1. Introduction
A heterocyclic compound is a cyclic compound which has atoms of at least two different
elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic
compounds, the rings of which are made of a single element. Since the beginning of the
search of medicinally important synthetic compounds heterocyclic chemistry always
remained the point of attraction because of their diverse biological properties. Substitution of
heterocyclic compounds on various positions produced medicinally important analogues
which are used in the treatment of various diseases.
The drugs containing thiadiazole moiety are the effective chemotherapeutic agents that are
designed to inhibit/kill the infecting organisms and have minimal effect on the host.
Thidiazole contains two nitrogen and one sulphur atom in its five membered ring system.
Thiadiazole moiety participates in binding either through hydrogen binding or by the
donation of two electrons. Various substitutions are carried out at the thiadiazole ring in order
to get the compound with better pharmacological action and low toxicity. Compounds
containing thiadiazole moiety are one of the most important category of drug that are
prescribed in the treatment of very simple infection to the serious life threatening disease like
cancer. Thiadiazole is a pentacyclic ring with diverse chemical reactivity and a broad
spectrum of biological activity, this compound is very important from medical point of view.
In search for new bioactive potent molecule, it was thought worthwhile to incorporate some
additional heterocyclic moieties in the thiadiazole nucleus and study their biological activity
and toxic level for higher vertebrates, including humans. Functional groups that interact with
biological receptors are attached to this ring and the compounds possessing outstanding
properties are obtained. There are four isomeric forms of thiadiazole viz. 1,2,3-thiadiazole;
1,2,5- thiadiazole; 1,2,4-thiadiazole and 1,3,4-thiadiazole. The literature review showed that
the thiadiazole nuclei have anti-inflammatory,
antibacterial,
[4]
antitumoural,
[5]
anticonvulsant,
[1]
antitubercular,
[2]
antifungiastic,
[3]
[7]
antileishmanial,
[8]
antidepressant,
[9]
antioxidant activity [10] and it also act as a carbonic anhydrase inhibitor [11].
2. Various biological activities of Thiadiazole:
2.1 Antimicrobial Activity
Rangappa et al. et al., 2006
[12]
synthesized the two series of 4,6-disubstituted 1,2,4-triazolo-
1,3,4-thiadiazole derivatives and checked for their efficacy as antimicrobials in-vitro against
Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas campestris pvs,
Xanthomonas
oryzae,
Aspergillus
niger,
Aspergillus
flavus,
Fusariumoxy-sporum,
Trichoderma sp. and Fusarium monaliforme. Compounds (11a) and (11b) showed potent
inhibition against all the bacterial and fungal strains tested and found to be non-strain
dependent.
N
N
N
H3C
N
S
N
H3C
11 b
11 a
[13]
S
N
Cl
Bao-An et al. 2007
N
synthesized 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole
and the structures were verified by spectroscopic data. In the antifungal bioassay, the
compounds (12a) and (12b) were found to possess higher antifungal activities against three
kinds of fungi i.e. Gibberella zeae, Botrytis cinerea, and Sclerotinia sclerotiorum. More over
these compounds had high inhibitory effects on the growth of G. zeae, P. grisea, C.
mandshurica, C. gloeosporioides, B. cinerea, S. sclerotiorum, P. oryzae, P.infestans, R.
solani, and F. oxysporum, with EC50 values ranging from 2.9 μg/mL to 93.3 μg/mL.
H3CO
N
N
O
H3CO
S
O
O
CH3
H3CO
12
Comp.
R
12a
-CH3
12b
-CH2CH3
Almajan et al. 2010
[14]
synthesized some fused heterocyclic [1,2,4] triazolo[3,4-
b][1,3,4]thiadiazole derivatives and were screened for their antimicrobial activities. The
preliminary results revealed that some of the compounds exhibited promising antimicrobial
activities against the Gram-positive bacteria (Staphylo-coccus aureus ATCC25923;
Staphylococcus epidermidis ATCC14990; Enterococcus faecalis ATCC29212; Bacillus
cereus ATCC13061), Gram-negative bacteria (Escherichia coli ATCC25922; Enterobacter
cloacae
ATCC49141;
Citrobacter
freundii
ATCC8090;
Acinetobacter
baumannii
ATCC19606; Pseudomonas aeruginosa ATCC27853) and Candida albicans ATCC90028 as
fungus. It was found that the presence of one or more halogen atom in the structure has
considerable increased in the biological activity of the molecules. The best antibacterial effect
was shown by 6-[(3-bromo-4-chloro)phenyl]-3-[4-(4 bromophenyl sulfonyl) phenyl][1,2,4]triazolo[3,4-b] [1,3,4] thiadiazole derivative (13).
Cl
Br
N
S
O
N
S
Br
N
N
O
13
Lenuta et al. 2007 [15] synthesized 1,3,4-thiadiazole, and 1,2,4-triazole compounds containing
a D,L-methionine moiety. The potential antimicrobial effects of the synthesized compounds
were investigated using the Staphylococcus aureus ATCC 25923, Bacillus antracis ATCC
8705, Bacillus cereus ATCC 10987, Sarcina lutea ATCC 9341 and Escherichia coli ATCC
25922 strains. The newly synthesized compounds (14) exhibited promising activities against
Bacillus antracis and Bacillus cereus.
H3CS
H2C
H2C
H
C
NHR
NH
CO
14
R= -C6H4-CH3
NO2
Mohd et al. 2009 [16] successfully synthesized 1,3,4-thiadiazole and imidazolinone derivatives
as useful antimicrobial agents. Corresponding 2-aryl-5-(6’-chloro-1’,3’-benzothiazole-2-yl-
amino)-1,3,4-thiadiazoles
(15a)
and
4-(4’-arylidene)-2-phenyl-1-(6’-chloro-1’,3’-
benzothiazole-2-yl-thiourido)-4,5-dihydroimidazolin-5-ones (15b) were obtained by the
reaction of thiosemicarbazide of 6-chloro-2-aminobenzothiazole with different aromatic
carboxylic acids in POCl3 and substituted azlactones in pyridine. All the compounds were
screened for both antibacterial and antifungal activities using cup-plate agar diffusion
method. Ofloxacin (50 μg/mL) was used as a standard drug for antibacterial activity and
ketoconazole (50 μg/mL) as a standard drug for antifungal activity. The antibacterial activity
was measured against E.coli, S. Aureus and P.aerugenosa and antifungal activity against
A.niger and C.albicans. The thiadiazole derivative 15i having a acetoxy-phenyl group
showed maximum activity against S. Aureus where 15g having 2-napthyl-methyl group
showed maximum inhibition against E.coli. The compound 15c having 2,4-dichloro-phenyl
group showed antimicrobial activity against E.coli, S. Aureus and P. Aerugenosa. The
imidazolinone derivatives 16a-e were also found to be active against all the microorganisms.
Thiadiazole derivative 15e having 2-aminophenyl group showed maximum inhibition against
A. niger where 15f having 2,4-Dichlorophenoxymethyl group showed good activity against
C. Albicans. Rest of the derivatives showed moderate antifungal activity.
O
R
S
N
NH
S
Cl
15 a-j
N N
S
N
N
R
Cl
N
S H
N
N
H
16a-e
Compound
15a
15b
15c
15d
15e
15f
15g
15h
R
Phenyl
4-Chlorophenyl
2,4-Dichlorophenyl
4-Nitrophenyl
2-Aminophenyl
2,4-Dichlorophenoxymethyl
2-Napthylmethyl
4-Methoxyphenyl
15i
15j
16a
2-Acetoxyphenyl
3-Pyridyl
Phenyl
16b
16c
16d
16e
4-Chlorophenyl
4-Flourophenyl
4-N,N-Dimethyl phenyl
3-Indolyl
Lamani et al. 2008 [17] Some of the novel methylene bridged benzisoxazolyl imidaozo [2,1-b]
[1,3,4] thiadiazoles and their bromo, nitroso and thiocyanato derivatives synthesized and
screened for antibacterial activity against S. aureus, B. subtilis and E. coli and also antifungal
activity against C. albicans and Aspergillus fumigatus. Some of the compounds displayed
very good antibacterial (17a-e) and antifungal activity (17f-k).
S
N
R
N
N
N
R'
O
17 a-k
Compound
R
R’
17a
Cl
H
17b
Br
H
17c
Cl
Br
17d
OMe
Br
17e
Cl
SCN
17f
H
H
17g
Br
H
17h
OMe
SCN
17i
3-Coumarinyl
H
17j
OMe
SCN
17k
3-Coumarinyl
SCN
Barve et al. 2009
[18]
synthesized a series of dichlorides followed by 1, 3, 4-Thiadiazol-2-
Amine by using various dicarboxylic acids. Synthesized compounds further reacted with
thiosemicarbazide in presence of sulphuric acid to convert them into corresponding 1, 3, 4Thiadiazol-2-Amine. The structures of these compounds were confirmed by IR, NMR
spectroscopy and Mass spectrometry. The synthesized compounds were evaluated for in vitro
antibacterial and antifungal activity against various strains Gram-positive bacterial strains:
Bacillus Subtillis; Staphylococcus aureus, Gram-negative bacterial strains: Escherichia coli;
Pseudomonas aeruginosa and Fungal strains Saccharomyces cerevisiae; Aspergillus niger,
Candida albicans. The results showed that compounds (18a), (18e), (18f) and (18h) exhibited
comparable antibacterial and antifungal activity
H2N
N
S
N
(CH2)n
N
N
S
18
NH2
Where n =No. of alkyl chains present in different Dicarboxylic acids, as follows:
18a= n = 1
18b= n = 2
18c= n = 3
18d= n = 4
18e= n = 5
18f= n = 6
18g= n = 7
18h= n = 8
Malonic acid
Succinic acid
Glutaric acid
Adipic acid
Pimelic acid
Suberic acid
Azelaic acid
Sebacic acid
2.2 Antitubercular Activity
Kolavi et al. 2006
[19]
synthesized a series of 2,6-disubstituted and 2,5,6-trisubstituted
imidazo [2,1-b][1,3,4] thiadiazole derivatives and screened for antitubercular activity against
Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system,
antibacterial activity against Escherichia coli and Bacillus cirrhosis, and antifungal activity
against Aspergillus niger and Penicillium wortmanni. Compounds (19a) and (19b) exhibited
moderate antitubercular activity with percentage inhibition 36, 30, respectively, at a MIC of
>6.25 μg/ml.
R3
N
N
R1
R2
S
N
19
R1
R2
R3
19a
Cyclohexyl
-H
-CHO
19b
Cyclohexyl
-Br
-CHO
Joshi et al. 2005
[20]
synthesized 1,3,4-thiadiazole heterocycles bearing Benzo [b] thiophene
nucleus and were screened for antimicrobial activity against mycobacterium tuberculosis
(H37 RV) .The antimycobacterial activity data were compared with standard drug Rifampin
at 0.25 μg/ml concentration which showed 98% inhibition. Compounds having 2-(3′-chloro5′-phenoxy-benzo[b]thiophen-2′-yl)-5-(p-methoxyphenyl)amino-1,3,4-thiadiazole derivatives
(20) showed higher activity than the others.
S
O
S
HN
N
R
N
Cl
R= Aryl
Foroumadi et al. 2003
[21]
20
synthesized a series of alkyl a-[5-(5-nitro-2-thienyl)-1,3,4-
thiadiazole-2-ylthio]acetic acid esters and evaluated for in vitro antituberculosis activity. The
antituberculosis activity of the synthesized thiadiazole derivatives against Mycobacterium
tuberculosis strain data indicated that methyl, propyl, buthyl and benzyl esters showed a
significant in vitro antimycobacterium tuberculosis activity (MIC-0.39-0.78 μg/ml). The best
activity was exhibited by propyl ester (MIC-0.39 mg/ml), but significant decrease in potency
was observed by ethyl ester with inhibition percentage of 58 (MIC-6.25 μg /ml).
N
O
N
SCH2COR
O2N
21
S
S
Compound
R
21a
Methyl
-CH3
21b
Ethyl
-CH3 CH2
21c
n-Propyl
-CH3 CH2 CH2
21d
n-Buthyl
-CH3 CH2 CH2 CH2
21e
Benzyl
H2C
Gadad et al. 2006
[22]
synthesized a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-
piperazinyl fluoroquinolonic derivatives. The antibacterial data of the tested Nsulfonylfluoroquinolones indicated that all the synthesized compounds was active against
Gram-positive bacteria S. aureus, E. faecelis, Bacillus sp. (MIC = 1–5 μg ml–1, respectively)
compared to reference drugs. The in vitro antitubercular activity reports of selected
compounds 22a, 22b against M. tuberculosis strain H37Rv showed moderate activity at MIC
of 10 μg ml–1.
R1
O
O
F
OH
R4
N
N
N
N
H2N
S
R2
S2
O
R
22
R3
S. no
R
22 a
22 b
-CH2 CH3
R1
R2
R3
R4
H
H
H
H
H
H
H
H
2.3 Anti-inflammatory activity
Asif et al. 2009
[23]
synthesized 2, 4- Disubstituted-5-Imino-1, 3, 4- thiadiazole derivatives
and evaluated for Anti-inflammatory activities. In the prepared thiadiazole series it seemed 2paminophenyl-4-phenyl-5-imino-Δ2-1,3,4-thiadiazole
(23)
exhibited
highest
anti
inflammatory activity (P <0.0001) with a percentage inhibition of 35.5.
S
N
NH
N
NH2
23
Mathew et al. 2007
[24]
synthesized several 3,6-disubstituted1,2,4-triazolo [3,4b]1,3,4
thiadiazole and their dihydro analogues against the pathogenic strains. Compounds (24a) and
(24b) showed maximum anti-inflammatory activity possessing indole ring at the sixth
position of the triazolo thiadiazole system.
N
S
N
N
N
R
R2
R1
N
24
H
Compo.
R
R1
24a
-H
-H
24b
-OCH3
-CH3
R2
5-Methoxy-3-Indolylmethyl
5-Methoxy-2-methyl-3-indolylmethyl
2.4 Anti-Depressant Activity
Ahmed et al. 2008
[25]
synthesized a number of new imine derivatives of 5-amino-1,3,4-
thiadiazole-2-thiol and their anti-depressant activity was tested using imipramine as reference
drug. Compound namely 5-{[1-(4-chlorophenyl)-3-(4-methoxy-phenyl)prop-2-en-1-ylidene]amino}-5 benzylthio-1,3,4-thiadiazole (24) has shown significant anti-depressant activity.
O
N
HN
Cl
N
C
S
S
25
2.5 Anti-leishmanial Activity
Alipour et al. 2010
[26]
synthesized a series of novel 2-substituted-thio-1,3,4-thiadiazoles
bearing a 5-nitroaryl moiety as potential anti-leishmanial agents. The target compounds were
evaluated against the promastigote form of Leishmania major using the tetrazolium bromide
salt (MTT) colorimetric assay. 1-(2-Chlorophenyl)-2-(5-(1-methyl-5-nitro-1H-imidazol-2yl)-1,3,4-thiadiazol-2-ylthio)ethanone (26) compound exhibited high activity against
Leishmania. major promastigotes with inhibitory concentrations 3.16 μM.
O
Cl
-
O
N+
N
S
S
O
N
N
N
26
Foroumadi et al. 2008
[27]
synthesized a series of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-
yl] and 1-[5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl]-4aroylpiperazines and evaluated for
in-vitro leishmanicidal activity against promastigote and amastigote forms of Leishmania. It
was concluded that 5-nitrofuran derivatives (27) were more active than the corresponding 5nitrothiophene analogues.
N
O
N
N
N
C6H4Cl
S
O
27
O2N
Siddique
et
al.
2009
[28]
designed
and
synthesized
various
N-(5-chloro-6
substitutedbenzothiazol- 2-yl)-N'-(substitutedphenyl)-[1,3,4] thiadiazole-2,5-diamines. All
the newly synthesized compounds were screened for their anticonvulsant activity and were
compared with the standard drug. It was found that compound (28) showed complete
protection against MES induced seizures.
Cl
NH
Cl
NH
Br
28
Kashaw et al. 2008 [29] synthesized a series of new 3-[5-substituted phenyl-1,3,4-thiadiazole2- yl]-2-styryl quinazoline-4(3H)-ones (29a, 29b) and the synthesized compounds were
examined in the maximal electroshock (MES) induced seizures and subcutaneous
pentylenetetrazole (scPTZ) induced seizure models in mice.
R
O
S
N
N
N
N
29
R1
Com.
R
R1
29a
-C6H5
p-ClC6H4
29b
m-ClC6H4
p-ClC6H4
2.6 Anti-tumor Activity
Ibrahim, 2009
[30]
synthesized a series of 3,6-disubstituted triazolo [3,4-b] thiadiazole
derivatives. It was evaluated that compounds 30a and 30b maintained the highest growth
inhibition activity at micromolar concentrations in different human tumor cell lines. The
compound 30a displayed high activity against NCI-H226 (log GI50 -5.14) cell line of nonsmall cell lung cancer sub-panel and against CCRF-CEM (log GI50 -5.0) cell line of
Leukaemia subpanel. Compound 30b exhibited the highest sensitivity against Renal, Colon
and Melanoma Cancer cell lines, the best results being against Renal Cancer A498 cell line
with log GI50 - 7.27.
N
S
HO
N
NH2
N
N
N
S
NH2
N
N
S
N
N
30a
R
Zheng et al. 2008
[31]
30b
R
R = - CH2-O- Ph(p-Cl)
R = - CH2-O- Ph(p-Cl)
synthesized N1-acetylamino-(5alkyl/aryl1,3,4 thiadiazole-2- yl)-5-
fluorouracil derivatives as a potential antitumor agents. Activity was compared with standard
drug 5-fluorouracil; compound (31a) showed higher activity against human lung cancer cell
and compound (31b) showed higher activity against human breast cancer cell.
O
O
F
F
O
F
HN
HN
N
C2H5
S
O
N
H
N
H
N
N
N
O
S
N
N
O
31b
31 a
2.7 Carbonic anhydrase inhibitors
Matulis et al. 2007
[32]
synthesized a series of Benzimidazo[1,2c][1,2,3]thiadiazole 7
sulfonamides as human carbonic anhydrase I (hCAI) and bovine carbonic anhydrase II
(bCAII). The strongest binder to both isozymes of carbonic anhydrase was compound (32a)
with the observed Kd of about 0.04 lM. The most specific binder of hCAI was compound
(32b) that bound about fourfold stronger to hCAI than to bCAII. The (32c) compound bound
threefold tighter to bCAII than to hCAI.
H
N
S
N
R
H2O2NS
N
32
Comp.
R
32a
-Cl
32b
-SO2CH3
32c
-N(CH2CH3)2
Bolboacă et al. 2007
[33]
developed a structure-activity relationships based on an original
molecular descriptors family method and applied on a sample of substituted 1,3,4thiadiazole- and 1,3,4-thiadiazoline-disulfonamides. Compounds were studied for their
inhibition activity on carbonic anhydrase I. The MDF-SAR model revealed that the inhibition
activity on CA I of substituted 1,3,4-thiadiazole- and 1,3,4-thiadiazoline-disulfonamides was
likely to be of geometry and topology nature, being related with two atomic properties, the
partial charge and relative atomic mass. The MDF-SPR model could be used in order to
predict the inhibition on CA I of new compounds from the same class without any
experiments and measurements, by using the MDF SAR Predictor application.
2.8 Anticonvulsant activity
Siddiqui et al. 2009
[34]
Various N-(5-chloro-6-substituted-benzothiazol-2-yl)-N'-(substituted
phenyl) [1,3,4]thiadiazole-2-yl urea derivatives (33) were designed and synthesized starting
from substituted acetophenones. Incorporation of 1,3,4-thiadiazole moiety into the second
position of the benzothiazole ring resulted in compounds having good anticonvulsant activity.
The neurotoxicity as well as liver toxicity of the compounds has also been evaluated.
Synthesized thiadiazole derivatives were injected intraperitoneally into mice and evaluated by
the maximal electroshock (MES), neurotoxicity screen using rotarod at the dose of 30 mg kg–
1
body mass and observations were carried out at two different time intervals of 0.5 and 4 h.
All the compounds showed anti-MES activity indicative of their ability to prevent seizure
spread. The compounds that showed 100 % protection against the MES model at 30 mg kg–1
body mass were 33b, 33c both after 0.5 and 4 h. In the neurotoxicity screen, compounds with
83–100 % protection were selected and checked for neurotoxicity at the dose of 30 mg kg–1.
None of the compounds displayed neurotoxicity, since they successfully passed the rotarod
test without any sign of motor impairment. In general, the disubstituted benzothiazole ring
with 5,6-Cl substituents had higher potency than the 5-Cl and 6-F substitution.
Cl
N
N
N
R1
S
R
H
N
NH
S
R = H, Br, Cl, F, CH3, CH3O
R1 = Cl, F
3. Conclusions
Due to rapid emergence of bacterial infection there is a need of development of effective
curative agent with more safety and low toxicity. Various research subscribed in this review
exhibiting the pharmacological activities of thiadiazoles derivatives has attracted
considerable attention owing to the usefulness of this moiety in the field of medicinal
chemistry. Further development can be carried out by establishing slight alterations in the
structure of thiadiazole compounds that would lead to drastic changes to yield better drug.
The importance of thiadiazole moiety can be magnified by carrying out further studies on its
possible substitution. To broaden the spectrum of antimicrobial action diverse functional
group can be attached to this moiety in order to get a single effective agent against the entire
causative organisms.
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