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INTRODUCTION AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR BIOLOGICAL SIGNIFICANCE

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Page 1: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

INTRODUCTION

AN OVERVIEW OF HETEROCYCLIC

COMPOUNDS AND THEIR

BIOLOGICAL SIGNIFICANCE

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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,

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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,

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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,

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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.

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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

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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

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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).

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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.

Page 35: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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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 .

Page 36: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 37: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 38: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 39: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 40: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 41: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 42: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 43: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.

Page 44: AN OVERVIEW OF HETEROCYCLIC COMPOUNDS AND THEIR …shodhganga.inflibnet.ac.in/bitstream/10603/102617/8/08_chapter 1.p… · heterocycles have constituted one the largest areas of

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.