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CHAPTER 1: INTRODUCTION
CHapter 1 Introduction
1.1. Introduction
Heterocyclic compounds are an important class of compounds, making up more
than half of all the known organic compounds. These compounds have shown
excellent biological activities in the area of both medicine and pesticide. Heterocycles
are present in a wide variety of drugs, most vitamins, many natural products,
biomolecules, and biologically active compounds including antitumor, antibiotic, anti
inflammatory, antidepressant, antimalarial, anti-HIV, antimicrobial, antibacterial,
antifungal, antiviral, antidiabetic, herbicidal, fungicidal, and insecticidal agents.
Hundreds of natural products and pharmaceutical active ingredients contain
heterocycles as central building blocks. Heterocyclic compounds are very widely
distributed in nature and are particularly important because of the wide variety of
physiological activities associated with this class of substances. Also, they have been
frequently found as key structural units in synthetic pharmaceuticals and
agrochemicals. Heterocyclic compounds are also of considerable interest because of
their synthetic utility as synthetic intermediates, protecting groups, chiral auxiliaries,
organic catalysts, and metal ligands in asymmetric catalysts. Therefore, substantial
attention has been paid to develop efficient new methods to synthesize heterocyclic
compounds.
A cyclic organic compound containing all carbon atoms in ring formation is
referred to as a carbocyclic compound. If at least one atom other than carbon forms a
part of the ring system, then it is designated as a heterocyclic compound [1]. The non-
carbon atoms in such rings are referred to as "heteroatoms". Nitrogen, oxygen and
sulphur are the most common heteroatoms, but heterocyclic rings containing other
hetero atoms are also widely known. The heterocyclic compounds having lesser
common atoms such phosphorus, tin, boron, silicon, bromine, etc. have been a subject
1
Cfiapterl Introduction
of much investigation in recent years. Several importEint compounds contain
heterocyclic rings e.g. the members of vitamin B complex, alkaloids, antibiotics,
chlorophyll, plant pigments, amino acids, dyes and drugs. HeterocycUc compoimds
form, by far, the largest of the classical divisions of organic chemistry. The majority
of pharmaceutical products that mimic natural products with biological activity are
heterocycles. These structures may comprise either simple aromatic rings or non-
aromatic rings.
1.2. Importance of Heterocyclic compounds to Life and Industry
Many heterocyclic compoimds are biosynthesized by plants and animals and are
biologically active. Some heterocycles are fundamental to life, such as haem
derivatives in blood and the chlorophyll essential for photosynthesis. Similarly, the
paired bases foimd in RNA and DNA are heterocycles, as are the sugars that in
combination with phosphates provide the backbones and determine the topology of
these nucleic acids.
Dye stuffs of plant origin include indigo blue, used to dye jeans. A poison of
detective novel fame is strychnine, obtained from the plant resin Ciuare. The
biological properties of heterocycles in general make them one of the prime interests
of pharmaceutical and biotechnology industries. Some of the active pyridine or
piperidine derivatives include natural products like nicotine (1) (addictive drug and an
insecticide), pyridoxine (vitaniiniB6), cocaine (a local anesthetic and drug of abuse)
and morphine (the diacetate derivative is Heroin) and two synthetic compoimds
nifedipine (2) (cardiovascular drug) and paraquat (3) (herbicide). There are many
thousands of other heterocyclic compounds (both natural and synthetic) of major
importance, not only in medicine but also in most other activities known to man.
Cfiapterl Introduction
O2N
MeOO' COOMe HCI +'=•
—N v\ /r\ /
=y HCI
1.3. Nitrogen containing Heterocyclic compounds
Nitrogen containing heterocycles are perhaps the most explored heterocyclic
compounds because of their occurrence in natural products and biologically active
compoimds. The most common examples of naturally occurring N-heterocycles which
are of fundamental importance to life are haemoglobin and chlorophyll. Haemoglobin
helps in oxygen transportation within the body while chlorophyll helps in light
harvesting that is further used for making ATP and NADPH. Both contain porphyrin
ring system. P-Lactam antibiotics such as penicillin (4) and cephalosporins (5),
nucleobases adenine (6), guanine (7), cytosine (8), thymine (9) and uracil (10);
alkaloids such as quinine an antimalarial and morphine a narcotic pain reliever
contain nitrogen as hetero atom.
S —NH
a
0 y—NH S ^
Cr py- ' P^'<' HO /=o /=o
NH2
HO
N- ~NH
N H ' ^ N ^ N H .
NHo
N H ^ O
8
w
H3C-.A, u o
NH
N H ^ O
o
9 10
chapter 1 Introduction
Most of the commercially synthesized drugs belong to heterocyclic class, e.g.
Indomethacin (11) (anti-inflammatory), Ciprofloxacin (12) (antibacterial).
Fluconazole (antifungal), Zidovudine (13) (anti-HIV), Diltiazem (14) (calciimi
chaimel blocker) etc.
HOOC
11
H0H2C^°vJ
N,
NH
13
12
COOH
14
Introduction of heteroatoms like nitrogen, sulphur, oxygen into a carbocyclic
compound makes a spectacular change in its chemistry and render it synthetically
much more attractive. For instance, depending on pH of the medium, heterocycles
may behave as acids or bases, forming anions or cations. Some interact readily with
electrophilic reagents, others with nucleophiles, yet others with both. In addition to
this, presence of heteroatoms brings tautomerism in heterocyclic series. Such a
versatile reactivity is associated with the electron distribution within heterocycUc
systems. Biologically active aromatic compounds constitute an important group of
pharmaceutical drugs, extensively utilized in various medicinal applications. The
Cfiapterl Introduction
heterocyclic compounds especially those containing sulphur and nitrogen atoms
possess a wide variety of biological activities [2, 3].
Heterocyclic compoimds, especially nitrogen heterocycles, are most important
class of compounds in the pharmaceutical and agrochemical industries, in which
heterocycles comprising around 60% are covered as a drug substance. Nitrogen-
containing heterocycles are particularly widespread in nature. The alkaloids, for
instance, are a special class of nitrogen-containing, naturally occurring heterocycles.
Furthermore, deoxyribonucleic acid (DNA), which is the carrier of genetic
information in all living beings, contains the nitrogen-containing heterocycles adenine
and guanine (purine bases), as well as cytosine and thymine (pyrimidine bases).
Ribonucleic acid (RNA) additionally contains the pyrimidine base uracil. Genetic
information is saved in the sequence of these purine and pyrimidine bases in the DNA
and RNA chains. Nitrogen-containing heterocycles (N-heterocycles) have tremendous
applications in pharmaceutical and material sciences. Their construction obviously
requires the introduction of a nitrogen-containing moiety through carbon-carbon and
carbon-nitrogen bond formation reactions.
1.4. Three membered nitrogen heterocycles
The chemistry of three membered heterocycles is dominated by ring strain. This
leads to enhanced reactivity in process in which the strain is relived. They are formally
derived from cyclopropane by replacing a carbon atom with a heteroatom. Three
membered saturated heterocyclic compound containing nitrogen is called aziridine
(15), aziridenes are good alkylating agents because of their tendency to undergo ring
opening reactions. The naturally occiuring mitomycin (16) containing the aziridine
ring shows antibiotic and antitumour activities. The other examples of nitrogen
containing three membered rings are diaziridine, 3H-diazirines and oxaaziridines.
5
chapter 1 Introduction
° CH2OCONH2
H N
15 16
1.5. Four membered nitrogen heterocycles
A four membered saturated heterocyclic compound containing nitrogen is
known as azetidine (17). The azetidine ring is much less strained than that of
aziridines. Azetidinone is present in many of the P- lactum derivatives which are
antibacterial agents, e.g. Clavulanic acid (18).
-O ^ O H
17 18
C"
1.6. Five membered nitrogen heterocycles
Pyrrole (19) is one of the most ubiquitous throughout the plant as well as animal
kingdom because of its involvement as a sub imit of haem, the chlorophyll, vitamin
B12 and some bile pigments. Pyrrole was first obtained by Rimge in 1834. Pyrrole
gives an intense red colour with p-dimethylamino benzaldehyde (Ehrlich test). The
Mly saturated tetrahydro pyrrole is designated as pyrrolidine (20).
H " " N
20 19
1.7. Five membered nitrogen heterocycles with two or more heteroatoms
The presence of additional nitrogen atoms in the ring has important effects on
the properties of the ring system, e.g. most azoles are stronger bases than pyrrole. The
Cfiapterl Introduction
azoles containing two nitrogen atoms in the 1,2 position are designated as pyrazole
(21), an oxygen and nitrogen at 1,2 positions designated as isoxazole (22) and a
sulphur, a nitrogen at 1,2 position designated as isothiazole (23).
{]> C^ {]> 21 22 23
When the two hetero atoms are present in 1,3-relationship, then they are
referred to as imidazole(24),oxazole(25) and thiazole(26).
H ^N^ / ° \ S
U U Q 24 25 26
Triazoles and tetrazoles
Derivatives of these heterocyclic compoimds have been used commercially as
pharmaceuticals, pesticides and dye stuffs e.g. raxil (27) a fungicide used for plant
protection and fluconazole (28) used for the treatment for fungal infections.
27 28
1.8. Six membered nitrogen heterocycles
Pyridine (29) is one of the most abundant aromatic six membered heterocycle
containing nitrogen. The pyridine ring occurs in many alkaloids; e.g. nicotine (30) and
in living systems e.g. pyridoxol (31)
CHapterl Introductwn
29 ^^ 30 31
1.9. Six membered heterocycles with two nitrogen atoms
The diazones are group of compounds formally derived from benzene by the
replacement of two ring carbon atoms by nitrogen. Three isomeric diazines are
possible with the nitrogren atoms in a 1,2 ;1,3; or 1,4 relationship giving rise to
pyridazine (32) pyrimidine (33) and pyrazine (34) respectively. Hexahydropiperazine
or piperazine (35) is used as a base in several reactions.
0 0 0 6 32 H
33 34 35
Several important sulfa drugs are pyrimidine derivatives namely sulphadiazine
(36) sulfamerazine (37) and sulfadimidine (38). These three are of considerable
biological importance because of their relation to the nitrogen bases present nucleic
acids, namely uracil, thymine and cytosine. The purine ring system obtained by the
fusion of pyrimidkie and imidazole nuclei is important because some of its derivatives
in particular adenine, guanidine are building blocks of RNA and DNA. A variety of
natural products such as alkaloids also contain pyrimidine ring system, these include
caffeine (39) and theophylline (40).
u iN^ 7l _ u N^ ^ o.M I O N
H j N ' ^ ^ H,N
36 37 38
CAapterl Introduction
I 39
0
I 40
The corresponding benzo derivatives of six membered heterocyclic
compounds are also known by trival names and are designated as cinnoline (41),
phthalazine (42), quinazoline (43) and quinoxaline (44).
N
N a) 41 42 43 44
Bicyclic pyridine derivatives
The pyridine ring fused with benzene nucleus in different ways results in the
formation of quinolone (45), isoquinoline (46) and quinoliziniimi salts (47).
45 46 47
Bicyclic six- membered aromatic compounds with nitrogen atom in both the
rings are called naphthyridines e.g. 1,5-naphthyridine (48), l,6-naphthyridine(49), 1,7-
naphthyridine (50), 1,8-naphthyridine (51), 2,6-naphthyridine (52), and 2,7-
naphthyridine (53).
48
N^
50
CRapterl Introduction
51 52
1.10. Seven membered nitrogen heterocycles
The seven membered heterocyclic rings containing one hetero atom are the
heterocyclic analogues of 1, 3, 5-cycloheptatriene. These are azepine (54), oxepin
(oxygen heteroatom) and theipin (sulphur hetero atom). The diazepines contain two
nitrogens in the monocyclic seven membered ring. There are three groups of
monocyclic diazepines, with the nitrogen atoms at the 1,2- (55), 1,3- (56) and 1,4- (57)
positions.
H
0 \ — /
/ = \
H
/ = \
H
/ =N u H
54 55 56 57
1.11. Importance of heterocyclic compounds containing Nitrogen as heteroatom
Nitrogen containing heterocycles represent an indispensable moiety in organic
chemistry. In 2010, of the top twenty drugs, eighteen drugs contained at least one
nitrogen heterocycle [4]; e.g. 4-amino pyridine (58) and Natazia (59) (Estrdiol
valerate).
NH,
N
58
59
10
Ctiapterl Introduction
The alkaloids form a major group of naturally occurring heterocyclic
compounds having varied biological activity. Most alkaloids contain basic nitrogen
atoms. Ergotamine, the indole based alkaloid exhibits antimigraine [5] activity.
Cinchonine, a quinolone class of alkaloid shows antimalarial activity [6].
Due to the immense biological activities associated with nitrogen containing
heterocyclic compounds, we have interested in the synthesis of various
imidazopyridines, triazolopyridines, imidazothiazoles, benzimidazothiazoles,
imidazomorpoline derivatives, thiadiazoles and oxadiazoles. The synthesized
compounds were evaluated for their biological activities.
1.11.1. Imidazopyridines
Introduction to imidazopyridines
Imidazole is incorporated in many important biological molecules, hnidazoles
were prepared in 1858 from glyoxal and ammonia. The imidazole ring system is of
particular importance because it is present in the amino acid, histidine and its
decarboxylation product, histamine. Histidine is present in many proteins and
enzymes and plays a vital role in the structure and binding functions of haemoglobin.
Imidazole has become an important part of many pharmaceuticals. Synthetic
imidazoles are present in many fimgicides, antiprotozoal and antihypertensive
medications. Many compounds of industrial and technological importance contain
imidazole derivatives. The thermostable polybenzimidazole (PBI) contains imidazole
fused to a benzene ring and linked to benzene, and acts as a fire retardant. Imidazole
can also be found in various compounds which are used for photography and
electronics.
11
Cfiapterl Introduction
Imidazopyridine derivatives are of great importance for their remarkable
biological properties. Their structures are similar to those of indoles and azaindoles,
two important heterocycles involved in many alkaloids. Many of them have been
demonstrated as inhibitors of the target enzymes and used as medicines, herbicides
and fungicides. The imidazopyridines comprise two isomers: imidazo [1, 2-a] pyridine
and imidazo [1, 5-a] pyridine. Derivatives of imidazole and pyridine are of special
interest in drug design. The condensed heterocyclic systems consisting of imidazole
and pyridine rings (imidazopyridines) often possess pharmaceutically valuable
properties which are not typical for either of the separate moieties. For example, a
popular soporific remedy, "Zolpidem" ("Ivadal"), is a fimctionalized imidazo [1, 2-a]
P3mdine.
Imidazopyridines are important class of heterocyclic compoimds. Synthesis of
imidazo [1, 2-a] pyridine derivatives has been the subject of considerable interest
because of their wide range of pharmaceutical, biological, and medicinal applications
[7-9]. These derivatives have been found to possess antibacterial [10], antiviral
[11,12], anti-inflanmiatory [13], antiulcer [14], antitubercular [15], anticancer [16],
antiparasitic [17], and antiprotozoa [18] activities. The imidazo [1, 2-a] pyridine units
appear as important building blocks in both natural and synthesis compoimds [19, 20].
Several imidazo [1, 2-a] pyridines already on the market include zolimidine (60) an
antiulcer drug, alpidem (61), a nonsedative anxiolytic and Zolpidem (62), a hypnotic
drug.
CI / ^ N ^
60
12
Cfiapterl Introduction
Synthesis of imidazo [1, 2-a] pyridines
Various methods have been reported for the synthesis of substituted imidazo[l,
2-a] pyridines:
1. By the condensation of a-halo carbonyl compound with 2-aminopyridine
[21-24]
2. One-pot condensations of 2-aminopyridines with isocyanides, aldehydes, and
alkynes [25-27]
3. Reactions of 2-chloropyridrne with 1, 2, 3-triazoles and subsequent
elimination of nitrogen [28]
4. Condensation of 2-aminopyridine with glyoxaltrimerdihydrate in aqueous
NaHSOj [29].
Majority of the imidazo [1, 2-a] pyridines (63) have generally been prepared
by the condensation of a-halo carbonyl compoxmd with 2-aminopyridine.
63
Recently Chuan He et al [30] synthesized imidazo [l,2-a]pyridines (64) by
cyclization between 2-aminopyridines and terminal alkynes. This approach provided
a simple way to construct heteroaromatic imidazo[l,2-a]pyridines. By using this
protocol, the marketed drug zolimidine (antiulcer) could be synthesized easily.
R
^ \ ^ + H^^R^ *- > T /V-R^ l" JL Dioxane ' ^ ^ N ^
64
Hayakawa et al [31] synthesized imidazo[l,2-a]pyridine (65) compounds in
which the thiazole derivative shown to inhibit tumor cell growth both in vitro and in
vivo, suggesting that it is a potential target in cancer treatment.
13
CRapterl Introduction
65
Praveen S et al synthesized imidazopyridine derivatives (66) by reacting
various acetophenones with 2-(4-bromophenyl) imidazo[l,2-a] pyridine-3-
carbaldehyde in the presence of alcoholic alkali. The screening data indicated that
tested compounds showed good antimicrobial activity [32].
66
Luke R. Odell and coworkers [33] have synthesized 6-substituted 3-amino-
imidazo [l,2-a]pyridines (67) which are active against Mycobacterium tuberculosis
glutamine synthetase inhibitors. Sebastien FoUot et al. [34] have synthesized 2-(4-
fluorophenyl)-6-iodo-3-pyridin-4-limidazo[l,2-a]pyridine (68) from 6-iodo-2-(4-
fluorophenyl)imidazo[l,2-a]pyridine and evaluated as anti-apoptosis agents .
67
Thus, the important role displayed by imidazo[l,2-a] pyridine and its
derivatives for various therapeutic and biological activities promoted us to synthesise
14
Cfiapterl Introdiiaion
some derivatives of imidazo[l,2-a] pyridine moiety in order to achieve compoimds
having better activities. Thus imidazo[l,2-a] pyridines were synthesized and
investigated for their activities.
1.11.2. Triazolopyridines
Pyridine was discovered in 1849 by the Scottish chemist Thomas Anderson as
one of the constituents of bone oil. The pyridine ring occurs in many important
compounds, including azines and the vitamins like niacin and pyridoxyl. Pyridine is
used as a precursor to many agrochemicals and pharmaceuticals and is also an
important solvent and reagent. Triazolopyridines are fused bi-heterocyclic ring
systems. Triazopyridines are known since 1960. Trazodone (69) a serotonin inhibitor
was the starting point of research on these structures. There are two isomers of
triazole; 1, 2,3 triazole (70) and 1,2,4-triazole (71).
- N N
N' H
D " ^ ^M'N
N H
70 71
l,2,4-Triazolo[l,5-a]pyridines constituted an important class of heterocyclic
compounds, which are of considerable interest due to their uses as active ingredients
in antihypertensive, bronchodilatory, antiinflammatory, analgesic and positive
inotropic agents [35-37].These [l,2,4]triazolo[l,5-a] pyridine derivatives exhibit
antifungal, anticancer and anti-inflammatory activities [38].
Synthesis of [l,2,3]triazolo[l,5-a]pyridines
Some commonly used synthetic methods are the annulation of 1, 2, 4-triazole
ring starting with amino substituted pyridines by a multistep procedure [39]. The
15
CHapterl Introduction
known preparative methods for the synthesis of [1, 2,4] triazolo [1, 5-a]pyridines
involve:
1. Reaction of 1,2-diaminopyridine derivatives with compounds such as
carboxylic acids and esters [40], 1, 3-diketones [41] and acetylene
derivatives [42]
2. Cyclization of 2-(N-substituted amino) pyridines [43]
3. Reaction of 1 -aminopyridinium salts with nitriles [44]
4. From 3-cyanomethyl [ 1,2,4] triazolo derivatives by reaction with
ketomethylene compovmds [45]
5. Ring transformation of triazolo [4,3-a] pyridines and 2-thioxopyrones [46]
6. Reaction of N-amino-a-pyridones with amides [47]
Abarca. B [48] reported many aspects of the chemistry of [1,2, 3]triazolo[l,5-
a]pyridines and their fluorescent behaviour. Benjamin J. Dugan [49] synthesized
l,2,4-triazolo[l,5-a]pyridine derivatives which shows promising anticancer activity.
Matthew M. Seavey [50] synthesized N-(3-(4-methylpiperazin-l-yl)phenyl)-
8-(4-(methylsulfonyl)phenyl)-[ 1,2,4]triazolo[ 1,5-a]pyridine-2-amine (72) which 4
shows prominent anticancer activity with reduced proliferation of tumour cells.
72
E. Himtsman et a/ [51] prepared [1, 2-4]triazolo[l,5-a]pyridines in good yields
from 2-aminopyridines by cyclization of A'-(pyrid-2-yl)formamidoximes under mild
reaction conditions with trifluoroacetic anhydride. Hajos et al [52] reported that 1,2-
16
CHapterl Introduction
diaminopyridinium tosylate readily reacts with aldehydes furnishing 2-substituted
triazolo [l,5-a]pyridines (73) in moderate to good yields.
NH2 KOH, air ^ ^ ^
+ R C H = 0 *• \ 1^ / > -R NH2 TsO
73
Yun Luo and Yangzhou Hu [53] synthesized a series of novel antifungal
triazole derivatives, 2-aryl-l,2,4-triazolo[l,5-a]pyridines and tested in vitro for their
growth inhibitory activities against C. albicans and T. rubrum. The MIC values
indicate that the activities of these compounds were superior or comparable to
fluconazole against both tested fimgi. Yang Li [54] synthesized triazolo pyridines by
reacting phenyl (l//-l,2,4-triazol-5-yl) methanone, ethyl 4-bromo-3-methylbut-2-
enoate, potassium carbonate and DMF. Michael Siu et al synthesized 2-amino-[ 1,2,4]
triazolo[l,5-a]pyridines (74-76) which on screening shows JKA2 inhibition properties
[55].
K. / > - N H
COOH
OCH,
75 74
Maribel Napoli's et al [56] synthesized [l,2,4]triazolo[l,5-a]pyridine (77) from
N'-[bis(methylthio)methylene]cyanoacethydrazide. Ramadan Ahmed Mekheimer et.
al., [57] synthesized novel [l,2,4]triazolo[l,5-a]pyridine derivatives among which,
some of the compound found to possess an anti-oxidative activity and found to extend
the life span of C. elegans under standard laboratory conditions.
17
CHapterl Introduction
H2N^
NC^
CN 1
Ar V 0
Ph -N
/^^SEt ^N
77
In view of the above very interesting pharmacological properties and as a part of
our studies on the design of new routes for the synthesis of novel heterocyclic ring
systems containing the 1,2,4-triazole skeleton, with potential pharmaceutical
activities, we have synthesized some novel l,2,4-triazolo[l,5-a]pyridines.
1.11.3. Thiazoles
Thiazoles are a class of organic compounds related to azoles with a common
thiazole functional group. Thiazole is aromatic, heterocyclic organic compoimd that
has a five-membered molecular ring structure (78&79), containing both nitrogen and
sulphur as part of the aromatic system.
1,3-thiazole isothiazole
78 79
Large numbers of thiazole derivatives have emerged as active pharmaceutical
ingredients in several drugs for their potential anti-inflammatory [58], anti-tumour
[59], anti-hyperlipidemic [60], anti-hypertensive [61] and several other biological
properties [62], and agrochemical compounds [63]. It plays a central role in the
biochemistry of life, being incorporated into the structure of vitamin Bl (thiamin),
which is vital for neural fiinction and the metabolism of carbohydrate. A
tetrahydrothiazole also appears in the skeleton of penicillin (80) which is one of the
first and most important broad spectrum antibiotics.
18
CHapter 1 Introduction
HN
O
HO
80
The compounds containing the thiazole ring are Fentiazac (81) drug used for
joint and muscular pain, Tiabendazole (82) a fimgiside, Amiphenazole (83) a
respiratory stimulant.
a N
N U f i H
81 82 83
The imidazo[2,lb]thiazole derivatives have been reported in the literature as
antibacterial [64], antifungal [65], antihehnintic [66], and antitumour [67] agents.
An imidazothiazole derivative, Levamisole (the levo isomer of tetramisole) is a broad
spectrum anthelmintic.
1.4.1 Synthesis of imidazo thiazoles
In general 2-amino thiazoles are known to react with 2-haloketones to form
imidazo[2,l,b]thiazoles (84) through cyclisation.
84
19
Cdapterl Introduction
Amrita at el [68] synthesized new analogues of imidazothiazoles. In this 5-
nitroso-6-p-chlorophenylimidazo[2,l-b]thiazole (85) showed potent antitubercular
activity. Farhad hatamjafar [69] have synthesized derivatives of imidazo[2,l-
b]thiazoles (86) by the condensation of 4-phenylthiazol-2-amine, aromatic aldehyde
and isocyanide in ethanol.
NH
85 86
Benzothiazole (87) is a privileged bicyclic ring system. It is an aromatic
heterocyclic compound and many of its derivatives have been shown to have
favourable bioactivities, such as inducing tumour cell apoptosis [70], antimicrobial
activity [71], antiviral activity [72], anti-convulsant activity [73] and have been used
to treat chronic diabetic complications [74]. In addition to the above properties,
benzothiazole derivatives have also been shown to exhibit inmnmosuppressive activity
[75].
/T a-87
Generally imidazo (2,l-6)-benzothiazoleshave been synthesized by reaction of
2-aminobenzotliiazoles and an appropriately a-bromo-phenyl-1-ethanones in the
presence of anhydrous ethanol. Andreania et al [76], synthesized 2-chloro-6-
phenylimidazo[2,l-b]thiazole which shows prominent antituberculosis activities. V.
20
Cfiapter 1 Introduction
G. Rajurkar et al [77] synthesized and evaluated the antimicrobial activity of novel
3,6-disubstituted imidazo [2,1-b] [l,3]thiazoles.
1.11.4. Imidazolo morpholine derivative
The insertion of polar groups in the organic molecules leads to change in the
absorption properties of the compoimd in the body. Cyclic secondary amines like
morpholine are an important class of compounds due to their biological significance in
the field of medicine and agriculture. Morpholines are the key pharmacophores in
various important drugs and biologically significant molecules.
Acylation or alkylation of morpholine (88) enhances the original biological
activity of the parent molecule. A number of N, O substituted morpholines have been
found to possess interesting pharmacological properties. Many morpholine derivatives
display varied activities like anti-bacterial, anti-viral, analgesic, anti-inflammatory, as
local anaesthetics and antiviral agents.
, 0 . o N' H
88
Morpholine, a six membered heterocyclic ring is hydrophilic in nature and it
changes the properties of the compound to which it is attached. Morpholine also called
tetra hydro-1,4-oxazine having the formula 0(CH2CH2)2NH. It is clear, coloiu-less,
hygroscopic liquid with ammonia-like odour. Morpholine has great industrial
importance and a wide range of applications. It is used as solvent, corrosive inhibitor
and fimgicide. The morpholine ring also present in the sedative hypnotic drug
trimetozine and anticonvulsant like Timoniimi methyl sulphate. It is also present in
some fungicides such as tridemorph (89), amorolifine (90), and fenpropimorph (91).
21
CHapterl Introduction
89 90 "l
Morpholine is a six-membered heterocyclic compound that features amine and
ether fimctionaUties, making it a commonly used compound in organic synthesis [78,
79]. Substituted morpholine derivatives are the core of various natural products and
biologically active compoimds. The morpholine has been used in the production of
many types of therapeutic agents such as antibacterials [80, 81], antimicrobials [82],
anticancers [83], antitussives [84], antimalarials [85], anticonvulsants [86], analgesics
[87] and antibiotic [88].
Mannich reaction
The Maimich reaction is an organic reaction which consists of an amino
alkylation of an acidic proton placed next to a carbonyl functional group . The study
of Mannich reaction attracted a great deal of attention to the chemists because it plays
a vital role due to their wide range of biological and industrial applications. Mannich
bases are also employed as intermediate in chemical synthesis. Several therapeutic
important molecules prepared through Mannich reaction have received more attention
in recent years [89, 90].
Literature survey reveals that piperazine or morpholine ring is important for
antimicrobial activity [91-92]. For instance, Linezolid, Eperezolid and Itraconazole,
which are currently important antibiotics used for the treatment of microbial
infections, contain a piperazine or morpholine ring in their structures.
Mannich reaction offers a convenient method for introduction of the basic
amino alkyl chain, which alters the biological profile and physicochemical
22
CHapter 1 Introduction
characteristics [93]. Various drugs obtained by Mannich reaction have proved more
effective and less toxic than their parent antibiotics [94]. The versatile utility of the
Mannich bases in polymers [95] dispersants in the lubricating oil [96] and
pharmaceutical chemistry [97] prompted us to prepare a series of aminomethyl
derivatives and evaluate their biological significance.
1.11.5. Oxadiazoles and Thiadiazoles
General aspects of 1,3,4-oxadiazole
1,3,4-Oxadiazole is a heterocyclic compoimd containing an oxygen atom and
two nitrogen atoms in a five-membered ring. It is derived fi-om fiiran by substitution of
two methylene groups with two nitrogen atoms [98-99]. There are foxir isomers of
oxadiazoles: 1,3,4-oxadiazole (92), 1,2,4-oxadiazole (93),l,2,3-oxadiazole (94) and
1,2,5-oxadiazole (95). However, 1,3,4-oxadiazole and 1,2,4-oxadiazole are better
known, and more widely studied by researchers because of their many important
chemical and biological properties.
"N-NS
1
92 ,3,4-oxadiazole
1
93 1,2,4-oxadiazole
0 1 94
1,2,3-oxadiazDle
0 1
95 1,2,5-oxadiazDle
Among heterocyclic compoimds, 1,3,4-oxadiazole has become an important
synthons in development of new drugs. Compounds containing 1,3,4-oxadiazole cores
have a broad biological activity spectrum, including antibacterial, antiftmgal,
analgesic, anti-inflammatory, antiviral, anticancer, antidepressant, anticonvulsant, and
anti-diabetic properties [100-105]. The ability of 1,3,4-oxadiazole heterocyclic
compoimds to undergo various chemical reactions has made them important for
molecule plaiming because of their privileged structiu-e, which has an enormous
23
CHapterl Introduction
biological potential. The compounds containing 1,3,4-oxadiazole unit currently used
in clinical medicine are: Raltegravir (96), an antiretroviral drug and Zibotentan (97),
an anticancer agent.
O A^OH
o ' o
96
Significances of 1,3,4-Oxadiazoles
97
Antihypertensive drugs: Oxadiazole nucleus is present in antihypertensive
drugs such as tiodazosin (98) nesapidil (99) and antibiotics such as furamizole (100).
I y-SCHoHCI \ J O —
N
HO
98 99
100
HIV-l integrase, muscle relaxants and anti-mitotic activities: Biologically
active molecules containing the oxadiazole moiety include the HIV integrase inhibitor
[106] and the antituberculosis agents [107]. The widespread use of 1,3,4-oxadiazoles
as a scaffold in medicinal chemistry is evident from the following examples. 2-
Amino-1,3,4-oxadiazoles exhibit muscle relaxants (101-103) and show anti-mitotic
activity.
24
CHapterl Introduction
•cr ir <x i d d
<>, / / HO' \HN' ^N-O "° ""G"^ H° n ,n\ /;
o \
o CI
101 102 103
Platelet aggregation inhibitor: 2,5-Diaryl-l,3,4-oxadiazoles (104) are platelet
aggregation inhibitors. 5-Aryl-2-hydroxymethyl-l,3,4-oxadiazole (105) display
diuretic, analgesic, anti-inflammatory, anticonvulsive, and antiemetic properties.
104 105
Anticonvulsant and light emitting agents: GABA-modulating 1,2,4-
oxadiazole derivatives are known for their anticonvulsant activity. 2,5-Disubstituted
1,3,4-oxadiazoles have also attracted great interest due to their applications in organic
light emitting diodes, photoluminescence, polymers and material science.
1.11.6.1,3,4-Thiadiazoles
Significance of 1,3,4-thiadiazoles
Tetrazole, thiadiazole, quinoline and indole derivatives are well known for their
significant biological activities. A large number of l,2,4-triazolo[3,4-b]-1,3,4-
thiadiazoles has been reported to exhibit various biological activities. Some 1,3,4-
thiadiazole and 1,2,3-triazole derivatives of condensed nucleus system found to have
diverse pharmacological activities such as, insecticidal, herbicidal, anti-tumor [108]
and CNS stimulant properties. They also find applications as dyes, lubricants,
25
Chapter 1 Introduction
analytical reagents and antiviral agents [109]. Examples of such compounds bearing
the 1,2,4-tnazole moieties are fluconazole, a powerful antifungal agent well as the
potent antiviral N-nucleoside ribavarin. 1,3,4-Thiadiazole analogs are associated with
diverse biological activities probably by virtue of toxophoric -N=C-S- group. 1,3,4-
Thiadiazoles have applications in many fields and majority of applications are
patented [110]. The earliest uses were in the pharmaceutical area as antibacterial with
properties similar to those of the well-known sulfonamide drugs. Some of the later
uses are as antifungal, antiangiogenic, antiglaucoma, antiischemic, and anti
inflammatory agents. They are also reported to be associated with antidepressant
[HI], anxiolytic [112], anti-bacterial, antiparasitic, antitumor, hypoglycemic anti
hypertensive and CNS depressant activities. Some of the thiadiazole analogue act as
nematicides and cefazolin (5-methyl-l,3,4-thiadiazole-2-tliiol derivative (106), is used
as an antibacterial agent.
NH
^C^^^f^^s-lJ. COOH
106
1,3,4-Thiadiazole analogues have displayed activity against hepatitis B virus.
2-Amino-l,3,4-thiadiazole-5-thiol is an effective radioprotective agent. The most
pronounced effect of amino thiadiazole on ribonucleotide pools of leukemia L 1210
cells is the lowering of guanine ribonucleotide pools.
The key intermediates hydrazine carbothioamides, commonly known as
thiosemicarbazides used for the synthesis of 1,2,3-triazoles and 1,3,4-thiadiazoles,
exhibit various kinds of biological activities. For instance, they are considered as
antiviral, anti HIV, anti-HSVl, anticancer, antibacterial, antifungal antiproteolytic,
antiphage, antithyroidal [113], antiamoebic [114], anticonvulsant, neurotoxicity [115],
26
CHapter 1 Introduction
insecticidal, herbicidal and also plantgrowth regulators agents. Many of them have
potential biological usage [116] and some have been tried for antituberculosis [117].
They act as potent orally active non-peptide antagonist for the bradykinin p2 receptor
and induce mortality in frog embryos [118]. Edward et al, [119] have synthesized a
series of thiosemicarbazides and investigated them as central cholecystokinin and
neurokinin receptors. Thiosemicarbazides are also considered as psychotropic agents.
The most important industrial uses of thiosemicarbazides are they act as corrosion
inhibitors of copper [120], and carbon-steel [121], in aqueous chloride solutions. Also
they act as thermal stabilizers for rigid poly vinyl chloride.
1.12. Plan of Work
The present work explains the synthesis of various heterocycles containing
imidazoles, 1,2,4-triazole, 1,3,4-oxadiazole, thiazoles, benzothiazoles and morpholine
derivatives of imidazo thiazoles. Substituted triazolopyridines derivatives were
synthesized by cyclisation of imidoxime pyridines followed by Suzuki reaction with
different boronic acids. A new series of thiazoles and benzothiazoles were synthesized
by the condensation of 2-amino thiazoles with different phenacyl bromides. Novel
imidazopyridines were synthesized by the condensation of aminopyridines with
phenacyl bromides. Novel route for the synthesis of imidazopyridines was carried
using microwave radiation. Due to the wide range of applications we have synthesized
heterocyclic compoimds containing nitrogen as a heteroatom and evaluated their
biological significances. In this regard the work is divided into seven chapters;
Chapterl: Introduction
Chapter 2: Synthesis of 6-bromo-2-(3,4-diclilorophenyl)imidazo[l,2-a]pyridines
using microwave and conventional method.
27
Cfiapterl Introduction
Chapter 3: Synthesis of 6-phenyl[l,2,4]triazolo[l,5-a]pyridine derivatives by Suzuki
reaction.
Chapter 4: Synthesis of 6-arylimidazo [2,1-6] [l,3]thiazole and 2-aryl-7-methoxy
unidazo[2,1 -6] [ 1,3 ]benzothiazole derivatives.
Chapter 5: Synthesis of 4-((2-(4-aryl)imidazo[a]pyridin-3-yl)methyl)morpholine
derivatives.
Chapter 6: Synthesis of diphenyl[l,2,4]triazolo[3,4-fe][l,3,4]thiadiazoles and
oxadiazoles
Chapter 7: Biological activity
28
Cfiapterl Introduction
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35
