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CHAPTER - 1
A GENERAL INTRODUCTION TO HETEROCYCLIC CHEMISTRY
1
1.1 Introduction
Literature survey revealed that the history of heterocyclic chemistry began in the
1800's, in step with the development of organic chemistry. Heterocyclic compounds offer
a high degree of structural diversity and have proven to be broadly and economically
useful as therapeutic agents. Heterocyclic compounds are cyclic compounds containing
at least one atom of carbon and at least one element other than carbon.1 A ring with only
heteroatom is called homocyclic compound and heterocycles are the counterparts of
monocyclic compounds. Thus incorporation of oxygen, nitrogen, sulphur or an atom of a
related element into an organic ring structure in place of a carbon atom gives rise to a
heterocyclic compounds.2
In the recent years, the incidence of fungal and bacterial infections has increased
dramatically. The widespread use of antifungal and antibacterial drugs in resistance to
drug therapy against fungal and antibacterial infections which led to serious health
hazards.3
It is well-known that heterocyclic compounds having azole nucleus are important
pharmacophore that appear extensively in various types of pharmaceutical agents, widely
implicated in biochemical processes and display diversity of pharmacological activities.
These heterocyclic compounds form a major part of organic chemistry; they are widely
distributed in nature and play a vital role in metabolism of living cells.4 Their practical
applications range from extensive clinical use to fields as diverse as medicine,
agriculture, photochemistry, biocidal formulation and polymer science. By virtue of their
therapeutic properties, they could be employed in the treatment of infectious diseases.
Many heterocyclic compounds synthesized in laboratories have been successfully used as
clinical agents. In the medicinal world, the chemistry of heterocycles has played a vital
role in combating many deadly diseases. A large number of heterocyclic compounds are
2
essential to our life and their functions are often of fundamental importance for living
systems.
A large number of heterocyclic compounds occur naturally. Many heterocyclic
compounds are found as key components in biological processes. Essential diet
ingredients such as Thiamin (Vitamin B1), Riboflavin (Vitamin B2), Nicotinamide
(Vitamin B3), Pyridoxal (Vitamin B6) and Ascorbic acid (Vitamin C) are heterocyclic
compounds. Two of the essential amino acids tryptofan and histidine are also
heterocycles. Nucleic acids, haemoglobin, chlorophyll and many enzymes are also
containing important heterocyclic nucleus.
Amongst the heterocyclic compounds Triazoles, thiadiazoles, pyrazoles,
oxadiazoles, attracted a tremendous attention, as they are full of many ramifications
especially in the biological and industrial applications. In this chapter we have given a
short introduction of these compounds. In view of the general observation that the
biological activities are invariably associated with a large variety of heterocyclic systems
such as 1,2,4-Traizoes, Pyrazoles, 1,3,4-Thaidaizole and 1,3,4-Oxadiazoles etc a large
number of their new derivatives have been synthesized and extensively studied for
various pharmacological properties.
1.2 Biological importance of heterocyclic compounds
1.2.1 Biological importance of 1,3,4-Oxadiazoles
Oxadiazole derivatives have been extensively studied in the past few decades. It is
five membered heterocyclic ring that exist in four isomeric forms. Out of its four isomers
1,3,4-Oxadiazole exhibited a wide range of biological activities. 1,3,4-Oxadiazoles are an
important type of oxygen and nitrogen containing aromatic heterocyclic compounds,
possess desirable electronic and charge-transport properties and the various functional
groups are easily introduced into the structurally rigid oxadiazole ring. These oxadiazole
3
are thermally stable and neutral Heteroaromatic molecules. These characteristics resulted
in the extensive potential applications of oxadiazole based derivatives in the field of
medicinal chemistry.
1,3,4-Oxadiazole moiety is of great importance to chemist as well as biologist
since it is one of the key building blocks for many of the naturally occurring compounds.
Among the numerous heterocyclic moieties of biological and pharmacological interest,
1,3,4-oxadiazoles ring is endowed with various activities, such as anti-inflammatory,
antimicrobial, antifungal, anticonvulsant etc. The fast growing literature on heterocycles
in recent years demonstrates their increasing significance in the pharmaceutical filed.
Keeping in view of the medical importance of different oxadiazole, a number of 1,3,4-
Oxadiazole derivatives containing biologically active functional groups at various
positions of it were synthesized and their in detail medicinal activities were explored.
The ability of 1,3,4-oxadiazole heterocyclic compounds to undergo various
chemical reactions have made them important for molecule planning because of their
privileged structure, which has enormous biological potential. Two examples of
compounds containing the 1,3,4-oxadiazole unit currently used in clinical medicine are:
Raltegravir (1)5, an antiretroviral drug and Zibotentan (2) an anticancer agent
6 (Fig. 1.1).
N
O
NHN
O
N
N
O
OH
NH
O
F
1
N
O
N
N
SNHO
O
N
N
O
2
Fig. 1.1: Structures of Raltegravir and Zibotentan, drugs that are in late stage clinical
development.
The 1,3,4,-oxadiazole have shown significant antimicrobial activity against a wide
variety of microorganisms like fungi, Gram +ve and Gram –ve bacteria. Keeping this in
4
mind the special emphasis is given on recently reported oxadiazoles possessing
antimicrobial activity. A detailed synthetic approach and literature survey on medicinal
properties of 1,3,4-oxadiazole has been dealt in Chapter-2. Based on these exploration
and literature survey, here we have presented some of the example containing 1,3,4-
oxadiazole derivatives in the field of medicinal chemistry.
It has been found that Song Cao et al, (2002)7 prepared and evaluated a series of
2-(5-trifluromethyl) pyridyloxy methyl-containing 1,3,4-oxadiazole derivatives (3) (Fig.
1.2). Among the group of compounds evaluated, especially those having fluorine on the
benzene ring exhibited a significant insecticidal activity on army worm, Leucania
separate Walker at 500 μg/mL.
NF3C
OO
NN
3
F
Fig. 1.2: 2-(5-Trifluoromethyl) pyridyloxy methyl-containing-1,3,4-oxadiazole
Almasirad and co-workers (2004)8 synthesized a series of 2-fluoro phenoxy
substituted 1,3,4-oxadiazoles (Scheme-1.1). The key intermediated (4) was converted in
to different cyclised 1,3,4-oxadiazole derivatives using different condition. All the
compounds (5-8) were screened for their anticonvulsant activity both in PTZ and MES
models. Some of the compound showed very good anticonvulsant activity against the
tested microorganism.
5
NHNH2
O
O
F
O
NNNH2
O
F
O
NHNS
O
F
O
NHN
O
O
F
O
NN
S
O
F4
56
78
CDI, THF
BrCN, NaHCO3CS2, KOH
I) CS2, KOH
2)MeI, NaOH
Scheme-1.1: Synthesis of 2-substituted-5- [2-(2-fluorophenoxy) phenyl]-1,3,4-
oxadiazoles
A series of pyrimidine substituted 1,3,4-oxadiazole derivatives (Fig. 1.3) (9) were
synthesized by Burbuliene et al, (2004).9 Most of the synthesized compounds showed
significant anti-inflammatory activities.
N
O
N
S
CN
SN
N
R
9
Fig. 1.3: 5-[(2-disubstitutedamino-6-methyl-pyrimidin-4-yl)-sulfanylmethyl]-3H-1,3,4-
oxadiazole-2-thiones
Synthesis of some 3-Acetyl-2-substituted phenyl -5-(3,4,5-trimethoxy phenyl) 1,
3,4-oxadiazoles (10) (Fig. 1.4) were synthesized by Jin et al, (2006),10
the synthesized
compounds were evaluated for their antiproliferative activities against some cancer cells
in vitro by MTT method. Some of selected compounds showed moderate activities
against Bcap37 and BGC823 cells.
NH N
HN
O
where R=
6
O
O
O
O
NNR
CH3
O
10
Where R=2-F, 3-F, 4-F, 2-CF3, 4-CF3, 3,4-2Cl, 2,5-2OMe2, 3,4,5-3OMe3, 4-Cl-3-NO2,
3,5-2Cl, 2,6-2Cl, 2,3-2OMe2
Fig. 1.4: 3-Acetyl-2-substituted phenyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1,3,4-
oxadiazole derivatives
Li et al, (2006)11
synthesized various 1,3,4-oxadiazoles containing different
aromatic substitution (Fig. 1.5) (11) and tested for their fungicidal activities activity
against R. solani.
NO
O
OMe
SO
NN
R
11
Fig. 1.5:(E)-α-(Methoxyimino)-benzene acetate derivatives containing 1,3,4-oxadiazole
Synthesis of some new 1,3,4-oxadiazole derivatives containing 3,4,5-trimethoxy
phenyl moiety (Fig. 1.6) was reported by Ch en and Song et al, (2007). 12
The compounds
have been shown to be fungicidally active. The compound (12) and (13) exhibit mycelia
growth by approximately 50% (EC50) AT 2.9-93.3 μg/mL in vitro against 10 different
kinds of fungi.
a: R = H,
b: R = 4-OMe,
c: R = 4-C6H5-CH2O,
d: R = 3-Cl,
e: R = 2,3-Cl2,
f: R = 2,4-Cl2,
g: R = 2,5-Cl2,
7
O
O
O
O
NN
SO
O
O
O
O
O
NN
S
O
O
C2H5
12 13
Fig. 1.6: 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives
It has been well established that fluorinated substituted heterocycles have got a
significant place in medicinal chemistry. Karthikeyan et al, (2008)13
synthesized a series
of 1,3,4-oxadiazole derivatives containing 2,4-dichloro-5-fluoro-phenyl moiety (Fig. 1.7)
(14). Some of the synthesized compounds were found to possess good bactericidal and
fungicidal activities.
N
O
NO
N
Cl
ClF
R
14Where: R=-2-Cl, 4-Cl, 2, 4-dichloro
Fig. 1.7: 2, 4-Dichloro-5-fluorophenyl containing oxadiazoles
Bhandari and co-workers, (2008)14
was developed new chemical entities as
potential anti-inflammatory agents with no GI toxicity (Fig. 1.8). Some of the compounds
(15) were found to have significant anti-inflammatory activity in the carrageenan induced
rat paw oedema model, with significant analgesic activity in the acetic acid induced
writhing model with no ulcerogenicity.
O
NN
SO
O
HNCl Cl
15
8
Fig. 1.8: S-Substituted phenacyl-1,3,4-oxadiazole derivative
Farshori et.al, (2010) 15
synthesised 5-alkenyl/hydroxyalkenyl-2-phenylamine-
1,3,4-oxadiazoles (Fig. 1.9), compound (16) shows very good in vitro antimicrobial
activities by disc diffusion method.
N
O
N
R NH 16
Fig. 1.9: 5-Alkenyl- 1,3,4-oxadiazole derivatives
Kumar et al, (2010)16
synthesised some novel 2-substituted-5-[isopropylthiazole]
clubbed 1,3,4-oxadiazoles (Fig. 1.10) and tested for antimicrobial activity by broth micro
dilution method. Among the various synthesised compounds (17) and (18) showed
improved antibacterial activity against tested Gram-positive bacteria.
N
O
N
N
SCl
17
N
O
N
RN
S
O
CH3
CH3
18
Fig. 1.10: 2-substituted-5-[isopropylthiazole] 1,3,4-oxadiazole
Recently Rashid et al, (2012)17
synthesized a series of benzimidazole bearing
oxadiazole nucleus (22) (Schme-1.2) by microwave irradiation. Initial screening of
compounds showed significant to good in vitro anticancer activity.
Where R= 4-ClC6H5,4-OCH3C6H5
Where R=
9
NH2
NH2
+ HO
O
O
O
OHN
N
O
O
OH
N
N
O
O
NN
R
R-CO2H, MW
(i)C2H5OH, H2SO4
(ii)N2H4
(iii)
22
1920
21
Where R= -CH2Cl
NH
NNH2
Cl
Scheme-1.2: 1-(1H-benzo[d]imidazol-2-yl)-3-(1,3,4-oxadiazol-5-substituted derivatives-
2-yl)propan-1-ones
Lai et al, (2013)18
synthesized a series of 1, 2-Benzisothiazol-3(2H)-ones and
1,3,4-oxadiazoles and screened against Dengue and West Nile virus proteases. Most of
the compounds showed greater than 50% inhibition against DENV2 and WNV proteases
([I] = 10 μM). The IC50 values of compound (23) (Fig. 1.11) against DENV2 and WNV
NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively.
S
N
O
NN
O
O23
Fig. 1.11: Novel 1, 2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives
Recently Debnath et al, (2013)19
synthesized a biologically important 5-aryl-3H-
[1,3,4] oxadiazol-2-ones (28) by heating the easily synthesized N-(chloro-aryl-
methylene)-tert-butylcarbazates (27) on basic alumina surface under solvent-free
condition (Scheme-1. 3).
10
Ar OH
O
+
Ar N
HN O
O
H
Ar N
Cl HN O
O
N
O
NH
OAr
Dry DMF, NCS, RT Basic alumina/ 85 0C
H2N
HN O
O24 2526
27 28
Scheme-1. 3: Synthesis of 5-aryl-3H-[1,3,4] oxadiazol-2-ones from N′-(chloro-aryl-
methylene)-tert-butylcarbazates using basic alumina
1.2.2 Biological importance of Pyrazoles
The pyrazole ring system consists of a doubly unsaturated five member ring
containing two adjacent nitrogen atoms. The procedures for its synthesis have been
extensively studied and such studies have been stimulated by various promising
applications, especially in the case of highly substituted pyrazole derivatives. In fact,
certain substituted pyrazoles are used as antimicrobial,20
anticancer,21
anti-
inflammatory,22
antidepressant,23
anticonvulsant,24
antihyperglycemic,25
antipyretic,26
antibacterial,27
antifungal activities,28
fungicidal,29
anti-arthritic 30
activities.
The knowledge of such applications has pointed out that trisubstituted pyrazole
are important target to be prepared to our interest on synthesis and molecular structure
determination of some types of pyrazole. A detailed synthetic approach and literature
survey on medicinal properties of pyrazole derivatives has been dealt in Chapter-3.
Some of the pyrazole derivatives that are having wide variety of activities are listed in the
below table.
11
Table-1.1: Pyrazole containing drugs.
Name of the Drug
IUPAC Name
Structure
Celecoxib
(Anti-inflammatory
drug)
4-[5-(4-Methylphenyl)-3-
(trifluoromethyl) pyrazol-1-
yl]benzenesulfonamide
NN
F
FF
SO ONH2 29
Lonazolac (Anti-inflammatory
drug)
[3-(4-chlorophenyl)-1-phenyl-
1H-pyrazol-4-yl]acetic acid
NN
OH
O
Cl
30
Crizotinib
(Non-small cell lung
carcinoma)
3-[(1R)-1-(2,6-Dichloro-3-
fluorophenyl) ethoxy]-5-(1-
piperidin-4-ylpyrazol-4-
yl)pyridin-2-amine
NN
NH
N
NH2
O
Cl
Cl
F
31
Tepoxalin
(Nonsteroidal anti-
inflammatory drug
approved for
veterinary use)
3-[5-(4-Chlorophenyl)-1-(4-
methoxy phenyl)pyrazol-3-
yl]-N-hydroxyl-N-
methylpropanamide
NN
O
O
N
HO
Cl
32
12
Deracoxib
(Anti-inflammatory
drug)
4-[3-(Difluoromethyl)-5-(3-
fluoro-4-methoxyphenyl)- 1H-
pyrazole-1-yl]
benzenesulfonamide
NN
S OO
NH2
F
O
F
F
33
Rimonabant
(Anti-obesity drug)
5-(4-Chlorophenyl)-1-(2,4-
dichloro-phenyl)-4-methyl- N-
(piperidin-1-yl)-1H-pyrazole-
3-carboxamide
NN
Cl
Cl
Cl
O
NH
N
34
Watson et al, (1994) 31
synthesized N- alkyl biaryl tetrazoles containing pyrazole
nucleus (Fig. 1.12), among the synthesized compound, (35) was found to be highly potent
antagonists of angiotensin II.
N NN
N
NN
Br
O
O
35
Fig. 1.12: C-linked pyrazole biaryl tetrazoles
1, 4-Diaryl pyrazole derivative (36) was synthesized by Kiyoshi et a l, (1997)32
this compound was tested for anti-inflammatory and analgesic activities to develop anti
inflammatory agents with fewer side effects than existing non-steroidal anti-inflammatory
drugs. The structure activity relationship was extensively studied (Fig. 1.13).
13
NN
C
F
SO
ON
36
Fig. 1.13: 1, 5-Diarylpyrazoles
Huang and co-workers (2000)33
synthesized 4-alkyl-1, 3, 5-triarylpyrazoles (Fig.
1.14 ) (37) which are useful as estrogen receptor.
R2
NN
Et
R1
37
R1=H, OH, OMe
R2=H, OH, OMe
Fig. 1.14: 1,3,5-Triaryl-4-alkylpyrazoles
The synthesis of novel series of structurally related 1H-pyrazolyl derivatives (38)
were described by the Bekhit and Abdel-Aziem (2004).34
All the newly synthesized
compounds were tested for their anti-inflammatory and antimicrobial activities. COX-1
and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were also
determined.
14
NN
N
N
H3C
S
Br
R
38
R=H, C6H5CO, C6H5NHCS, CH3CO
CHO, CH3SO2, 4-CH3C6H4SO2
Fig. 1.15: Thiophene containing diarylpyrazoles
Park et al, (2005)35
synthesized a series of Pyrazole oxime ether derivatives (43)
and examined its cytotoxicity activities. Among those, 5-phenoxypyrazole exhibited very
potent cytotoxicity comparable to Doxorubicin (Scheme-1.4).
Where R1= Me, Ph, 2-Py
R2= Me, Pri
R3= H, Cl,
R4=CH2Ph-3-OMe, CH2Ph-4-CF3
CH2Ph-4-NO2, CH2Ph-2-Me-3-Ph
CH2Ph-4-CO2Et
NN
R1
R2
ONN
Cl
R1
R2
O
H
NN O
R1
R2
O
H
R3
NN
O
R1
R2
N
H
R3
OH
NN
O
R1
R2
N
H
R3
O R4
POCl3/DMFHOPh-R3 NH2OH, NaOH, MeOH
R4-Cl or Br/KOH/DMSO
39 40 41 42
43
Scheme-1.4: pyrazole oxime ethers derivatives
A series of pyrazole derivatives (44) via 1,3-dipolar addition of sydnone and nitro
furan acetylenic ketones (Fig. 1.16) were reported by Rai et al, 36
(2006).
15
O
NN
R2
R1O
NO2
44
Fig. 1.16: 1-Aryl-3-(5-nitro-2-furyl)-4-aroylpyrazoles
Sanjay and his co-workers (2006)37
synthesized a series of 1,5-diaryl and 1,3-
diaryl substituted pyrazoles (Fig. 1.17) and evaluated for their ability to inhibit enoyl-
ACP reductase of Plasmodium falciparum. The inhibitory activity of these synthesized
compounds was evaluated in a continuous spectrophotometric assay. Of all the analyzed
compounds (45) and (46) inhibited the enzyme with IC50 values of 30μM and 50μM,
respectively.
NN
CHO
H3C
N N
F3C 45
NN
CF3
O2N
46
Fig. 1.17: 1, 5-diaryl and 1, 3-diaryl substituted pyrazoles
Jorand-Lebrun et al, (2007)38
synthesized pyrazoles (Fig. 1.18) (47) as low
molecular weight luteinizing hormone receptor agonists.
R1= H, Me, Cl;
R2= H, Me, OCH3
16
NN
NH
O
OH
ONH2
N
47
Fig. 1.18: Pyridine substituted pyrazoles
Farag et al, (2008)39
reported N-pyrazole derivatives (Fig. 1.19) used as
antimicrobial. Among the compounds tested for antimicrobial, compound (48) shown
very good activity against pathogenic mould (Aspergillus).
NN
HN
O Br
48
Fig. 1.19: Novel N-phenyl pyrazole derivatives
Zhao et al, (2008)40
Synthesized and discovered a novel pyrazole derivative (49)
as an inhibitor of apoptosis through modulating integrin β4, ROS, and p53 levels in
vascular endothelial cells (Fig. 1.20).
NN
O
O
Cl
49
Fig. 1.20: N-phenyl -3-2-chlorophenyl substitituted pyrazole derivatives
17
Menozzi et al, (2008)41
synthesized a set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles
and evaluated in vitro for their affinity on human CB1 and CB2 receptors (Fig. 1.21).
Among the synthesized compounds (50) was the closest rimonabant analogue and showed
competitive binding of 79% and 37% against CB1 and CB2 receptor respectively.
NN
ONH
Cl
Cl
Cl
N
50
Fig. 1.21: N-dichloro phenyl-pyrazole derivatives
Isloor and co-workers (2009)42
reported the synthesis and anticancer activity of
new 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (Fig. 1.22) containing
pyrazole moiety (51).
N
N
N
N
S
NH
N
R2
R1
51
Fig. 1.22: 1,2,4-Triazolo [3, 4-b]-1,3,4-thiadiazoles containing Pyrazole derivatives
Rai et al, (2009)43
synthesized a series of 1,3,4-oxadiazole containing pyrazole
derivatives and studied its antibacterial activities. Among the synthesized compounds, 2-
[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-
oxadiazole (Fig. 1.23) (52) was found to exhibit significant antibacterial activity.
18
NN
OH3C
Cl
O
NN
F
52
Fig. 1.23: 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-
phenyl)-[1,3,4] oxadiazoles
Ragavan et al, (2010)44
synthesized a series of 1,5-diary pyrazole derivatives
(Scheme-1.5) (56) and screened for their antibacterial activity against Escherichia coli,
Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumonia. Similarly
all these compounds were screened for their antifungal activity against Aspergillus flavus,
Aspergillus fumigates, Penicillium marneffei and Trichophyton mentagrophytes. Some of
the synthesized compounds exhibited good antibacterial and antifungal activity.
NN
Cl
F
R
O
O
Cl
O
Cl
LiHMDS
Diethyl oxalate
O
OEt
ON N
Cl
F
EtO
O
NHNH2
F
EtOH
i) LiOH/THF/water
iii) R-NH2/TEA
ii) (COCl2)/DCM
Where R=N Cl
N
O
56
53 54
55
Scheme-1.5: Synthesis of novel 1, 5-diaryl pyrazoles
Thumar et al, (2011)45
synthesized a series of 4-pyrazolyl-N-arylquinoline-2,5-
dione derivatives (57) (Fig. 1.24) and are screened, against some of the bacterial
19
pathogens using broth micro dilution MIC (minimum inhibitory concentration) method.
Some of the compounds were found to be equipotent or more potent than commercial
drugs.
N N
CH3
N
OCl
R2
R1
O
R2
R
57
Where R=3-Cl, 4-Me
R1=H, Me
R2=F, OMe,
Fig. 1.24: Carbostyril derivatives of 1H-pyrazole
Faidallah et al, (2011)46
synthesized fluorinated pyrazoles (60) (Scheme-1.6); it
has been observed that Preliminary biological screening of the prepared compounds
revealed significant antidiabetic and antibacterial activities.
NHNH2HCl
SO2NH2
R CF3
OO
NN
SO2NH2
CF3
R Br/CCl4NN
R
CF3Br
SO2NH2
6058
59
Scheme-1.6: 3-Trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives
Recently Isloor et al, (2011)47
synthesized a series of novel imidazole derivatives
containing substituted pyrazole moiety (Fig. 1.25). Among the synthesized compounds,
compound (61) was found to be potent antimicrobial agent. The acute oral toxicity study
Where R=CH3, Furyl
20
for the compound (61) was carried out and the experimental studies revealed that
compound is safe up to 3000 mg/kg and no death of animals were recorded.
NNH
S
N
N
N
S
O
61
Fig. 1.25: New pyrazole incorporated imidazole derivatives
A series of pyrazole-sulfonamide derivatives (62) and (63) were synthesized (Fig.
1.26), characterized, and the inhibition effects of the derivatives on human carbonic
anhydrases (hCA I and hCA II) were investigated as in vitro by Balseven et al, (2013)48
.
Almost all of the compounds have good inhibition effects on the CA I and CA II
isoenzymes.
NN
CN
NH
O
SO2NH2
O
HO
NN
N
NH
O
SO2NH2
O
HO
N
OH62 63
Fig. 1.26: Synthesis of novel pyrazole-sulfonamides
A concise ‘one-pot’ synthesis of a variety of 4-substituted 1,5-diaryl-1H-pyrazole-
3-carboxylates has been developed in moderate to good yields (Scheme-1.7) with
excellent regioselectivity by Jian et al, (2013).49
21
O
R1
R2
Diethyl oxalate
t-BuOLi, THF
OLi
R1
O
O
OEt
R2
O O
R1
OEt
OR2
R3
NHNH2
NN
CO2EtR1
R2
R3
AcOH, reflux
6667
6465
Scheme-1.7: Synthesis of 4-substituted 1, 5-diaryl-1H-pyrazole-3-carboxylates via
lithium tert-butoxide medium
1.2.3 Biological importance of 1,2,4-Triazole
The search for new drug molecule is one of the most challenging tasks to the
medicinal chemist. The synthesis of high nitrogen containing heterocyclic systems has
been attracting increasing interest over the past decade because of their utility in various
applications, such as propellants, explosives, pyrotechnics and especially chemotherapy.
In recent years, the chemistry of Triazoles and their fused heterocyclic derivatives has
received considerable attention owing to their synthetic and effective biological
importance. The derivatization of Triazole is considered to be based on the phenomenon
of bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen
atom yields triazole analogue.
1,2,4-Traizole moiety is of great importance to chemists as well as biologist as it
is chemically useful molecules having diverse biological activities. Triazole, a
heterocyclic nucleus has attracted a wide attention of the medicinal chemist in search for
the new therapeutic molecules. Out of its two possible isomers, 1,2,4- triazole is which
posses almost all types of biological activities. Some of the drugs which are having
22
Triazole as core molecule are given below (Fig. 1.27), several 1,2,4-Traizole containing
compounds are used as drugs for instance Fluconazole (72) is used as an antimicrobial
drug, while Vorozole (68), Letrozole and Anastrozole (70) are used as non steroidal
drugs used for the treatment of cancer. Loreclezole (69) is used as an antifungal agent.
Cl Cl
O
O
N
NN
O
NN
N NN
O
Itraconazole
F
F
NN
N
OH
N
N
N
Fluconazole
Cl
N
NN
N
N
N
Vorazole
Cl
Cl
Cl
NN
N
Loreclezole
NN
N
NC
CN
Anastrozole
6968 70
71
72
Fig. 1.27: 1,2,4-traizole containing drugs
Zamani and his co-workers (2003)50
synthesized a series of l, 5-(isomeric
pyridyl)-4-aryl-1,2,4-triazole-3-thiol, -thioethyl, thiomethyl, thiobenzyl derivatives from
pyridine carboxylic acid hydrazide (73) (Fig. 1.28).
N
N
NN
SR
73 Where R= CH3, C2H5, CH2Ph,
CH2COOH
Fig. 1.28: New Pyridine substituted 1,2,4-triazole
23
Series of 3-benzylsulfanyl derivatives of 1,2,4-triazole were synthesized by
alkylation of starting triazole-3-thiol with appropriately substituted benzyl halide (Fig.
1.29) (74) by Klimesova et al, (2006).51
All members of the set were evaluated for in
vitro antimycobacterial activity. The compounds exhibited only a moderate or slight
antimycobacterial activity. Minimum inhibitory concentrations fall into a range of 32-
>1000 μmol/l. The most active substances bear two nitro groups or a thioamide group on
the benzyl moiety.
N
NH
N
S
N
NN
HN
74
Fig. 1.29: 3-Benzylsulfanyl derivatives of 1,2,4-triazole
Karthikeyan et al, (2006)52
reported the synthesis of some new Schiff bases
bearing 2,4-dichloro-5-fluorophenyl moiety (Fig. 1.30) (75) by condensing triazole with
aromatic aldehydes. Newly synthesized compounds were tested for their antimicrobial
activity.
N
N
N
S
N OCl
Cl
F
N
R
75
Fig. 1.30: Schiff and Mannich bases bearing 2, 4-dichloro-5-fluorophenyl moiety
24
Shridhar et al, (2007)53
studied anticonvulsant activity Thiazolidinone-triazole
derivatives (76). By the treatment of (2-chloroacetyl)-2-arylimino-5-[(Z)-
arylmethylidene]-1,3-thiazolan-4-ones with 5-(1-phenoxyethyl)-4H-1,2,4-triazole-3-thiol
in identical conditions provided a set of bulkier derivatives which have also shown the
anticonvulsant potential (Fig. 1.31).
CH3
N
NNS
N
O
SN
Ar
Ar'
O
76
Fig. 1.31: Thiazolidinone substituted triazole derivatives
Havaldar et al, 54
synthesized 3-[4-(4-substituted phenyl-5-thioxo-4, 5-dihydro-
1H-1,2,4 triazol-3-ylmethoxy)-phenyl]-2-phenyl-3H-quinazolin-4-one (Fig. 1.32) (77).
The synthesized compounds were evaluated in vitro for their antibacterial activity against
Staphylococcus aureus, Escherichia coli and Bacillus subtilis by the ditch-plate technique
using concentrations of 50 μg/mL. The compounds synthesized were screened for their
antifungal activity against. Aspergillus niger, Candida albicans and Cryptococcus
neoformans by paper-disc diffusion method at concentrations of 50 μg/mL.
N
N
O ON
NHN
R1
R2
S
77
Fig. 1.32: 3-[4-(4-substituted phenyl-5-thioxo-4, 5-dihydro-1H-1,2,4 triazol-3-
ylmethoxy)-phenyl]-2-phenyl-3H-quinazolin-4-one
25
Shalini et al, (2009)55
synthesized some substituted diphenyl-1,2,4-triazole-3-ones
by the condensation of substituted benzoyl chlorides and substituted phenyl
semicarbazides. The anticonvulsant activities of these compounds were screened by using
different animal models. Results show that compound (Fig. 1.33) (78) exhibited
anticonvulsant activity in all the four animal models of seizure.
HN
N
N
O
CH3
H3C 78
Fig. 1.33: Diphenyl-1,2,4-triazole-3-ones
Xue Qin et al, (2009) 56
presented a series of N-(5-((1H-1,2,4-triazol-1-yl)
methyl)-4-tertbutylthiazol-2-yl)-4-carboxamide derivatives from 3, 3-dimethyl butan-2-
one. The studies suggested that the presence of fluorine atom at position 2, 3, 4 of phenyl
ring are crucial for exhibited plant-growth regulatory activities and the substitution with
chlorine atom at both 2nd
position and 4th
position of benzene ring caused a decrease of
the activity while the presence of a strong electron-withdrawing group such as nitro-
group led to decrease in activity. Compound (79) having fluorine atom at 4th
position
connected to the phenyl ring produced excellent plant-growth regulatory activity.
(Fig1.34)
N
N
NS
N
NH
O
F
79
Fig. 1.34: N-(5-((1H-1,2,4-triazol-1-yl) methyl)-4-tertbutylthiazol-2-yl)-4-carboxamide
derivatives
26
1,2,4-triazoles incorporated diphenyl sulfone was synthesized by Barbuceanu et
al, (2009).57
The synthesized compounds were tested for its antibacterial activity (Fig.
1.35). The compounds were tested for their in vitro growth inhibitory activity against the
following Gram-negative bacteria and Gram-positive bacteria using the paper disk
diffusion method. Among these compound (80) showed more active against the tested
strains.
SN
NN
O
O
Br
SO
80
Fig. 1.35: S-alkylated 1,2,4-triazoles incorporating biphenyl sulfone moiety
Bayrak et al, (2009)58
synthesized some new 1,2,4-triazoles and their Schiff and
Mannich bases (Scheme-1.8) (83-85) and screened for their antimicrobial activities.
Some of the screened compounds showed good activity.
N
N
N
S
N
NHNH2
O
N
N
N
SN
OEt
O
N
N
NS
N
HN
O
N R
N
N
NS
N
O
NN
SH
N
N
N
SN O
NN
S
NH NO
CS2, KOH
R-NH2, HCHO
RCHO
82
83
84
85
81
Scheme-1.8: 1,2,4-Triazoles, their Schiff and Mannich bases
27
Eswaran et al, (2009)59
synthesized a new class of quinoline derivatives
containing 1,2,4-triazole moiety (Fig. 1.36) (86). The compounds were evaluated for their
in vitro antibacterial and antifungal activities against four strains each. Preliminary results
indicated that most of the compounds demonstrated very good antimicrobial activity,
comparable to the first line standard drugs. The most effective compounds have exhibited
activity at MIC of 6.25 μg/mL.
N
FF
F
R2NN
NHS
R1
86
H2NH2N H2N O
NH
Ph,-CH2PH, -CH2-CH2OMeWhere R1=
R2=
Fig. 1.36: Quinoline derivatives carrying 1,2,4-triazole moiety
Ilango et al, (2010),60
synthesized a new series of 3, 6-disubstituted-1,2,4-triazolo-
[3,4-b]-1,3,4- thiadiazoles. The compounds (Fig. 1.37) (87) were screened for antifungal
activity against Candida albicans and Aspergillus Niger using Ketoconazole as standard
and antioxidant activity by DPPH and Nitric oxide methods using Ascorbic acid standard.
HN
N
NN
N
S
Ar
Cl
Cl 87
Fig. 1.37: 3, 6-disubstituted-1,2,4-triazolo-[3, 4-b]-1,3,4- thiadiazoles
Jubie et al, (2010)61
have synthesized some novel Ciprofloxacin analogues (88) as
antimicrobial agents. Ciprofloxacin have been incorporated to the new series of Schiff
28
and Mannich reaction (Fig. 1.38). The new compounds have been evaluated in vitro for
their antimicrobial activity against B. subtilis, K. pneumoniae, and P. aeruginosa at
10μg/mL concentration. All the compounds showed in vitro gram positive and gram
negative activity generally comparable or superior to that of reference ciprofloxacin.
N
N
NS
NN
N
O
OH
OF
CHR
88
Where R=
Cl Cl OH
OOH
N O
Fig. 1.38: Some novel ciprofloxacin containing 1,2,4-traizole analogues
Patil et al, (2010)62
synthesized a series of sulfone containing 1,2,4- triazole
derivatives (Fig. 1.39). The newly synthesized compounds were screened for their
antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Staphylococcus
epidermidis, Escherichia coli and Pseudomonas aeruginosa. The antifungal activity was
tested against Rhizopus oryzae, Aspergillus Niger, Aspergillus flavus, Candida
albicans and Saccharomyces cerevisiae. Among all the compounds synthesized,
compound (89) exhibited significant antibacterial activity.
N
NN
O
S
O
O
O
R
89
Where R=2-F, 3-F, 4-F, 4-Br, 3-CF3, H
Fig. 1.39: 2-(4-methoxy-phenyl)-5-methyl-4-(2-arylsulfanyl-ethyl)-2, 4-dihydro-[1,2,4]
triazolo-3-ones
29
Recently Sugane et al, (2011)63
synthesised and evaluated a new series of glycine
transporter 1 inhibitors derived from a high-throughput screening hit (Fig. 1.40). A
pharmacokinetic study was showed that compound (90) showed very good oral
bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
N
N
N
F
90
Fig. 1.40: 3-Biphenyl-4-yl-4-phenyl-4H-1,2,4-triazoles
Recently a series of novel isoindoline-1,3-diones containing 1,2,4-triazole moiety
were synthesized via a one-pot reaction by Zhao et al. (2012) 64
(Scheme-1.9). Antifungal
and cytotoxic activities of these compounds were evaluated. Antifungal studies of the
novel compounds showed promising activity (94). Some compounds displayed much
stronger antitumor activity than Fluorouracil.
NN
N
NH2
SHR1 + O
O
O
O
O
O
NN
N
R1
HS
O
O
O
NN
N
R1
S
R2
TEA, ZnBr2, Toulene
RT
R2-Br
93
94
91 92
Scheme-1.9: Novel isoindoline-1,3-dione derivatives bearing 1,2,4-triazole derivatives
Recently Sarnpitak et al. (2013)65
developed a new two-step synthesis of medicinally
important 1,2,4-triazoles from isocyanides and thiosemicarbazones (Scheme-1.10). The
30
method is based on the recently discovered TMSCl-promoted reaction of isocyanides that
yields rare N1, N
3-disubstututed formamidrazones (98).
H2NNH
NH2
S
R1 N
HN NH2
SR1 N
N N
H
R2
N
N
N
R2
R1
R1-CHO R2NC
Pd/C
95 96 97
98
Scheme-1.10: Syntheisis of novel 1,2,4-triazoles from isocyanides and
thiosemicarbazones Isloor et al, (2013)
66 synthesized series of new 1,2,4-triazole derivatives. All the
synthesized compounds were screened for their analgesic activity by the tail flick method
(Fig. 1.41). The antimicrobial activity of the new derivatives was also performed by MIC
by the serial dilution method. The results revealed that the compound having 2,5-
dichlorothiophene substituent on pyrazole moiety and a triazole ring (99) showed
significant analgesic and antimicrobial activity.
NNH
Ar1
N
NN
SH
Ar
99
Fig. 1.41: pyrazole containing 1,2,4-triazoles
31
1.2.4 Biological importance 1,3,4-Thaidiazoles
Heterocyclic compounds occupy a central position among those molecules that
makes life possible. The chemistry of heterocyclic compounds has been an interesting
field of study for a long time. Heterocyclic nucleus 1,3,4-thiadiazole constitutes an
important class of compounds for new drug development. The synthesis of novel
Thiadiazole derivatives and investigation of their chemical and biological behaviour have
gained more importance in recent decades. During the recent years there has been intense
investigation of different classes of thiadiazole compounds, many of which possess
extensive pharmacological activities.
Thiadiazole is a heterocyclic compound featuring both two nitrogen atom and one
sulphur atom as part of the aromatic five-membered ring. Thiadiazole and related
compounds are called 1,3,4-thiadiazole (two nitrogen and one other heteroatom in a five-
membered ring). They occur in nature in four isomeric forms as. 1,2,3-thiadiazole; 1,2,5-
thiadiazole; 1,2,4-thiadiazole and 1,3,4-thiadiazole. 1,3,4-thiadiazole are important
because of their versatile biological actions. In particular, compounds bearing the 1,3,4-
thiadiazole nucleus is known to have unique antibacterial and anti-inflammatory
activities. Differently substituted thiadiazole moieties have also been found to have other
interesting activities such as analgesic, antimicrobial, antitubercular, anticonvulsant and
anti-hepatitis B viral activities. In this review article different compounds having
heterocyclic nucleus have been shown to possess different activity. It was found that
among the important pharmacophore responsible for various activities.
Han Song Chen and associates (1999)67
concentrated on the synthesis of new
fungicidally active Pyrazolyl-Substituted 1,3,4-thiadiazole compounds (Fig. 1.42), The
preliminary bioassay tests indicated that compounds (100) and (101) have fungicidal
activity.
32
NN
S
NHN
S
H3C
CH3
Cl
NN
S
NN
S
H3C
CH3
Cl
R
100 101
Where R=Methyl, propyl, Allyl, Amyl
Fig. 1.42: New fungicidally active pyrazolyl-substituted 1,3,4-thiadiazoles
Gadad et al, (2004)68
synthesised a series of 2-sulfonamido/trifluoromethyl-6-
substituted imidazo [2,1-b]-1,3,4-thiadiazole derivatives (102) (Fig. 1.43). The selected
compounds were evaluated for their preliminary in vitro anti-tuberculosis activity
against Mycobacterium tuberculosis. Some of the compounds exhibited moderate to good
anti-tubercular activity.
N
S
N
R1
N
R3R2
102
R1= -SO2NH2, -(CH3)2N-C=N-SO2-CH3, CF3
R2= CH3, Cl, OMe, Trimethoxy, NO2
R3= H, -SCN, -C=N-NH-C=NH-NH2
Fig. 1.43: 2-sulfonamido/trifluoromethyl-6-substituted imidazo [2, 1-b] [1,3,4]
thiadiazole derivatives
Foroumadi et al. (2005)69
synthesized and studied their antibacterial activity of N-
(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl)
piperazinyl quinolone derivatives (103) against Gram-positive and Gram-negative
microorganisms (Fig. 1.44). Some of these derivatives exhibit high activity against Gram
positive bacteria Staphylococcus aureus and Staphylococcus epidermidis, comparable or
more potent than their parent N-piperazinyl quinolones norfloxacin and Ciprofloxacin as
reference drugs.
33
N
S
NN
S
N
N
O
CO2H
R
F
R1
(O)n
Where R= ethyl, cyclopropyl
R1= H, NO2
n=0,2
103
Fig. 1.44: N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-
thiadiazol-2-yl) piperazinyl quinolone derivatives
Rzeski et al, (2007)70
synthesized a set of N-substituted 2-amino5-(2,4-
dihydroxyphenyl)-1,3,4-thaidaizole derivatives (Fig. 1.45). Among these compound
(104) showed a very good anticancer and neuroprotective activity.
N
S
N
NH
F
OHHO
104
Fig. 1.45: 2-Amino-substituted-1,3,4-thiadiazole
A new series of selective cox-2 inhibitors with 2-amino-5-sulfanyl-1,3,4-
thiadiazole derivatives (105) (Fig. 1.46) were synthesized by Sharma et al, (2008)71
these
compounds were selective inhibitiors of COX-2 and potentiated the activity of COX-1
enzyme. The presence of sulphonamide group is a required pharmacophore for selective
inhibition of COX-2 enzyme.
34
NH S
NN
S
R1
R2105
R1= F, CH3, CF3, SO2NH2
R2= SO2NH2,
Fig. 1.46: 2-Amino-5-sulfanyl-1,3,4-thiadiazoles
Pattan et al, (2009)72
have been introduced the synthesis of various compounds
and evaluated for antidiabetic activity (Fig. 1.47). Among of these compounds (106) have
shown significant antidiabetic activity.
S
NN
NH N
O
O2N106
Fig. 1.47:1,3,4-Thaidiazole-piperidine carboxamide derivatives
Moise et al, (2009)73
were showed the 1,3,4-thiadiazole, that containing a
phenylalanine moiety were synthesized by intramolecular cyclization of 1,4-
thiosmicrbazides (107) (Fig. 1.48), in acid and alkaline media and the synthesized
compounds was evaluated by anti-inflammatory activity.
NH
S
NNNH
R
O
O2N107
Fig. 1.48: 1,3,4-Thiadiazole containing a Phenylalanine Moiety
35
Padmavathi et al, (2009)74
have found that 2-(arylmethanesulfonylmethyl)-5-aryl-
1,3,4-thiadiazoles (108) (Fig. 1.49) exhibited high activity on both Gram (+ve) and Gram
(-ve) bacteria.
SS
NN
R2
R1
O O
( )n
108
Fig. 1.49: 2-Phenyl-5-phenylmethanesulfonylmethy-substituted-[1,3,4] thiadiazole
Hilfiker et al, (2009)75
have carried out the investigation to identify new selective
antagonists, and they found that aminothiadiazole (Fig. 1.50) that is compound (109) was
identified from a high throughput screen as having good antagonist activity for human
EP3.
N
S
NNH
O
O
O
109
Fig. 1.50: 2, 3-Dihydro-benzo [1, 4] dioxine-6-carboxylic acid [5-(1-ethyl-propyl)-[1,3,4]
thiadiazol-2-yl]-amide
Mohammad Asif1 and Chhavi Asthana have (2010)76
prepared derivatives of 2,4-
Substituted diphenyl-5-imino-Δ-2-1,3,4-thiadiazole (110) and evaluated their
antimicrobial properties (Fig. 1.51). The newly synthesized compounds exhibited
promising antimicrobial activity.
36
NN
SHN
R3
R4
R2
R1
110
Fig. 1.51: 3, 5-Diphenyl-substituted-3H-[1,3,4] thiadiazol-2-ylideneamine
Salimon et al, (2010)77
synthesized a series of 1,3,4-thaidaizoles, the newly
synthesized compounds were screened for their in vitro antibacterial activity (Fig. 1.52).
All the newly synthesized compounds (111) were initially screened for their in vitro
antibacterial activities against the Gram-positive (S. aureus, S. cerevisiae and C.
diphtheriae) and the Gram negative (E.coli and P. aeruginosa) bacteria by agar cup-plate
method not disc diffusion method.
NS
N
S S
NN
S S
NN
NH2
111
Fig. 1.52: 5-[5-(5-Methyl-[1,3,4] thiadiazol-2-ylmethylsulfanyl)-[1,3,4] thiadiazol-2-
ylsulfanylmethyl]-[1,3,4] thiadiazol-2-ylamine
A series of 2-amino-5-aryl-thiazolo [1,3,4]-Thiadiazole derivatives were prepared
by Asif et al, (2011)78
. Some of the synthesized compounds showed very good anti-
tubercular activity (Scheme-1.11).
R1 R2 R3 R4
H H H H
H H NO2 NO2
Cl H H H
Cl H NO2 NO2
H Cl H H
H Cl NO2 NO2
H NH2 H H
H NH2 NO2 NO2
37
R H
OSH
OH
O
S
R OH
O
OHNH2
HN NH2
S
S
O
OH
RNH
NH
NH2
S
S
NH
O
NHR
NH2
S
S
N
NR
NH2
SH
S
N
S
NRNH2
-H2O
-H2OH2SO4
-H2O
117
113 114
115 116
112
Where R= Ph, 4-MeC6H4,4-OHC6H4, -NO2C6H4, 4Me2NC6H4, 2ClC6H4,
4-ClC6H4, 2,4-Cl2C6H3, 2OMeC6H4, 3-OMeC6H4
Scheme-1.11: One pot synthesis of 2-Amino-5-aryl-5H-Thiazaolo-[4,3-b]-1,3,4-
thiadiazoles
Alagawadi et al, (2011)79
together proved that new 2,4-Thiazolidinediones
bearing Imidazo[2,1-b][1,3,4]Thiadiazole derivatives (121) (Scheme-1.12) show very
good antimicrobial activity.
N
S
N
S
H2N
O
O
NH2
BrO
N
S
NN
SH2N O
O
R
N
S
NN
S
O
ONN
N
S
NN
S
O
ONN
HN
SO
O
HO
EtOH
POCl3/DMF S
HN
O
O
Piperidine/AcOH,
Toulene
R R
R
118119
120 121
Scheme-1.12: 2, 4-Thiazolidinediones bearing imidazo [2,1-b][1,3,4] thiadiazole
derivatives
R= H, 4-Br, 4-Cl, 2, 5-(OMe) 2, 4-
CH3, 4-OMe, 4-NO2
38
Bhat et al, (2011)80
synthesized series of 3-(1,3,4-Thiadiazole-2-yl) quinoline
derivatives (122) (Fig. 1.53) from chloroquinone with an aim to explore their effect on in
vitro growth of microorganisms causing microbial infection.
N Cl
X
S
NN
N
O
O
R
122
X= H, Cl, CH3
R=H, Cyclohexyl, O-tolyl,
4-nitrophenyl, cyclopentyl,
2,5-difluoro phenyl,
Fig. 1.53: 3-(1,3,4-Thiadiazole-2-yl) quinoline derivatives
Kamal et al, (2011)81
synthesized 6-aryl-2-(2-aryl-2H-1,2,3-triazol-4-yl) imidazo
[2,1-b]-1,3,4- thiadiazoles (123) (Fig. 1.54). Some of these compounds were found to
possess slight to moderate activity against the microorganisms Staphylococcus aureus,
Candida albicans, Pseudomonas aeruginosa, and Escherichia coli.
N
N N S
NN
N
I
R2
R1
123
Fig. 1.54: Imidazo [2,1-b]-1,3,4-thiadiazoles
Cancer is a class of disease in which cell, or a group of cells display uncontrolled
growth, invasion, and sometimes metastasis. It affects people at all ages with the risk of
most types increasing with age. It caused about 13% of all human death in 2007.
Recently M. N. Noolvi et al, (2012)82
synthesized a series of 2-cyclopropyl Imidazo [2,1-
b] [1,3,4]-Thiadiazole derivatives (Scheme-1.13). Among the compounds tested,
compound (128) found to be the most active candidate of the series at five dose level
screening with degree of selectivity towards Leukemic cancer cell line.
39
O
Cl
+ H2N
HN NH2
SN
S
NN
RBrN
S
N
NH2
N
S
N
N
ClBr
Where R=H, 4-Cl, 4-Br, 4-F, 2,4-Di-Cl, 2,4-di-OH, 3-NH2, 4-NH2, 3-NO2, 4-NO2,
126 127
128
124 125
Scheme-1.13:2, 6-Disubstituted imidazo [2, 1-b] [1,3,4] thiadiazoles
Recently Alegaon et al, (2012)83
synthesized a series of novel Imidazo [2, 1-b]
[1,3,4]-thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents
(129) (Fig. 1.55). Among synthesized compounds, some of the compounds showed very
good vitro antitubercular activity against M. tuberculosis.
N
S
N
N
F
F
F
N
S
S
O
O
R
129 Where R = H, Cl, Br, F, CH3, OCH3, NO2
Fig. 1.55: Novel imidazo [2,1-b] [1,3,4] thiadiazole carrying rhodanine-3-acetic acid
A regioselective, reagent-based method for the cyclization reaction of 2-Amino-
1,3,4-thiadiazole core skeletons (133) is described by Yang et al, (2013).84
The
thiosemicarbazide intermediate was reacted with EDC·HCl in DMSO or p-TsCl,
triethylamine in N-methyl-2-pyrrolidone to give the corresponding 2-amino-1,3,4-
40
oxadiazoles 4 and 2-amino-1,3,4-thiadiazoles through regioselective cyclization processes
(Scheme- 1.14).
R1 N C S R1NH
NH
SHN R2
O
N
S
N
R2NH
R1
N
S
N
R2N
R1
R3
131 132
133
130
Where R1=Bn, 4-MeO-Bn, 4-CF3-Bn, Ethyl, Ph, 4-F-Ph, 4-NO2-Ph
R2= Ph, 4-MeO-Ph, 4-F-Ph, 4-NO2-Ph, Ph.
Reaction condn: (i)Treithyl amine, THF, RT, (ii) EDC.HCl, DMSO, 60 oC,
(iii) p-TsCl, TEA, NMP, RT (iv) Electrophiles, NaH, NMP, RT
Scheme-1.14: 2-Amino-Substituted 1,3,4-Thiadiazole derivatives
Recently Botros et al, (2013)85
synthesized phenytoin derivatives and studied its
anticonvulsant activity (Scheme-1.15). Among the synthesized compounds, only phenyl
substituted (136) showed promising anticonvulsant activity.
HN
N
O
O
NHO
NH2
HN
N
O
O
NHOHN
HN
S
R
HNN
O
OS
NN
NH
R
(i)(ii)
(i) RNCS, abs EtOH (ii) Conc. H2SO4
134135 136
Where R= C2H5, C6H5, 4-CH3C6H4, 4-OMe-C6H4, 4-Cl-C6H4
Scheme-1.15: Phenytoin derivatives
41
Scope and Objectives of the present work
At present, only a limited number of antimicrobials are available to treat
multidrug resistant strains of infectious bacteria and resistance to even the latest antibiotic
are appearing. Increasing antibiotic resistance in microbial populations has necessitated
the search for new antimicrobial agents. Moreover, some of the currently available drugs
have been shown to exhibit unfavourable side effects and toxicity. It is well established
that small modifications in the structure of the targets are altering their biological
character as well as their physiochemical properties. Both steric and electronic factors are
claimed to be prime determinants in the variation of biological activity. Generally, factors
such as presence of hydrophobic and hydrophilic groups, binding site and solubility of the
molecules are desirable features to exhibit medicinal activity to a great extent.
Stereochemistry of the molecule also plays an important function in their biological
activity.
Generally, a rational drug design process for a new antimicrobial agent could be
achieved in many ways. One of the strategies is the identification of new targets through
better understanding of molecular mechanisms of infections. Another way is to modify
the structure of already existing drugs by improving the binding affinity to the receptor.
Also, the correlation between structure activities of the new compounds would impart
valuable information to assist the development of new types of drugs in new millennium.
Furthermore, the results of research may be useful in understanding the mechanism of
drug action.
The main objectives of the present research work are as follows:
Synthesis some new substituted 1, 2,4-Triazole, Pyrazole, 1,3,4-Oxadiazole and 1,3,4-
Thiadiazole derivatives.
Development of synthetic routes for the newly prepared compounds.
42
Characterization of new compounds by IR, 1H NMR,
13C NMR, Mass spectral studies
and also by X-Ray crystallography and elemental analysis
Evaluation of biological activities of new compounds, such as antibacterial,
antifungal activity.
The thesis comprises of six chapters.
Chapter 1: This is an introductory chapter, which deals with a brief account of synthesis,
reactions and biological activities of some 1,3,4-oxadiazole derivatives based on the
publications appearing in the chemical literature up to Feb-2013. Main objectives of the
present research work were also explained here.
Chapter 2: This chapter describes synthesis, characterization and biological studies of
some new some new 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety.
Structures of newly synthesized compounds were characterized by spectral studies. New
compounds were screened for antifungal and antibacterial activities. The results and
discussion of such studies are presented in this chapter.
Chapter 3: This chapter includes, two series of pyrazole ester derivatives synthesised by
the condensation of Ethyl-3-(dimethylamino)-2-[(phenyl) carbonyl] prop-2-enoate with
different aromatic/aliphatic hydrazines. Further this pyrazole ester was converted in to its
carboxamide derivatives. The newly synthesized compounds were characterized by IR,
1H NMR,
13C NMR, mass spectral analyses. New compounds were screened for their
antibacterial studies. Molecular structure of some compounds was also confirmed by
single crystal X-ray analysis.
Chapter 4: This chapter explained about the synthetic approach and biology studies of
some new 3 (2,6-difluoro-benzyl sulfanyl)-4-(substituted)-5-(3,4,5-trimethoxy phenyl)-
4H-[1,2,4]triazole derivatives. A series of 1,2,4-Triazole derivatives were synthesized
from the commercially available 3,4,5-trimethoxyphenyl benzoic acid through
43
esterification, and hydrazidation. Further this acid hydrazide was then treated with
different aliphatic and aromatic isothiocayante to afford different substituted
carbothioamide derivatives. Cyclization of this intermediate with sodium hydroxide under
reflux condition afford different substituted 1,2,4-triazole derivatives. The newly
synthesized compounds were characterized by IR, 1H NMR,
13C NMR, mass spectral
analyses. New compounds were screened for their antibacterial studies. Molecular
structure of some compounds was also confirmed by single crystal X-ray analysis.
Chapter 5: This chapter focused on the synthesis some new substituted 1,3,4-
Thiadiazole and Imidazo [1,3,4]-Thiadiazole derivatives. Two series of 1,3,4-thiadiazole
derivatives were synthesized by cyclising 4-Fluoro-3-nitrobenzoic acid with Phosphorous
oxychloride and Thiosemicarbazide. The newly synthesized compounds were
characterized by IR, 1H NMR,
13C NMR, mass spectral analyses. New compounds were
screened for their antibacterial studies.
Chapter 6: The summary and conclusions of present research work have been discussed
in this chapter.
In conclusion, the present research work, involving design, synthesis, and
characterization of new, 1,2,4-Triazole, Pyrazole, 1,3,4-Oxadiazole and 1,3,4-Thiadiazole
derivatives and evaluation of their preliminary antibacterial, antifungal activities, has
been aimed at development of new active antimicrobials, which may have future
commercial applications. Further, the optimized synthetic methods and purification
techniques developed these derivatives would be highly useful for future researchers. The
research study is expected to add some more data to the chemistry of new heterocyclic
compounds. The utility of above new heterocyclic compounds may be explored in other
area of applications also.
44
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