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CHAPTER 1
“Introduction to heterocyclic chemistry”
Chapter 1
Page 1
1.1. OVERVIEW OF HETEROCYCLES
Compounds classified as heterocyclic, probably constitute the largest and most
varied family of organic compounds and heterocycles dominate the fields of
biochemistry, medicinal chemistry, dye stuffs, photographic science and are of
increasing importance in many others including polymers, adhesive, material
chemistry and molecular engineering.
Nitrogen, oxygen and sulfur are the most common hetero atoms but
heterocyclic rings containing other hetero atoms are also widely known. An enormous
number of heterocyclic compounds are known and this number is increasing rapidly.
Accordingly the literature on the subject is very vast. The vast distribution of
heterocycles in natural products they are also the major components of biological
molecules such as DNA and RNA. DNA is without doubt the most important
macromolecule of life. Three out of twenty natural amino acids are heterocyclic, as
are many essential vitamins. The range of applications of heterocyclic compounds is
very wide. They are of specific importance as they are associated with a wide variety
of physiological activities. 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, antibacterial, antifungal, antiviral, antidiabetic, herbicidal, fungicidal and
insecticidal agents. Also, they have been frequently found as a key structural unit in
synthetic pharmaceuticals and agrochemicals. Some of these compounds exhibit a
significant solvatochromic, photochromic and biochemi-luminescence properties.
Moreover, they act as organic conductors, semi-conductors, molecular wires,
photovoltaic cells, and organic light-emitting diodes (OLEDs), light harvesting
systems, optical data carriers, chemically controllable switches, and liquid crystalline
Chapter 1
Page 2
compounds. In addition, they have applications in supra molecular and polymer
chemistry, especially in conjugated polymers. Heterocycles are also of considerable
interest because of their synthetic utility as synthetic intermediates, protecting groups,
chiral auxiliaries, organo catalysts, and metal ligands in asymmetric catalysts,
inorganic synthesis. Therefore, substantial attention has been paid to develop efficient
new methods to synthesize heterocycles.
The alkaloids form a major group of naturally occurring heterocyclic
compounds having varied biological activity. Most alkaloids contain basic nitrogen
atom. Ergotamine, the indole based alkaloid exhibits antimigraine activity.
Cinchonine, a quinolone class of alkaloid shows antimalarial activity. Posaconazole is
a triazole antifungal drug. It is active against candida, asperigillus and zygomycetes.
The ability of many heterocycles to produce stable complexes with metal ions has
great biochemical significance. The fusions of five membered ring with six membered
heterocyclic rings are interesting and pharmacologically active. Heterocyclic
compounds have provided a platform for the rapid exchange of research in the areas
of organic, pharmaceutical, analytical, and medicinal chemistry. In the pharmaceutical
industry over 75% of the top two hundred branded drugs have heterocyclic fragments
in their structures.
1.2. PHARMACEUTICAL APPLICATIONS OF AZOLES
Azole containing compounds exhibit wide spectrum of biological activities.
Among the various azoles, pyrazole and thiazole heterocyclic rings find numerous
applications in medicinal chemistry. Many azole containing drugs such as indiplon,
zaleplon, zolpidem, alpidem, celecoxib, CDPPB, lonazolac, crizotinib, tepoxalin,
surinabant, deracoxib, mepiprazole, rimonabant are in clinical practice. Due to their
immense important biological activities, pyrazole and thiazole moieties are
Chapter 1
Page 3
extensively studied. Many research groups have incorporated these heterocyclic rings
to obtain derivatives with enhanced biological activities. A brief literature survey is
described below.
PYRAZOLE:
Literature survey revealed that pyrazole derivatives possess diverse
pharmacological activities. Some pyrazole derivatives are extensively studied and
used as antimicrobial agents.1-22
Pyrazoles are an important class of heterocyclic
compound and many pyrazole derivatives are reported to have a broad spectrum of
biological activities like anti-inflammatory,23,24
herbicidal,25
antitumor,26
cytotoxic27
and antiviral28,29
activities. Pyrazole derivatives also act as antiangiogenic agents,30
A3 adenosine receptor antagonists,31
neuropeptide YY5 receptor antagonists,32
kinase
inhibitor for treatment of type 2 diabetes, obesity33
and thrombopiotinmimetics.34
Recently, urea derivatives of pyrazole have been reported as potent inhibitors of p38
kinase.35
The high electro negativity of halogens (particularly chlorine and fluorine) in
the aromatic part of the drug molecules plays an important role in enhancing their
biological activity. The various activities shown by pyrazole containing compounds
are summarized below.
Antimicrobial activity
Bondock, S. et al.36
synthesized a series of substituted N-(benzo[d]thiazol-2-
yl)-7-methyl-2-(phenylamino)pyrazolopyrimidine-3-carboxamide derivatives, (1)
which was found to exhibit the most potent in-vitro antifungal activity. Radi, S. et
al.37
synthesized novel 2-3,5-disubstituted-1H-pyrazol-1-yl-ethanol derivatives and
evaluated for their antimicrobial activity. These derivatives (2) were found to be most
potent.
Chapter 1
Page 4
S
NNH
O N
N
N
HNPh
ArN
N R
H3C
X
HO
1 2
Sridhar, R. et al.38
synthesized 1-H pyrazole carboxylate derivatives and
screened for antimicrobial activities. Compounds (3 and 4) showed significant
antimicrobial activity.
NN
R2
R1OOC
NO2
O2NN
N
EtOOC
OHC
NO2
O2N
3 4
Prakash, O. et al.39
synthesized and reported promising antibacterial activity of
2,3-dimethoxy-3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl)chromanones (5). Sadasiva,
M. et al.40
synthesized several hydroxyl aryl-pyrazole derivatives (6) and tested them
for antibacterial as well as antifungal activity.
O
OH
OMe
OMe
N
NPh
Ar
O
OH
NN
R
R1
5 6
Gautam, V. et al.41
synthesized a series of 1,3,5-trisubustituted pyrazole
derivatives (7) and showed that the synthesized compounds possess promising
antimicrobial activity. Mohareb, R. F. et al.42
synthesized a series of pyrazole
derivatives of potential antimicrobial activity. Out of all synthesized compounds, 3-
Chapter 1
Page 5
(3a-4,5,6,7,7a-hexahydro-4,5,7a-trimethyl-1H-inden-1-yl)-1-phenyl-1H-pyrazole (8)
exhibited better activity.
N
N
CH3
Cl
H3C
NN
7 8
Sharma, R. N. et al.43
reported series of aryl pyrazole derivatives, of which
compound (9) possess significant antibacterial activity. Nadaraj, V. et al.44
synthesized series of condensed pyrazole derivatives. Among the synthesized
compounds, compound (10) registered good antimicrobial activity against most of the
bacteria and fungi.
N
ClCl
O O
N
NN
O
Ph9 10
N NN
ONH2
R
Sharma, R. N. et al.45
synthesized a series of 1-[(N-cinnamoyl)2,3-
dichloroanilinomalonyl]3,5-dimethyl-4-(unsubstituted/substitutedphenylazo)pyrazole
derivatives (11) which were found to possess good antibacterial activity against Gram
positive as well as Gram negative bacteria. Shah, N. K. et al.46
synthesized a series of
2-amino-4-(substituted-1H-pyrazol-4-yl)-carbonitrile pyrazole derivative (12) which
showed good antimicrobial activity.
Chapter 1
Page 6
N
ClCl
O O
N
N
N
NO
Ph 11
N NPh
Cl CH3
N
OH Ph
NH2
CN
12R
Sahoo, U. et al.47
synthesized a series of microwave assisted novel pyrazole
derivatives in which pyrazole ring was attached to a pyrazoline ring. Compound (13)
showed better activity against C. albicans and A. niger. Singaravel, M. et al.48
synthesized a series of novel sulphur bridged pyrazoles derivatives. Among these,
pyrazole derivative (14) showed antimicrobial activity.
N
O
N N
PhN
N
Ph
O
N
NN
O
Ph
SN
O
N
NH2
CN
S
13 14
Anticancer activity
Al-Saadi, M. S. M. et. al.49
synthesized a series of pyrazole fused ring systems
substituted with sulphonamide aryl substituents. Compound (15) proved to be the
most active antitumor agent. Kalirajan, R. et al.50
synthesized a series of pyrazole
derivatives. Studies revealed that 2-(3-(2-chlorophenyl)-1H-pyrazol-5-yl)-1H-
benzo[d]imidazole (16) possess significant anticancer activity.
Chapter 1
Page 7
N
N
H3C
S
O
NHO
O NH
Ph
NH
N
HN N Cl
15 16
Anti-inflammatory activity
Bekhit, A. A. et al.51
synthesized 5-substituted amino-1,3,4-thiadiazol-2-yl
derivatives of 1H-pyrazole. It was found that compound (17) showed significant anti-
inflammatory activity by the cotton pellet granuloma method of rat paw edema
bioassay. Dadiboyena, S. et al.52
synthesized N-methyl-2-(2-(1,3-diphenyl-1H-
pyrazol-5-yl)propan-2-yl)benzenamine pyrazole derivatives (18) which were found to
possess good anti-inflammatory activity.
N N
SO
O
N N
17
N
N
HNCH3
R
18
N
NS
RHN
Arunkumar, S. et al.53
synthesized (3,4,5-trihydroxyphenyl)(5-phenyl-3-
(phenylamino)-1H-pyrazol-1-yl) methanone (19) which was found to exhibit good
anti-inflammatory activity. Coli, B. et al.54
synthesized 1-benzyl-3-substituted-1H-
indazole pyrazole derivatives (20) and evaluated for their anti-inflammatory activity.
Most of the synthesized compounds were found to acquire anti-inflammatory activity.
Chapter 1
Page 8
HO
HO
OH
O
N
N
Ph
HN Ph
NN
O
R
Ph
19 20
Antiviral activity
Rashad, A. E. et al.55
synthesized thieno [2,3-d] pyrimidine substituted
pyrazole derivatives (21). These derivatives showed promising antiviral activity
against hepatitis A virus and Herpes simplex virus type-1 using plaque infective
assay.
N N
R2
R1
N
N
S
21
Antitumor activity
Christodoulo, M. S. et al.56
synthesized a series of trisubtituted pyrazole
derivatives (22) and screened the compounds for anticancer activity. Compounds
containing fused pyrazole [4,3-c] quinoline motifs emerged as potent anticancer
compounds. Lin, R. et al.57
synthesized 3,4-disubstituted pyrazole derivatives. The
analogues (23 and 24) showed potent antitumor activity.
Chapter 1
Page 9
HON
N
O
OH
R1
R2
R3
R4
N
NH
N
NH
N
OMeN
NH
N
NH
N
CF3
22 23 24
Antihelmintic activity
Sreenivasa, G. M. et al.58
synthesized a series of pyrazole containing
benzthiazolyl sulphonamide and furan derivatives. Synthesized compounds were
tested for antihelmintic activity against earthworm P. posthuma. It was found that
compound (25) showed significant activity as compared to standard albendazole.
S
NN
S
O
O
NN N
O
O
NH2
NHPh
25
H
Cytotoxic activity
Zahar, E. et al.59
reported a series of 2-(2-(3,4-disubstituted-1H-pyrazol-1-yl)-
2-oxoethoxy)-6-(benzofuran-2-yl)-4-phenylpyridine-3-carbonitrilepyrazole
derivatives, compound (26) was found to exhibit good cytotoxic activity.
26
O
N O
O
NN
Ph
CN
Chapter 1
Page 10
Herbicidal activity
Noriaki, K. et al.60
synthesized 1,5-diarylpyrazole derivatives. Among the
synthesized compounds, methyl 4-chloro-1-(2,5-difluorophenyl)-5-(4-flurophenyl)-
pyrazole-3-carboxylate (27) exhibited good activity.
NN
O
O
F
F
F
Cl
27
Insecticidal activity
Song, B. et al.61
reported synthesis and insecticidal activities of novel
acetamido derivatives containing N-pyridylpyrazole carboxamides (28). Liu, Y. et
al.62
reported synthesis, and insecticidal activity of novel pyrazole derivatives
containing 4,5-dihydrooxazole moieties (29).
N
NN
HN
O
NH
ROBr
ClN
N
R1
O
N
R2
28 29
THIAZOLE:
Thiazole and its derivatives possess great importance in medicinal chemistry
and are used for the synthesis of numerous heterocyclic compounds with different
biological activities such as antibacterial, anti-tubercular, anti-cancer, antifungal and
anti-inflammatory.
Recently the applications of thiazole were found in drug
development for the treatment of allergies,63
hypertension,64
inflammation,65
Chapter 1
Page 11
schizophrenia,66
bacterial,67
HIV infections,68
hypnotics,69
and more recently for the
treatment of pain.70
A brief literature survey is presented below
Antimicrobial activity
Patten, S. R. et al.71
have reported the synthesis and antimicrobial activity of
N-3-(4-(4-chlorophenyl) thiazolo-2-yl)quinazoline-4-3H)-one (30). Clemence, F. et
al.72
have reported the synthesis and pharmacological evaluation of various 4-
hydroxy-N-(2-thiazolyl)-3-quinoline carboxamide derivatives (31).
30
N
OH HN
O
R2
HNBoc
R1
S
N
31
N
N
O
S
N
NH
R
Cl
Shingare, M. S. et. al.73
reported the synthesis and antimicrobial activity of 4-
aryl-3-(4-aryl-2-methylthiazole-5-yl)-5-mercapto-1,3,4-triazoles (32 and 33).
32
N S
H3C
N
NN SH
R'
R
N
S
H3C
S
NN
R
NH
R'
33
Pandeya, S. N. et al.74
synthesized a series of Schiff and Mannich bases from
isatin. N-[4-(4'chloropheyl)thiazol-2-yl]thiosemicarbazides (34) showed high
antimicrobial activity. Xin, Z. et al.75
reported new oxazolidinone derivatives
containing substituted thiazole/fused bicyclic [imidazo[1,2-
Chapter 1
Page 12
b]pyradazine/imidazo[2,1-b]thiazole groups and compound (35) displayed promising
antibacterial activity comparable to that of Linezolid against S. aureus.
N O
NNH
O
NH
N
SCl
NN
N
N
F
O
NH R
34 35
Vicini, P. et al.76
reported a new series of 2-thiazolylimino-5-arylidene-4-
thiazolidinones and tested for their antimicrobial activity against Gram positive and
Gram negative bacteria. Compound (36) was found to be potent against Gram positive
bacteria. Dundar, O. B. et al.77
synthesized thiazolyl thiazolidine-2,4-dione derivatives
and screened them for their antibacterial and antifungal activities against methicillin
resistant S. aureus, E. coli and C. albicans bacteria. Compound (37) was found to be
moderately potent against screened microorganisms.
N
S
N
HN
S
RO
R
R1
XN S
S
N
Cl
ClO
36 37
Cukurovali, A. et al.78
reported a series of schiff’s bases containing 2,4-
disubstituted thiazole, cyclobutane rings and hydrazone moieties in the same
molecule and evaluated them for antibacterial and antifungal activities. Among the
tested compounds, compound (38) was found to be most effective. Zitouni, G. T. et
al.79
reported thiazole derivatives of triazole and evaluated for antifungal and
antibacterial activities against C. albicans (two strains), C. glabrata, E. coli, S.
Chapter 1
Page 13
aureus, P. aeruginosa. The result showed that compound (39) exhibited excellent
antifungal activity.
Ph
Me
S
NHN
N
OH
OH
Cl O
Me NN
N SNH
O
N
S
EtOOC
Ph
38 39
Abdel-Wahab, B. F. et al.80
synthesized a series of 1-(benzofuran-2-yl)-4-nitro-
3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-
thiazol-2-yl]-1H-pyrazoles of all the synthesized compounds, compound (40) showed
a significant activity against E. coli, higher than that of the control drug. Desai, N.C.
et al.81
reported new series of novel 1,3,5-triazine based thiazole derivatives (41) and
screened for antimicrobial activity. The results showed that compounds found to
possess good antimicrobial activity.
N
NH
HN
N N
N NH
HN
SN
O
RO
NN
Ph
N
SMe
40 41
Karegoudar, P. et al.82
reported some novel 2, 4-disubstituted thiazoles (42-44).
The results showed that compounds possess excellent antimicrobial activity.
N
S
R
ClCl
Cl
N
S
ArClCl
Cl
N
ClCl
N
SAr
NH
42 43 44
Chapter 1
Page 14
Bobade, V. D. et al.83
reported synthesis and biological evaluation of some
novel thiazolyl-triazol-3-ones (45 and 46) as antimicrobial agents. All these
compounds showed promising antimicrobial activities.
S
S
N N N
NO R
S
SS
NN N
N
O R
45 46
Narayana, B. et al.84
reported synthesis and anti-fungal activity of 2-bromo-
5-methoxy-N′-[4-(aryl)-1,3-thiazol-2-yl]benzohydrazide derivatives (47). Narayana,
B. et al.85
synthesized a series of 5-(2-substituted–1,3-thiazol-5-yl)-2-
alkoxybenzamides and 5-(2-N-(substitutedaryl)-1,3-thiazol-5-yl)-2-alkoxybenzamide
derivatives. The synthesized compounds were evaluated for their antifungal activity,
compound (48) exhibited significant activity.
47 48
NH
OHN
N
S
Ar
R
O
Me
H2N
O
N
S Cl
Beuchet, P. et al.86
reported polymethoxylated and polyhydroxylated
derivatives of 2-amino-4-aryl thiazoles with a halogeno benzene sulfonamide (49)
which showed good antifungal activity in comparison to econazole. A new series of 2-
thiazolylhydrazone derivatives were synthesized by Chimenti. F. et al.87
Out of all the
synthesized compounds compound (50) was found to possess significant antifungal
activity.
N
S
NH
SO
O
halogen
(OH)n
N
HNN
S
CH35049
Chapter 1
Page 15
Anticancer activity
Colabufo, N. A. et al.88
synthesized a novel series of 2-aryl thiazole
derivatives. Compounds (51 and 52) exhibited significant anticancer activity.
N
SN
O
O
N
SN
N
R
R
5152
Antitumor activity
El-Subbagh, H. et al89
reported synthesis and biological evaluation of 2,4-
disubstituted thiazole, (53-55) and screened for antitumor activity. Compounds
showed promising antitumor activity.
53
N
S
NH
HN XO
HN
NR
HS
N
S
NH
HNO
HN
NR
HS
R'
H
S
S
N
NR
ClNO2
54 55
El-Messery, S. M. et al.90
synthesized a novel series of 2-acetamido derivatives
of substituted thiazole (56) which exhibited broad spectrum antitumor activity. Bruno,
S. et al.91
reported antitumor activity for (2S)-3-amino-1-(5-aminothiazol-2-yl)-2-
methylpropan-1-ol (57). Ibrahim, D. A. et al 92
have reported synthesis and biological
evaluation of 3,6-disubstituted [1,2,4]triazole[3,4-b][1,3,4]thiadiazole derivatives (58)
as a novel class of potential antitumor agents.
Chapter 1
Page 16
56 57
S
N
NH
ClO
H2N S
N
NH2
OHN
N
N
N
S
RS
NHO
NH2
58
Ramla, M. M. et al.93
synthesized a variety of 1-substituted-2-methyl-5-
nitrobenzimidazoles (59) and found them to have significant anti-tumor activity.
Popsavin, M. et al.94
reported a set of 2-(2,3-anhydrofuranosyl)thiazole-4-
carboxamide (2',3'-anhydrothiazofurin) derivatives and screened them for their
antitumor activity. The compound (60) was found to be most active against K562
malignant cells, with IC50 values ranging from 0.09-0.49 μM. Gulsory, E. et al.95
synthesized a series of arylidene hydrazides from [6-(4-bromophenyl)imidazol-
3yl]acetic acid hydrazide and evaluated one dose primary cytotoxicity assay.
Compound (61) was demonstrated as the most effective agent on a prostate cancer
cell lines.
N
S
NH2
OOHO
O
N
NS
NH
O
NAr
Br59 60 61
N
NCH3
SN
S
O2N
NH2
CH3
Antitubercular activity
Kulkarni B. S. et al.96
have synthesized substituted thiazolyl thiocarbanilides
(62-66) and some of them showed antitubercular activity.
Chapter 1
Page 17
N
S
R2
R3
R1
N
S
NH
R2
R1
S
NH
R5
R4
N
S
R1
R3
HN
S
HN
OR
N
SR1
R2
NH
S
NH
R4
R5
NS
R1
R3
N
S
R1
R3
NH
S
NH
62 63 64
65 66
Shiradkar, M. R. et al.97
reported a new series of N-{4-[(4-amino-5-sulfanyl-
4H-1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-2-substituted amide derivatives (67-
68). Most of the synthesized compounds showed moderate to good activity against M.
tuberculosis strain H37 Rv.
NS
NH
Cl
N N
N
HN
O
Ph
N N
N
H2N
O
N
SHN
MeN N
N
N O
SOO
NH
Br
HN
Me
O
O
67 68
Shiradkar, M. R. et al.98
reported synthesis of thiazolyl triazole derivatives.
Among all the compounds (69-70) showed good antitubercular activity.
N
SHN
MeN N
N
NH
S
O
NN
N
H2N SHN
S
HN
Cl
NN
N
HN
O
Ph
S
OO
NH
N Cl
6970
Ph
O
Chapter 1
Page 18
Turan-Zitouni, G. et al.99
reported synthesis and antituberculosis activity of
new thiazolylhydrazone derivatives (71). All the compounds showed remarkable
activity.
N
SN
N
CH3
R1
R2
H
71
Anticonvulsant activity
A new series of substituted coumarinyl thiazolines, was synthesized and
evaluated for anticonvulsant activity by Amin, K. M. et al.100
Compounds (72 and 73)
were the most active of the series against PTZ induced seizures. Dawood, K. M. et
al.101
synthesized a series of compounds containing thiazole, benzofuran and 1,2,3
triazole and evaluated them for anti-inflammatory and anti-convulsant activity. The
newly synthesized compound (74) showed good anticonvulsant and anti-inflammatory
activity.
7472 73
N
SH3CO
N O O
Me
N
SH3CO
N O O
Me
EtOOC O O
NNNS
NEtO C6H5
Anti-inflammatory activity
Kumar, A et al.102
reported synthesis of 3-[4'-(4-chlorophenyl)-thiazol-2'-yl]-
2-[(substitutedazetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones
as anti-inflammatory agent (75). Kalkhambkar, R. G et al.103
reported synthesis of
novel triheterocyclic thiazoles as anti-inflammatory and analgesic agents (76). Few of
the compounds show promissing activity.
Chapter 1
Page 19
N
N
O
S
N
HN
N
SCl
Cl
ON
SNHHN
O
O
O
Cl
Br
75 76
Holla, B. S et al.104
reported synthesis of some new 2,4-disubstituted thiazoles
as possible antibacterial and anti-inflammatory agents (77 and 78). Some of the
compounds showed good antibacterial and anti-inflammatory.
Cl
Cl
F
N
S
NH
Br
N
S
NH
NO
O
Cl
Cl
F77 78
Kalkhambkar, R. G. et al.105
reported triheterocyclic thiazoles containing
coumarin and carbostyril (1-aza coumarin). The synthesized compounds (79 and 80)
showed significant anti-inflammatory activity.
N
SNH
HN
O
O
O
Cl
Br
N
SNH
HN
O
O
O
Cl
Br
Br
79 80
Rostom, S. A. F. et al.106
reported compounds (81 and 82) having remarkable
anti-inflammatory activity.
Chapter 1
Page 20
NN
NH N
S
BrPhNC
H3C
ON
N
HN N
S
HNO
H3C
H3C
O
S
HN
S
Ph
PhCH3
O
81 82
OXADIAZOLE-THIOL:
1,3,4 oxadiazole-2-thiol are found to be biologically potent and have attracted
considerable attention because of their biological importance. 1,3,4 oxadiazole-2-thiol
and its derivatives have been frequently employed in drug synthesis, various
commercial and industrial applications. A brief literature summary of biological
activity of 1,3,4 -oxadiazoles-2-thiol is presented below.
Antimicrobial activity
1,3,4-oxadiazole-2-thiol is an important class of biologically active compound
and number of reports on their synthesis and antimicrobial activity of 1,3,4-
oxadiazole-2-thiol has been done. Desai, N.C et al.107
reported antimicrobial
screening of 1,3,4-oxadiazole and clubbed thiophene derivatives (83). Some of the
compounds showed good antimicrobial activity. Novel biphenyl tetrazole derivatives
(84) bearing 1,3,4-oxadiazole were synthesized and screened for the antimicrobial
activity by Chao, J. S. et al.108
All these compounds showed remarkable antimicrobial
activity.
N
N
O
N
SO
HN
S83 N
NNH
N
S
N
O
N
Ar
84
Dabhi, T. P. et al.109
designed and synthesized new 1, 3, 4-oxadiazole
derivatives (85) which were shown to possess good antimicrobial activity compared
Chapter 1
Page 21
to standard drug Norfloxacin. Samad, A. et al.
110 synthesized 5-substitued phenyl-
1,3,4-oxadiazole-2-thiol (86) derivatives. Few of the compounds showed promising
activity.
O
N
SH
N
N N
O
RHNO2S
SX
85 86
R
Rehman, A. et al.111
reported antimicrobial evaluation and hemolytic activity of 2-
[[5-alkyl/arylsubstituted-1,3,4-oxadiazol-2-yl]thio]-N-[4-(4-morpholinyl)phenyl]
acetamidederivatives (87). El-Emam, A. A. et al.112
showed the antimicrobial and
anti-HIV-1 activity (using XTT assay) of certain 5-(1-adamatyl)-2-substituted thio-
1,3,4-oxadiazoles (88).
N
O
NS
O
HN
NO
87 N N
O S R
88
Hai-Liang, Z. et al.113
reported novel 1,3,4-oxadiazole derivatives as dual
anticancer and antimicrobial agents (89). Few of the compounds were found to
possess dual activity. Kalluraya, B. et al.114
reported biphenyl-1,3,4-oxadiazole
derivatives possess antimicrobial and analgesic activity (90). Jain, N. et al.115
synthesized novel 2-[5-(aryl)-1,3,4-oxadiazole-2-ylsulfanyl]alkanoic acids and
screened for antibacterial activity (91).
NN
OAr S
OH
O
R
N N
OSRR
91
O
N
S
N
N
N
NO2
Ar
89 90
Raval, J. P. et al.116
reported remarkable antibacterial activity of novel
oxoethylthio-1,3,4 oxadiazole derivatives (92). Tewari, R. K. et al.117
reported the
Chapter 1
Page 22
study of disulphides 1,3,4-oxadiazol-2-thiones (93) that exhibited promising
antifungal activity.
N
O
N
SNHN
92 93
O NN
OR S S
NN
O R
Liu, Z. et al.118
reported fungicidal activity of diheterocyclic compounds
containing 1,2,4-triazolo[1,5-a]pyrimidine and 1,3,4-oxadiazole rings (94). Li, Y. et
al.119
synthesized (E)-α-(methoxyimino)-benzene acetate derivatives containing 1,3,4-
oxadiazole nucleus (95) that were found to posses fungicidal activitiy.
S
N N
O PhO
OMe
N
OMe
N
N
N
N
SCH2N
NO
SRCH3
CH3 94 95
Maslat, A. O. et al.120
reported bis-1,3,4-oxadiazole derivatives (96) and
screened for antibacterial, antifungal and genotoxic activity. Some of these
compounds were found to be more active against the bacterial and fungal strains.
Patel, R. V et al.121
reported benzimidazolyl-1,3,4-oxadiazol-2-ylthio-N-phenyl
acetamides as antibacterial, antifungal and anti-tubercular agents (97).
NN
OPhH2CS (CH2)n NN
OSCH2Ph
N
N
O
NN
S
O
HN
96 97
Anti-inflammatory activity
Bhandari, S. V. et al122
reported design, synthesis and evaluation of anti-
inflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-
1,3,4-oxadiazole-2-thiol derivatives (98). Karmer, J. B. et al.123
reported some 1,3,4-
Chapter 1
Page 23
oxadiazole DTBP derivatives (99) that found to exert anti-inflammatory effect via
cyclooxygenase and 5-lipoxygenase inhibitory activity.
NH
ClCl
S ON N
O
S O
N
SH
N
DTBP
98 99
R
Synthesis and anti-inflammatory activity of 1,3,4-oxadiazole derivatives (100
and 101) has also been reported by Kumar, A. et al.124
All these compounds showed
better anti-inflammatory activity.
N
N
S
O
Cl
OO
N N
N
R
N
X
N NN
SO
O
O
N N
NS
100 101
Burbuliene, M. M. et al.125
reported anti-inflammatory activity of 5-[(2-
disubstituted amino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-oxadiazole-
2-thione derivatives (102). Kumar, A. et al.126
reported anti-inflammatory activity of
substituted acridinyl pyrazoline derivatives (103). Few of the compounds showed
promising anti-inflammatory activity.
N
N
NRR'
S O
N N
R NNO
S O
N N
N
102 103
Chapter 1
Page 24
Anti-tubercular activity
2,5-disubstituted-1,3,4-oxadiazoles (104 and 105) were designed, synthesized
and tested for anti-tubercular activity against M. tuberculosis H37Rv by Macaev, F. et
al.127
All the synthesized compound showed excellent activity.
O
N
S
N
O
O
N
S
N
S
N
NH2
Ar
104 105
Bakal, R. L. et al.128
reported 2, 5-disubstituted oxadiazole (106) as potential
candidate for treatment of XDR and MDR tuberculosis. Krasovskii, A. N. et al.129
synthesized 5-aryl (heteroaryl)-1,3,4-oxadiazol-2-thiones (107) and showed them to
possess excellent antimicrobial and tuberculostic activity.
106 107
O
N
S
N
R
R
O
N N
R SR1
O
NNH
R2
Macaev, F. et al.130
reported structure antituberculosis activity of 5-aryl-2-thio-1,3,4-
oxadiazole derivatives (108 and 109). Some of the compounds were found to be
active.
O
N
S
N
R
NCS
O
NN
SO
O
Ar
109108
Tan, T. M. et al.131
synthesized a series of 2-substituted-sulfanyl-5-
benzenesulfonyl alkyl-1,3,4-oxadiazoles (110) and evaluated for their anti-hepatitis-B
Chapter 1
Page 25
virus activity. Some of the tested compounds were found to be active. Ananthan, S. et
al.132
synthesized 1,3,4-oxadiazole derivatives (111) that showed good anti-tubercular
activity against M. tuberculosis H37Rv.
N
O
N
R1S
R2R3
O
SO
N
S
N
R
O
OR
110 111
Anti-cancer activity
Zhu, H. L. et al.133
reported anticancer and antimicrobial activity of 1,3,4-
oxadiazole thioether derivatives (112). Manda, S. et al.134
reported remarkable
anticancer activity of 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-
one derivative (113).
O
N
S
N
N
N
NO2Ar
NH
N
O N
O
N
SH
112 113
Zhu, H. L. et al.135
reported synthesis and molecular docking studies of
2-chloropyridine derivatives (114) possessing 1,3,4-oxadiazole moiety as potential
antitumor agents. Poojarya, B. et al.136
reported design and synthesis of a novel series
of 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety as
anticancer agents (115).
S O
N
R
N
N
Cl
114 115
N NMe
N
SR
NCF3
Liu, K. et al.137
synthesized and reported the anti-cancer activity of 2-
(benzylthio)-5-aryloxadiazole derivatives (116). Zaied, M. A. A. et al.138
synthesized
Chapter 1
Page 26
and reported high antitumor activitiy (117) in vitro against 2-cell lines MCF7 (breast)
and HEPG2 (liver).
NH2
O
N
S
N NN
N
O
SRN
116
117
Sarragiotto, M. H. et.al.139
reported synthesis and anti-tumor activity of novel
3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-oxadiazol-3-yl)b-
carboline derivatives (118). Some of the compounds showed remarkable activity.
Zhu, H. L. et al.140
reported synthesis and molecular docking studies of 1,3,4-
oxadiazole derivatives possessing 1,4-benzodioxan moiety as potential anticancer
agents (119)
NH
N
N
O SMe
N N
O S
N
O
O
R
118 119
Antiviral activity
A facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-1,3,4-
oxadiazoles (120) was reported by Tan, T. M. C. et al.141
which subsequently showed
good anti-HBV activity. Iqbal, R. et al.142
reported inhibitory activity for compounds
(121) against the human immune deficiency virus type 1 (HIV-1) which was also
determined using the XTT assay on MT-4 cells.
Chapter 1
Page 27
SO
N
S
N
R
O
OR
120 121
S
N
O
N
SH
H2NO
O
OXADIAZOLE:
Biological activities of oxadiazole
Most of the heterocyclic compounds containing 1,3,4-oxadiazole nuclei showed
various types of biological activities such as anti-inflammatory,143
hypoglycemic,144
anti-HIV,145
antitumor,146
antibacterial,147
antifungal,148
antihypertensive,149
anti-
tubercular,150
analgesic,151
anticonvulsant152
and herbicidal153
activities. A brief review
of biological activities of oxadiazoles is presented below.
Antimicrobial activity
Oxadiazoles shows a broad spectrum of activity on various pathogens and
considerable research has been done on the synthesis of new potent antibacterial and
antifungal oxadiazoles. Ansari, K. F. et al.154
reported antimicrobial activity of some
new benzimidazole-1,3,4-oxadiazole derivatives (122). Choudhari, B. R. et al.155
described the antimicrobial activity in 2,5-disubstituted 1,3,4-oxadiazole (123)
derivatives.
N
NR
NN
O R1
122
NH
SO
NNNHAr
CH3
123
Ahsan, M. J. et al.156
have reported promising antimicrobial and anti-
tubercular activity of 5-aryl 1,3,4-oxadiazole derivatives (124).
Chapter 1
Page 28
NN
ONH
N N
O
Ar
124
Li, Y. et al.157
described the synthesis of series of secnidazole analogues based
on oxadiazole scaffold. All the synthesized derivatives (125 and 126) exhibited strong
antibacterial activities compared with standard drug kanamycin.
N
N NO2
N
N NO2
N N
O
N N
OR1 R2
125 126
Rane, R. A. et al.158
reported the synthesis and promising antibacterial activity
of nitropyrrole 1,3,4-oxadiazole derivatives (127). Jha, K. K. et al.159
reported good
antimicrobial activity of series of novel 2,5-disubstituted 1,3,4-oxadiazole (128).
N
R
O2N
N N
O R1
NN
O R1R
127 128
Chandrakantha, B. et al.160
have synthesized some novel 1,3,4-oxadiazole
bearing 2-Flouro-4-methoxyphenyl moiety (129) and tested for antifungal activity
against C. albicans.
F
H3COO
NN
R129
Chapter 1
Page 29
Fuloria, N. K. et al.161
reported promising in vitro antimicrobial activity of 2-
(5-substituted-1,3,4-oxadiazol-2-yl)-1,3-benzothiazole (130). Bhardwaj, N. et al.162
reported 2-substituted-5-indole-1,3,4-oxadiazoles as antimicrobial agents (131). Some
of these compounds possess antimicrobial activity.
O
N N
R
N
S
O
NN
RNH
130 131
Rauf, A. et al.163
reported antimicrobial activity of 2-(substituted)-5-(benzo
triazomethyl)-1,3,4-oxadiazole derivatives (132). Desai, N.C. et al.164
reported in vitro
antimicrobial screening of quinoline containing 1,3,4-oxadiazole and 2-azetidinone
derivatives (133) and few of them found to possess good antimicrobial activity.
N Cl
H3CO
NN
O
Cl
N
H3C
R
N
O
NN
R
N
N
132 133
Anti-tubercular activity
Joshi, S. D. et al.165
have reported excellent anti-tubercular activity of 1-(5-(4-
(1H-pyrrol-1-yl)phenyl)-2-substituted-1,3,4-oxadiazole-3-(2H)-yl)ethanone(134).
Mallikarjuna, B. P. et al.166
also reported promising anti-tubercular activity of 2-(4-
chlorophenyl)-5-(4-isopropylthiazol-2-yl)-1,3,4-oxadiazole (135).
NN
OCl
N
S
NN
ON
R
COCH3
134 135
Chapter 1
Page 30
Vazquez, G. N. et al.167
prepared a series of 4-alkyl-(2-(4-pyridyl)-2-yl)-1,3,4-
oxadiazole (136) showed remarkable antitubercular properties. Szarka, Z. et al168
reported a new set of steroidal 1,3,4-oxadiazole derivatives (137) and demonstrated
their anti-inflammatory, antitubercular, and antimicrobial activity. Kucukguzel, S. G.
et al.169
prepared and characterized some novel 1,3,4-oxadiazoles (138) and screened
them towards M. tuberculosis. These compounds revealed good activity.
NH
O
NNNH
O
OO
NN
C15H31N
NN
O
R
O
136 137 138
R
A series of 2,5-disubstituted-1,3,4-oxadiazole derivatives have been
synthesized by Shaharyar, M. A. et al.170
and tested for their in vitro anti-tubercular
activity. The 2-(2-naphthyloxymethyl)-5-phenoxymethyl-1,3,4-oxadiazole (139)
exhibited > 90% inhibition at MIC~6.25 µg/ml .
O
NNO PhO
139
Anti-inflammatory activity
Akhter, M. et al.171
reported a series of derivatives based on aryl propionic acid
(140) that possess good to moderate anti-inflammatory activity.
O
NHN
R'
O
R
140
Chapter 1
Page 31
Indole containing oxadiazole (141) [Ar = halo phenyl and 4-fluoro cinnamyl]
are also reported by Narayana, B. et al.172
that possess good activity comparable to
indomethacin.
2-(1-Adamantyl)-5-substituted-1,3,4-oxadiazoles (142) were
synthesized by Kadi, A. A. et al.173
and these compounds displayed strong dose-
dependent inhibition of carrageenin-induced edema.
O
NN
NH
ArO2N
O
NN
R1
142141
Husain, A. et al.174
reported synthesis and anti-inflammatory activity of 2-[3-
(4-bromophenyl)-propane-3-ones]-5-(substitutedphenyl)-1,3,4-oxadiazoles(143).
Mohammad Amir et al.175
reported 1,3,4-oxadiazole derivative (144) which exhibited
good anti-inflammatory activity.
O
O
NNR
Br
O
O
NN
R143 144
Ramalingam, T. et al.176
reported anti-inflammatory activity of benzal-3-
pentadecylaryloxyalkyl carboxylic acid hydrazides and 2-benzalamino-5-(3’-
pentadecylaryloxyalkyl)-l,3,4-oxadiazoles (145) and compounds showed good anti-
inflammatory activity. Jayashankar, B. et al.177
reported 1, 3, 4-oxadiazole bearing bis
(heterocycle) derivatives (146) as anti-inflammatory and analgesic agents. Some of
these compounds show remmarkable activity.
O
CHR1
O
NN
N
OCH3
R
C15H31 145
O
N NR O
O
N
R
146
Chapter 1
Page 32
Antitumour activity
Holla, S. et al.178
reported a set of 2-chloro-1,4-bis-(5-substituted-1,3,4-
oxadiazol-2-ylmethyleneoxy)-phenylene derivatives (147) possessing anticancer
activity. Kumar, D. et al.179
reported a series of 5-(3-indolyl)-2-(substituted)-1,3,4-
oxadiazole derivatives (148) that possess potent cytotoxicity and selectivity against
human cancer cell lines.
O
NN
OO
O
NN
R1
O
NN
NHN
148147
Antiviral activity
A QSAR study on 1,3,4-oxadiazole substituted naphthyridine derivatives
(149) as HIV inhibitors was performed to design new active derivatives for better
understanding of inhibition of the HIV-1 IN reaction by Veerasamy, R. et al.180
N
N
OH
O
N NR2
R1
149
Anticonvulsant activity
Afshin, Z. et al.181
reported a new series of 2-substituted-5-{2-[(2-halobenzyl)
thio)phenyl}-1,3,4-oxadiazoles (150 and investigated for anticonvulsant activity.
Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that some
of the synthesized compounds had significant anticonvulsant activity and also series
of new 2-substituted-5-(2-benzyl -oxyphenyl)-1,3,4-oxadiazoles)(151) have been
synthesized and evaluated as anticonvulsant agents.
Chapter 1
Page 33
S
N
NO
R1
O
N
NO
R1
R R150 151
Chapter 1
Page 34
1.3. AIMS AND OBJECTIVES OF THE RESEARCH
Due to wide spectrum of biological activities of azoles, the main focus of the
present study was to design molecules bearing preferably more than one azole.
Among the azoles, pyrazole ring was extensively studied and hence was incorporated
in the synthesis of novel heterocyclic compounds. During the course of research work,
several entities of heterocyclic compounds were designed, synthesized, characterized
using spectral studies and evaluated for their antimicrobial activities.
The research work presented in the thesis is summarized as follows:
1. Synthesis of novel pyrazole oxadiazole derivatives.
2. Synthesis of novel pyrazole carboxamide and thiazole derivatives.
3. Synthesis of novel pyrazole-thiazole containing oxadiazole derivatives.
4. Synthesis of novel pyrazole-thiazole containing carboxamide and thiazole
derivatives.
5. Structure confirmation of these newly synthesized derivatives using
spectroscopic techniques like IR, 1H and
13C NMR, NOE and mass.
6. Evaluation of antimicrobial activity of these newly synthesized compounds.
Chapter 1
Page 35
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