WORLD

Srivastava JOURNAL OF
et al. PHAJournal
World RMACofYPharmacy
AND PH ARPharmaceutical
and MACEUTICSciences
AL SCIENCES
SJIF Impact Factor 2.786

Volume 3, Issue 9, 1198-1212. Review Article ISSN 2278 4357

THIADIAZOLE: A BRIEF REVIEW

Samiksha Srivastava*1, Raj K. Prasad2, Rakesh Saini3

1, 2
Shambhunath Institute of Pharmacy, Jhalwa, Allahabad, India-211012
3
Pranveer Singh Institute of Technology, Kanpur, India-208020.

Article Received on
ABSTRACT
06 July 2014, Thiadiazole is a heterocyclic compound and exhibits a wide variety of
Revised on 29 July
2014, pharmacological activities such as anticancer, antitubercular,
Accepted on 22 August 2014
antibacterial, antifungal, antimicrobial, antiinflammatory, analgesic,
anticonvulsant, diuretic and anti-secretory activities. It occur in nature
*Correspondence for Author
in four isomeric forms as 1,2,3-thiadiazole; 1,2,5-thiadiazole; 1,2,4-
Samiksha Srivastava
Shambhunath Institute of
thiadiazole and 1,3,4-thiadiazole. Differently substituted thiadiazole
Pharmacy, Jhalwa, Allahabad, moieties have different activity. In this article we have discussed about
India-211012. different isomers of thiadiazole and their properties, various method of
synthesizing different isomers of thiadiazole and several
pharmacological activity of 1,3,4-thiadiazole.

Key words: Heterocyclic compound, thiadiazole, 1,3,4-thiadiazole, properties, synthesis,

pharmacological activity.

INTRODUCTION
Many infectious diseases once considered incurable and lethal are now amenable. Today a
major worldwide problem is resistance towards the available drug therefore in order to deal
with resistance new compounds has to be synthesized. During recent year remarkable
progress has been made in the development of thiadiazole and imidazo
[2,1b][1,3,4]thiadiazole compounds, many of which are known to possess interesting
pharmacological properties such as anticancer, antitubercular, antibacterial, antifungal,
antimicrobial, antiinflammatory, analgesic anticonvulsant, and antisecretory activities.
Moreover, much interest has also been focused on the cardiotonic, diuretic and herbicidal
activities displayed by compounds incorporating this heterocyclic system.[1]

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Thiadiazole is a heterocyclic compound containing both two nitrogen atom and one sulfur
atom as part of the aromatic five-membered ring. It is a versatile moiety that exhibits a wide
variety of biological activities. Thiadiazole moiety acts as hydrogen binding domain and
two-electron donor system[2] . Thiadiazoles act as bioisosteric replacement of thiazole
moiety. It is also bioisosteres of oxadiazole, oxazole and benzene. Substitution of these
heterocycles with a thiadiazole typically leads to analogues with improved activities because
the sulfur atom imparts improved liposolubility[3] Thiadiazole 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.The most
fully investigated of these being the 1,2,4- and 1,3,4-thiadiazoles. Differently substituted
thiadiazole moieties have different activity.

S S N S

N N S N
N
N N N
1,2,3-thiadiazole 1,2,4-thiadiazole 1,2,5-thiadiazole 1,3,4-thiadiazole
Fig.1

Isomers of thiadiazole
Compounds that contain thiadiazole ring are acetazolamide, methazolamide, sulfamethazole,
etc. Other thiadiazole containing drugs include, cefazolin sodium (CFZL; and cefazedone
(CFZD;)first-generation cephalosporins; timolola nonselective -adrenergic receptor
blocker used for the treatment of hypertension, angina, tachycardia and glaucoma;
xanomelinea selective agonist of muscarinic acetylcholine receptor subtypes M1 and M4;
and megazolan anti-parasitic drug.[4] Newly synthesized compounds are SCH-202676 in
2001 as a promising allosteric modulator of G-protein coupled receptors in 1998, KC 12291
as cardio protective action and in 2002 the small heterocyclic thiadiazolidinones (TDZD) as
the first non-ATP competitive glycogen synthase kinase 3 inhibitors[5]

PROPERTIES OF THIADIAZOLE
It is a clear to yellowish liquid with a pyridine like odor. It is soluble in alcohol and ether and
slightly soluble in water. Thiadiazoles carrying mercapto, hydroxyl and amino substituents
can exist in many tautomeric forms.

Metal complexes having 1,3,4- thiadiazole nucleus has been used as anti- corrosion paints
and anti- fouling in marine [6] Thiadiazole derivatives also possess fluorescence properties.[7]

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Structure and Aromatic Properties: Bak et al. analyse the spectra of 1,3,4-thiadiazole and
three isotopically substituted species. Using the analysis of difference between the measured
bond lengths and covalent radii, it was concluded that the aromatic character, as measured by
the -electron delocalization decreases in the order 1,2,5-thiadiazole > thiophene > 1,3,4-
thiadiazole.[8]

Dipole Moment: Bak et al. recorded the microwave spectra of 1,3,4-thiadiazole (I) and [34S]
1,3,4-thiadiazole (II) in the 15,00030,000 Mc/sec region and measured the dipole moment
of 1,3,4-thiadiazole in the gas phase by microwave technique and found a value of 3.28+-0.03
D. [9]

METHOD OF SYNTHESISING THIADIAZOLE

SYNTHESIS OF 1,3,4-THIADIAZOLE
From thio-semicarbazide: 1,3,4-thiadiazole can be synthesized by the cyclization of
thiosemicarbazides[10] or ferric ammonium sulphate or ferric chloride catalysed oxidation
cyclization of thiosemicarbazones.[11]

HNO3.AcOH
AC2OH
O2N S CHO
O2N S CH(OCOCH 3) 2

Thiosemicarbazide
NH4Fe(SO4) 2.12H2O

N N

O2N S S NH 2

Fig. 2

From arylhydrazide: Desai et al. synthesized various 2,5-(4-chloro benzyl)-N-aryl-1,3,4-

thiadiazole-2-amine by the cyclization of 2-(2-(4-chlorophenyl)acetyl)-N-aryl hydrazine
carbothioamides with sulphuric acid.[12]

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Cl
Cl
O
H
H N S
N Conc.H2SO4
N
H Ar NH
S N N
Ar

Fig. 3

From triethyl orthoalkanates: This is the one pot synthesis of 1,3,4-thiadiazole by using
hydrazide and triethyl orthoalkanates in presence of phosphorous pentasulfide on alumina.[13]

O N N

NHNH 2
R2 O P4S10/Al2O3 S R2

MW
R1 O O
R1

Fig. 4

SYNTHESIS OF 1,2,3-THIADIAZOLE
Cyclization of hydrazones with thionyl chloride (HurdMori Synthesis): Hydrazone
derivatives that are substituted at N-2 with an electron- withdrawing group (Z = CONH2,
COOMe, COR, SO2R) and possess an adjacent methylene group can cyclize in the presence
of thionyl chloride to form 1,2,3-thiadiazoles.

R1 R1
R1 CH 3
SXOYCl2 N
N
R2
N N
N R2
NHZ Z S
H S

Fig. 5

Cycloaddition of diazoalkanes onto a C=S bond (Pechmann Synthesis): When diazo

compounds react with various thiocarbonyl compounds (thioketones, thioesters, thioamides,
carbon disulfide, thioketenes, thiophosgene and isothiocyanates) 1,2,3-thiadiazoles are
formed. The reaction of diazoalkanes with thioketones gives mixtures of 1,3,4-thiadiazolines
and 1,2,3-thiadiazolines. The ratio of the regioisomers depends on the solvent polarity and

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steric effect. Increasing the solvent polarity and decreasing the steric hindrance favors the
formation of the 1,2,3-thiadiazoles.[14]

R3
R1 R2 H R3
N N N
R3 R1
R1
N
S N2
H S R2
S R2

Fig. 6

SYNTHESIS OF 1, 2, 4-THIADIAZOLE
Condensation of aryl thioamides with methyl bromocyanoacetate: 1,2,4-thiadiazole can
be synthesized when methyl bromocyanoacetate was allowed to react with the aryl
thioamide using different solvents. This reaction undergoes rapid condensation and provide
quantitative yield.[15]

O
S S
N
CN
R
O
R NH2 N
Br R

Fig. 7

From isothiocyanate: 1, 2, 4-thiadiazole is formed when 3-aminoisoxazole is treated with

isothiocyanates following skeletal (Dimroth) rearrangement of the intermediate thiourea
derivative.[16]

NHCO2R
NH 2 H
N
MeO2C N
KSCN/ClO2R S
N N
N
MeO O S
MeO O NHCO2R

Fig. 8

SYNTHESIS OF 1,2,5-THIADIAZOLE
From acetonitrile: Treatment of an acetonitrile solution of the 1,2,3-dithiazoles with
aqueous ammonia gave in three cases the corresponding 1,2,5-thiadiazoles.[17]

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Cl Cl
R R

NH4OH, MeCN

S N 20-80 C, 2 h N
N
S S
Cl
Fig. 9
R= Cl, CN, SMe, Ph, 4-NO2.C6H4

From aminocarboxamide: One common synthetic method for 1,2,5-thiadiazoles is to treat

an -aminocarboxamide with an electrophilic sulfur species such as S2Cl2 or PhNSO.[18]

N
H2 N S2Cl2 or PhNSO
S

NH 2 N
HO
Fig. 10

PHARMACOLOGICAL ACTIVITY OF THIADIAZOLES

Table.1 Some pharmacological active compounds and their structure

Active
S.No Derivative Name Activity
compound
N N Carbonic
5-amino-1,3,4-thiadiazole-2- anhydrase
1 R= H
SH
thiol inhibitors[19], [20]
R HN S inhibits CA
isozymes, the
cytosolic human
N NH
R=H, 2-benzylidene-N-(5-thioxo- isozymes I and
2
R1
S R1= C6H5,. 4,5-dihydro-1,3,4-thiadiazol- II, and tumor-
C N HN OC N
H
S
2-yl)hydrazinecarboxamide associated hCA
R
IX.

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Br

5-bromo-6-(4-chlorophenyl)-
R= 4-Cl
3 N N 2-cyclopropylimidazo[2,1-
N b][1,3,4]thiadiazole
S

N 4-(3-((4- Anti cancerous

S
N R= -CH2-O- chlorophenoxy)methyl)- [21], [22], [23]
4 N
NH2 Ph(p-Cl) [1,2,4]triazolo[3,4-
N
b][1,3,4]thiadiazol-6-
R
yl)aniline
O

N N 2-phenylimidazo[2,1-
5 N R= H, X=S b][1,3,4]thiadiazol-6(5H)-
R
X
one
S Anti
N CH R' Ar = C6H7N R diabetic[24],[25]
6 Ar
= C5H6O
N N

Compound with
R=CH3, R=CH3
reduced the
level of sugar in
N N O R= CH3, R= N-(5-(4-methoxybenzyl)- the blood by
7 RO CH 2
NHS R' CH3 1,3,4-thiadiazol-2-yl)-4- 19.7%.[25]
S
O
methylbenzenesulfonamide

R3
R1 =
2-cyclohexyl-6-
Cyclohexyl
phenylimidazo[2,1-
8 N N R2 R2= -H R3 = -
b][1,3,4]thiadiazole-5- Anti
CHO
tubercular[26],
N
carbaldehyde
R1 S [27]
N
N 2-phenylamino-5-(4-
Ar= C6H4F R=
9 R fluorophenyl)-1,3,4-
H
Ar S N
H
thiadiazole
N N
R' 5-(4-chlorophenyl)-N-(2,3-
R= 4-Cl R=
10 N dimethylphenyl)-1,3,4-
S H 2,3-diCH3 Anti oxidant
R thiadiazol-2-amine
activity[28], [29],
[30]
N N
R= -CH2CH3
2-(5-ethyl-1,3,4-thiadiazol-2-
11 R'= -
ylamino)ethanethiol
R
NHCH2CH2SH
S R'

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N N

R N S 6-(1-chloronaphthalen-2-yl)-
Cl
3-phenyl-5,6-dihydro-
12 HN R= C6H5
H
[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole

O N N

R (E)-2-(4-chlorostyryl)-3-(5-
N S
R= -C6H5 R1=
13 phenyl-1,3,4-thiadiazol-2-
N p-ClC6H4
yl)quinazolin-4(3H)-one
Anti
convulsant[31],
R1

N N
O
N-(5-((1H-indol-3- [32]
H
yl)methyl)-1,3,4-thiadiazol-
R = C6H5 R=
S N N N R
H

14 2-yl)-2-((3-
N
H 4-OH
hydroxyphenyl)(phenyl)meth
R'
ylene)hydrazinecarboxamide
S

N (E)-5-(benzylthio)-N-((E)-3-
N N
R1 = OCH3, R2 (4-chlorophenyl)-1-(3-
15
= Cl methoxyphenyl)allylidene)-
1,3,4-thiadiazol-2-amine

R1
R2
Anti
N N depressant[33],
[34]

S S
HN
4-(5-(4-chlorophenylamino)-
R= SO2NH2
16 1,3,4-thiadiazol-2-
R1= Cl
ylthio)benzenesulfonamide

R
R1
N

N 5-((1H-
R1= H, benzo[d][1,2,3]triazol-1-
17 N N N
R1 R2= C6H5 yl)methyl)-N-benzylidene-
N C 1,3,4-thiadiazol-2-amine Analgesic[35], [36]
S R2
4-fluoro-N-(5-oxo-4-
O2 R= H
R S N N
(phenylsulfonyl)-4,5-
18 R=
dihydro-1,3,4-thiadiazol-2-
O 4-Fluorophenyl
O S N
H
C R'
yl)benzamide
R
7-chloro-1-(4-(5-(5-
Anti
S N X=O R= nitrofuran-2-yl)-1,3,4-
19 N
O leishmanicidal
C6H4Cl thiadiazol-2-yl)piperazin-1- [37], [38]
O2N
X
N N
yl)hepta-2,4,6-triyn-1-one

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N NH 5-(3-(2-
R2 R1 = H
methoxyphenyl)propyl)-N,4-
20 R2 = OCH3
S NH diphenyl-1,3,4-
R1
thiadiazolidin-2-amine

3-(imidazo[2,1-
R=H
b][1,3,4]thiadiazol-6-yl)-
21 R1= H,
N
4a,5,6,7,8,8a-hexahydro-2H-
N O
N
chromen-2-one
O
R1 S

R1
N N
O Anti
H2
H C C microbial[39],[40]
N S
S 1-phenyl-2-(5-((2,4,5-
R1, R2, R3 = Cl
trichlorophenylamino)methyl
22 R4 = H
)-1,3,4-thiadiazol-2-
R2
ylthio)ethanone
R3
R4

N N

5-methyl-3-((5-
S NHR 1 (methylamino)-1,3,4-
N
23 R1= CH3 thiadiazol-2-
O yl)methyl)benzo[d]oxazol-
2(3H)-one Anti
O
inflammatory
[41],[42]
N
S
R (4-(2-((6-methylbenzofuran-
N
R= CH2OH 3-yl)methyl)imidazo[2,1-
24 N
b][1,3,4]thiadiazol-6-
yl)phenyl)methanol
O
H3C
H 3CO
N N O
2-(benzylsulfonyl)-5-(3,4,5-
R= C6H5-CH2
25 H3 CO S R trimethoxyphenyl)-1,3,4-
S thiadiazole
O
H 3CO Anti
O fungal[43],[44]
S R N-(5-(benzyloxy)-1,3,4-
R= p-OCH2Ph
26 thiadiazol-2-
N
H yl)cyclopropanecarboxamide
N
N

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THIADIAZOLE CONTAINING COMPOUNDS

Table 2. Some marketed thiadiazole containing drugs.
Brand
S.No Drug Structure Activity
name
N N
O
O
1 Acetazolamide Diamox S NH 2 Diuretic
HN S
H3C
O
N N COOH

Ancef,
S CH2
Cefacidal, H3 C S N
O
2 Cefazolin Antibiotic
Cefamezin, S
N
NH N
Cefrina, N

N
OCH 3

NH 2
H 3CO N

Ceptra,
3 Co-trimoxazole Antibiotic
bactrim N
H 3CO

NH 2

O Non-
Betimol, N N
selective
Blocadren, beta-
4 Timolol maleate S
Istalol, N
CH 3 adrenergic
Timoptic, O NH CH3 receptor
OH CH3 antagonist
O N N
A
Brulan, nonselective
5 Tebuthiuron Brush, broad
N N S
Bullet H spectrum
herbicide
Heng Nuo S
SH
1,3,4- HS
6 Bismuthiol I Anti viral
thidiazole-
2,5-dithiol N N
N
S
NH 2 Leishmanici
Metronidazole, O 2N
7 Megazole dal
Diloxanide N
N N
CH 3

H 2N O2 S
S O
Neptazane, Carbonic
8 Methazolamide glauctabs N N CH 3 anhydrase
N
inhibitors
CH 3

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N N

CH3
Ayerlucil, HN S
Sulphamethazol Famet, O Antibacteria
9
e Lucosil, S l
Methazol O

NH 2

CONCLUSION
Thiadiazole are the most important classes of heterocyclic compounds. Among the different
isomers of thiadiazole 1,3,4-thiadiazole is most investigated compound due to its various
pharmacological activities such as as anticancer, antitubercular, antibacterial, antifungal,
antimicrobial, antiinflammatory, analgesic anticonvulsant, and antisecretory activities,
cardiotonic, diuretic and herbicidal activities. Thiadiazole can be prepared by using different
reagents, appropriate rearrangements, ring opening and substitution reaction.

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