Innovare International Journal of Pharmacy and Pharmaceutical Sciences

Academic Sciences ISSN- 0975-1491 Vol 6, Issue 9, 2014

Review Article
1,3,4-THIADIAZOLE: A BIOLOGICALLY ACTIVE SCAFFOLD

HABIBULLAH KHALILULLAH1,*, M U KHAN1, DANISH MAHMOOD2, JAWED AKHTAR1, GAMAL OSMAN1

1Department of Pharmaceutics and Pharmaceutical Chemistry, Unaizah College of Pharmacy, Qassim University, Kingdom of Saudi Arabia,
2Department of Pharmacology, Unaizah College of Pharmacy, Qassim University, Kingdom of Saudi Arabia.

Email: [email protected]
Received: 04 Jun 2014 Revised and Accepted: 02 Sep 2014
ABSTRACT
There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, anti-inflammatory,
anti allergic, antipsychotic, antimicrobial, antimycobecterial, antitumour, antiviral and antitubercular activities. 1,3,4-thiadiazole constitute an
important class of compound for new drug development. They have interesting pharmacophore that display a broad spectrum of biological activity.
The 1,3,4-thiadiazole scaffold is an interesting building block that has been used to synthesize a variety of useful bioactive compounds. The stability
of thiadiazole nucleus has inspired medicinal chemist to carry out various structural variation in the ring. The marketed drugs such as
acetazolamide, methazolamide, globucid proved their therapeutic potential Therefore; many researchers have synthesized these compounds as
target structures and evaluated their biological activities. These observations have been instrumental in the development of new 1,3,4-thiadiazole
derivatives. This review highlights the various biological activities associated with 1,3,4-thiadiazole ring system.
Keywords: 1,3,4-Thiadiazole, Thiadiazole, Azole.

INTRODUCTION S
Among heterocyclic compounds, 1,3,4-thiadiazole has become an
important construction motif for the development of new drugs. N N
Compounds containing 1,3,4-thiadiazole scaffold have a broad
biological activity spectrum including antimicrobial, 1,3,4-Thiadiazole
antituberculosis, anti-inflammatory, carbonic anhydrase inhibitors,
anticonvulsants, antihypertensive, antioxidant, anticancer and During recent years there has been intense investigation of different
antifungalproperties. The ability of 1,3,4-thiadiazole heterocyclic classes of compounds bearing five membered heterocyclic ring in
compounds to undergo various chemical reactions has made them their structure have an extensive spectra of biological activities.
important for molecule planning because of their privileged Therefore new derivative of triazoles, oxadiazoles and thiadiazoles
structure, which has enormous biological potential. Two examples of have been synthesized and evaluated biologically. The present
compounds containing the 1,3,4-thiadiazole unit currently used in review, emphasizes on the biological activities exhibited by
clinical medicine are: acetazolamide and methazolamide as carbonic substituted 1,3,4-thiadiazoles. The review covers advances made in
anhydrase inhibitors. the last decade.

The synthesis of novel 1,3,4-thiadiazole derivatives, and Biological activities associated with 1,3,4-thiadizole ring system
investigation of their chemical properties and biological behavior
There are several reports in the literature discussing the 1,3,4-
has accelerated in the last two decades. In recent years, the number
thiadiazole derivatives for their diverse biological activities and the
of scientific studies with these compounds has increased
most relevant and recent studies have revealed that 1,3,4-
considerably.
thiadiazole derivatives have a broad spectrum of pharmacological
Taking into account the importance of these compounds to both activities that can be classified into the following categories.
heterocyclic and medicinal chemistry, we have decided to present
Analgesic and anti-inflammatory activity
the broad spectrum of pharmacological activities reported in the
literature. Mathew et al.1 have synthesized several 3,6-disubstituted-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazole and their dihydro analogues and
1,3,4-thiadiazole moiety is a five membered heterocyclic nucleus
evaluated them for anti-inflammatory and analgesic activity. Among
bearing nitrogen and sulphur. There are several isomers of
the synthesized compounds, compound 1 showed good anti-
thiadiazole, including 1,2,3 Thiadiazole, 1,2,5 Thiadiazole, 1,2,4
inflammatory and analgesic activities.
Thiadiazole and 1,3,4 Thiadiazole.
MeO
S S S
S N N
N N N N
MeO
N N N S H 3C
N N NH
N
1,2,3-Thiadiazole 1,2,5-Thiadiazole 1,2,4-Thiadiazole 1,3,4-Thiadiazole (1)

1,3,4 Thiadiazole is the isomer of thiadiazole series. From the OCH 3

literature survey it was revealed that more studies have been
carried out on the 1,3,4-thiadiazole moiety as compared to its other Kucukguzel et. al.2have synthesized a series of 2-substituted-1,3,4-
isomers combined. thiadiazoles and evaluated them for antinociceptive activity and found
5-(2ʹ,4ʹ-difluoro-4-hydroxy biphenyl-5-yl) -4-(4-methoxy phenyl)-
The ending -azole designates a five membered ring system with two 1,3,4-thiadiazole (2) to be the most potent compound in the series
or more heteroatoms, one of which is Nitrogen. The numbering of exhibiting similar antinociceptive activity with the standard drug .
monocyclic azole system begins with the heteroatom that is in the
highest group in the periodic table and with the element of lowest Hilfiker et al.3 have carried out the investigation to identify new
atomic weight in that group. Hence the numbering of 1,3,4 selective antagonists, for human EP3 and identified compound 3
Thiadiazole is done in following manner. having good antagonist activity for human EP3. In addition,
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

compound 3 demonstrated excellent selectivity against other EP toxicity. In order to reduce the toxicity Amir et al.8 have replaced the
subtypes as well as the DP, FP, TP, and IP prostenoid receptors. carboxylic acid group of 2-(4-isobutylphenyl) propanoic acid and
biphenyl-4-yloxy acetic acid by a composite system, which combines
H both the triazole and the thiadiazole nucleus in a ring to give a
N N
N compact and planar structure. It was interesting to note that seven
cyclized compounds 8a, 8b, 9a, 9b, 10a, 10b and 10c were found to
S
have anti-inflammatory properties comparable to their standard
OCH3 reference drugs ibuprofen and flurbiprofen. When these compounds
F OH were subjected to analgesic activity by tail immersion method in
mice, all compounds exhibited moderate to good activity. These
(2) compounds were also tested for ulcerogenic activity and lipid
F
peroxidation, and showed superior GI safety profile along with
Further, while studying the structure activity relationship of this reduction in lipid peroxidation as compared with ibuprofen and
compound they found that Compound 4 was a potent antagonist flurbiprofen.
against human EP3 receptors.
N N O Cl N N N N
N N O Et
O Ar N S Ar N S
S N R
N N N
H S N R N
(3) (8) (10) H
O Cl H 10a, R = R 10b, R = phenyl
(4) O 8a, R= 2-aminophenyl, 8b, R= 4-aminophenyl
9a, R= 2-chlorophenyl, 9b, R= 4-chlorophenyl 10 c, R= 4-fluorophenyl

Non-steroidal anti-inflammatory drugs (NSAIDs) continue to be one

Schenone et al.9 synthesized two series of N-[5-oxo-4-(arylsulfonyl)-
of the more widely used groups of therapeutic agents, which inhibit
4,5-dihydro-1,3,4-thiadiazol-2-yl]-amides (11) and tested in vivo for
cyclooxygenase-1 (COX-1), COX-2, and tromboxane synthase with a
their analgesic and anti-inflammatory activities. All the new
varying degree of selectivity. Researchers have recently focused on
compounds possess good analgesic action in the acetic acid writhing
selective COX-2 inhibitors which are believed to reduce
test.
inflammation without influencing normal physiologic functions of
COX-1.
Gadad et al.4 have synthesized a series of 2-trifluoromethyl/ R SO 2
sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole N N
derivatives. They found that the compounds 5 and 6 have shown COR'
O
selective inhibitory activity toward COX-2 (80.6–49.4%) over COX-1 S N
(30.6–8.6). These compounds also exhibited significant anti- (11) H
inflammatory activity (70.09–42.32%), which is comparable to that
of celecoxib in the carrageenan-induced rat paw edema method. Amir et al.[10] synthesized 1,3,4-thiadiazole derivatives of
diclofenac which showed anti-inflammatory activity from 79.04% to
82.85%. The maximum activity (82.85%) was shown by compound
12 having p-fluoro phenyl amino group at second position.

SO2CH3
N
F
N N N
S R=
N NH R
F3C S N R
(5) Cl Cl H

OCH3
(12)

Antimicrobial and antifungal activity

SO2CH3
Khazi et al.[11] synthesized novel methylene bridged benzisoxazolyl
N N imidazo [2,1-b][1,3,4]-thiadiazoles. The investigation of antibacterial
N screening revealed that some of the tested compounds showed
H2NO2S S moderate to good bacterial inhibition. Particularly compounds 13a,
(6)
13b, 14a, 14b and 15a have shown very good antibacterial activity.
Kelekci et al.5 have synthesized some 1,3,4-thiadiazole derivatives. Compound 15a has exhibited highest antibacterial activity.
They found that the analgesic effects of compound 7 were higher
than those of both morphine and aspirin. S
S N
N N N
N N
N
CH3 N NN O
S N O Br R
H 3C N H R
(13 a-c) (14 a-b)
O a, R=Cl; b, R=NO2
a, R= Cl; b, R=Br; c, R= 3-coumarinyl
O (7)
S
Currently available non-steroidal anti-inflammatory drugs (NSAIDs) N
like ibuprofen, flurbiprofen, fenbufen and naproxen exhibit gastric N N
toxicity. Literature survey revealed that modification of the carboxyl N
function of representative NSAIDs resulted in increased anti- O SCN R
inflammatory activity with reduced ulcerogenic effect[6,7]. (15 a-b)
Compounds bearing 1,2,4-triazole and 1,3,4-thiadiazole nuclei
possess significant anti-inflammatory activity with reduced GI a, R= Cl; b, R= OMe

9
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

The high activity is attributed to the presence of electron

withdrawing chloro and bromo functional groups. Antifungal results
indicated that compounds 13b, 13c and 15b have shown good N N
activity. Compound 13b showed very good antifungal activity
comparable to that of standard. Padmavathi et al.[12] found that 2- N
(arylmethanesulfonylmethyl)-5-aryl-1,3,4 thiadiazoles (16a–d) and H S
3-(arylmethanesulfonylmethyl)-5-aryl-4H-1,2,4-triazol-4-amines
(17a–d) exhibited high activity on both Gram (+ve) and Gram (-ve)
(20)
bacteria. In fact, compounds 16d and 17d showed pronounced
activity towards Gram (+ve) bacteria. He et al.[16]reported the synthesis of a series of 5-(1-aryl-1H-
tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-thiadiazole-2-
amine derivatives and investigated in vitro antibacterial activity
O O N N against S. aureus. Among the synthesized compounds, only
O O N N R
R R'
S
R' S
N compound 21 was found to be the most active against tested strain
S n and none of them showed activity against tested fungal strains.
n H2N
(16 a-d) 17 a-d NN
a, R = H, R' = H; b: R = H, R' = 2-Cl a, R = H, R' = H; b: R = H, R' = 2-Cl N OHOH
c: R = 4-Cl, R' = H; d: R = 4-Cl, R' = 2-Cl c: R = 4-Cl, R' = H; d: R = 4-Cl, R' = 2-Cl
N N HO
n = 1,3,5,7,9,11 n = 1,3,5,7,9,11 N S
S O
N
Further it was found that compounds 2-(4-chlorobenzyl (21) H
sulfonylmethyl)-5-(2-chlorophenyl)-1,3,4-thiadiazole (16d) and 3-
(4-chlorobenzylsulfonylmethyl)-5-(2-chlorophenyl)-4H-1,2,4-triazol
Jazayeri et al.[17] synthesized and evaluated antibacterial activity of
-4-amine (17d) displayed greater activity against spore germination
gatifloxacin derivatives incorporated with 5-(5-nitroheteroaryl)-
of tested fungi A. niger, F. solani and C. lunata
1,3,4-thiadiazol-2-yl groups at C-7 position. The presence of
Padmavathi et al.[13] also reported synthesis and biological nitrofuran (22) at C-2 of thiadiazole ring caused complete inhibition
screening of some novel sulfone-linked bis heterocycles. In which of DNA gyrase or DNA topoisomerase IV and exhibited more potent
the compounds 18a showed excellent activity against Gram-positive inhibitory activity against Gram-positive bacteria
bacteria (inhibitory zone >25 mm), good activity against Gram- including S. epidermidis (MIC = 0.0078 μg/mL), B. subtilis
negative bacteria (inhibitory zone >20 mm). The compounds (18a- (MIC = 0.0039 μg/mL), E. Faecalis (MIC = 0.125 μg/mL),
c) have shown high inhibitory effect towards tested fungi. nd M. luteus (MIC = 0.125 μg/mL).

O O N N
R F O
S S N
N CO OH
O
N
N O 2N (22) N
NH S
N
HS
(18 a-c) Talath et al.[18] synthesized a series of 7-[4-(5-amino-1,3,4
a, R = H; b, R = Me; c, R = Cl thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolone derivatives
23a–23d and evaluated their antibacterial activity. All the
synthesized compounds exhibited moderate to good activity against
Abdel-Wahab et al.[14] reported the synthesis of new 1,3,4- S. aureus, E. faecelis, Bacillus sp (MIC = 1–5 μg/mL) and showed poor
thiadiazole derivatives of 5-(benzofuran-2-yl)-1-phenylpyrazole activity against the Gram-negative bacteria. Substitution with
moiety. All the synthesized compounds were screened against bacterial methoxy group at C-8 and free -NH2 group of 7-(4-aminophenyl-
strains and among them compound 19 was found to possess significant sulfonyl) piperazinyl fluorquinolonine was found to be the active
activity against Escherichia coli and C. albicans. The tested compounds compound in this series against all the tested Gram-positive strains
did not exhibit any activity against Gram-(+) strains. of bacteria.
F R4
R R1 R1 R3 R4

O a
N N R1 O H H H H
S N
S N COOH b H H H H
H 2N O
R3 c NH 2 F CH 3 CH 3
N
O N N (23a-d) R2 R d H OCH 3 H CH 3
N
O N S O
N N H
H 3C Padmavathi et al.[19] synthesized a series of pyrazole containing
(19) 1,3,4-thiadiazoles derivatives and evaluated them for antimicrobial
activity. Among the synthesized compounds 5′-[4-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazole-3-sulfonylmethyl]-[1′,3′,4′]thiadiazole-2′-
Kadi et al.[15]synthesized of a new series of 5-(1-adamantyl)-1,3,4- thiol (24) showed moderate antibacterial activity against the Gram-
thiadiazole derivatives and evaluated them for their antimicrobial positive bacteria
activity which revealed that all the synthesized compounds,
exhibited better activity than reference drugs (gentamicin and Chen et al.[20] synthesized a series of 5-(3,4,5-trimethoxyphenyl)-2-
ampicillin) on E. coli and Pseudomonas aeuroginosa. SAR studies sulfonyl-1,3,4-thiadiazoles derivatives and evaluated their
have shown that antibacterial activity was greatly diminished on antifungal activity. Thiadiazole ring instead of oxadiazole did not
introduction of the benzyl- or 4-substituted benzyl moieties and show significant activity, substitution with 2-methylsulphonyl-3-
antifungal activity increased on substitution with adamantly moiety methoxyphenyl (25) at C-5 of thiadiazole ring showed higher
(20) on C-5 of thiadiazole nucleus. antifungal activities against G. zeae, B. cinerea, and S. sclerotiorum.

10
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

Cl Antitubercular activity
MeO OMe
N N O Rollas et al.[25,26] found that one of the thiadiazole derivative,
M eO S namely 2-(4-chlorophenylamino)-5-(4-aminophenyl)-1,3,4-
O O N N S
S O thiadiazole (30), showed 57% inhibition against Mycobacterium
SH MeO (25)
HN N S tuberculosis. Further, they found that compound 30 exhibited the
(24) highest inhibitory activity (69%inhibition) against in vitro growing
Mycobacterium tuberculosis.
Demirbas et al.[21]synthesized a series of 4-amino-2-[(5-arylamino-
4,5-dihydro-1,3,4-thiadiazol-2-yl)methyl]-5-(4-methylphenyl)-2,4- F
dihydro-3H-1,2,4-triazol-3-ones and investigated its antimicrobial
activity. Thiadiazole (26) with 2-({5-[(4-methoxyphenyl) amino] S
group was found to possess most potent antibacterial activity, N
NH
whereas N-alkylation at C-5 of thiadiazole ring did not resulted in N
improved antibacterial activity. (3 0 )

OMe This compound while not active enough to be considered as

N N therapeutics, are definitely lead compounds in the search for novel
N agents to combat resistance.
S H
N N
O (2 6)
Foroumadi et al.[27] synthesized two series of 2- and 3-[5-
N (nitroaryl)-1,3,4-thiadiazol-2-yl-thio, sulfinyl and sulfonyl] propionic
NH2 acid alkyl esters and screened for antituberculosis activity against
Mycobacterium tuberculosis and found that the compound 31 that is
1,3,4-Thiadiazole and 2-azetidinones derivatives of 2-methyl-1H-
propyl 3-[5-(5-nitrothiophen-2-yl) -1,3,4-thiadiazol-2-ylthio]
benzimidazoles were tested for antibacterial, antifungal activity and
propionate was the most active one.
some of the tested compounds had comparable activity
against B. subtilis and E. coli with reference to ampicillin (25 μg/mL). Ar
Compounds (27) having o-chloro, o-methyl, p-methoxy, o-hydroxy, S
and p-amino group in phenyl ring showed good antibacterial N
activity. Antifungal activity data indicated that some of the N S COO-CH 2 CH 2 CH 3
derivatives revealed a broad spectrum of activity against tested (31)
fungi; however, none of the derivatives showed a better spectrum of
activity when compared to the reference drug[22]. Ar = 5-nitro-2-thienyl

Anticonvulsant activity
Stillings et al.[28] described the anticonvulsants properties of a
number of substituted 2-hydrazino-1,3,4-thiadiazole. Further they
found that, 2-(aminomethyl)-5-(2-biphenylyl)-1,3,4-thiadiazole (32)
possess potent anticonvulsants properties in rat and mice and
compared favorably with the standard anticonvulsants drug
phenytoin, phenobarbital and carbamazepine in a number of test
situations.
Maresca et al.[23]synthesized a series of (R)-/(S)-10-
camphorsulfonyl-substituted aromatic/heterocyclic sulfonamides Ph
and evaluated the inhibition of several mammalian isoforms of the NH 2
S
zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Compounds having
R- and S-10-camphorsulfonyl moiety represented more N N
susceptibility toward to inhibition against mitochondrial isoform
hCA VA. Generally the R-enantiomer (28) was more active than the (32)
corresponding S-isomer.
Dogan et al.[29]synthesized a number of compounds and found that
compound 33a and 33b showed anticonvulsants activity. They also
noticed that these two compounds may be considered promising for
the development of new anticonvulsant agents.
O
S
N N
S N S O 2N H 2 NH
O N N S R
(2 8 )
OH
Nishimori et al.[24]investigated the inhibition of various
sulfonamides and sulfamates on two β-carbonic anhydrases (CAs, EC (33)
4.2.1.1) isolated from the bacterial pathogen Salmonella enterica 33a, R = ethyl, 33b, R=m-fluorophenyl
serovar Typhimurium. Compound 3-Fluoro-5-chloro-4-
aminobenzolamide (29) showed an inhibition constant of
51 nM against stCA 1 and of 38 nM against stCA 2, while Anticancer activity
acetazolamide inhibited stCA 1 and stCA2 with KI of 59 and 84 nM,
respectively. Revelant et al.[30] synthesized a series of 5-aryl-2-(3-thienylamino)-
1,3,4-thiadiazoles starting from thiophen-3-isothiocyanates. Those
Cl compounds as well as the thiosemicarbazide intermediates were
O N N O screened for their antiproliferative activity against a panel of six
H 2N S N S NH2 cancer cell lines. Among them, two 5-aryl-2-(3-thienylamino)-1,3,4-
S
O H O thiadiazoles (34a and 34b) have shown very interesting results with
F (2 9 ) IC50 < 10μM on three cell lines

11
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

R1 N N O
N N
N S R2 N
S H Se S R
(3 9 )
34a, R 1=C 6H 5, R 2 = 4-OMeC 6H4 3 9 a , R = P h , 3 9 b , R = 2 -O C H 3 -P h
34b, R 1=C 6H5, R 2 = 4-OHC 6H4 3 9 c , R = 3 ,4 ,5 -(O C H 3 ) 3 -P h
A series of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan
Matysiak et al.[31] have synthesized a series of new 5-substituted 2-
have been synthesized to screen for FAK inhibitory activity[35].
(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles and evaluated for their
Compound 40a has shown the most potent biological activity
antiproliferative activity against the cells of human cancer lines. He
against HEPG2 cancer cell line (EC50 = 10.28 μg/mL for HEPG2 and
found that derivatives 35 and 36 of different structures prove to be
EC50 = 10.79 μM for FAK), which was comparable to the positive
the most active. They exhibited higher inhibitory activity against
control. Docking simulation was performed to position compound
T47D cells (human breast cancer cells) than cisplatin.
40a into the FAK structure active site to determine the probable
binding model. The results of antiproliferative and Western-blot
NN NN assay demonstrated that compound 40a possessed good
HO HO
S S
antiproliferative activity against HEPG2 cancer cell line. Therefore,
O compound 40a with potent FAK inhibitory activity may be a
OH CH3 OH
C
(36) CH3 potential anticancer agent against HEPG2 cancer cell.
(35) O
H3C CH3
N N
O NHCOR
Histone deacetylase (HDAC) inhibitors are a new class of anticancer S
agents, targeting the biological processes including cell cycle, (40)
apoptosis and differentiation. Guan et al.[32] synthesized a series of O
1,3,4-thiadiazole based hydroxamic acids derivatives which were
found to be potent HDAC inhibitors. Some of them showed good 40a, R =
inhibitory activity in HDAC enzyme assay and potent growth
inhibition in some tumor cell lines. Among the synthesized
compound 37 (IC50 = 0.089 lM), exhibited good inhibitory effect. Yang et al.[36] synthesized a series of cinnamic acyl 1,3,4-thiadiazole
amide derivatives and evaluated their tubulin polymerization
inhibitory activity. Among the synthesized compounds, 41a was
H OH found to be the most potent, which inhibited the growth of MCF-7
S N NH and A549 cell lines with IC50 values of 0.28 and 0.52 μg/mL,
n
R respectively. Compound 41a also exhibited significant tubulin
N N O O
polymerization inhibitory activity (IC50 = 1.16 μg/mL). Docking
(37) simulation was performed to determine the probable binding model.
37a, n = 6, R= 37b, n=6, R= R2
N N H
N
Kumar et al.[33] synthesized a series of 2-arylamino-5-aryl-1,3,4- S
thiadiazoles and screened them for their anticancer activity against O
various human cancer cell lines. The novel one-pot synthesis of R1 (41)
1,3,4-thiadiazoles was carried out by refluxing aryl aldehydes,
hydrazine hydrate, and aryl isothiocyanates in methanol followed by 41a, R1 = OCH3, R2 = OCH3
oxidative cyclization with ferric ammonium sulfate. The compounds
38 having trimethoxyphenyl at the C-5 position exhibited potent
anticancer activity with at least twofold selectivity (IC50:4.3–9.2 Antidepressant activity
μM). The nature of substituent on the C-2 arylamino ring is important in Ahmed et al.[37] synthesized a number of new imine derivatives of
determining the selectivity towards a particular cancer cell. 5-amino-1,3,4-thiadiazole-2-thiol, and their anti-depressant activity
R was tested using imipramine as reference drug. Two compounds
namely 5-{[1-(4-chlorophenyl)-3-(4-methoxy-phenyl)prop-2-en-1-
N N ylidene]-amino}- 5-benzylthio-1, 3,4 –thiadiazole (42a) and 5-{[1-
R1 (4-chlorophenyl)-3-(4-dimethyl-aminophenyl)-prop-2-en-1-ylidene]
N amino}-5-benzylthio-1,3,4-thiadiazole (42b) have shown significant
S
H anti-depressant activity, which decreased immobility time by
R2 (38) 77.99% and 76.26% compared to the standard imipramine (82%).
R3 These compounds in the series have passed neurotoxicity tests also.
S
Luo et al.[34] synthesized a series of novel 1,3,4-thiadiazole-
containing benzisoselenazolone derivatives by the condensation of S N
2-chloroselenobenzoyl chloride and 2-amino-5-substituted-1,3,4- N
thiadiazole and evaluated them for their in vitro antiproliferative N
activities in SSMC-7721, MCF-7 and A-549 cells. Among the
synthesized compounds, the compound 39a showed significant
antiproliferative activities in SSMC-7721, MCF-7 and A-549 cells,
with IC50 values of 7.15, 3.44 and 3.24 μM, respectively. The (42) R2
compound 39b was found to be the most potent compound in A-549 R1
cells, with IC50 values 2.48 μM. Similarly, the compound 39c also 42a, R 1= OCH 3 , R 2 =Cl
showed highly effective antiproliferative activities in MCF-7 and A-
549 cells, with IC50 values of 3.92 and 3.12 μM, respectively. 42b, R 1 =(CH 3)2 N , R 2 =Cl

12
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

Anti-Helicobacter pylori activity effects on human carbonic anhydrase (hCA II). The results revealed
that some derivatives were very effective inhibitors for hCA II. Some
Foroumadi et al.[38] synthesized and evaluated in vitro anti- compounds have been investigated for their antihypoxic effects, the
Helicobacter pylori activity of N-[5-(5-nitro-2-heteroaryl)-1,3,4- survival time of mice administered with synthesized derivatives was
thiadiazol-2-yl]thiomorpholines and some related compounds. They much longer than that of acetazolamide. In addition, the binding
found that nitrofuran analog (43) containing thiomorpholine-S,S- mode of the tested compounds inside the hCA II active site was
dioxide moiety was the most potent compound tested. predicted using a docking technique initially. Among the synthesized
compounds 47a, 47b and 47c have shown potent activity.
N N O
N S
O O S O O N N O
N (43) R1 S N S NH2
S
O R2
O (4 7 ) O
Shafiee et al.[39] synthesized a series of 5-(nitroaryl)-1,3,4- 4 7 a , R 1 = 4 -C H 3 -P h S O 2 , R 2 = n -C 1 2 H 2 5
thiadiazoles bearing certain sulfur containing alkyl side chain 4 7 b , R 1 = 4 -C H 3 -P h S O 2 , R 2 = n -C 1 2 H 2 5
similar to pendent residue in tinidazole molecule and evaluated 4 7 c, R 1 = 4 -C H 3 -P h SO 2 , R 2 = 4 -F -Ph -C H 3
against Helicobacter pylori. They found that compound 44a
containing 2-[2-(ethylsulfonyl)ethylthio]-side chain from Cecchi et al.[43] synthesized a library of sulfonamides by using
nitrothiophene series was the most potent compound tested against benzolamide as lead compound. The new derivatives were
clinical isolates of H. pylori, however, nitroimidazoles 44b and 44c investigated as inhibitors of the cytosolic isozymes human carbonic
were found to be more promising compounds because of their anhydrase (hCA I and II), as well as the tumor-associated isozyme
respectable anti-H. pylori activity. hCA IX. New compounds exhibited excellent inhibitory activities
against all three isozymes ranging from 0.6–62 nM against hCA I,
N N Compound 44a, Ar = 5-NO2-thiophene, n=2
Ar Compound 44b, Ar = 1-Me-5-NO2-imidazole n=2 0.5–1.7 nM against hCA II and 3.2–23 nM against hCA IX, respectively.
S(O)nEt
S S Compound 44c, Ar = 1-Me-5-NO2-imidazole n=0 Among the synthesized compounds, 48 showed maximum activity
(44) against the tested isoenzymes. The sulfanilamides acylated at the 4-
amino group with short aliphatic/aromatic moieties incorporating
Mucomembranous protector 2–6 carbon atoms have shown modest hCA XIV inhibitory activity.

Mathew et al.[40] discoverd some novel imines of 2-amino, 5-thio, Ozensoy et al.[44] reported carbonic anhydrase inhibitory activity of
1,3,4-thiadiazole as mucomembranous protector. A series of some aromatic and heterocyclic sulphonamides. They attached diverse
novel imines of 2-amino, 5-thio 1,3,4-thiadiazole connected to tails on amino group to alter physicochemical properties of the
benzimidazole chalcones were prepared. All the newly synthesized molecule. Compounds 49 and 50 substituted with bromo and nitro
compounds were screened for their antiulcer activity in the pylorus- group at 4th position of phenyl ring demonstrated 3.15–4.10 folds
ligated rats. Free radical scavenging activity of all final derivatives more activity than the lead compound acetazolamide.
was determined by DPPH Diphenyl picryl hydrazide) method. Turkmen et al.[45] synthesized a series of sulfanilamide derivatives
Compound 45 showed the best result. by incorporating heterocyclic amines like morpholine, piperidines,
SH and piperazines using tail approach. Newly synthesized compounds
were evaluated for carbonic anhydrase inhibitory activity.
S Derivative 51 exhibited much better inhibition of carbonic
N anhydrase isoenzymes namely hCA I, hCA II and hCA IX than the
N
N parent compounds. Among sulfanilamide derivatives, the derivatives
N containing morpholine ring revealed best inhibitory activity
N N N
O O SO2NH2
H OH S
S
S N
(45) H
N N
OH H H (48)

Anti-leishmanial activity N N
N N O SO2NH2
Taghighi et al.[41] synthesized a novel series of 5-(5-nitrofuran-2- O O SO2NH2 N S
S
yl)-1,3,4-thiadiazol-2-amines by introducing N-[(1-benzyl-1H-1,2,3- N S R2N H (51)
H
triazol-4-yl)methyl] moiety as a new functionality on the C-2 amine R R = morpholine, piperazine, piperidine
of thiadiazole ring via click chemistry. The compounds were 49, R = Br; 50, R = NO2
evaluated for their in vitro anti-leishmanial activity against
promostigote form of the Leishmania major. 4-methylbenzyl analog
46 was found to be the most active compound against
promostigotes which significantly decreases the number of Diacylglycerol acyltransferase type 1 (DGAT-1) inhibitory
intracellular amastigotes per macrophage, percentage of activity
macrophage infectivity and infectivity index. Triacylglycerides (TG) are the principal form of energy storage in
N N eukaryotes. An imbalance in the metabolism of triacylglycerides can
N participate in the pathogenesis of several metabolic disorders such
N
S H N N as obesity, insulin resistance and type 2 diabetes. DGAT-1,
O R
(46) diacylglycerol acyltransferase type 1 catalyses the last step of
O 2N triacylglyceride biosynthesis, transforming diacylglycerol and acyl-
46a, R= 4-Me, 46b, R = 2-F-6-Cl CoA into triacylglycerides. Mougenot et al. [45] synthesized new
DGAT-1 inhibitors by combining ligand-based modeling from known
Carbonic anhydrase inhibitory activity DGAT-1 inhibitors, high throughput parallel synthesis (HTPS) and
rescaffolding chemistry to generate leads. Three lead series were
Xiao et al. [42] synthesized a new series of 1,3,4-thiadiazole-2- found with IC50s below 100 nM in a DGAT-1 enzymatic assay. The
sulfamide (47) derivatives. Target compounds were assessed by the most potent inhibitors belonged to a 2-aminothiadiazole series
tool of Dock6. The compounds have been tested for their inhibitory represented by compound 52 which displayed an IC50 of 0.03 μM in

13
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

the enzymatic assay. To understand loss of activity, compound 52 11. Lamani RS, Shetty NS, Kamble RR, Khazi IAM. Synthesis and
and 53 was compared by using ligand-based 3D alignment model antimicrobial studies of novel methylene bridged
and was found that the thiadiazole in 53 is geometrically distorted benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazole derivatives.
compared to 52. This observation led to modification of the linker Eur J Med Chem 2009;44:2828–33.
between the thiadiazole and the phenylcyclohexyl group. Amide 12. Padmavathi V, Sudhakar Reddy G, Padmaja A, Kondaiah P, Ali-
group was preferred as linker. This choice was supported by the Shazia. Synthesis, antimicrobial and cytotoxic activities of
ligand-based alignment for compounds 52 and 54 (with CO 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Eur J
inserted) which showed that the amide linker retains a high shape Med Chem 2009;44:2106–12.
similarity and provides excellent matching of the thiadiazoles. The 13. Padmavathi V, Thriveni P, Sudhakar Reddy G, Deepti D.
use of the amide linker restored DGAT-1 inhibition with compound Synthesis and antimicrobial activity of novel sulfone-linked bis
54 displaying good enzymatic activity (IC50 = 0.036 μM). heterocycles. Eur J Med Chem 2008;43:917-24.
14. Abdel-Wahab BF, Abdel-Aziz HA, Ahmed EM. Synthesis and
antimicrobial evaluation of some 1,3-thiazole, 1,3,4-thiadiazole,
N 1,2,4-triazole, and 1,2,4-triazolo[3,4-b] [1,3,4]-thiadiazine
N N
S O O N derivatives including a 5-(benzofuran-2-yl)-1-phenylpyrazole
S moiety. Monatsh Chem 2009;140:601–5
HN OH
N HN 15. Kadi AA, Al-Abdullah ES, Shehata IA, Habib EA, Ibrahim TM, El-
H OH
(52)
(53) O Emam AA. Synthesis, antimicrobial and anti-inflammatory
activities of novel 5-(1-adamantyl)-1,3,4-thiadiazole
NN derivatives. Eur J Med Chem 2010;45:5006–11.
R NH
S 16. He Y, Cao L, Zhang J, Wang D, Aisa HA. Synthesis and bioactivity of
O OH 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-
(54) O oxa(thia)diazol-2amines. Carbohydrate Res 2011;346:551–9.
17. Jazayeri S, Moshafi MH, Firoozpour L, Emami S, Rajabalian
S, Haddad M, et al. Synthesis and antibacterial activity of
CONFLICT OF INTERESTS nitroaryl thiadiazole–gatifloxacin hybrids. Eur J Med Chem
2008;44:1205–9.
Declared None 18. Talath S, Gadad AK. Synthesis, antibacterial and antitubercular
activities of some 7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-
REFERENCES
piperazin-1-yl]fluoroquinolonic derivatives. Eur J Med Chem
1. Mathew V, Keshavayya J, Vaidya VP, Giles D. Studies on 2006;41:918–24.
synthesis and pharmacological activities of 3,6-disubstituted- 19. Padmavathi V, Thriveni P, Reddy GS, Deepti D. Synthesis and
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro antimicrobial activity of novel sulfone-linked bis
analogues. Eur J Med Chem 2007;42:823-40. heterocycles. Eur J Med Chem 2008;43:917–24.
2. Kucukguzel SG, Kucukguzel I, Tatar E, Rollas S, Sahin F, Gulluce M, 20. Chen C, Song B, Yang S, Xu G, Bhadury PS, Jin L, et al. Synthesis
et al. Synthesis of some novel heterocyclic compounds derived and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-
from diflunisal hydrazide as potential anti-infective and anti- sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-
inflammatory agents. Eur J Med Chem 2007;42:893-901. sulfonyl-1,3,4-oxadiazole derivatives. Bioorg Med Chem
3. Hilfiker MA, Wang N, Xiaoping H, Zhimin D, Pullen MA, Nord M, 2007;15:3981–9.
et al. Discovery of novel aminothiadiazole amides as selective 21. Demirbas A, Sahin D, Demirbas N, Karaoglu SA. Synthesis of
EP3 receptor antagonists. Bioorg Med Chem Lett some new 1,3,4-thiadiazol-2-ylmethyl-1,2,4-triazole
2009;19:4292-5. derivatives and investigation of their antimicrobial
4. Gadad AK, Palkar MB, Anand K, Noolvi MN, Boreddy TS, Wagwade activities. Eur J Med Chem 2009;44:2896–903.
J. Synthesis and biological evaluation of 2-trifluoromethyl/ 22. Ansari KF, Lal C. Synthesis and evaluation of some new
sulfonamido-5,6-diaryl substituted imidazo[2,1-b]-1,3,4- benzimidazole derivatives as potential antimicrobial
thiadiazoles: a novel class of cyclooxygenase-2 inhibitors. Bioorg agents. Eur J Med Chem 2009;44:2294–9.
Med Chem 2008;16:276–83. 23. Maresca A, Supuran CT. (R)-/(S)-10-Camphorsulfonyl-
5. Salgın-Goksen U, Gokhan-Kelekci O, Goktas Y, Koysal E, Kılıc S, substituted aromatic/heterocy-clic sulfonamides selectively
Isık G, et al. 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)- inhibit mitochondrial over cytosolic carbonic
thiones, 1,3,4-thiadiazoles and hydrazones containing 5- anhydrases. Bioorg Med Chem Lett 2011;21:1334–7.
methyl-2-benzoxazolinones: Synthesis, analgesic-anti- 24. Nishimori I, Minakuchi T, Vullo D, Scozzafava A, Supuran CT.
inflammatory and antimicrobial activities. Bioorg Med Chem Inhibition studies of the β-carbonic anhydrases from the
2007;15:5738–51. bacterial pathogen Salmonella enterica serovar Typhimurium
6. Kalgutar A, Marnett A, Crews B, Remmel R, Marnett L. Ester and with sulfonamides and sulfamates. Bioorg Med Chem
Amide derivatives of the nonsteroidal antiinflammatory drug, 2011;19:5023–30.
Indomethacin, as Selective Cyclooxygenase-2 Inhibitors. J Med 25. Karakus S, Rollas S. Synthesis and antituberculosis activity of
Chem 2000;43:2860-287. new N-phenyl-N′-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-
7. Duflos M, Nourrison M, Brelet J, Courant J, Le Baut G, Grimaud N, yl)phenyl]thioureas. Farmaco 2002;57:577-81.
et al. Synthesis of some novel heterocyclic compounds derived 26. Oruc EE, Rollas S, Kandermirli F, Shvets N, Dimoglo AS. 1,3,4-
from diflunisal hydrazide as potential anti-infective and anti- Thiadiazole derivatives. Synthesis, structure elucidation, and
inflammatory agents. Eur J Med Chem 2001;36:545-53. sructure−antituberculosis activity relationship investigation. J
8. Amir M, Kumar H, Javed SA. Condensed bridgehead nitrogen Med Chem 2004;47;6760-7.
heterocyclic system: synthesis and pharmacological activities 27. Foroumadi A, Kargar Z, Sakhteman A, Sharifzadeh Z,
of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of Feyzmohammadi R, Kazemi M, et al. Synthesis and
ibuprofen and biphenyl-4-yloxy acetic acid. Eur J Med Chem antimycobacterial activity of some alkyl [5-(nitroaryl)-1,3,4-
2008;43:2056-66. thiadiazol-2-ylthio]propionates. Bioorg Med Chem Lett
9. Schenone S, Brullo C, Bruno O, Bondavalli F, Ranise A, Filippelli 2006;16;1164–7.
W, et al. New 1,3,4-thiadiazole derivatives endowed with 28. Stilings MR, Welbourn AP, Walter DS. Substituted 1,3,4-
analgesic and anti-inflammatory activities. Bioorg Med Chem thiadiazoles with anticonvulsant activity. 2. Aminoalkyl
2006;14:1698-705. derivatives. J Med Chem 1986;29:2280-4.
10. Amir M, Shikha K. Synthesis and anti-inflammatory, analgesic, 29. Dogan HN, Duran A, Rollas S, Sener G, Uysal MK, Gulen D.
ulcerogenic and lipid peroxidation activities of some new 2- Synthesis of new 2,5-Disubstituted-1,3,4-thiadiazoles and
[(2,6-dichloroanilino) phenyl]acetic acid derivatives. Eur J Med preliminary evaluation of anticonvulsant and antimicrobial
Chem 2004;39:535-45. activities. Bioorg Med Chem 2002;10:2893-8.

14
 Khalilullah et al.
Int J Pharm Pharm Sci, Vol 6, Issue 9, 8-15

30. Revelant G, Gadais C, Mathieu V, Kirsch G, Hesse S. Synthesis 39. Foroumadi A, Rineh A, Emami S, Siavoshi F, Massarrat S, Safari
and antiproliferative studies of 5-aryl-2-(3-thienylamino)- F, et al. Syntheses and anti-depressant activity of 5-amino-1,
1,3,4-thiadiazoles. Bioorg Med Chem Lett 2014, 3,4-thiadiazole-2-thiol imines and thiobenzyl derivatives.
doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.043. Bioorg Med Chem Lett 2008;18:3315-20.
31. Matysiak J. Evaluation of electronic, lipophilic and membrane 40. Mathew B, Chidambramnath N, Anbajghan S. Discovery of some
affinity effects on antiproliferative activity of 5-substituted-2- novel imines of 2-amino, 5-thio, 1, 3, 4-thiadiazole as
(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles against various mucomembranous protector. J Saudi Chem Soc 2013.
human cancer cells. Eur J Med Chem 2007;42:940-7. 41. Tahghighi A, Razmi S, Mahdavi M, Foroumadi P, Ardestani SK,
32. Guan P, Sun F, Hou X, Wanga F, Yi F, Xu W, et al. Design, Emami S, et al. Synthesis and anti-leishmanial activity of 5-(5-
synthesis and preliminary bioactivity studies of 1,3,4- nitrofuran-2-yl)-1,3,4-thiadiazol-2-amines containing N-[(1-
thiadiazole hydroxamic acid derivatives as novel histone benzyl-1H-1,2,3-triazol-4-yl)methyl] moieties. Eur J Med Chem
deacetylase inhibitors. Bioorg Med Chem 2012;20;3865–72. 2012;50:124-8.
33. Kumar D, Vaddula BR, Chang K, Shah K. One-pot synthesis and 42. Xiao Z, Duan R, Cui W, Zhang Y, Zhang S, Chen F, et al. Synthesis
anticancer studies of 2-arylamino-5-aryl-1,3,4-Thiadiazoles. and evaluation of new carbonic anhydrase inhibitors. Bioorg
Bioorg Med Chem Lett 2011;21:2320–3. Med Chem 2011;19:3221–8.
34. Luo Z, Chen B, He S, Shi Y, Liu Y, Li C. Synthesis and antitumor- 43. Cecchi A, Winum J, Innocenti A, Vullo D, Montero J, Scozzafava
evaluation of 1,3,4-thiadiazole-containing benzisoselenazolone
A, et al. Carbonic anhydrase inhibitors: Synthesis and
derivatives. Bioorg Med Chem Lett 2012;22:3191–3.
inhibition of cytosolic/tumor-associated carbonic anhydrase
35. Sun J, Yang Y, Li W, Zhang Y, Wang X, Tang J, et al. Synthesis,
isozymes I, II, and IX with sulfonamides derived from 4-
biological evaluation and molecular docking studies of 1,3,4-
isothiocyanato-benzolamide. Bioorg Med Chem Lett
thiadiazole derivatives containing 1,4-benzodioxan as potential
2004;14:5775–80.
antitumor agents. Bioorg Med Chem Lett 2011;21:6116–21.
44. Ozensoy O, Nishimori I, Vullo D, Puccetti L, Scozzafava
36. Yang X, Wen Q, Zhao T, Sun J, Li X, Xing M, et al. Synthesis,
biological evaluation, and molecular docking studies of A, Supuran CT. Carbonic anhydrase inhibitors: inhibition of the
cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel human transmembrane isozyme XIV with a library of
antitubulin agents. Bioorg Med Chem 2012;20:1181–7. aromatic/heterocyclic sulfonamides. Bioorg Med Chem
37. Yusuf M, Khan R, Ahmed B. Syntheses and anti-depressant 2005;13:6089–93.
activity of 5-amino-1, 3, 4-thiadiazole-2-thiol imines and 45. Turkmen H, Durgun M, Yilmaztekin S, Emul M, Innocenti
thiobenzyl derivatives. Bioorg Med Chem 2008;16:8029–34. A, Vullo D, et al. Carbonic anhydrase inhibitors. Novel
38. Mirzaei J, Siavoshi F, Emami S, Safari F, Khoshayand MR, sulfanilamide/acetazolamide derivatives obtained by the tail
Shafiee A, et al. Synthesis and in vitro anti-Helicobacter approach and their interaction with the cytosolic isozymes I
pylori activity of N-[5-(5-nitro-2-heteroaryl)-1,3,4-thiadiazol-2- and II, and the tumor-associated isozyme IX. Bioorg Med Chem
yl]thiomorpholines and related compounds. Eur J Med Chem Lett 2005;15:367–72.
2008;43:1575-80. 46. Mougenot P, Namane C, Fett E, Camy F, Dadji-Faïhun R, Langot G, et
al. Thiadiazoles as new inhibitors of diacylglycerol acyltransferase
type 1. Bioorg Med Chem Lett 2012;22:2497–502.

15