application of a low voltage. Other related structures are being examined
for similar electro-optical activity.66 Another new application of heterocyclic compounds
is in the field of ionic liquids. These compounds generally are quaternary salts of certain
heterocyclic bases, and they are finding use as high-boiling polar solvents for extractions
or as reaction media. Common among the ionic liquids known so far are salts of
imidazole. 67
1.5. NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS
The heteroaromatic ring system is the pivotal part of any biologically active drug
molecule. Heteroaromatic rings are essential because they provide similarity with respect
to the biologically active compounds within our body. Among many heteroaromatic
rings present, nitrogen heterocycles are abundant in nature and are of great significance,
Chapter - 1
13
to life because their structural sub-units exist in several natural products such as vitamins,
hormones, amino acids, proteins, chlorophyll, haemin, enzymes, antibiotics and alkaloids.
They are also major components of biological molecules such as DNA, which is the most
important macro-molecule of life.68, 69 Nitrogen heterocycles appear in the core structure
of several drugs marketed worldwide and these heterocycles comprising around 60% are
covered as a drug substance. Due to the importance of nitrogen heterocycles in medicinal
chemistry, pharmaceutical industry, various drug development areas and their importance
in the material science enough importance are given for their synthesis and
characterization. Based on these observations, researchers interested in the synthesis of
the nitrogen containing heterocycles like, oxadiazole, pyrrolidine, piperidine, pyridine,
pyrimidone, oxazoline, thiazole etc.70, 71
As per the review about the recent trends in the chemistry of nitrogen containing
heterocyclic compounds, it is oxadiazole, a five-membered ring containing two nitrogen
and one oxygen atom which has a broad spectrum of biological activities and ubiquitous
feature of many pharmaceutical products.72, 73 Among the plethora of oxadiazole nucleus
discovered, the 1,3,4-oxadiazoles have been explored extensively. The presence of 1,3,4-
oxadiazole motifs in diverse types of compounds prove its importance in the field of
medicinal chemistry, such as anticancer,74 anti-inflammatory,75 antiproliferative,76
anticonvulsant,77 hypoglycemic,78 anti- hypertensive,79 antimicrobial,80-83 antioxidant,84
anti-inflammatory and antiviral85 properties.
The synthesis of novel 1,3,4-oxadiazole derivatives, and investigation of their
chemical properties and biological behavior, though established about 80 years back it
has been accelerated in the last two decades. In recent years the number of scientific
studies with these compounds has increased considerably. The literature survey on 1,3,4-
oxadiazole, demonstrate its relevance for heterocyclic chemistry. For instance,
Chapter - 1
14
oxadiazoles, has attracted an extensive attention of the researchers in the search for the
new therapeutics, such as compounds (12) as anticancer86 and (13) as HIV-integrase
inhibitor87 agents.
N
N
HO O
NH
O
NHO
F
N
N
O
12 13
Cl
O
F
O
Br
O
O
Cl
F
Cl
N
O
N
Besides, 1,3,4-oxadiazoles has attracted an interest in medicinal chemistry as ester
and amide bioisosteres for a number of biological targets.88 As such their peptidomimetic
ability has been explored and reported in the development of Phe-Gly mimetic of
dermorphin, a hepta-peptide.89 1,3,4-Oxadiazole molecules are also used as
pharmacophores due to their favorable metabolic profile and ability to engage in
hydrogen bonding.90
In our efforts towards designing novel nitrogen containing heterocyclic
compounds with potential pharmacological activity, a simple and efficient synthesis and
anticancer and antimicrobial properties of some novel 2,5-di substituted-1,3,4-
oxadiazoles and benzophenone appended 1,3,4-oxadiazoles has been performed and
described in chapter- 2 and 4, respectively. Besides, synthesis of benzophenone bearing
various nitrogen containing heterocylic analogues via an amide linkage were also
synthesized and evaluated for xanthine oxidase inhibitory activity and represented in
chapter-3 of this thesis.
Chapter - 1
15
1.6. SYNTHETIC FEATURE OF 1,3,4-OXADIAZOLE ANALOGUES
Taking into account the importance of 1,3,4-oxadiazoles to both heterocyclic and
medicinal chemistry, a few of the synthetic approaches reported in the literature for the
preparation of substituted 1,3,4-oxadiazoles are outlined in different schemes as
mentioned below. There were several routes for the synthesis of 1,3,4-oxadiazoles
reported in the literature among which the most important aspects of synthesis were
discussed as under. 85
1,3,4-Oxadiazole are generally obtained from acyclic precursors and such
reactions are mainly one bond or two bond cyclization. The most widely applicable routes
to 2,5-disusbstituted-1,3,4-oxadiazole is the thermal or acid catalyzed cyclization of 1,2-
diacylhydrazines91 (SCHEME - 1.1) or using diethylaminodifluorosulfinium tetrafluoro
borate as a cyclo dehydration reagent.92
NN
O R
RH or R= H, alkyl, aryl.
heteroaryl
SCHEME - 1.1
([Et2NSF2]BF4)
R NH
HN R
O
O
Cl
O
F
O
NHHN
O
O
O
O
F
Cl
Cl
O
F
O
O
O
F
Cl
NO
N
Triflic anhyride,
Pyridine
DCM, 0°C, 3 h
SCHEME - 1.2
Chapter - 1
16
In recent times, 2,5-dibenzophenone-1,3,4-oxadiazole were synthesized starting
from acetyl hydrazines with pyridine and triflic anhydride in good yield as shown in
(SCHEME - 1.2).86, 93 Wherein phenyl oxadiazole analogue was synthesized from
phenylisoxazoyl N-benzyledineacetohydrazide in presence of ethanol and chloramine-T
(SCHEME - 1.3). 94
.
N OO
NH
O N
Chloramine-T
Ethanol
N O O
O
NN
H3C
CH3
H3C
CH3
SCHEME-1.3
Moreover, 1,3,4-oxadiazole systems have been developed based on microwave
assisted synthesis using acetohydrazide as a source of two contiguous nitrogen atoms, and
cyanogen bromide95 (SCHEME - 1.4).
NN
ONH2
OArBrCN
ONH
NH2
O
Ar
MW
SCHEME - 1.4
An alternative to cyanogen bromide is phenyl cyanate, which reacted with
acetohydrazide to give amino oxadiazole analogue as shown in SCHEME - 1.5. 96
NN
O NH2
N
C6H5OCN
N
O
HN
NH2
SCHEME - 1.5
Chapter - 1
17
The synthesis of 1,3,4-oxadiazole analogues was focused on aryl-2-trifluoro
methyl-1,8-naphthyridine-3-carbonyl hydrazide as starting material in the presence of
acetic anhydride (SCHEME-1.6). 97
N N
NH
N
Ar
O
CF3
Ac2O
N N CF3
NN
O
O
Ar
SCHEME - 1.6
Whereas these types of analogues were also obtained from semicarbazide in the
presence of phosphorous oxychloride (SCHEME - 1.7). 98
N N
HN
HN
O
NH
O
POCl3
N N
HN
O
N
N
SCHEME - 1.7
In addition, Hansong Chen et al.99 has synthesized 1,3,4-oxadiazole analogues by
the reaction of hydrazide and aromatic acid in the presence of POCl3 (SCHEME - 1.8).
NN
Cl
HN NH2
O
POCl3
NN
Cl
NN
OAr
+ Ar-COOH
SCHEME - 1.8
Conveniently 2,5-disubstituted 1,3,4-oxadiazole was accomplished by
cyclodehydration of 1,2-diacylhydrazine either by using chlorosulphonic acid 100 or
phenyl dichorophosphite in dimethylformamide (SCHEME - 1.9). 101
NN
OR2R1
HN
O
NH
O
R1 R2
SCHEME - 1.9
ClSO3H/Cl2POPh
R1 and R2 = Alkyl or aryl
In a related reaction, 1,1,2-triacetylhydrazine with trimethylsilylchloride/triethyl
amine gave oxadiazolinyl silylether102 (SCHEME - 1.10).
Chapter - 1
18
NN
O
R2
R1
O
OSi(CH3)3
HN
O
N
O
R1 R2
O
(CH3)3SiCl
(Et)3N
R1 and R2 = AlkylSCHEME - 1.10
NN
OOPhPhO
HN
O
NH
O
PhO OPh
POCl3/PCl5
SCHEME - 1.11
Nevertheless cyclodehydration of hydrazinyl diester using PCl5/POCl3 gave the
diphenyloxyoxadiazol103 (SCHEME-1.11). Oxidation of acylhydrazones derived from
aldehydes has been developed into a useful route to disubstituted oxadiazoles (SCHEME
- 1.11). The use of potassium permanganate with acetone as a solvent was claimed to give
better yields than the use of other oxidizing agents like halogens. 104, 105
N
HN
R1
R2
O
NN
OR2R1
KMnO4 R1= Alkyl; R2 = Aryl
SCHEME - 1.12
A series of 2,5-disubstituted 1,3,4-oxadiazoles were synthesized starting from
1-aroyl-2-arylidine hydrazides with potassium permanganate as an oxidizing agent on the
surface of silica gel. Nevertheless the same reaction was also performed in a mixture of
acetone and water under microwave irradiation106 (SCHEME - 1.13).
NN
OR2R1
HN
O
N
R1
R2 SiO2
MW
KMnO4
R1 and R2 = ArylSCHEME - 1.13
Recently, a mild, convenient, and efficient one-pot synthesis of amino-1,3,4-
oxadiazoles was described by Guda et al. (SCHEME - 1.14).107 Wherein, in
Chapter - 1
19
situ preparation of various thiosemicarbazides by the reaction of different carboxylic acid
hydrazides with trimethylsilyl isothiocyanate, followed by cyclodesulphurization of thio
semicarbazides under basic conditions in the presence of I2/KI resulted in 2-amino-1,3,4-
oxadiazoles in high yield.
R NH
NH2
OSi
N S
EtOH, reflux
Base, I2/KI
NN
ONH2R
R = Alkyl/Aryl
SCHEME - 1.14
R NH
NH2
ONN
ONHR
R NH
NH
O
R1NCX
HN
R1
X
Cyclization
R1
R & R1= Alkyl/Aryl
SCHEME - 1.15
Nevertheless, a one pot synthesis of 2-amino-1,3,4-oxadiazoles mediated by
tosylimino phenyl iodane has been described by Prabhu et al. In this protocol
acylthiosemicrbazides obtained from corresponding acyadrazides undergo efficient
cyclodesulphurization (SCHEME - 1.15) . 108
1.7. IMPORTANCE OF OXADIAZOLS IN PHARMACOLOGICALLY
1,3,4-Oxadiazole is a versatile lead compound for designing potent bioactive
agents 109 and it has become an important construction motif for the development of new
drugs.110, 111 In recent years the number of scientific studies with these compounds has
increased considerably. Taking into account the importance of these compounds to both
heterocyclic and medicinal chemistry, the researcher has described the main synthesis
approaches used for obtaining the heterocyclic nucleus, as well as the broad spectrum of
pharmacological activities.87, 112, 113 as mentioned below.
Chapter - 1
20
1.7.1. ANTICANCER AGENTS
Cancer, the second cause of mortality in the world, after cardiovascular disease. 114
is continuing to be a major health hazard in developing as well as in undeveloped
countries.115 Design and development of anticancer drugs with fewer or no side effects
are important for the treatment of cancer. The search for such potential anticancer drugs
has led to the discovery of synthetic molecules with anticarcinogenic activity. Therefore,
cancer has become a major challenge to mankind, 116 and it has opened up myriad new
avenues for advance drug design and discoveries. Cancer may affect people at all ages,
even fetuses, 117 but the risk of different types of cancer varies with age. In the present-
day, there are three main methods of cancer treatments are surgery, radiation therapy and
chemotherapy. With the development of molecular biology, chemotherapy is becoming a
more important therapeutic method. Therefore, designing new anti-cancer drugs with high
competence and wide spectrum activity is an extensive study platform today.
Cl
O
F
O
O
O
F
Cl
N
O
N
NH
N
N
NO
Cl
Cl
O
14 15
Cl
Br
Based on these observations, researchers synthesized and investigated 1,3,4-
oxadiazole analogues as anticancer agents. For instance, our group86 has synthesized
benzophenones bearing oxadiazoles and structural activity relationship suggests that the
position and the type of substituent on the aromatic ring are important for anticancer
activity. Compound (14) with chloro and bromo group play a dominant role in inhibiting
Chapter - 1
21
the leukemic cell proliferation. Whereas, benzimidazoles bearing oxadiazole nucleus (15)
exhibited remarkable anticancer activity against most of the tested cell lines. 118
Furthermore, in search of a new agent for the treatment of cancer benzimidazole
bearing 1,3,4-oxadiazole (15) was synthesized as a lead compound with a broad spectrum
of anticancer activities. 119 1,3,4-Oxadiazoles present ample opportunities for scientists in
drug discovery. The widespread use of them as a scaffold in medicinal chemistry
establishes this moiety as a member of the privileged structures class.
HN N
N N
O
Br
NH2
O
Br
16 17
N
N
O
S
N
N NO2
O2N
In particular, 1,3,4-oxadiazole analogue (21) has been found to exhibit excellent
anticancer activity. The in vitro anticancer activity of this compound was evaluated
against three cancer cell lines by the MTT method, which has shown activity superior to
the positive control.120
1.7.2. XANTHINE OXIDASE INHIBITORY AGENTS
An increasing number of researchers during the past decade have suggested that
xanthine oxidase (XO) plays an important role in various forms of ischemic and other
types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure.121
XO is a complex metalloflavoprotein that catalyzes the conversion of hypoxanthine to
xanthine and xanthine to uric acid with concomitant production of hydrogen peroxide and
superoxide anions.122 Increase in uric acid level in serum eventually leads to the
Chapter - 1
22
deposition of microand macroscopic deposits of sodium hydrogen urate monohydrate
crystals in the joints of humans that leads to the hyperuricemic condition called gout.123
NHN
OS
TsO
NN
O
HN
O
18 19
Gout is a common disease with a higher prevalence in men older than 30 years
and in women older than 50 years.124 These findings highlight the need for emerging
treatments to effectively lower urate levels.125, 126 These observations and researcher
interest in the pharmaceutical chemistry of heterocyclic compounds promoted them to
synthesize a series of different derivatives of 1,3,4-oxadiazole and investigated them in
the reduction of swelling and pain. In this connection, compounds (18)127exhibited
potential inhibition response towards the reduction of pain with lower IC50 value.
Correspondingly compound (19)128 shown strong inhibition towards the enzyme
compared to the standard drug allopurinol.
1.7.3. ANTIMICROBIAL AGENTS
Infections diseases represent a critical issue for health and the major cause of
morbidity and mortality worldwide. Despite significant progress in human medicine,
infections diseases caused by microorganisms are still a serious threat to public health. 129
The impact is even greater in developing countries due to unavailability of medicine in all
the locations, the practice of self-medication and the emergence of microorganism drug
resistance.130 The development of resistance to current antibacterial therapy continues to
drive the search for more effective agents. In addition, primary and opportunistic fungal
infections continue to increase the number of immune compromised patients, those
suffering from such as AIDS or cancer or who have undergone organ transplantation.131
In recent years, the incidence of fungal and bacterial infections has increased
Chapter - 1
23
dramatically. The widespread use of antibacterial and antifungal drugs resulted in
resistance to drug therapy against bacterial and fungal infections, which led to serious
health hazards. 132 The resistance of the wide spectrum antibacterial and antifungal agents
has initiated discovery and modification of the new antibacterial and antifungal drugs. 133
N
N
O
O
N
20 21
N
O Cl
O
NN
C6H4Br
O
O
Cl
Cl
The literature study reveals that oxadiazoles are an important pharmacophore and
exhibits outstanding microbial activity. For example, oxadiazole analogue (20)83 was
synthesized and evaluated for antifungal activity. Interestingly, it has shown almost
equivalent antibacterial activity to standard drug.
Moreover, 2,5-di substituted oxadiazole bearing aryl moiety were synthesized and
screened in vitro for their efficacy as antimicrobial agents against bacterial and fungal
strains by broth dilution method. Among the series, compound (21) showed potent
antimicrobial activity against candida albicans and aspergillus flavus screened strains.134
1.8. COMMERCIAL APPLICATIONS
The analogues of 1,3,4-oxadiazole, have a wide number of commercial
applications. For instance, they are commercially used for modification and/or regulation
of plant growth to provide beneficial effects which are appreciated by the agricultural art.
Among the most well recognized classes of plant growth regulatory chemicals are plant
growth stimulants. Thus, oxadiazole analogues have been applied to fruits such as pears,
lemons, grapes and cherries to increase the size and/or amount of fruit developed; to
vegetables such as asparagus, celery and lettuce to promote vegetative growth; to seeds of
Chapter - 1
24
crops such as oats, peas, cotton, rye, soybeans and wheat to promote the rapid emergence
and to ornamentals to produce earlier blooming or more profuse or larger flowering. 135
During the past decade, organic electronics have attracted a great deal of interest
due to its applicability in a wide range of applications and high potential for commercial
success. These applications, notably range from organic light emitting diodes to organic
photovoltaics and sensors. Organic diodes undoubtedly have the potential to redefine
many present day lighting solutions if the performances and device stability are
significantly improved. Over the years, several basic structures have received the
attention of researchers for the design of these appealing materials, namely
triphenylamines and oxadiazoles that can respectively act as the hole-transporting and
electron-transporting moieties in these ambipolar materials.136
Furthermore, 1,3,4-oxadiazole analogues have been used as a pi-conjugation relay
to prepare a number of donor-acceptor molecules carrying a pi-electron rich aromatic
ring. Therefore, these compounds may be a good candidate for optical material or
biologically active chemicals.137 1,3,4-Oxadiazoles have proved to be useful in material
science as a probe for their fluorescence and scintillation properties.138 In addition, 1,3,4-
oxadiazole derivatives have been widely used as electron conducting and hole blocking
material in molecules based as well as polymeric light emitting devices.139
1.9. IMPORTANCE OF AMIDE LINKAGE
The amide formation reaction being a key reaction in organic chemistry and the
amide bond is widely prevalent in both naturally occurring and synthetic compounds. It is
increasingly important in pharmaceutical chemistry, being present in 25% of available
drugs, with amidation reactions being among the most commonly used reactions in
medicinal chemistry. There is considerable interest in the development of new approaches
Chapter - 1
25
to direct amidation and amide bond formation is one of the most important reactions used
in the industry for which better reagents are required.140
The amide functionality is a common feature in small or complex synthetic or
natural molecules. For example, it is ubiquitous in life, as proteins play a crucial role in
virtually all biological processes Amides also play a key role for medicinal chemists.141
This can be expected, since carboxamides are neutral, are stable and have both hydrogen-
bond accepting and donating properties. Amide linkages142 are not only the key chemical
connections of proteins, but they are also the basis for some of the most versatile and
widely used synthetic heterocyclic compounds, materials and polymers. Chemical
reactions for their formation are among the most executed transformations in organic
chemistry. In living systems, most amide bonds are formed by the complex factors that
are ribosomes. Long, complex proteins are assembled amino acid by amino acid, using a
templated amidation of amines and the active esters of amino acid monomers and RNA.
In addition, the amide bond is commonly found as a key structural element in
agrochemicals and in products from the fine chemicals industry.
1.10. SYNTHETIC FEATURE OF AMIDE LINKAGE
Amide bond formation is a fundamentally important reaction in organic synthesis,
and is typically mediated by one of a myriad of so-called coupling reagents (SCHEME -
1.16).
R1
OH
O
+
Coupling
reagents
Base
Solvent
R1
NH
O
R2
R1 & R2 = Alkyl/Aryl
SCHEME - 1.16
Chapter - 1
26
The various coupling reagents used for the formation of amide linkage are N-
hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 1-hydroxy benzo-
triazole, 6-chloro-1-hydroxy benzotriazole, 1-hydroxy-7-azabenzotriazole, dicyclohexyl-
carbodiimide and more recently 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine and its
aza derivative.143, 144
Formally, the amide bond is formed through the condensation of a carboxylic acid
and an amine with the release of one equivalent of water. This reaction has been
considered challenging due to the competing acid–base reaction. Although there are a
large range of reagents and strategies for amide bond formation available, few can really
be considered ideal. Currently there is a focus on the development of novel, atom-
economical, benign methods for amidation, and there have been many recent
developments in this field. An important consideration here is the ease with which the
reagent or catalyst can be separated from the resulting product. Alternatively, a number of
metal-based catalytic systems have also been reported, under strictly anhydrous
dehydrating conditions. 145, 146 Nevertheless, 3,4,5-trifluorobenzeneboronic acid as a
catalyst was found to be the most active and for the reaction of benzylamine with 4-
phenylbutyric acid, to afford amide in 96% yield as shown in SCHEME-1.17.147
NH2
O
HO
+
NH
O
B)OH)2F
F
F
SCHEME - 1.17
3,4,5-Trifluorobenzeneboronic acid is also an effective catalyst for the poly
condensation of carboxylic acids and amines.148 Direct polycondensation is desirable both
environmentally and industrially. The direct polycondensation of adipic acid and
Chapter - 1
27
hexamethylenediame was examined for the formation of nylon-6,6 with a yield of 89%
This amidation procedure has been employed in the synthesis of several active
pharmaceutical ingredients. 149, 150
Formation of amide linkage was also focused on the thermal amidation151 as
depicted in SCHEME-1.18.
NH2
+
NH
OHO
110o
C
O
SCHEME - 1.18
In recent years, it has been reported that simple borate esters are effective reagents
for the direct synthesis of amides from carboxylic acids or primary amides.152 Boron
mediated amidation reactions have attracted considerable attention, and in most cases, the
amide products can be purified by a simple filtration procedure using commercially
available resins, with no need for aqueous workup or chromatography (SCHEME-1.19).
R1, R2, R3 & R4 = Alkyl /Aryl
SCHEME-1.19
The use of microwave irradiation has been reported to simplify and improve a
number of organic reactions, often leading to higher conversions and shorter reaction
times.153 Preparation of amides by the heating of carboxylate ammonium salts obtained
Chapter - 1
28
from the mixture of an amine and carboxylic acid has been examined under microwave
irradiation conditions in the absence of a catalyst and of solvent (SCHEME-1.20).
R
O
OHR1
NH
R2R
O
ONH2R1R2
+
R
O
NR1R2
MWMW
R, R1 & R2 = Alkyl/Aryl
SCHEME - 1.20
For example, benzylamine reacted with benzoic acid affording the corresponding
amide in high yield (80%). However, when the same reaction was heated using an oil
bath, only 8% yield of the amide was isolated.
1.11. PHARMACOLOGICAL IMPORTANCE OF AMIDE LINKAGE IN
HETEROCYCLIC COMPOUNDS
Amides are versatile organic compounds since all the three atoms in the O-C-N
chain are potentially reactive. This result partly due to the delocalization of the
π-electrons along the O-C-N chain. The partial double-bond character in the CO-NH bond
generates a 1,3-dipole, with nitrogen bearing the partial positive charge and oxygen the
partial negative charge. The consequences of partial double bond character are the planar
nature of the amide group and the existence of configurational isomers, whereas donor-
acceptor properties of the amide moiety manifest in acid base and complexing
interactions and a tendency to self associate are a consequence of its dipolar structure.154
The versatility of the amide group in forming partial bonds with itself and many other
functional groups is partly responsible for the structural subtleties of the biologically
important proton derivatives. The SAR also indicated that the major interactions of RT
enzyme are through the amide group.155
The amide linkage highlight how this chemical bond factor in the design of
enzyme inhibitors, cyclic peptides, antibacterial agents, and emerging nanotechnology
applications. Because of the broad functions exhibited by the various members of the
Chapter - 1
29
fatty acid amide family, a wide range of indications could benefit from a fatty acid amide-
targeted drug, including cancer, cardiovascular disease, inflammation, pain, drug
addition, eating disorders, anxiety and depression.156, 157 Looking to the importance of
amide linked compounds, research in this area is stimulated with methods of synthesis,
and pharmacology of amide linked heterocyclic compounds as briefed below.
1.11.1. ANTICANCER AGENTS
In the current scenario, development of anticancer drugs with specific targets is of
prime importance in modern chemical biology. Observing the importance of amide linked
hetericyclic analogues, it would be worthwhile to design and synthesize novel compounds
as potent anticancer agent. In this connection, our research group has synthesized and
investigated compound (22) in vitro against the Michigan Cancer Foundation-7 and
Ehrlich’s ascites tumor cell lines.158 Further, investigation resulted in the achievement of
compound (23) endowed with excellent antiproliferative potency with significant IC50
value and in vivo antitumor effect of the same compound against murine EAC and solid
DL tumor model system was evident by the extended survivality. 159
O
ONH
O HN
O
O
O
Br
O
H3C
Br O
HN
NH
O
O
O
O
22 23
1.11.2. XANTHINE OXIDASE INHIBITORY AGENTS
The increasing prevalence of gout has been accompanied by a growing number of
patients intolerant to or with disease refractory to the available urate-lowering therapies.
This metabolic disease is a common disease with a higher prevalence in men older than
Chapter - 1
30
30 years and in women older than 50 years. These findings highlight the need for
emerging treatments to effectively lower urate levels.
O
O
CH3
HN
N
O
S
O
OCH3
I
NHO
HNO
NN
O
24 25
In this view, amide linked pyrimidone (24)160 was synthesized and investigated as
XO which exhibited good inhibitory activity. Also, amide linked thiazolidone (25) with
methoxy substituent was demonstrated as potent inhibitors of XO. 161
1.11.3. ANTIMICROBIAL AGENTS
There is an increasing demand for the development of compounds having
improved properties and which can be used against several different diseases, such as the
treatment of an infection caused by a microorganism. Concerning microbial diseases,
antibiotic research at the industrial level has been focused on the identification of more
refined variants of already existing drugs.162
O
CH3
O
O
N
H
HN
Cl
O
N CH3
26 27
O
N
NO
S
O
HN
SN
O
Chapter - 1
31
Despite the rapidity with which new chemotherapeutic agents are introduced,
microbes have shown a remarkable ability to develop resistance to these agents and the
search for new drugs, such as amide linked heterocyclic compounds, is in progress. These
drugs have a different mode of action compared to the commonly used commercial drugs.
For instance, the compound (26)163 was recognized as persuasive compounds towards
both the bacterial and fungal strains. Moreover compound (27)164 containing amide
linkage with benzthiazole, oxadiazole and coumarin heterocyclic ring exhibited good
antimicrobial activity.
1.12. AIMS AND OBJECTIVES:
In the pharmaceutical field, there has always been and will continue to be a need
for new and novel chemical entities with diverse biological activities. Our efforts focus on
the introduction of chemical diversity in the molecular framework in order to synthesize
pharmacologically interesting compounds of widely different composition. During the
course of research work, several entities have been designed, generated and characterized
using spectral studies. Besides, biological activities of the generated entities were carried
out. The details are as under.
Overview of literature survey of the biological activity of heterocyclic compounds
in particular, nitrogen containing heterocycles.
Synthesized several analogues like various heterocyclic ring appended
benzopheone analogues via amide linkage, benzophenones bearing oxadiazole
nucleus analogues, substituted nicotinic acid based 4-aryloyl aryloxyacet
hydrazides and 2,5-diphenyl alkoxy 1,3,4-oxadiazoles.
Characterized all the synthesized compounds for structure elucidation using
spectroscopic techniques like IR, 1H NMR, 13C NMR and mass spectral studies.
Chapter - 1
32
Heterocyclic ring appended benzopheone analogues via an amide linkage were
screened for xanthine oxidase inhibition.
Evaluated benzophenones bearing oxadiazole nucleus for the better drug's
potential against different strains of bacteria and fungi.
Substituted nicotinic acid based 4-aryloyl aryloxyacethydrazides were screened
for antiproliferative and apoptogenic properties against Dalton’s lymphoma by
both in vitro and in vivo analysis.
Evaluated anticancer activity of the 2,5-diphenyl alkoxy 1,3,4-oxadiazoles.
1.13. REFERENCES
1. Joule JA and Mills K, Heterocyclic Chemistry, 4th edn, Blackwell Science,
Oxford, 2000.
2. Katritzky AR, Rees CW, Scriven EFV, Comprehensive Heterocyclic
Chemistry II, A Review of the Literature 1982–1995, vols. 1-11, Pergamon
Press, Oxford, 1996.
3. Valverde MG and Torroba T, Sulfur-Nitrogen Heterocycles Molecules, 2005,
10, 318.
4. Gilchrist TL, Heterocyclic Chemistry, 2nd edn. Longman/Wiley,
Harlow/Chichester, 1992.
5. Katritzky AR, Handbook of Heterocyclic Chemistry, Pergamon Press,
Oxford, 1985.
6. Katritzky AR and Rees CW, Comprehensive Heterocyclic Chemistry, vols.
1-8, Pergamon Press, Oxford, 1984.
7. Katritzky AR, Karelson M and Malhotra N, Heterocyclic Aromaticity in
Heterocycles, 1991, 32, 127.
Chapter - 1
33
8. Eichner T and Hauptmann S, The Chemistry of Heterocycles, Second Edition,
Wiley-VCH, Weinheim, Germany, 2003.
9. Pozharskii AF, Soldatenkov AT, Katritzky AR, Heterocycles in Life and
Society, An Introduction to Heterocyclic Chemistry and Biochemistry and the
Role of Heterocycles in Science, Technology, Medicine and Agriculture,
Wiley, New York, 1997.
10. Johnson TC, Martin TP, Mann RK, Pobanz MA, Bioorg. Med. Chem, 2009,
17, 4230.
11. Muehlebach M, Boeger M, Cederbaum F, Cornes D, Friedmann AA, Glock J,
Niderman T, Stoller A, Wagner T, Bioorg. Med. Chem, 2009, 17, 4241
12. Kleschick WA, Gerwick BC, Carson CM, Monte WT, Snider SWJ, Agric J.
Food Chem, 1992, 40, 1083.
13. Katritzky AR, Ramsden CA, Screeven EFV, Taylor RJK, Comprehensive
Heterocyclic Chemistry III, Elsevier, New York, 2008.
14. Kiyota H and Marine, Natural Products, in Topics in Heterocyclic Chemistry,
Springer, Berlin, Germany, 2006, 5.
15. Chen Z, Wannere CS, Cominboeuf C, Puchta R, and Schleyer PVR, Chem.
Rev, 2005, 105, 3842.
16. Katritzky AR, Akhmedov NG, Doskocz J, Mohapatra PB, Hall CD, G¨uven A,
Magn. Reson. Chem, 2007, 45, 532.
17. Liu RS. Pure Appl. Chem, 2001, 73, 265.
18. Reddy GPV, Kiran YB, Reddy SC, Reddy DC, Chem. Pharm. Bull, 2004, 52,
307.
19. Hafez A, Eur. J. Med. Chem, 2008, 43, 1971.
Chapter - 1
34
20. Henke BR, Aquino CJ, Berkimo LS, Croom DK, Dougherty RW, Ervin GN,
Grizzle MK, Hirst GC, James MK, Johnson MF, Queen KL, Sherrill RG, Sugg
EE, Suh EM, Szewczyk JW, Unwalla RJ, Yingling J, Willson TM, Med J.
Chem, 1997, 40, 2706.
21. Faulkner DJ, Natural Products Reports, 2000, 17, 5.
22. Chen-Yi Chen, Liberman David R, Larsen Robert D, Reamer Robert A,
Verhoeven R, Thomas, Reider, Paul J, Bioog. Med. Chem. Lett, 1994, 4,
6981.
23. Kang YK, Shin KJ, Yoo KH, Seo KJ, Hong CY, Lee CS, Park SY, Kim DJ,
Park SW, Bioog. Med. Chem. Lett, 2000, 10, 95.
24. Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer JL,
Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS, Seibert ,.
Journal. Med. Chem, 2000, 43, 775.
25. Giovannoni MP, Vergelli C, Ghelardini C, Galeotti N, Bartolini A, KalPiaz
VJ, Med. Chem, 2003, 46, 1055.
26. Li WT, Hwang DR, Chen CP, Shen CW, Huang CL, Chen. TW, Lin CH,
Chang YL, Chang YY, Lo YK, Tseng HY, Lin CC, Song JS, Chen HC, Chen
SJ, Wu S. H, Chen CT. Journal Med. Chem, 2003, 46, 1706.
27. Cordell, GA, Quinn-Beattie ML, Diazines, Farnsworth NR, Phytother Res,
2001, 15, 183.
28. Hughes EH and Shanks JV, Metab. Eng, 2002, 4, 41.
29. Michael JP, Nat. Prod. Rep, 2003, 476.
30. Kumar SK, Hager E, Pettit C, Gurulingappa H, Davidson NE, J. Med. Chem,
2003, 46, 2813.
31. Sadanandam YS, Shetty MM , Diwan PV, Med. J. Chem, 1992, 27, 87 .
Chapter - 1
35
32. Pathak R, Roy AK, Kanojiya S, Batra S, Tetrahedron Lett, 2005, 46, 5289.
33. Pozharskii AF, Soldatenkov AT, Katritzky AR, Heterocycles in life and
society, an introduction to Heterocyclic Chemistry, Biochemistry and
Applications, 2nd edition, John Wiley and sons Ltd, 2011.
34. Komeilizadeh H, Iranian J. Pharm. Res, 2006, 5, 229.
35. Koehn FE and Carter GT, Nat. Rev. Drug Discov, 2005, 4, 206.
36. Lipshutz BH, Chem. Rev, 1986, 86, 795.
37. Chin YW, Balunas MJ, Chai HB, Kinghorn AD, Drug Discov. Natural
Sources, AAPS J, 2006, 8, 239.
38. Koehn FE and Carter GT, Nat. Rev. Drug Discov, 2005, 4, 206.
39. Gupta UC, Bhatia S, Garg A, Sharma A, Choudhary V, Perspect Clin.
Res, 2011, 2, 13.
40. Bradley D, Mod. Drug Discov, 2001, 4, 32.
41. Mittal A, Synthetic Nitroimidazoles, Biological Activities and Mutagenicity
Relationships, Sci. Pharm, 2009, 77, 497.
42. Larhed M and Hall berg A, Drug Discov, Today 2001, 6, 406.
43. Wathey B, Tierney J, Lidrom P, Westman J, Drug Discov. Today, 2002, 7,
373.
44. Drews J, Science, 1960, 2000, 287.
45. Wess G, Urmann M, Sickenberger B, Angew. Chem. Int. Ed. 2001, 40, 3341.
46. Lombardino JG, Lowe III JA, Nat. Rev. Drug Discov, 2004, 3, 853.
47. Horton DA, Bourne GT, Smythe ML, Chem. Rev, 2003, 103, 893.
48. Gomtsyan, Chem. Heterocycl. Compds, 2012, 48, 7.
49. Mittal A, Sci. Pharm, 2009, 77, 497.
Chapter - 1
36
50. Joule JA and Mills, Heterocyclic Chemistry, 4th Ed., Blackwell Publishing,
2000, 369.
51. Nekrasov DD, Chem. Heterocycl. Compds, 2001, 37, 263.
52. Lijun W, Na S, Simon T, Xuejun Z, David RB, Biochem, 2006, 45, 13750.
53. Das U, Pati HN, Panda AK, DeClercq E, Balzarini J, Molnar J, Barath Z,
Ocsovszki I, Kawase M, Zhou L, Sakagami H, Dimmock. JR. Bioorg. Med.
Chem, 2009, 17, 3909.
54. Louis J, Lombardo, Francis Y, Lee, Ping Chen, Derek Norris et al. J. Med.
Chem, 2004, 47, 6658.
55. Gilligan PJ, Robertson DW, Zaczek RJ, Med.Chem, 2000, 43, 1641.
56. Norman, SR, Drug Design, Hiding in Full View, Drug Development Res,
2008, 69, 15.
57. Katritzky AR and Rees CW, Eds. Comprehensive Heterocyclic Chemistry,
Vol. 1, Pergamon, Oxford, UK, 1984.
58. Pozharskii AF, Soldatenkov AT, and Katritzky AR, Heterocycles in Life and
Society, An Introduction to Heterocyclic Chemistry and Biochemistry and the
Role of Heterocycles in Science, Technology, Medicine and Agriculture,
Wiley, New York, 1997.
59. Arthur D. Olin Advances in chemistry 1968, Chapter 14, 254.
60. Chauhan PMS, Kumar, Comb A, Chem. High Throughput Screen, 2002, 5, 93.
61. Yang RY and Kaplan AP, Tetrahedron Lett, 2001, 42, 4433.
62. JánMalík, Gilbert Ligner, Polymer Science and Technology Series , 1998, 1,
353.
63. Saron C, Felisberti MI, Zulli F, Giordano M, Braz J. Chem. Soc, 2007, 18,
900.
Chapter - 1
37
64. JacekLubczak*, RenataLubczak, IwonaZarzyka-Niemiec J. Appl. Poly. Sci,
2003, 90, 3390.
65. Gephart III RT, Williams NJ, Reibenspies JH, De Dousa AS, Hancock RD,
Inorg. Chem, 2008, 47, 10342.
66. Fave C, Cho TY, Hissler M, Chen CW, Luh TY, Wu CC, and R´eau RJ. Am.
Chem. Soc, 2003,125, 9254.
67. Singh RP, Verma RD, Meshri DT, Shreeve JM, Angew. Chem. Int. Ed, 2006,
45, 3584.
68. Balaban AT, Oniciu DC, Katritzky AR, Chem. Rev, 2004, 104, 2777.
69. Hamada Y, Takeuchi IJ. Org. Chem, 1977, 42, 4209.
70. Lagoja IM, Chem. Biodivers, 2005, 2, 1.
71. Saha R, Tanwar O, Marella A, Alam MM, Akhter M, Mini. Rev. Med. Chem,
2013, 13, 1027.
72. Khan MK, Zia-Ullah, Rani M, Perveen S, Haider M, Choudhary, M. I. Org.
Chem. Lett. 2004, 1, 50.
73. Sumangala V, Boja P, Punith B, Chidananda N, Arul Moli T, Shalini S, Der
Pharma Chemica, 2011, 3, 138.
74. Vidya G, PCT Int. Appl. WO 2009090548, 2009, 82.
75. Gilani S, Khan S, Siddiqui N, Bioorg. Med. Chem. Lett, 2010, 20, 4762.
76. Zheng Q, Zhang X, Xu Y, Cheng K, Jiao Q, Zhu H, Bioorg. Med. Chem,
2010, 18, 7836.
77. Bhat M, Al-Omar M, Siddiqui N, Pharma Chemica, 2010, 2, 1.
78. Bao-Lei W, Zheng-Ming L, Yong-Hong L, Su-Hua W, Xuexiao G, Xuebao H,
2008, 29, 90.
Chapter - 1
38
79. Bankar G, Nampurath G, Nayak P, Bhattacharya S, Chem. Biol. Interact,
2010, 183, 327.
80. Ranganatha VL, Al-Ghorbani M, Naveen P, Begum BA, Prashanth T,
Khanum SA, Der. Pharma. Chemica, 2013, 5, 240.
81. Girisha V, Khanum NF, Gurupadaswamya HD, Khanum SA, Russ. J. Bioorg.
Chem, 2014, 40, 330.
82. Gurupadaswamy HD, Kantharaju P, Khanum NF ,Khanum SA. Int. J. Med.
Pharmaceuti Sci, 2013, 1, 1.
83. Khanum SA, Shashikanth S, Sathyanarayana SG, Lokesh S, Deepak SA, pest
manage. Sci, 2009, 65, 776.
84. Mehta DK, and Das R, Int. J of Phar Sci and Res. 2011, 2, 2959.
85. Oliveira CS, Lira BF, Barbosa-Filho JM, Lorenzo JGF, de Athayde-Filho PF,
Molecules, 2012, 17, 10192.
86. Gurupadaswamy HD, Girish V, Kavitha CV, Raghavan S C, Khanum SA ,
Eu. J. Med. Chem, 2013, 63, 536.
87. Savarino A, Expert Opin. Investig. Drugs, 2006, 15, 1507.
88. Leung D, Du W, Hardouin C, Cheng H, Hwang I, Cravatt BF, Boger DL,
Biorg. Med. Chem. Lett, 2005, 15, 1423.
89. Borg S, Vollingra R, Labarre CM, Payza K, Terenius L, Luthman K, J. Med.
Chem, 1999, 42, 4331.
90. Polshettiwar V and Varma RS, Tetrahedron Lett, 2008, 49, 879.
91. Belkadi M and Othman AA, ARKIVOC, 2006, xi, 183.
92. Pouliot MF, Angers L, Hamel JD, Paquin JF, Org. Biomol. Chem, 2012, 10,
988.
93. Ranganatha VL, Khanum SA, Russ. J. Bioorg. Chem, 2014, 40, 206.
Chapter - 1
39
94. Jayashankara B, Lokanath Rai KM, Bhaskarn N, Satish HS, Eu. J. Med.
Chem, 2009, 44, 3898.
95. Khanum SA, Shashikanth S, Sudha BS, Het. Atom. Chem, 2004, 15, 37.
96. Hetzheim A, Mueller G, Vainilavicius P, Girdziunaite D, Pharmazie, 1985, 40,
17.
97. Mogilaiah K, Sakram B, Indian J. Heterocycl. Chem, 2004, 13, 289.
98. Ramesh D, Sreenivasuhi B, Indian J. Heterocycl. Chem, 2003, 13,163.
99. Chen H, Li Z, Han Y, Agric J. Food Chem, 2002, 48,5312.
100. Chiriac C, Rev. Chim. (Bucharest), 1983, 34, 1131, Chem. Abstr, 1984, 100,
174735.
101. Rigo P, Cauliez D, Fasseur D, Couturier D, Synth. Commun, 1986, 16, 1665.
102. Kalinin A, Khasapov B, Aposav E, Kalikhman I, Ioffe S, Izv, Akad Nauk
SSSR Ser. Khim.1984, 694; Chem. Abstr, 1984, 101, 91045.
103. Theocharis A and Alexandrou N, J. Heterocycl. Chem, 1990, 27, 1685.
104. Reddy P, Ind. J. Chem. Sect. B, 1987, 26, 890.
105. Hiremath S, Goudar N, Purohit M, Ind. J. Chem. Sect. B, 1982, 21, 321.
106. Rostamizadeh S, Ghasem SA, Tetrahedron Lett, 2004, 45, 8753.
107. Guda DR, Mo Cho H, Euy Lee M, RSC Adv, 2013, 3, 6813.
108. Prabhu G, Madhu C, Sureshbabu VV, Ind. J. Chem, 2014, 53, 865.
109. Sharma S, Sharma PK, Kumar N, Dudhe R, Der Pharma Chemica, 2010, 2,
253.
110. Isloor AM, Kalluraya B, Pai KS, Eur. J. Med. Chem, 2009, 30, 1.
111. Zarghi A, Faizi M, Shafeghi B, Ahadian A, Khojastephpoor HR, Zanganeh V,
Tabatabi SA, Shaffire A, Bioorg. Med. Chem. Lett, 2005, 15, 3126.
Chapter - 1
40
112. Patraoa P, Khadera AMA, Kallurayaa B, Vinayachandrab, Der. Pharma.
Chemica, 2013, 5, 24.
113. Kumar R and Khokara SL, Int. J. Inst. Pharm. Life Sci, 2012, 2, 2249.
114. Gibbs JB, Science, 2000, 287, 1969.
115. Eckhardt S, Curr. Med. Chem, 2002, 3, 419.
116. Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Böhm-Vélez M,
Pisano ED, Jong RA, Evans WP, Morton MJ, Mahoney MC, Larsen LH, Barr
RG, Farria DM, Marques HS, Boparai K, JAMA, 2008, 18, 2151.
117. Murphey GP, CA-cancer statistics, 1999, 49, 20.
118. Rashid M, Husain A, Mishra R, Eu. J. Med. Chem, 2012, 54, 855.
119. Husain A, Rashid M, Mishra R, Parveen S, Shin DS, Kumar D, Bioorg. Med.
Chem. Lett. 2012, 22, 5438.
120. RuDua Q, Dong Li a D, Pi Y, Li J, Sun J, Fang F, Zhong W, Gongc H, Zhu H,
Bioorg. Med. Chem. 2013, 21, 2286.
121. Harrison R, Drug Metab. Rev, 2004, 36, 363.
122. Berry CE and Hare JM, J. Physiol. Lond, 2004, 555, 589.
123. Beedkar SD, Khobragade CN, Chobe SS, Dawane BS, Yemul OS, Int. J. Biol.
Macromol, 2012, 50, 947.
124. Hille R, Chem. Rev, 1996, 96, 2757.
125. Harris MD, Siegel LB, Alloway JA, Am. Fam. Physician, 1999, 59, 925.
126. Pacher P, Nivorozhkin A, Szabo C, Pharmacol. Rev, 2006, 58, 87.
127. Yong L, Yong Z, Bo C, Jing-yu Y, Fang-yang W , Shao-jie W, Chinese. J.
Med. Chem, 2012, 22, 1.
128. Singh AK, Lohani M, Parthsarthy R, Iranian. J. Pharm.Res, 2013, 12, 319.
129. Suree N, Jung, ME, Clubb RT, Mini-Rev. Med. Chem, 2007, 7, 991.
Chapter - 1
41
130. Buzzini P, Arapitsas P, Goretti M, Branda E, Turchetti B, Pinelli P, Ieri F,
Romani A, Mini-Rev. Med. Chem, 2008, 8, 1179.
131. Ghannooun MA and Rice LB, Clin. Microbiol. Rev, 1999, 12, 501.
132. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, Edwards
JE, Clin. Infect. Dis, 2000, 30, 662.
133. Khanum SA, Shashikanth S, Umesha R, Kavitha, Eur. J. of Med. Chem, 2005,
40, 1156.
134. Fuloria NK, Singh V, Shaharyar M, Ali M, Molecules, 2009, 14, 1898.
135. Blem AR, Plant HL , Richard R, Regis, 1990, US4919703 A.
136. Dumur F and Goubard F, New. J. Chem, 2014, 38, 2204.
137. Dabiri M, Salehi P, Baghbanzadeh M, Bahramnejad M, Tetrahedron Lett, 2006,
47, 6983.
138. Hays FN, Rogers BS, Off DG. J. Am. Chem. Soc, 1955, 77, 1850.
139. Brown AR, Bradley DDC, Burns PL, Burroughes JH, Friend RH, Greenham
NC, Burn PL, Appl. Phys. Lett, 1992, 61, 2799.
140. Rachel Lanigan M, Tom Sheppard D, Eu. J. Org. Chem. 2013, 7453.
141. Ghosh AK, Thompson WJ, McKee SP, Duong TT, Lyle TA, Chen JC, Darke
PL, Zugay JA, Emin, EA, Schlei WA, Huff JR, Anderson PSJ, Med. Chem,
1993, 36, 292.
142. Houghten RA, Pinilla C, Blondelle SE, Appel JR, Dooley CT, Cuervo JH,.
Nature, 1991, 354, 84.
143. Valeur E and Bradley M, Chem. Soc. Rev, 2009, 38, 606.
144. El-Faham A and Albericio F, Chem. Rev, 2011, 111, 6557.
145. Allen CL and Williams JMJ, Chem. Soc. Rev, 2011, 40, 3405.
146. Roy S, Gribble GW, Tetrahedron, 2012, 68, 9867.
Chapter - 1
42
147. Ishihara K, Ohara S, Yamamoto H, J. Org. Chem, 1996, 61, 4196.
148. Ishihara K, Ohara S, Yamamoto H, Macromol, 2000, 33, 3511.
149. Ishihara K, Tetrahedron, 2009, 65, 1085.
150. Mylavarapu RK, Kondaiah GCM, Kolla RN, Veeramalla, Koilkonda P,
Bhattacharya A, Bandichhor R, Org. Process Res. Dev, 2007, 11, 1065.
151. Allen CL, Chhatwal AR,Williams JMJ, Chem.Commun, 2012, 48, 666.
152. Lanigan MR, PavelStarkov, Sheppard D T, J. Org. Chem, 2013, 78, 4512.
153. Varma RS, Green Chem, 1999, 1, 43.
154. Barton SD, and Ollis WD, in “Comprehensive organic chemistry: The synthesis
and reactions of organic compounds.” Ed.; 1st Sutherland, C. J. Pergamon:
Oxford. New York , 1979, 2, 1003.
155. Wyatt PG, Bethell RC, Cammack N, Charan D, Dodic N, Dumaitre B, Evans
DN, Green DVS, Hopewell PL, Humber DC, Lamont RB, Orr DC, Plested SJ,
Ryan DM, Sollis SL, Storer R, Weingarten GG, J. Med. Chem, 1995, 38, 1657.
156. Di Marzo V, Bisogno T, De Petrocellis L, Chem. Biol, 2007, 14, 741.
157. Starowicz K, Nigam, S. Di Marzo V, Pharmacol. Ther, 2007, 114, 13.
158. Ranganatha VL, Zameer F, Meghashri S, Rekha ND, Girish V,
Gurupadaswamy HD, Khanum SA, Arch. Der Pharm, 2013, 346, 901.
159. Vijay ABR, Thirusangu P, Ranganatha VL, Firdouse A, Prabhakar BT,
Khanum SA, Eu. J. Med. Chem, 2014, 75, 211.
160. Gurupadaswamy HD, Girish V, Zameer F, Hegdekatte R, Chauhan JB,
Khanum SA, Arch. Pharm. Chem. Life Sci, 2013, 346, 1.
161. Ranganatha VL, Begum AB, Naveen P, Zameer F, Hegdekatte R, Khanum SA
Arch. Pharm. Chem. Life Sci, 2014, 347, 589.
Chapter - 1
43
162. Ranganatha VL, Khanum NF, Khanum SA, Internation. J. Med. Pharmaceuti
Sci, 2013, 3, 97.
163. Mitic D, Milenkovic M, Milosavljevic S, GoCevac D, Miodragovic Z,
AnCelkovic K, Miodragovic D, Eur. J. Med. Chem, 2009, 44, 1537.
164. Begum AB, Khanum NF, Naveen P, Gurupadaswamy HD, Prashanth T,
Khanum SA, International J. Sci. Res. Publi, 2014, 4,1.
165. Patel RV, Kumari P, Rajani DP, Chikhalia K.H, Med. Chem. Res, 2012, 21,
3119.