Accepted Manuscript

1,3,4-Thiadiazoles: A Potent Multi Targeted Pharmacological Scaffold

Saqlain Haider, Mohammad Sarwar Alam, Prof., Hinna Hamid
PII:

S0223-5234(14)01144-1

DOI:

10.1016/j.ejmech.2014.12.035

Reference:

EJMECH 7595

To appear in:

European Journal of Medicinal Chemistry

Received Date: 26 August 2014

Revised Date:

15 December 2014

Accepted Date: 20 December 2014

Please cite this article as: S. Haider, M.S. Alam, H. Hamid, 1,3,4-Thiadiazoles: A Potent Multi
Targeted Pharmacological Scaffold, European Journal of Medicinal Chemistry (2015), doi: 10.1016/
j.ejmech.2014.12.035.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

1,3,4-Thiadiazoles: A Potent Medicinal Scaffold

Saqlain Haider, Mohammad Sarwar Alam and Hinna Hamid.
Cl

N N
N

RI
PT

S
NH

O2N

H3C
N

S
N
H

M
AN
U

1,3,4-thiadiazole
S
N N

TE
D

OH

AC
C

EP

H
N

N N

NH
S

C4H9

HO

N
H

SC

Cl

N N

N
O

N N
O

H
N
CH3

ACCEPTED MANUSCRIPT

1,3,4-Thiadiazoles : A Potent Multi Targeted Pharmacological Scaffold

Saqlain Haidera,b, Mohammad Sarwar Alamb* and Hinna Hamidb
a

National Center for Natural Products Research (NCNPR), School of Pharmacy, University

of Mississippi, MS 38677, USA

Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University) New

Delhi -110 062, India.

*

RI
PT

Correspondence to Prof. Mohammad Sarwar Alam, Jamia Hamdard, New Delhi-

110062,Email ID. msalam@jamiahamdard.ac.inmsalam5555@gmail.comPhone: +91 11

SC

26059688(5555), Fax: +91 11 26059663

Abstract

M
AN
U

Despite a significant work on thiadiazoles, continuous efforts are still being made to identify
novelheterocyclic compounds with potent biological activities. This review may help the
medicinal chemists to develop new leads possessing 1,3,4-thiadiazole nucleus with higher
efficacy and reduced side effects. This review throws light on the detailed synthetic
approaches which have been used for the synthesis of thiadiazoles.This has been followed by

Keywords:

1,3,4-thiadiazole,mesoionic,syndones,

anticancer,

anti-inflammatory,

AC
C

EP

hyperlipidemia.

TE
D

the in depth analysis of the thiadiazoles with respect to their medicinal significance.

ACCEPTED MANUSCRIPT

1. Introduction
It has been observed that the compounds containing five-membered heterocyclicring
display

exceptional

chemical

behaviour

and

broad

spectrum

of

versatile

biologicalactivities.Five membered heterocyclic compounds exhibit a variety of biological

RI
PT

activities, amongst them 2,5-disubstituted 1,3,4-thiadiazoles are associated with diverse

biological activities probably by virtue of N=C-S- group. Thiadiazole is a five membered
ring system containing sulphur and nitrogen atom.Thiadiazole moiety act as a hydrogen
binding domain and two-electron donor system. They occur in four isomeric forms viz.,

Figure 1

SC

1,2,3-thiadiazole; 1,2,4-thiadiazole; 1,2,5-thiadiazole and 1,3,4-thiadiazole (Figure 1).

This review highlights the thiadiazoles on the basis of their therapeutic potential,

M
AN
U

emphasizing theversatility of this scaffold in medicinal chemistry. It is not surprising that

thiadiazoles exhibit significant therapeutic potential if we consider the fact that thiadiazoles
are the bioisostere of pyrimidine and oxadiazole. The thiadiazolestherefore act as third and
fourth generation cephalosporin[1].Thiadiazoles are easily capable of crossing the
cellularmembranes due to their mesoionic nature and their better liposolubility is attributed to
the presence of sulfur atom.1,3,4-thiadiazoles are mesoionic systems[2-3] i.e. they are a polyheteroatomic system and contain a five-membered heterocyclic ring associated with

TE
D

conjugated p and electrons and discrete regions of positive and negative charges(Figure 2).
Figure 2

Mesoionic systems are dense and highly polarizable, with a net neutral electron
charge and it is due to these characteristics that mesoionic compounds are capable of crossing

EP

the cellular membranes and interact with biological targets with distinct affinities. The good
liposolubility of the sulfur atom in this heterocyclic moiety might also have a positive effect

AC
C

on the biological activity andpharmacokinetic properties of thiadiazole-containing

compounds.Although thiadiazoles have advantages over other commonly found therapeutic
scaffolds yet their toxicity still remains a major concern. Currently the market is encumbered
with many thiadiazole-containing drugs like acetazolamide and methazolamide which are
diuretic and act by inhibiting carbonic anhydrase.The derivatives of these drugsexhibit
otheractivitiessuch as anticonvulsantand anticipatedinhibition of carbonic anhydrase[4].
Some other thiadiazole containing drugs present in the market include cefazolin sodium,
cefazedone, timolol, xanomeline and megazol(Figure 3).
Figure 3

ACCEPTED MANUSCRIPT

Cefazolin sodium and cefazedone are the first generation cephalosporins, whereas
timolol is a nonselective -adrenergic receptor blocker used for the treatment of hypertension
and angina. Xanomeline acts as a selective agonist of muscarinic acetylcholine receptor
subtypes M1 and M4 and megazol is an antiparasitic drug respectively.

2.1. Rearrangements

RI
PT

2. Chemical properties of 1,3,4-thiadiazoles

1,3,4-thiadiazoles are relatively stable against the acids but are readily cleaved by
bases[5] and are liable to nucleophilic attack. It has been shown (Scheme 1) that 2-amino1,3,4-thiadiazole

and

2-methylamino-1,3,4-thiadiazole

(R=H

and

CH3)

undergo

Scheme 1

SC

rearrangement at 150C by methylamine in methanol into their isomeric triazolinethiones[6].

M
AN
U

When 2-Amino 1,3,4-thiadiazole (Scheme 2) was refluxed withbenzyl amine in xylene, an

equimolar mixture of 2-benzylamino-1,3,4-thiadiazole and 4-benzyl-1,2,4-triazolin-3(2)thione were produced. The same two products were produced in thereaction between 2chloro-1,3,4-thiadiazole and benzylamine[7].

Scheme 2

2-alkyl-5-chloro-1,3,4-thiadiazole (Scheme 3)on heatingwith an excess of hydrazine hydrate

gives 4-amino-1,2,4-triazolin-3(2)-thiones. Similarly 2-amino-5-chloro-1,3,4-thiadiazole

TE
D

(Scheme 4) and 2-amino-1,3,4-thiadiazolin-5(4)-thione (Scheme 5) produced a mixture of

3,4-diamino-1,2,4-triazoline-5(1)-thione
thione[8].

and

3-hydrazino-4-amino-1,2,4-triazoline-5(1)-

Schemes 3, 4 & 5

EP

1-benzyl-1-(1,3,4-thiadiazole-2-yl) hydrazine

(Scheme 6) on refluxing with dilute

AC
C

hydrochloric acid, gave triazolinethion (R=H) in a quantitative yield.

Scheme 6

However when the same reaction was performed in the presence of acetic acid,a mixture of
(R=H) and (R=CH3) was formed (Scheme 7).
Scheme 7

2.2. Substitution Reaction

Even though Albert [9] has classified the 1,3,4-thiadiazole ring as a -electron excess system,
yet the presence of two nitrogen atoms reduces the electron density on the carbon atoms and
hence no electrophilic substitution has been observed in theunsubstituted 1,3,4-thiadiazole
systems. Abromine adduct of the simple 1,3,4-thiadiazole was synthesized but it decomposed
and lost bromine in the air [5]. However the nitration could not be achieved evenunder drastic
3

ACCEPTED MANUSCRIPT

conditions. When 2-phenyl-1,3,4-thiadiazole was treatedwith amixture of concentrated nitric

acid and sulphuric acid at 0oC, a mixture of the three isomeric 2-nitrophenyl-1,3,4thiadiazoles in the ratio p: m: o = 2:3:1was formed, but there was no formation of 2-phenyl5-nitro-1,3,4-thiadiazole [10].

RI
PT

2.3.Ring opening
The ring opening of 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole (Scheme 8) results in the
formation of thioketene intermediatethat reacts with an O- or N-nucleophile, forming an
ester or an amide of the aryl-substituted thioaceticacid. The thioacetic acid derivative further
undergoes intermolecular cyclizationvia nucleophilic substitution of halogenin the aromatic

SC

ring resulting in the formation of N-substituted indole-2-thiol (in case of an N-nucleophile) or

a 2-alkoxysubstitutedbenzo[b]thiophene (in case of an O-nucleophile) [11].

M
AN
U

Scheme 8

2.4. Pd/Cu-Catalyzed CH Arylation of 1,3,4-Thiadiazoles

The direct CH arylation of 1,3,4-thiadiazoles can be carried out under Pd/Cu-catalyzed

condition using a wide range of (hetero)aryl iodides, bromides andtriflates. This methodology
(Scheme 9) can be utilised for the substrates possessingelectron-donating or electronwithdrawing substituents andalso supports sterically hindered aryl halides[12].
Scheme 9

TE
D

3. Strategies for the synthesis of Thiadiazoles

The aryl(R) methyl ester on reaction with hydrazine monohydrate is converted into hydrazide
which on further reaction with methyl oxalyl chloride in the presence of Et3N gives a diacyl
hydrazide intermediate[13] which is finally cyclized (Scheme 10) into 1,3,4-thiadiazole on

EP

treatment with Lawessons reagent. The synthesized compounds were found to act as potent
inhibitors of fatty acid amide hydrolase (FAAH). The compound 1 exhibited an IC50 value of

AC
C

0.03M against FAAH.

Scheme 10

Several thiadiazole based amines and ureaswere synthesized as Stromelysin-selective urea

matrix metalloproteinase inhibitors (Scheme 11). The synthesis of thiadiazole amines
involves the reaction of isothiocyanate with hydrazinehydrate followed by direct treatment
withcarbon disulfide in DMF at 60C.The thiadiazole ureaanalogues[14] wereprepared by the
condensation of 2-amino-1,3,4-thiadiazole-2-thiol with different isocyanates. The compound
2 exhibited an IC50 value of 29 M against stromelysin-1.
Scheme 11

ACCEPTED MANUSCRIPT

6-substituted-3-(4-methyl-1,2,3-thiadiazolyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadizoles

were

synthesised by the condensation of 3-(4-methyl-1,2,3-thiadiazolyl)-4-amino-1,2,4-triazole-5thione with various carboxylic acids and phosphorus oxychloride (Scheme 12)and screened
for their antifungal activity [15]. The compound 3 exhibited an EC50 value of 2.5 g/mL

Scheme 12

RI
PT

against the Pellicularia sasakii fungus.

2-amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles have been prepared in good yields (Scheme

[16].
Scheme 13

SC

13) by the cyclisation of 1-acylthiosemicarbazides with cold concentrated sulphuric acid

Synthesis of 1,2,3-thiadiazoles and1,2,3-selenadiazoles has been achieved conveniently

M
AN
U

(Scheme 14) by using an ionic liquid as a novelsoluble support [17].

Scheme 14

A series of 2-aryl-5-hydrazino-l,3,4-thiadiazoleswas synthesized by three methods (Scheme

15) and further evaluated for their antihypertensive and anticonvulsantactivity[18].The
compound 4viz. 5-(2-Biphenylyl)-2-(1 -methylhydrazino)-l,3,4-thiadiazole exhibited potent
anticonvulsant activity with ED50 value of 18 mg/Kg in the maximum electric shock test
(MES).

TE
D

Scheme 15

5-nitroarylcarboxaldehyde on treatment with thiosemicarbazide in presence of HCl in ethanol

affords thiosemicarbazone which on cyclization with ammonium ferric sulfate yields 2amino-1,3, 4-thiadiazole (Scheme 16). Diazotization of 2-amino-1,3,4-thiadiazole in the

EP

presence of copper powder gives 2-chloro-1,3,4-thiadiazole which finally yields 5-(nitroaryl)1,3,4-thiadiazole-2-thiol on refluxing with thiourea in ethanol [19]. The compound5 exhibited

AC
C

potentin vitroanti-Helicobacter pylori activity showing a zone of inhibition of 7.7 mm at

1g/disc in comparison to metronidazole whose zone of inhibition was 16.3 mm.
Scheme 16

Treatment of 1,1-cyclopropanedicarboxylic acid[20] with thiosemicarbazide and phosphorous

oxychloride results in the formation of 1,1-bis(2-amino-1,3,4-thiadiazol-5-yl)cyclopropane
(Scheme 17).
Scheme 17
The Sommelet reaction (Scheme 18)which allows the synthesis of aldehydes from
benzylhalides by the reaction with hexamethylenetetramine HMTA (urotropine) and

ACCEPTED MANUSCRIPT

subsequent acidic hydrolysis of the resulting quaternary ammonium salt has been used for the
synthesis of 1,3,4-thiadiazoles [21].
Scheme 18
1,2,3-thiadiazole derivatives (Scheme 19) have been synthesized from the ketones using

RI
PT

corresponding semicarbazones. The Hurd-Mori procedure has been used in this synthesis[22].
Scheme 19

Thionation of amides, 1,4-diketones, N-(2-oxoalkyl)amides and N,N'-acylhydrazines with the

use of a fluorous Lawesson's reagent leads to thioamides, thiophenes, 1,3-thiazoles, and

simple filtration[23].
Scheme 20

SC

1,3,4-thiadiazoles in high yields (Scheme 20). In most cases the final product is obtained by

M
AN
U

This method [24] involves the synthesis of 1,3,4-thiadiazoles from 1,3,4-oxadiazoles which
on their reaction with thioureas produce thiadiazoles (Scheme 21).
Scheme 21

Hoggarthhas prepared[25] a number of 2-amino-5-aryl-1,3,4-thiadiazoles (Scheme 22) using

phosphoric acid as the dehydrating agents. An example of smooth cyclization in high yield by
phosphoric acid is the formation of 2-benzamido-5-phenyl-1,3,4-thiadiazole from 1,4dibenzoylthiosemicarbazide.

TE
D

Scheme 22

When thiosemicarbazide is treated with carbon disulphide and potassium hydroxide, the
potassium salt ofthiosemicarbazide-4-dithiocarboxylic acid is formed (Scheme 23). Heating
this potassium salt of thiosemicarbazide-4-dithiocarboxylic acid to 140C causes cyclization

EP

to the salt of 2-amino-5-mercapto-1,3,4-thiadiazole [26].

Scheme 23

AC
C

When 3-acyldithiocarbazic esters are treated with acids (Scheme 24), they cyclize to form
substituted thiadiazoles [27-28].
Scheme 24

Thioacylhydrazines may often serves as starting materials for the preparation of 1,3,4thiadiazole. If thiobenzoylhydrazine is heated with ethylorthoformate (Scheme 25), 2-phenyl1,3,4-thiadiazole is formed [29].
Scheme 25
Stolle found that benzoylhydrazine[30] or N, N-dibenzoylhydrazines[31] reacts with
phosphoruspentasulfide to form 2,5-diphenyl-1,3,4-thiadiazole. The reaction of N, N-

ACCEPTED MANUSCRIPT

diacylhydrazine withphosphorus pentasulfide was used by Stolle (Scheme 26) for the
synthesis of a large number of 2,5-disubstituted 1,3,4-thiadiazole.
Scheme 26
Bithiourea when treated (Scheme 27) with 3%hydrogen peroxide[32] is cyclized to 2,5-

RI
PT

diamino-1,3,4-Thiadiazole.
Scheme 27

Hilfiker et al have synthesized 5-aryl-2-aminothiadiazole derivatives [33] by the

condensation of semicarbathiazide with the desired carboxylic acid (Scheme 28) and
converted it into corresponding amides through a BOP-mediated coupling with the requisite

SC

carboxylic acid. The synthesized compounds were found to beselective EP3 receptor
antagonist. Introduction of an aromatic group in the fifth position of the thiadiazole ring

M
AN
U

resulted in the enhancement of rat dystrophia myotonica protein kinase (DMPK) properties in
comparison to the simple alkyl substitution at the same position.
Scheme 28

The oxidative cyclization (Scheme 29)of the thiosemicarbazones with an aqueous solution of
ferric chloride [34] resulted in the formation of conformationally restricted 1,3,4-thiadiazole
capsaicin analogues. The synthesized compounds acted as transient receptor potential
vanilloid 1 (TRPV1) antagonists. The compound 6 exhibited an IC50 value of 0.18 nM in
to

N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)

TE
D

comparison

tetrahydropyrazine-1

(2H)-carbox-amide (BCTC) whose IC50 value was 4.86 nM.

Scheme 29

Indolylhydrazides on treatment[35] withdifferent aryl isothiocyanates (Scheme 30) yielded

EP

thiosemicarbazides which upontreatment with acetyl chloride produced the 2-arylamino-5(indolyl)-1,3,4-thiadiazoles in good yields. They were screened for their anticancer activity

AC
C

against the human cell lines i.e. MCF-7, LnCap, MDA-MB-231, DU145, HeLa, Ovcar-3.
Amongst the synthesized compounds, 2-arylamino-5-(indolyl)-1,3,4-thiadiazole exhibited
potent activity against all the tested cancer cell lines (IC50 = 0.15-1.18 M).
Scheme 30

Novel Chloroquinone based 1,3,4-thiadiazoles were synthesized by Abdul et al (Scheme 31)

and evaluated for their [36] in vitro anti-microbial activity against Staphylococcus aureus,
Streptococcus pyogenes, Salmonella typhimurium and Escherichia coli. The results were
compared with amoxicillin by calculating the percent inhibition area/mg of the compounds.
Scheme 31

ACCEPTED MANUSCRIPT

1-adamantylisothiocyanate[37] on reaction with some carboxylic acid hydrazides in ethanol

(Scheme 32)produced thecorresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides which
were finally cyclized into the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4thiadiazole derivatives. The synthesized compounds were evaluated for their in vivo anti-

Pseudomonas aeuroginosa and Candida albicans.

Scheme 32

RI
PT

inflammatory and antimicrobial activities using Bacillus subtilis, Escherichia coli,

Indole-3-carboxylic acid[38] on treatment with aryl orheteroaryl hydrazides yieldedthe N,N/diacylhydrazines, which on further treatment with Lawessonsreagent resulted in the

SC

formation of indolyl-1,3,4-thiadiazoles (Scheme 33). 3-[5-(4-Benzyloxy-3-methoxy-phenyl)[1,3,4]thiadiazol-2-yl]-5-bromo-1H-indole exhibited significant anticancer activity (IC50 1.5

M
AN
U

M) against many tumor cell lines, prostate cell lines (LnCaP, DU145 and PC3), breast cell
lines (MCF-7 andMDA-MB-231) and pancreatic cancer cell lines(PaCa2).
Scheme 33

The

synthesis

of

2-alkyl/arylamino-5-((6-(4-bromophenyl)imidazo[2,1-b]thiazol-3-

yl)methyl)-1,3,4-thiadiazoles [39] has been carried out using 6-(4-bromophenyl)imidazo[2,1b]thiazole-3-acetic acid hydrazide as a starting material (Scheme 34). All the compounds
were screened for their antibacterial and antifungal activities. The antimicrobial activities of

TE
D

the compounds were assessed by the microbroth dilution technique.

Scheme 34

The synthesis of imidazo[2,1b]1,3,4thiadiazoles has been carried out by using

Polyethylene glycol (PEG) in presence of potassium carbonate (Scheme 35). The use of

EP

Polyethylene glycol (PEG)as an inexpensive and nontoxic medium is the reason for the
success of this reaction [40].

AC
C

Scheme 35

The condensation betweenethyl (5-methyl-1-H-imidazole-4-carboxylate) and hydrazine

hydrate resulted[41] in the formation of acylthiosemicarbazide derivatives (Scheme 36)

which were subsequently converted into 1,3,4-thiadiazoles by cyclodehydration with H2SO4.

The synthesized compounds showed weak antibacterial and antifungal activities in
comparison to the standard drugs like chloramphenicol (antibacterial) and ketoconazole
(antifungal).
Scheme 36

ACCEPTED MANUSCRIPT

1,4-Disubstituted thiosemicarbazides (Scheme 37)onreaction with ethenetetracarbonitrile in

dimethylformamide [42] resulted in the

formation of 2-substituted 5-phenyl-1,3,4-

thiadiazoles and 2-substituted 5-phenyl-1,3,4-oxadiazoles.

Scheme 37

RI
PT

2-bromoimidazo[2,1-b][1,3,4]thiadiazole derivatives have been prepared by Suzuki-Miyaura

crosscoupling reaction [43] to obtain a new class of imidazo[2,1-b][1,3,4]thiadiazole
derivatives substituted in the 2- and 6-positions by alkyl, ester, or substituted aryl groups
(Scheme 38). This new strategy is successful and can be useful for a number of electron-

Scheme 38

SC

withdrawing, electron-donating and acid-sensitive groups.

The sodium salt of 2,6-diisopropyl phenol on condensationwith carbon disulfide followed by

M
AN
U

alkylation with ethyl chloroacetate producedthe thioester derivative[44] which on treatment

with hydrazine hydrate produced thiohydrazide (Scheme 39). Thiohydrazide on treatment
with carbon disulfide produced5-(4-Hydroxy-3,5-diisopropyl-phenyl)-3H-[1,3,4]thiadiazole2-thione which was found to exhibit COX-2 selectivity in the murine macrophage cell line
(J774A.1)

Scheme 39

Amir et al have [45] synthesized several benzothiazole containing 1,3,4-thiadiazoles (Scheme

TE
D

40) and evaluated their antibacterial activity against Staphylococcus aureus, Escherichia coli
and Pseudomonas aeruginosa using ofloxacin as the standard drug.
Scheme 40

2-(aryl-methanesulfonylmethyl)-5-aryl-1,3,4-thiadiazoles(Scheme 41) were synthesized by

EP

Padmavathi et al[46] and evaluated for their in vitro antimicrobial activity against Gram
positive bacteria S.aureus, B. subtilis; Gram negative bacteria Klebsiella pneumoniae,

AC
C

Proteus vulgaris and fungi Fusarium solania, Aspergillus niger. It was concluded that the
compounds containing benzylsulfonyl group and chloro substituents showed significant
activity.

Mathew

et

al[47]

synthesized

Scheme 41
many

3,6-disubstituted-1,2,4-diazole

[3,4-b]-1,3,4-

thiadiazoles3 and their dihydro analogues (Scheme 42) and evaluated them for their for their
antibacterial and antifungal activities. It was found that the compounds containing 2-flouro
pyridine group at sixth position of the triazolothiadiazole system showed potent activity.
Scheme 42

ACCEPTED MANUSCRIPT

Synthesis and the antimicrobial activity of1,2,4-triazolo thiadiazoles carrying4-methyl/ethyl

thio and methyl sulfonylurea phenoxy moieties (Scheme 43)at position threehas been carried
out by Karabasanagouda et al[48].
Scheme 43

RI
PT

Novel 1,2,4-triazolo thiadiazoles [49] bearing 2,3,5-trichlorophenyl moietywere synthesized

by Karegoudar et al. The newly synthesized compounds (Scheme 44)were screened for their
antibacterial activity against Escherichia coli (ATTC-25922), Staphylococcus aureus
(ATTC-25923), Pseudomonas aeruginosa (ATCC-27853) and Klebsiella pneumoniae

moderate to significant activity.

Scheme 44

SC

(recultured) bacterial strains by serial plate dilution method. The compounds exhibited

M
AN
U

A series of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol2-yl) derivatives of piperazinyl quinolones were synthesized [50]andevaluated for
antibacterial activity against Gram positive and Gram negative microorganisms (Scheme 45).
The synthesized molecules exhibited potent antimicrobial activityagainst Gram-positive
bacteria S. aureusand S. epidermis.

Scheme 45

Lamani et alsynthesized[51] some novel methylene bridged benzisoxazolyl imidaozo [2,1-b]

TE
D

[1,3,4] thiadiazole derivatives (Scheme 46)and screened them for antibacterial activity
against S. aureus, B. subtilis and E. coli and antifungal activity against C. albicans and
Aspergillus fumigatus.

Scheme 46

EP

Vasoya et al [52]synthesized 1,3,4-thiadiazoles and screened them for their antimicrobial

activity by using the cupplate agar diffusion method against bacterias likeEscherichia coli,

AC
C

Pseudomonas aeruginosa, Bacillus megaterium,Staphylococcus aureus and fungus

Aspergillus niger at 40 g/ml concentration using amoxycillin, benzyl penicillin,
ciprofloxacin, erythromycin and griseofulvin as standards. The synthesized compounds
(Scheme 47) were also found to exhibit potent antitubercular activity.
Scheme 47

Andanappa et al [53] have synthesized 5-guanylhydrazone 1,3,4-thiadiazole derivatives

(Scheme 48)and evaluated them for their antibacterial activity against both Escherichiacoli
and Staphylococcus aureus, using sulfamethoxazole and norfloxacin as the standard drugs.
The synthesized compounds were also screened for their anti-inflammatory activity.
Scheme 48
10

ACCEPTED MANUSCRIPT

Muralikrishna et al [54] have synthesizedpyrrolyl/pyrazolylarylaminosulfonylmethyl1,3,4thiadiazoles and screened them for their antimicrobialactivity against Pseudomonas
aeruginosa

usingchloramphenicol

as

standard

drug

and

against

Penicilliumchrysogenumusing ketoconazole as the standard drug. The chloro-substituted

RI
PT

compounds (Scheme 49)

showed potent antibacterial activity in comparison to chloramphenicol.
Scheme 49

A series of pyridyl and napthyl substituted 1,3,4-thiadiazoleshave been synthesized (Scheme

aureusand E. coli.
Scheme 50

SC

50) by Zamaniet al [55]and further screened for their antimicrobial activity against S.

M
AN
U

Moshafi et al [56] have synthesized 1,3,4-thiadiazole derivatives(Scheme 51)and screened

them for their antibacterialactivity against Helicobacter pyloriby using the disc diffusion
method. The zone of inhibition of 3,5-dimethyl-1-[5-(1-methyl-5-nitro-1H-imidazol-2-yl)[1,3,4]thiadiazol-2-yl]-piperazine was found to be 30.9 mm in diameter which was five times
larger than that observed for the standard drug metronidazole which exhibited a 6mm zone of
inhibition.

Scheme 51

TE
D

A series of novel 3-heteroarylthioquinolinederivatives were synthesized by Chitra et aland

screened [57] for their in vitro activity against M. tuberculosisH37Rv. The compounds 2-[2(4-bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole
chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole

and

(Scheme

2-[2-(452)were

EP

found to be the most active with MIC of 3.2 and 3.5 mM respectively against MTB.
Scheme 52

AC
C

Camoutsis et alhave synthesized some thiadiazoleswhich exhibited potent antibacterial as

well as antifungal activity[58]. The synthesized compounds (Scheme 53) exhibited potent
antifungal activity as compared with the standard drug bifonazole. They also showed
significant antibacterial activities against E. coli, S. aureus, and P. aeruginosa.
Scheme 53

Kucukguzelet alsynthesized some diflunisal hydrazide derivatives and screened them for
antimicrobial and antiviral effects[59].The phenyl substituted derivative (Scheme
54)exhibited significant antibacterial activity as compared to cefepime i.e. 31.25 mgmL-1
against E. coli A1and Streptococcus pyogenes ATCC.
Scheme 54
11

ACCEPTED MANUSCRIPT

A series novel 1,3,4-thiadiazoles

synthesized

by Liesen et al [60]was screened for

theirantimicrobial and antiparasitic activities. The synthesized compounds (Scheme 55)

exhibited significant activity against the Toxoplasma gondiiin comparisontohydroxyurea and
Amongst

the

different

thiadiazoles,[5-(5-Methyl-1H-imidazol-4-yl)-

RI
PT

sulfadiazine.

[1,3,4]thiadiazol-2-yl]-phenyl-amine exhibited most potent activity against intracellular

parasites.
Scheme 55

Amir et al [61] synthesized and evaluated the anti-inflammatory activity of 1,2,4-triazolo

SC

[3,4- b][1,3,4]thiadiazole derivatives (Scheme 56)of ibuprofen and biphenyl-4-yloxy acetic.

It was found that the compounds having 2,4-dichlorophenyl and n-butyl amino groups

M
AN
U

respectively showed significant activity in comparison to flurbiprofen.

Scheme 56

Goksen et al [62] synthesized and screened the anti-inflammatory activity of various2benzoxazolinone derivatives (Scheme 57). The phenyl substituted compounds exhibited the
most potent activity.

Scheme 57

Schenone et al [63] have synthesized and evaluated novel N-[5-oxo-4-(arylsulfonyl)-4,5-

TE
D

dihydro-1,3,4-thiadiazol-2-yl]-amide derivativesfor their anti-inflammatory and analgesic

activities.The synthesized compounds (Scheme 58)were also found to exhibit less irritation
of the gastric mucosa as compared to indomethacin.
Scheme 58

EP

A series of novel 3,6-disubstituted-1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles and their dihydro

derivatives (Scheme 59) have been synthesized by Mathew et al[64] and evaluated for its

AC
C

anti-inflammatory activity. The tested compounds, especially that containing indole ring at
the sixth position of the triazolothiadiazole system exhibited significant anti-inflammatory
activity.

Scheme 59

Mullican et al [65] have synthesized 1,3,4-thiadiazole derivatives of di- tert-butylphenol and

evaluated them for their COX and LOX inhibitory activities. These derivatives (Scheme 60)
exhibited a wide range of log P (2.3 to >4) and pKa(5.5-12) values. Amongst the tested
compounds,

5-[3,5-bis(l,l-dimethylethyl)-4-hydrosyphenyl]-1,3,4-thiadiazole-2(3H)-thione,

choline salt was found to be a potent inhibitor of 5-LO (IC50 = 2.8 M) and CO (IC50 = 0.8
M).
12

ACCEPTED MANUSCRIPT

Scheme 60
A series novel 5-(1-adamantyl)-1,3,4-thiadiazole derivatives (Scheme 61)have been
synthesized by Kadi et al [66]and screened for theiranti-inflammatory activity using
indomethacin as the standard drug.

RI
PT

Scheme 61
Mavrova et al [67]synthesized novel of 2,5-substituted-1,3,4-thiadiazoles derivatives
(Scheme 62) and evaluated them fortheir cytotoxicity. The results of the biological activity
demonstrated

thatthe

compoundn-ethyl-5-(4,5,6,7-tetrahydro-1-benzothien-2-yl)-1,3,4-

of 5.2 x 10-6M.
Scheme 62

SC

thiadiazole-2-aminepossessed highin vitrocytotoxicity against thymocytes with an IC50value

M
AN
U

Matysiak et al[68]synthesized (Scheme 63)a series of novel 5-substituted 2-(2,4dihydroxyphenyl)-1,3,4-thiadiazoles and screened them for their antiproliferative activity.
The substitution pattern included alkyl, alkoxy, aryl and heteroaryl groups.
Scheme 63

Matysiak et al [69] have synthesized number of N-substituted 2-amino-5-(2,4dihydroxyphenyl)-1,3,4-thiadiazoles

(Scheme

64)and

screened

them

for

their

antiproliferative activity in four human cell lines i.e. SW707 (rectal), HCV29T (bladder),

TE
D

A549 (lung) and T47D(breast).The highest antiproliferative activity was observed for 2-(2,4dichlorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole with ID50twice as lower as
compared to cisplatin.

Scheme 64

EP

A series of novel 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolederivatives

(Scheme 65) has been synthesized by Ibrahim et al[70]and screened for antitumor activity

AC
C

against different cancer cell lines at a concentration of 10-5M - 10-7M.

Scheme 65

Wei et al [71]have synthesized a series of novel chiral -substituted butenolide molecules

containing 1,3,4-thiadiazole moiety (Scheme 66) and screened their invitroanticancer activity
against Hella cell lines. The compound having 1-menthyl substitution showed a significant
inhibitory activity i.e. IC50 of 0.9 M.
Scheme 66
Sevgi et al [72] synthesized a series of novel 5-[4-(4-fluorobenzoylamino)phenyl]-2substitutedamino-1,3,4-thiadiazole derivatives (Scheme 67) and screened them for their

13

ACCEPTED MANUSCRIPT

cytotoxic activity using HeLa (ATCC CCL-2) and normal cell lines according to MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay.
Scheme 67
Gupta et al [73] synthesised novel substituted 1,2,4-thiadiazoles (Scheme 68) and tested their

RI
PT

anticonvulsant activity. It was observed that the synthesized compoundsexhibited potent

activity against MES-induced seizures.
Scheme 68

Yar et al [74]synthesized a series of novel thiadiazoles (Scheme 69) and screened them for
their anticonvulsantactivity by maximal electroshock seizure (MES) test. Amongst the
compounds,

(4-Chloro-phenyl)-(5-pyridin-4-yl-[1,3,4]thiadiazol-2-yl)-

SC

synthesized

amineexhibited a 100% protectionagainstshock-induced seizures in comparison to phenytoin

M
AN
U

sodium.
Scheme 69

Dawood et al. have synthesized 1,3,4-thiadiazole derivatives (Scheme 70)and evaluated them
for their anticonvulsant activity[75] using a MES test and subcutaneousmetrazole (ScMet)
assay in mice.The synthesized compounds were also evaluated for their antiinflammatory and
antinociceptive activities using aspirin as the standard drug.
Scheme 70

TE
D

A series of novel 2,5-disubstituted 1,3,4-thiadiazoles has been synthesized by Harish et al[76]

and the synthesized compounds (Scheme 71)have been screened for their anticonvulsant
activity using the standard drugs carbamazepine and phenytoin.
Scheme 71

EP

Dogan et al[77] have synthesized some2,5-Disubstituted-1,3,4-thiadiazoles(Scheme 72)

exhibiting anticonvulsant activity. They concluded that the compounds containing ethyl and

AC
C

m-fluorophenyl substituents acted as potent anticonvulsant agents.

Scheme 72

Foroumadi et al [78]have synthesized a series of novel 2-amino-5-[4-chloro-2-(2chlorophenoxy) phenyl]-1,3,4-thiadiazole derivatives (Scheme 73) and screened them for
their anticonvulsant activity using maximal electroshock (MES) method.
Scheme 73
Yusuf et al [79]have synthesized (Scheme 74) and screened the antidepressant activity of
novel 5-amino-1,3,4-thiadiazole-2-thiol derivatives. Amongst the synthesized compounds,
the molecules with methoxy and dimethyl amino group exhibited potent antidepressant
activity.
14

ACCEPTED MANUSCRIPT

Scheme 74

RI
PT

Pattanayak et al [80] synthesized and evaluated (Scheme 75)the antidepressant activity of 2amino-5-sulfanyl-1,3,4-thiadiazole derivatives and screened them for their antidepressant
activity.
Scheme 75

A series of novel 3-[5-substituted phenyl-1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-

antidepressant activity using the forced swim test method.

M
AN
U

Scheme 76

SC

ones(Scheme 76)have been synthesized[81]by Jatav et al and screened for their

Carbonic anhydrase also known as carbonate dehydratase is a family of enzymes

which catalyses the fast interconversion of carbon dioxide and water to bicarbonate and
protons in a reversible reaction which otherwise occurs very slowly [82] in its absence.
Carbonic anhydrase is classified in the category metalloenzymes as it contains a zinc ion.
This enzyme plays a key role in maintaining acid-base balance in blood and other tissues. It is
a potential therapeutic target for the treatment of diseases like, glaucoma, edema, obesity,

TE
D

cancer, osteoporosisand epilepsy.

Smaine et al [83] have synthesized a series of novel 2-substituted-1,3,4-thiadiazole-5sulfamide derivatives (Scheme 77)and screened them against some Carbonic anhydrase
isoforms i.e. the mitochondrial CA, VA and VB, the cytosolic CAI and II and the membrane-

EP

associated CAIV. The selectivity ratios for inhibiting the mitochondrial enzymes against CA
II were in the range of 67.5415, thus making these sulfamides the first selective CA VA/VB

AC
C

inhibitors.

Scheme 77

Casey et al [84] have carried out the synthesis of charged sulfonamides containing 1,3,4thiadiazole moiety and screened them against several Carbonic anhydrase isoforms (Scheme
78). The synthesized compounds exhibited higher affinity in comparison to the standard
drugs like acetazolamideand methazolamide. The highest affinity for the Carbonic anhydrase
isoforms was reported for 1-[4-(5-Sulfamoyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]pyridinium perchlorate whose Kivalues were 3, 0.2, 2 and 6 nm against hCA I, hCA II, bCAV
andhCA IX, respectively.
Scheme 78
15

ACCEPTED MANUSCRIPT

Bernard et al [85]have synthesized some aromatic/heterocyclic sulfonamides incorporating

valproyl moieties and screened their affinities for carbonic anhydrase (CA) isozymes.The

RI
PT

synthesized compounds showed very high inhibitorypotency against three carbonic anhydrase
(CA) isozymes, such as CA I, CA II, and CA IV. 5-valproylamido-1,3,4-thiadiazole-2sulfonamide derivativeswere found to exhibit very strong anticonvulsant (Scheme 79)
properties in MES test in mice.
Scheme 79

SC

A series of novel mercaptan based1,3,4-thiadiazoles (Scheme 80)has been synthesized by

Almajan et al and screened against threeCarbonic anhydrase isoforms viz. the cytosolic

M
AN
U

human isozymes I and II, tumor-associated hCA IX and the transmembrane [86].
Scheme 80

Menchise et al studied the X-ray crystal structure of the complex of 5-amino-thiophene-2sulfonic acid amide with human (h) CA II and found that hydrogenbonding[87] and van der
Waals forces are responsible for the interaction of thiadiazole ring with hCA II.The amino
group of the thiadiazole ring binds with water molecule and the sulfamide group interacts
with Zn2+ in hCA II through the hydrogen bonding. It has also been discovered that the

TE
D

activity was further enhanced if an acyl or sulfonyl group is introduced at the 5-amino
positionprobably due to the formation of additional hydrogen bonds with hCA II[88-89].
Thus it may be concluded that thiadiazoles interact strongly with carbonic anhydrase
isoforms which in turn are the target for several health disorders liketremor and Parkinsons

EP

disease[90],intracranial pressure[91-95], epilepsy[96],tardive dyskinesia[97], hypokalemic

periodic paralysis [98-99],mountain sickness [100-101] andgenetic hemiplegic migraine

AC
C

andataxia[102].

Cressier et al [103]studied the antioxidant activity (Scheme 81) of thiadiazole derivatives of

thiol, thiosulfonic acid and phosphorothioate. Thiol and aminothiol compounds act as
effective chemical radioprotectors.
Scheme 81

Kus et al [104] have synthesized 5-[(2-(substituted phenyl)-1H-benzimidazole-1-yl)methyl]N-methyl-1,3,4- thiadiazole-2-amines (Scheme 82) and screened their in vitro antioxidant
activity.
Scheme 82

16

ACCEPTED MANUSCRIPT

Paddmavathi et al[105] have synthesized a series of novel of bis heterocycles (Scheme

83)containing

sulfone

linked

pyrazolyl

oxadiazoles

and

thiadiazolesfrom

Z-

Scheme 83

RI
PT

styrylsulfonylacetic acid and screened their antioxidant and antimicrobial activities.

A series of novel 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 2,5disubstituted-1,3,4-thiadiazoleshas been synthesized by Khan et al[106] and evaluated for
their antioxidant and urease inhibitory activities (Scheme 84). N-(2,4-Dimethylphenyl)-5-(4-

standarddrugn-propyl gallate.

M
AN
U

Scheme 84

SC

nitrophenyl)-1,3,4-thiadiazol-2-amineexhibited more potent antioxidant activity than the

The disease caused by the Leishmania parasite is known as Leishmaniasis[107]. It is

transferred to humans by sandflies.Tahghighi et al [108]have synthesized and series of novel
5-(5-nitrofuran-2-y1)-1,3,4-thiadiazoles

with

piperazinyl-linkedbenzamidine

substituent

(Scheme 85). The synthesized compounds exhibited significant activity in both promastigote
and amastigote.It was found that N-propyl-4-(4-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-

inpromastigote model.

TE
D

yl)piperazin-1-yl) benzamidine hydrochloride exhibited an IC50 value of 0.08 mM

Scheme 85

Zhanet al[109]carried out (Scheme 86) the synthesis of novel 2-(4-(naphthalen-2-yl)-1,2,3thiadiazol-5-ylthio)acetamide derivativesand evaluated their HIV-1 reverse transcriptase

EP

inhibitory activity.Amongst the tested compounds the most potent inhibitors exhibited an
EC50=0.17 0.02, 0.360.19 and 0.390.05 M and showed comparable inhibition with

AC
C

NVP(EC50= 0.208 M) and DLV (EC50 = 0.320 M).

Scheme 86

Zhanet al[110] have synthesized 1,2,3-thiadiazole thioacetanilide derivatives (Scheme 87)

and screened their anti-HIV activity in MT-4 cells. Amongst the synthesized compounds, 2[4-(2,4-dichlorophenyl)-1,2,3-thidiazol-5-ylthiol]-N-(2-nitrophenyl)acetamideexhibited

an

EC50= 0.0590.02 M, CC50> 283.25M and SI > 4883.

Scheme 87
A series of novel 1,3,4-thiadiazoles has been synthesized (Scheme 88) by Hamadet al [111]
and screened forin vitro anti-HIV-1 (strain IIIB) and anti-HIV-2(strain ROD) activity using

17

ACCEPTED MANUSCRIPT

MTT assay. It was found that 2-(naphthalen-2-yloxy)-N-((5-(phenylamino)-1,3,4-thiadiazol2-yl)methyl) acetamideexhibited an EC50 values of0.96 l g/mL.
Scheme 88
Al-Soud et al [112] carried out the synthesis of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

RI
PT

derivatives under the microwave conditions. The synthesized compounds (Scheme 89)were
screened for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4.It
was found that 3-(3,4-Dichloro-phenyl)-6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
exhibitedan EC50value of 1.97 /mL.
Scheme 89

SC

Akhtar et al [113] have synthesized2-substituted 5-(4-chlorophenylamino)-1,3,4-thiadiazoles

and screened (Scheme 90) them against HIV-1 and HIV-2 in MT-4 cells. The compound N-

M
AN
U

[5-(4-Chloro-phenylamino)-[1,3,4]thiadiazol-2-ylmethyl]-4-methyl-

benzenesulfonamideexhibitedan EC50 value of 23.9g/mL and 9.9 g/mL against HIV-1 and
HIV-2.

Scheme 90

Ashwin et al [114] have synthesized a series of novel 2-piperidinopiperidine thiadiazoles

(Scheme 91) and screened them as histamine H3 receptor antagonists. Amongst the
synthesized

molecules,

4-(5-([1,4-bipiperidin]-1-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-

TE
D

yl)morpholineshowed potent activity with Ki(h) = 3 1.0 nM and Ki(m) = 4 2 nm

respectively in comparison to the target molecule of the study which exhibited Ki(h) = 49
3.0 nM and Ki(m) = 47 15 nm.

4. Conclusion

EP

Scheme 91

AC
C

It may be concluded that thiadiazoles exhibit a broad spectrum of biological activities like
anti-inflammatory, anticancer, antibacterial, antidepressant, antifungal, antiviral, antiparasitic,
anticonvulsant, anti-HIV and herbicidal etc. Thus the thiadiazole scaffold still remains as
therapeutic target for the development of new leads in the modern medicinal chemistry. The
physical, chemical and the pharmacokinetic properties of thiadiazoles still maintains the
importance of this moiety inspite of the rising levels of drug resistance in todays era.

5. Acknowledgements

18

ACCEPTED MANUSCRIPT

The authors thank Dr. G.N. Qazi, Vice-Chancellor, Jamia Hamdardfor providing necessary
facilities to the Department of Chemistry. One of the authors (SH) is also thankfulto CSIR for

AC
C

EP

TE
D

M
AN
U

SC

RI
PT

awarding the senior research fellowship.

19

ACCEPTED MANUSCRIPT

References
[1] J.K. Gupta, R.K. Yadav, R. Dudhe, P.K. Sharma, Inter. J. Pharm. Tech. Res.2 (2010)
1493-1507.
[2] N. Grynberg, A.C. Santos, A. Echevarria, Anti-Cancer Drugs.8 (1997)88-91.

Cancer. 91 (2004)297-304.

RI
PT

[3] A. Senff-Ribeiro, A. Echevarria, E.F. Silva, C.R. Franco, S.S. Veiga, M.B. Oliveira, Br. J.

[4] B.Masereel, S. Rolin, F. Abbate, A. Scozzafava, C.T. Supuran, J. Med. Chem. 45 (2002)
312-320.

[5] J. Goerdeler, J. Ohm, O. Tegtmeyer, Chem. Ber. 89 (1956) 1534-1543.

SC

[6] J. Goerdeler, J. Galinke, Chem. Ber.90 (1957) 202-203.

[7] H. Saikachi, M. Kanaoka, Y. zasshi 81 (1961) 1333, Chem. Abstr.56 (1962)7304.

M
AN
U

[8] H. Saikachi, M. Kanaoka, Yakugakuzasshi 82 (1962) 683, Chem. Abstr.58 (1963) 4543.
[9] A. Albert, Heterocyclic chemistry, Oxford University Press (Athlone) London and New
York. 1959, pp 60-62.

[10] M. Ohta, R. Hgiwara, Y. Mizushima, J. Pharm. Soc. Japan. 73 (1953) 701.

[11] A. Dmitry,Androsov, C. Douglas, Neckers, J. Org. Chem. 72 (2007) 5368-5373.
[12] D.D. Vachhani,A. Sharma,E. Van der Eycken, J. Org. Chem. 77 (2012) 8768-8774.
[13] J. Garfunkle, C. Ezzili, T.J. Rayl, D.G. Hochstatter, I. Hwang, D.L. Boger, J.

TE
D

Med.Chem. 51 (2008)4392-4403.

[14] E.J. Jacobsen, M.A. Mitchell, S.K. Hendges, K.L. Belonga, L.L. Skaletzky, L.S. Stelzer,
T.J. Lindberg, E.L. Fritzen, H.J. Schostarez, T.J. OSullivan, L.L. Maggiora, C.W.
Stuchly, A. L. Laborde, M.F. Kubicek, R.A. Poorman, J.M. Beck, H. R. Miller, G.L.

EP

Petzold, P.S. Scott, S.E. Truesdell, T.L. Wallace, J.W. Wilks, C. Fisher, L.V. Goodman,
P.S. Kaytes, S.R. Ledbetter, E.A. Powers, G. Vogeli, J.E. Mott, C.M. Trepod, D.J.

AC
C

Staples, ET. Baldwin, B. C. Finzel, J. Med. Chem. 42(1999)1525-1536.

[15] Z. Fan, Z. Yang, H. Zhang, N. Mi, H. Wang, F. Cai, X. Zuo, Q. Zheng, H. Song, J.
Agric. Food Chem. 58 (2010)2630-2636.

[16] W.R. Sherman, J. Org. Chem. 26 (1961) 88-95.

[17] A. Kumar,M.K. Muthyala,S. Choudhary,R.K. Tiwari, K. Parang, J. Org. Chem. 77
(2012)9391-9396.
[18] C.B. Chapleo, M. Myers, P.L. Myers, J.F. Saville, A.C.B. Smith, M.R. Stillings, I.F.
Tulloch, D.S. Walter, A.P. Welbourn, J. Med. Chem. 29(1986)2273-2280.
[19] A. Foroumadia, M. Sorkhia, M.H. Moshafib, M. Safavia, A. Rineha, F. Siavoshic, A.
Shafieea, S. Emamid, Med. Chem. 5 (2009)529-534.
20

ACCEPTED MANUSCRIPT

[20] A.H.K. Sharba, R.H. Al-Bayati, N. Rezki, M.R. Aouad, Molecules.10 (2005)1153-1160.
[21] G. Serban, S. Cuc, E. Egri, A. Salvan, Farmacia.58 (2010) 818-824.
[22] M.A. Hosny, T.H. El-sayed, E.A. El-sawi, E-Journal Chem. 9 (2012) 1276-1287.
[23] Z. Kaleta, B.T. Makowski, T. Soos, R. Dembinski, Org. Lett.8 (2006) 1625-1628.

RI
PT

[24] V. Padmavathi, G.S. Reddy, A.V.N. Mohan, K. Mahesh, Arkivoc.17 (2008) 48-60.
[25] Hoggarth, J. Chem. Soc. (1949) 1160-1163.
[26] P.C. Guha, J. Am. Chem. Soc.44(1922) 1510-1517.
[27] Fuji, J. Chem. Soc. Japan. 74 (1954) 1056.

[29] Anisworth, J. Am. Chem. Soc. 77 (1955) 1148-1150.

[30] Stolle, Kind, J. Prakt. Chem. 70 (1904) 423.

M
AN
U

[31] Stolle, J. prakt. Chem. 69 (1904)145.

SC

[28] R.W.Young, K.H. Wood, J. Am. Chem. Soc. 77 (1955) 400-403.

[32] E. Fromm, E. Layer, K. Nerz, Ann. 433 (1923) 1.

[33] M.A. Hilfiker, N. Wang, X. Hou, Z. Du, M.A. Pullen, M. Nord, R. Nagilla, H.E. Fries,
C.W. Wu, A.C. Sulpizio, J.P. Jaworski, D. Morrow, R.M. Edwards, J. Jin. Bio. Org.
Med. Chem. Lett. 19 (2009) 4292-4295.

[34] C.L. Rebolledo, P.S. Hitshfeld, S. Brauchi, M. Zrraga, Euro. J. Med. Chem. 66 (2013)
193-203.

TE
D

[35] D. Kumar, N.M. Kumar, B. Noel, K. Shah, Euro. J. Med. Chem. 55 (2012) 432-438.
[36] A.R. Bhat, Tazeem, A.Azam, I. Choi, F. Athar, Euro. J. Med. Chem. 46 (2011) 31583166.

[37] A.A. Kadi, N.R. El-Brollosy, O.A. Al-Deeb, E.E. Habib, T.M. Ibrahim, A.A. El-Emam,

EP

Euro. J. Med. Chem. 42 (2007) 235-242.

[38] D. Kumar, N.M. Kumar, K. Chang, K. Shah, Euro. J. Med. Chem. 45 (2010)4664-4668.

AC
C

[39] N.U. Gzeldemirci, . Kkbasmac, Euro. J. Med. Chem. 45 (2010) 63-68.

[40] M. Kidwai, D. Bhatnagar, R. Chauhan, J. Heterocyclic Chem.50(2013) 234-236.
[41] A.P. Liesen, T.M. Aquino , C.S. Carvalho, V.T. Lima, J.M. Arajo, J.G. Lima, A.R.
Faria, E.J.T. Melo, A.J. Alves, E.W. Alves, A.Q. Alves, A.J.S. Ges, Euro. J. Med.
Chem. 45 (2010) 3685-3691.

[42] A.A. Hassan, K.M. El-Shaieb, R.M. Shaker, D. Dopp, Hetro Chem.16(2005) 12-19.
[43]C. Copin, N. Henry, F. Buron, S. Routier, Eur. J. Org. Chem. 16 (2012)3079-3083.
[44] Y. Song, D.T. Connor, A. D. Sercel, R.J. Sorenson, R. Doubleday, P.C. Unangst, B.D.
Roth, V.G. Beylin, R.B. Gilbertsen, K. Chan, D.J. Schrier, A. Guglietta, D.A.
Bornemeier, R.D. Dyer, J. Med. Chem. 42 (1999)1161-1169.
21

ACCEPTED MANUSCRIPT

[45] M. Amir, A. Kumar, I. Ali, S. A. Khan, Indian J of chem. 48 (2009)1288-1293.

[46] V. Padmavathi, G.S. Reddy, A. Padmaja, P. Kondaiah, Ali-Shazia, Eur. J. Med. Chem.
44 (2008) 2106-2112.
[47] V. Mathew, J. Keshavayya, V.P. Vaidya, D. Giles. Eur. J. Med. Chem. 42 (2007) 823-

RI
PT

840.
[48] T. Karabasanagouda, A.V. Adhikari, N.S. Shetty, Eur. J. Med. Chem. 42 (2007) 521529.

[49] P. Karegoudar, D.J. Prasad, M. Ashok, M. Mahalinga, B. Poojary, B.S. Holla, Eur. J.
Med.Chem.43 (2008) 808-815.

SC

[50] A. Foroumadi, S. Emami, A. Hassanzadeh, M. Rajaee, K. Sokhanvar, M.H. Moshafi, A.

Shafiee, Bioorg. Med. Chem. Lett.15 (2005) 4488-4492.

M
AN
U

[51] R.S. Lamani, N.S. Shetty, R.R. Kamble, I.A.M. Khazi, Eur. J. Med. Chem. 44 (2008)
2828-2833.

[52] S.L. Vasoya, D.J. Pagdhar, P.T. Chovatia, H.S. Joshi. J. of Sciences, 16 (2005) 33-36.
[53] G.Andanappa, M. Palkar, K. Anand, N. Malleshappa, S. Noolvi, J. Thippeswamy, B.
Wagawade, Bioorg. Med. Chem.16 (2008) 276-283.

[54] A. Muralikrishna, B.C. Venkatesh, V. Padmavathi, A. Padmaja, P. Kondaiah, N.S.

Krishna, Eur. J. Med. Chem.54 (2012) 605-614.

TE
D

[55] K. Zamani, K. Faghihi, T. Tofighi, M.R. Shariatzadeh, Turk J. Chem. 28 (2004) 95-100.
[56] M.H. Moshafi, M. Sorkhi, S. Emami, M. Nakhjiri, A. Yahya-Meymandi, A.S.
Negahbani, F. Siavoshi, M. Omrani, E. Alipour, M. Vosooghi, A. Shafiee, A.
Foroumadi, Arch. Pharm. 344 (2011) 178-183.

EP

[57] S. Chitra, N. Paul, S. Muthusubramanian, P. Manisankar, P. Yogeeswari, D. Sriram, Eur.

J. Med. Chem. 46 (2011) 4897-4903.

AC
C

[58] C. Camoutsis, A. Geronikaki, A. Ciric, M. Sokovic, P. Zoumpoulakis, M. Zervou,

Chem. Pharm. Bull. 58 (2010) 160-167.

[59] S.G. Kucukguzel, I. Kucukguzel, E. Tatar, S. Rollas, F. sahin, M. Gulluce, E.De Clercq,
L. Kabasakal, Eur. J. Med. Chem. 42 (2007) 893-901.

[60] A.P. Liesen, T.M. de Aquino, C.S. Carvalho, V.T. Lima, J.M. de Araujo, J.G. de Lima,
A.R. de Faria, E.J. de Melo, A.J. Alves, E.W. Alves, A.Q. Alves, A.J. Goes, Eur. J. Med.
Chem. 45 (2010) 3685-3691.
[61] M. Amir, H. Kumar, S.A. Javed,Eur. J. Med. Chem. 43 (2008)2056-2066.
[62] U.S. Goksen, N.G. Kelekci, O. Goktas, Y. Koysal, E. Kilic, S. Isik, G. Aktay, M. Ozalp,
Bioorg. Med. Chem.15 (2007) 5738-5751.
22

ACCEPTED MANUSCRIPT

[63] S. Schenone, C. Brullo, O. Bruno, F. Bondavalli, A. Ranise, W. Filippelli, B. Rinaldi,

Capuano, G. Falcone, Bioorg. Med. Chem. 14 (2006) 1698-1705.
[64] V. Mathew, J. Keshavayya, V.P. Vaidya, D. Giles, Eur. J. Med. Chem. 42 (2007) 823840.

RI
PT

[65] M.D. Mullican, M.W. Wilson, D.T. Connor, C.R. Kostlan, D.J. Schrier, R.D. Dyer, J.
Med. Chem.36 (1993)1090-1099.

[66] A.A. Kadi, E.S. Al-Abdullah, I.A. Shehata, E.E. Habib, T.M. Ibrahim, A.A. El- Emam,
Eur. J. Med. Chem. 45 (2010) 5006-5111.

(2009) 63-69.

SC

[67] A.T. Mavrova, D. Wesselinova, Y. A. Tsenov, P. Denkova, Eur. J. Med. Chem. 44

[68] J. Matysiak, A. Nasulewicz, M. Pelczynska, M. Switalska, I. Jaroszewicz, A. Opolski,

M
AN
U

Eur. J. Med. Chem.41 (2006) 475-482.

[69] J. Matysiak, A. Opolski, Bioorg. Med. Chem. 14 (2006) 4483-4489.

[70] D.A. Ibrahim, Eur. J. Med. Chem. 44 (2009) 2776-2781.

[71] M.X. Wei, L. Feng, X.Q. Li, X.Z. Zhou, Z.H. Shao, Eur. J. Med. Chem. 44 (2009) 33403344.

[72] S. Karaku, U. oruh, B.B. Durgun, E.M.V. Lpez, S.. Turan, J. Akbua, S.
Rollas.Marm.Pharma. J. 14 (2010) 84-90.

TE
D

[73] A. Gupta, P. Mishra, S.N. Pandeya, S.K. Kashaw, V. Kashaw, J.P. Stables. Eur. J. Med.
Chem. 44 (2009) 1100-1105.

[74] M.S. Yar, M.W. Akhter, Acta Pol. Pharm. 66 (2009)393-397.

[75] K.M. Dawood, H. Abdel-Gawad, E.A. Rageb, M. Ellithey, H.A. Mohamed, Bioorg.

EP

Med. Chem. 14 (2006) 3672-3680.

[76] H. Rajak, N. Aggarwal, S. Kashaw, M.D. Kharya, P. Mishra, J. Korean Chem. Soc.54

AC
C

(2010) 158-164.

[77] H.N. Dogan, A. Duran, S. Rollas, G. Sener, M.K. Uysal, D. Gulen, Bio.Org.Med.Chem.
10 (2002) 2893-2898.

[78] A. Foroumadi, V. Sheibani, A. Sakhteman, Daru. J. Pharma. Sci.15 (2007) 89-93.

[79] M. Yusuf, R.A. Khan, B. Ahmed.Bioorg. Med. Chem.16 (2008) 8029-8034.
[80] P. Pattanayak, R. Sharma, P.K. Sahoo, Med. Chem. Res.18 (2009) 351-361.
[81] V. Jatav, P. Mishra, S. Kashaw, J. P. Stables, Eur J Med Chem. 43 (2008) 1945-1954.
[82]M.R. Badger, G.D. Price, Annu.Rev. Plant Physio. Plant Mol. Biol. 45 (1994) 369-392.
[83] F.Z. Smaine, F. Pacchiano, M. Rami, V.B. Montero, D. Vullo, A. Scozzafava,
J.Y.Winum, C.T. Supuran, Bioorg. Med. Chem. Lett.18 (2008) 6332-6335.
23

ACCEPTED MANUSCRIPT

[84] J.R. Casey, P.E. Morgan, D. Vullo, A. Scozzafava, A. Mastrolorenzo, C.T. Supuran,
J. Med. Chem. 47 (2004) 2337-2347.
[85] B. Masereel, S. Rolin, F. Abbate, A. Scozzafava, C.T. Supuran,J. Med. Chem. 45
(2002)312-320

RI
PT

[86] G.L. Almajan, A. Innocenti, L. Puccetti, G. Manole, S. Barbuceanu, L. Saramet,

AScozzafava, C. T. Supuran, Bioorg. Med. Chem. Lett. 15 (2005) 2347-2352.

[87] V. Menchise, G. De Simone, A. Di Fiore,A. Scozzafava, C.T. Supuran, Bioorg.Med.

Chem. Lett. 16 (2006) 6204-6208.

[88] B.S. Avvaru, J.M. Wagner, A. Maresca, A. Scozzafava, A.H. Robbins, C. T. Supuran,

SC

R. McKenna, Bioorg. Med. Chem. Lett. 20 (2010) 4376-4381.

[89] M.K. Abdel-Hamid, A.A. Abdel-Hafez, N.A. El-Koussi, N.M. Mahfouz, A. Innocenti,

M
AN
U

C.T. Supuran, Bioorg. Med. Chem. 15 (2007) 6975-6984.

[90] R.J. Uitti, Geriatrics. 53 (1998) 46-48.

[91] C.T. Supuran, A. Scozzafava, ExpertOpin.Ther. Pat. 10 (2000) 575-600.

[92] C.T. Supuran in Carbonic Anhydrase and Modulation of Physiologic and Pathologic
Processesin the Organism, Puscas, I, Ed. Helicon: Timisoara, Roumania, 1994, pp 29111.

[93] W.R. Chegwidden, Y. Edwards, N. Carter in The Carbonic AnhydrasessNew horizons,

TE
D

Basel, Switzerland, 2000 (and references therein).

[94] T. H. Maren, Physiol. Rev. 47 (1967) 595-781.
[95] A.M Scarrow, R. Segal, T.A. Medsger, M.C. Wasko, Neurosurgery. 43 (1998) 14701473.

EP

[96] W.G Reiss, K.S. Oles, Ann. Pharmacother.1996, 30, 514-519.

[97] M.A. Cowen, M. Green, D.N. Bertollo, K. Abbott, J. Clin.Psychopharmacol.17 (1997)

AC
C

190-193.

[98] R.C. Griggs, R.T. Moxley, J.E. Riggs, W.K. Engel, Ann. Neurol. 3 (1978) 531-537.
[99] T.P. Links, A.J. Smit, W.M. Molenaar, M.J. Zwarts, H.J. Oosterhuis, J. Neurol. Sci.
122 (1994) 33-43.

[100] W.N. Bernhard, L.M. Schalik, P. A. Delaney, T.M. Bernhard, G.M. Barnas, Aviat.
Space. Environ. Med. 69 (1998) 883-886.
[101] R.P. Shank, J. F. Gardocki, J.L. Vaught, C.B. Davis, J.J. Schupsky, R.B. Raffa, S.J.
Dodgson, S.O. Nortey, B.E. Marianoff, Epilepsia. 35 (1994) 450-460.
[102] S. Battistini, S. Stenirri, M. Piatti, C. Gelfi, P. G. Righetti, R. Rocchi, Neurology. 13
(1999) 38-43.
24

ACCEPTED MANUSCRIPT

[103] D. Cressier, C. Prouillac, P. Hernandez, C. Amourette, M. Diserbo, C. Lion, G. Rima,

Bioorg.Med. Chem. 17 (2009) 5275-5284.
[104] C. Kus, G. A. Kilcigil, S. Ozbey, F.B. Kaynak, M. Kaya, T. Coban, B.C. Eke, Bioorg.
Med.Chem.16 (2008) 4294-4303.

RI
PT

[105] V. Paddmavathi, S.N. Reddy, K. Mahesh, Chem. Pharm. Bull.57 (2009) 1376-1380.
[106] I. Khan, S. Ali, S. Hameed, N.H. Rama, M.T. Hussain, A. Wadood, R. Uddin, Z. UlHaq, A. Khan, S, Ali, M. I. Choudhary, Euro. J. Med. Chem. 45 (2010) 5200-5207.

[107] M. Navarro, F.E.J. Cisneros, M.M. Fernandez, D. Arrieche, E. Marchan, J.

Inorg.Biochem.97 (2000) 364369.

SC

[108] A. Tahghigh, F.R. Marznaki, F. Kobarfard, S. Dastmalchi, J.S. Mojarrad, S. Razmi, S.

K. Ardestani, S. Emami, A. Shafiee, A. Foroumadi, Euro. J. Med. Chem. 46 (2011)

M
AN
U

2602-2608.

[109] P. Zhan, X. Liu, Z. Fang, Z. Li, C. Pannecouque, E. De Clercq, Euro. J. Med. Chem. 44
(2009) 4648-4653.

[110] P. Zhan, X. Liu, Y. Cao, Y. Wang, C. Pannecouque, E. De Clercq, Euro. J. Med.

Chem. 18 (2008) 5368-5371.

[111] N.S. Hamad, N.H. Al-Haidery, I.A. Al-Masoudi, M. Sabri, L. Sabri, N.A. Al-Masoudi,
Arch Pharm Chem Life Sci. 343 (2010) 397-403.

TE
D

[112] Y.A. Al-Soud, N. A. Al-Masoudi, R. Loddo, P. La Colla, Arch. Pharm. Chem. Life
Sci. 341 (2008) 365-369.

[113] T. Akhtar, S. Hameed, N.A. Al-Masoudi, K.M. Khan, Hetero. Chem. 18 (2007) 316322.

EP

[114] A.U. Rao,N.Shao,R.G. Aslanian,T.Chan, S.J. Degrado,Li Wang, B. McKittrick, M.

Senior, R.E. West, S.M. Williams, R.L. Wu,J. Hwa, B. Patel,S. Zheng,C. Sondey,A.

AC
C

Palani, Med. Chem. Lett. 3 (2012) 198-202.

25

ACCEPTED MANUSCRIPT

Figure captions:
Figure 1: Isomers of Thiadiazoles.

AC
C

EP

TE
D

M
AN
U

SC

Figure 3: Thiadiazole containing drugs.

RI
PT

Figure 2: Mesoionic systems.

26

ACCEPTED MANUSCRIPT

Schemes

N N

CH3NH2 / 150oC

NHR

CH3OH

N NH
CS
N
R

Scheme 2:
Benzyl amine

Benzyl amine

M
AN
U

Cl

N N

TE
D
N N

EP

N N

AC
C
S

Cl

N NH
CS
N

H
N

Xylene

Scheme 3:

H2N

H
N

Xylene

N N

Scheme 4:

N N

NH2

N NH
CS
N

SC

N N

RI
PT

Scheme 1:

N2H4

Cl

N2H4

H2N

N NH
CS
N
NH2

H2N

N NH
CS
N
NH2

N NH
CS
N
NH2

H
H2N N

N NH
CS
N
NH2

Scheme 5:

N NH

H2N

N2H4

H
H2N N

N NH
CS
N
NH2

Scheme 6:
27

ACCEPTED MANUSCRIPT

dil HCL

N N

NH2

N
NH2

Scheme 7:

NH2

Scheme 8:
NO2

NO2
B-

N
N
Cl

N
NH2

H3C

Cl

TE
D

Cl

H
Cl

SH

C
S

MeOH

RNH2

EP

AC
C
N N

NO2

NO2

O2N

Scheme 9:

N
NH2

BH

-N2 , -BH

N N

N N

M
AN
U

CH3COOH

SC

N N
R

RI
PT

N N
R

O2N

SH

N
R

N N

Ar Pd(OAc)2, Xanthophos, Cs2CO3

CuI, Dioxane, 105oC, 12h
X

S
R

Ar

R = H, Me, Cl
Ar = Aryl, Heteroaryl
X = I, Br, OTf

Scheme 10:
28

ACCEPTED MANUSCRIPT

N2H4.H2O

H
N

OMe

Cl
O

NH2

Et3N

H
N

R
O

N N
OMe Lawesson's Reagent

N
H

OMe

RI
PT

MgBr

N N
R

Scheme 11:
HN N

M
AN
U

N2H4.H2O
C2H5OH

R1NCS

HN R1

SC

R=

CS2
KOH

S
HN NH2

NH R2NCO
R1 THF

HN N

R2
NH

N
R1

R1 = H, R2 = 4-F Ph

Scheme 12:
CH3

TE
D

N
N
S

1. N2H4.H2O

2. CS2 / KOH
C2H5

NHNHCSSK

1. N2H4.H2O
2. HCl

CH3

N
N
S

H2N

NH
S
RCOOH / POCl3

EP

CH3

N
N
S

N NH

AC
C

H3C
R = CCl3

N
N S

N
N

Scheme 13:
O2N

O
NH
H2N

RSCN

O2N

NH
NH

H
N R
S

H2SO4

O2N

NHR

N N

29

ACCEPTED MANUSCRIPT

Scheme 14:
O
H
S N NH2
O

Ionic Liquid

CH3

R
N
N

O
H
S N N
O

Ionic Liquid

R
CH3

Scheme 15:

X = COOH
1. SOCl2
2. H2NNHCSNH2
3. PPA

N
N

(CH2)n

H2N
S

N
N

(CH2)n

H2N

TE
D

X = CHO
1. H2NNHCSNH2
2. FeCl3

H2N

N
Se

Na2SO4

M
AN
U

X
(CH2)n

X = COOH
PPA, H2NNHCSNH2

SeO2

SC

SOCl2

RI
PT

N
N

AC
C

EP

(CH2)n

S
n=0-2

N N

NH
CH3

30

ACCEPTED MANUSCRIPT

Scheme 16:
S

H2N

N
CHO
N
CH3

Ar
N
N

H2 O

S
NH2

H2N

RI
PT

O2N

N CHAr
Ammonium ferric sulphate
HN
S

NH2
N
H
Ethanol / Reflux

HCl / NaNO2
Cu

N
O2N

N
CH3

H3C
N
S

HS

NO2

1. Thiourea / Ethanol

POCl3
NH2NHCSNH2

M
AN
U

HOOC COOH

H2N

Scheme 18:

Scheme 19:

N2H4

TE
D

NH3

CS2

NH 4

NH

NH2

EP

CH3

AC
C

ArCHO

NH2

ArHC N

S
R H

N NH2
H

X
NH SOCl
2

CH3

N CHAr
S

Cl

Ar

N N

2. Conc. HCl

N N

Scheme 17:

Cl

SC

Ar

N N

Cl

Cl
R

X = CSNH2

Scheme 20:
O O

Ar/

Lawessons Reagent Ar

Y X

THF

Ar/
P Ar

S
550C, 4-17 h

Ar =
Y
X

(CH2)4 (CF2)6F

R
X, Y : NH, CH, OMe

31

ACCEPTED MANUSCRIPT

Scheme 21:

O
R/

Thiourea

S
NH NH

Scheme 23:
KOH

K S

TE
D

H2 N

S
N NH2
H

EP

R/

N N

H3PO4

NH

SC

N N

M
AN
U

Scheme 22:

Scheme 24:

S C S

R/

N N

NH2

NH

R/

N N

NH2

RI
PT

N N

N NH
H

H+

140 0C

S
K

S
N N

NH2

NH2

AC
C

HN NH

S
S

(CF3CO)2O

CF3

HN NH2

Scheme 25:

NH
NH2

CH2(OC2H5)2
N N

32

ACCEPTED MANUSCRIPT

Scheme 26:
S

NH
HN

P2S5

NH
HN

N N
-H2S

RI
PT

Scheme 27:
S

H2 N

NH
HN

N N

NH2

H2O2

H2 N

NH2

Scheme 28:
COOH

N N

POCl3

NH
NH2

60 0C / 18 h

Scheme 29:
MeO

MeO

CHO

TE
D
S

O X

AC
C

Scheme 30:

1. EtOH / H
2. R1X / NaH

N N
X
X = H, I

H
N R
2

HN NH
NH
NH2

NH2

S
RCOCl
HO
Pyridine

N
R1

Glacial CH3COOH
CH3OH
1h

MeO
H
N

OH

NH2NHCSNH2

H3COCO

EP

R = (CH2)7CH3 ; X = H

N
H

CHO

N N

MeO

N
H

MeO

H2SO4

HO
I

25 C

NH2

Ac2O

CH3OH / Ice bath / 1 h

HO

CHO

NaOCl / KI

N N

BOP / (iPr)2NEt / DMF

M
AN
U

H2N

SC

N N
O CH COCl
3

R2NCS

N
R1

S
R

N
R1

NH
R2

33

ACCEPTED MANUSCRIPT

Scheme 31:
O

KOH

RNH2

CS2

ClCH2COONa

HOOC
HCl

S
S

RHN

HN

N2H4.H2O

NH2

RHN

RHN
O
O
N N

M
AN
U

X = H, Cl, CH3

ArCONHNH2 EtOH

CS2
KOH

N
H

NH

NCS

NH2

TE
D

Scheme 32:

NH

1. (CF3CO)2O / DMF

2. NaOH aq / Reflux

Scheme 34:

AC
C

Br

HN

OC2H5

H2N

S
N
N

NH

R1

HN

O
NH

HN

N
N

Lawesson's reagent
THF, rt

COOH

N
H

R1

S
Br

C2H5
O

N2H4.H2O

Br

R
H2SO 4

EDCl, HOBt
R1CONHNH2
THF, rt

Cl

EP

N
H

NHR

Cl

Scheme 32:

NH

SC

Ac2O

N
R

Cl

RI
PT

NaOOC

N
N

Br

N
HN
H
NH

RNCS

O
S

H2SO4

Br
S
N
R = CH3, C2H5, C3H7, C4H9, C6H5

N N

H
N
R

34

ACCEPTED MANUSCRIPT

Scheme 35:
O

R2
Br

N
N

S
R1

K2CO3 (10 mol%)

R2

PEG 400, 800C, 1h

N N
R1

N2H4.H2O / EtOH

Reflux, 6 h

O RPhNCS / EtOH HN

HN

NH
NH2

H3C
HN

Reflux 4-8 h

H2SO4

H
N

N N

-H2O

H
N

Ph

N
H

NHR

CN

NC

CN

Scheme 38:

Br

EP
S

NH2

AC
C

Br

NHR

-H2S

Ph

N N
NHR

Br

R1

Ph

N N

DMF, rt

TE
D

NC

R = H, OCH3, Cl, F

M
AN
U

Scheme 37:

NH H
N
HN
S

SC

RI
PT

H2N

Scheme 36:
HN

N
N

R2B(OH)2 / Pd

R2

R1

N N
S

R1

Scheme 39:

HO

1. NaH
2. CS2
3. ClCH2COOEt

OH

S
HO
S

N2H4.H2O

COOC2H5

S
HO
NH
NH2

CS2

N
HN

S
S

Scheme 40:
35

ACCEPTED MANUSCRIPT

Cl

N
NH2
S

Cl

1. CS2, Ethanol
2. NH2NH2.H2O

RCOOH
POCl3

N
HN

NH

Cl

N N
R

HN
NH2

R = C6H5, pClC6H4, pNO2,

oNH2C6H5, pOCH3C6H5

Scheme 41:
O
S

COOH

R1

H2SO4
CH3OH

O
S

COOCH3

NH2NH2.H2O

R1

R1

CONHNH2

SC

RI
PT

POCl3 R2C6H4COOH

R1

Scheme 42:
N N

Scheme 43:

Ar'-COOH

SH
N
NH2

R1

R2

POCl3

TE
D

Ar

Thiourea / THF

O N N

M
AN
U

O N N

R2

Ar'

N N

Ar

HS

H2N N

POCl3 / ArCOOH

EP

AC
C

N
N

Ar

N
S

O
N
N

R = SCH3, SC2H5, SO2CH3

Ar = C6H5, CH2C6H5, 4-OCH3C6H4,
4-CH3C6H4, 4-NH2C6H4

36

ACCEPTED MANUSCRIPT

Scheme 44:
Cl

Cl

Cl

Cl

Cl

Cl
N
N
S

Cl

M
AN
U

Scheme 45:

N N

N
HN

COOH
N
R

NaOH / EtOH 80%

rt / 12 h

Scheme 46:

COOH

EP
O

AC
C

Scheme 47:

Cl

H
N NH2

N
H

N
N

O
COOH

N
R

R1= H, NO2

H2N

R1

TE
D

R = Ethyl, Cyclopropyl

N
SH
NH2

POCl3 / ArCOOH

Cl

Ar = 4-OCH3C6H4, phenoxymethyl,
N
5-quinolyl, pyridyl, 2-bromopyridyl N

Cl

SC

Ar

N N

CONHNH2 1. CS2 / KOH

2. NH2NH2H2O

RI
PT

1. KMnO4
2. MeOH / H2SO4
3. NH2NH2H2O

CHO
Cl

Cl

Cl

N N

POCl3
Reflux

NH2

NH2

N
O

Cl
O
R-N=C=S
S

H H
N N
O

H
N

S
Conc. H2SO4

Cl
N N

O
S

N R
H

37

ACCEPTED MANUSCRIPT

Scheme 48:
R

R2

H3PO4
R1

(CF3CO)2O

Br2 / CHCl3

R1
S

R1

Br

H2 N

RI
PT

HOOC

N
N

P2O5 / EtOH / Reflux

SC

R1

N N

Scheme 49:
O O
H
N

HN NH2
S

HO

H
N

N N

TE
D

EP
AC
C

R
O

S
O

S
O

CONHNH2

S
H
CONHNHC N

NCS

CS2 / NH3
Pb(NO3)2

O
O
S

NH2CSNH2
THF

O
O
S

NH2

N N

H
N

Scheme 50:

M
AN
U

R2

N
N
H2SO4
N N
N

NH

38

ACCEPTED MANUSCRIPT

Scheme 51:
H
N N

O2N
O2N

EtOH

O2N

RI
PT

O2N

FeNH4(SO4)2
H2O

NO2

OHC
N N
R1

N
N

Piperazine derivatives

N
N

Scheme 52:

NH2

Ph

O
N N
H3C
NH2

YbCl3 / CH3CN

M
AN
U

Ph

H3CO

COOC2H5

HN

R
R

SO2Cl

TE
D

NH
Ar

AC
C
F

Ar

CH3

NH2.NH2.H2O

H3CO

H3CO

SO2
N
R R

1. CH3OH / H2SO4
2. NH2NH2.H2O
3. RNCS / EtOH

H3CO

HN
Ar

COOH

CONHN
H2
SO2
N
R R

ArNCS

CONHNH

H3CO

OH

SO2
N
R R

EP

SO2
N
R R

H2SO4

COOC2H5

H3CO

N N

H3CO

H3CO

S
S

Reflux
1-2 h

Ar

Scheme 53:

Scheme 54:

SC

Cl

H3CO

O2N

Cu / 0OC

R2

H3CO

N N

NaNO2 / HCl

NaHCO3 / EtOH / Reflux

R3

NH2

Thiosemicarbazide

KMnO4

CH2OH

N
H
OH

H
N

NH

N
H

H
N R

N
N

H2SO4
S

OH
F

39

ACCEPTED MANUSCRIPT

Scheme 55:
HN

1. NH2NH2.H2O
2. Ar-N=C=S

HN

H H
N N

HN

H
N Ar

H2SO4

RI
PT

N N

N N
N NH2 1. CS2 / KOH/ EtOH
Ar
H
2. NH2NH2.H2O

POCl3
SH
RCOOH

N
NH2

M
AN
U

Cl
O

O
K2CO3

Scheme 58:

R1 = H, CH3

O
S C N

R2

THF

N
NH2

Ar2-COOH / POCl3
SH Microwave Irradiation

N N

O
O
R = CH3, C2H5, C6H5

O
S

R1

Ar1

EP

AC
C
N N

N
H

O
S
O
H
S N NH C N C R2
H
O
CH3COONa
Phosogene
rt 12 h

R1

R2 = 4CF3CH2C6H4, 4OC3C6H4, 4FC6H4, 4-furoyl

Scheme 59:

N N

1.NH2NH2.H2O / EtOH
2. RNCS / EtOH
3. H3PO4

TE
D

O
S N NH2
H
O

R1

N
N

Scheme 57:

H
N

Ar

SC

Ar

H
N Ar

N N

Scheme 56:

Ar1

N
S

N
H

R2

N
Ar2

Ar1 = 3-indolylmethyl
5-methoxy-3-indolylmethyl,
5-methoxy-2-methyl-3-indolylmethyl

Scheme 60:
N N

O S
Ar

NH2
HN NH

MeSO3H / Toluene
Ar
Reflux

NH2

40

ACCEPTED MANUSCRIPT

Scheme 61:

2. H2SO4

NH2

R N

N NH

1. CS2 / KOH/ EtOH

H
N

NH

HCHO

R2
S
S

NH

R2

Conc. H2SO4

H
H2N N

STB

TE
D

H
H2N N

NH

HO

HO

HN NH

R1

N N

Scheme 63:

1. NH2NH2.H2O
2. Ethylisothicyanate
Ethanol

M
AN
U

R1

OC2H5

SC

R2

R2
R1
R2
Thioglycolate
C C
O Pyridine
Cl
R1
THF

RI
PT

Scheme 62:
DMF, POCl3
Trichloroetylene

R1

N R

N N

OH

OH

S
OR

OR

Scheme 64:

EP

STB = 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles

AC
C

H2N N
H

HO

HO

OH

N R
H

OH

H
N

N N

R = alkyl, aryl, morpholinoalkyl

STB

Scheme 65:
HO

SH
N
N

N NH2
R

HN

COOH
Polyphosphoric acid

N
N

HN
O

NH2

N N

41

ACCEPTED MANUSCRIPT

Scheme 66:
Br
S

RO
O

N N

SH
R

NaOH / H2O, TBAB

Benzene

N
N

S
H

Br
O
O

RI
PT

Br

R = 1-menthyl

Scheme 67:
O2H5

Dry Ether

H2N

H
C N
O

CH3

SC

C Cl
O

1. NH2NH2.H2O
2. Ar-N=C=S
3. H2SO4

M
AN
U

N N

HN

TE
D

Scheme 68:

Ar-NH2

NH4SCN

Scheme 69:
R

NCS

EP

Heat

HCl

CONHNH

Ar NH

H
N

2. NaOH

H2N

Conc. H2SO4

AC
C

NH
Ar

H
N

N N

EtOH
CONHNH2

Ar

Ar
HN

1. H2O2

Scheme 70:
O

O
C 1. PhNCS / DMF / KOH

N N
N

HS
O

2. HCl
O

NHPh

Cl
N
N N

Ph

H
N
N

O
S

Ph

EtOH / TEA

N
N
N

Ph

N N

43

ACCEPTED MANUSCRIPT

Scheme 71:
NH2
NH2

1. NH2NHCSNH2
1,4-dioxane
CH3
2. H2SO4

1. CH3COOH / H2O / NH3

2. ClCH2COOC2H5 / K2CO3
CH3COCH3

CH2COOC2H5

CH3

N N

N
H

NH2

RI
PT

1. NH2NH2.H2O
2. ArCHO / EtOH

CH3

O
C NH
NH N
HC
Ar

N N

SC

Scheme 72:
NH

N N

O
OH

M
AN
U

H2N

1. RNCS
2. H2SO4

(CH3CO)2O

TE
D

OH

OH

AC
C

EP

Cl

Cl

O
CH3
R = C2H5, m-fluorophenyl

1. Nah, DMF
2. Cu powder, DMF
3. H2SO4

Cl

N
H

OH

Scheme 73:

Cl

N
H

N N

OH
Cl

O
Cl

N N
NH R
S

Thiosemicarbazide
Polyphosphoric acid

O
Cl

44

ACCEPTED MANUSCRIPT

Scheme 74:
SH
O

S
H2N

R1

SH
N

N
N

Cl

N N

R1

RI
PT

R1
R2

Scheme 75:
N N

ArCl / KOH / H2O

SH

H2N

N N

HN

SAr

M
AN
U

O
C Cl

SC

N N
H2N

Cl

R2

R2

SAr

Ar = 4-C6H4SO2Cl, 4-C6H4SO2NH2, 4-C6H4CF3

Scheme 76:

HO

(CH3CO)2O

Ar-CHO

N N

R
N
N

EP

NH2

R
S

TE
D

Scheme 77:

N
N

H2N

N N

H2N

N N

N N

1. t-BuOH, ClSO2NCO, NEt3, CH2Cl2

2. TFA, CH2Cl2

S
Ar

O
S NH2
N
H O

AC
C

Scheme 78:

H2N

O
S N
H
O

R3

N N
S

SO2NH2

R4

R2

R5

O
R1
ClO-4
Et3N

R2

R1

O
H
S N
O

R3
R4

R5

ClO-

N N
S

SO2NH2

45

ACCEPTED MANUSCRIPT

Scheme 79:

S
HN

EDC.HCl

N N

HN

O
S
O
HN
HN

OH

SO2NH2

H2N

RSCl

SH

N N

N N

RNCO

N
H

TE
D

THF, Et3N

EP
O

CH3

N
H

N
H

CH3

CH3

R2

R1

N
1. NH2NH2.H2O / EtOH
2. CH3-N=C=S

R2

N N
S

N
H

N
R1

SH

KOH / DMSO

N N

O
C

Cl

H
N

R1

H3 C

NH2

AC
C

Scheme 82:

Cl

SH

R N
H

Scheme 81:

SH

M
AN
U

N N

SO2NH

SC

O
C
R
N
H

RCOCl

Scheme 80:

N N

RI
PT

O
H2SO4
N

N
R2

R1

S
H
H
N N C N CH3
H

N
R2

46

ACCEPTED MANUSCRIPT

Scheme 83:
H

Ph
HSCH2COOH / NaOH / MeOH

Ph

O
S

H2O2 / AcOH H
OH

Ph

O
S
O

OH
O

O
S
O

HN N
H

N N
S

CH2N2 / Et3N

Ph
H

Ar

O
S
O

RI
PT

ArCONHNH2
POCl3

NH2CSNH2 / THF Ph

N N
Ar

SC

Ph

Scheme 84:
O

O
1. MeOH / H2SO4
2. NH2NH2.H2O / EtOH

N
H

NH2

1. Ar-N=C=S
2. PPS

M
AN
U

OH

Scheme 85:
H
N

O2N
O

TE
D

K2CO3

N
N

AC
C

O2N

EP

N N
S

N N
N Ar
H

N
CN

O2N

Cl

CN

Ar

N N

N N

O
S
O

NH .HCl

N
R1 R2

CH2Cl2 / EtOH
HCl(g)
N N

NHR1R2

S
O
O2N

NH .HCl
OEt

47

ACCEPTED MANUSCRIPT

Scheme 86:
O

O
O

1. Br2 / AcOH
2. SHCH2CH2COOCH3

S
O

N S
N

Scheme 87:
O

Br2 / AcOH

HSCH2CO2Et
Na2CO3, EtOH

TE
D

Br

O
p-tosyl hydrazine, toluene

O
O
S

SOCl2

HN
N

EP

SOCl2

M
AN
U

R = 2-Nitrophenyl, 2-Chloropyridin-3yl, 4-Acetylbromophenyl

SC

1. MeONa / MeOH
2. ClCH2CONHR / EtOH

RI
PT

H
N

NH2NHCONH2
AcONa, EtOH

O
N S
N

NH
N

H2N

AC
C

Scheme 88:

H
N

R1 = OMe, NHNH2

R1

R2NCS / EtOH
O

H
N

H
N
N
H

NHR2
S

H2SO4
H
N

N N

R2
NH

48

ACCEPTED MANUSCRIPT

Scheme 89:
SH

N
N

(NH2NH)2C=S
Pyridine

NH2

RCOOH
DMF

Ar

Scheme 90:

Ts

Cl

O
N
H

NCS

NH2

CH3OH

R
N

Ar

H
N

RI
PT

Ar-COOH

Ts

H
N

N
H

H
N

NH

Cl

SC

H2SO4

H
N

M
AN
U

NH
Ts

Cl

Scheme 91:

H2N NH
O

O-

S-K+
H C
N N S
H

RCOCl
O
O

-O
H

N
N
S
R

AC
C

EP

TE
D

CS2 / KOH -O

49

N
N

RI
PT

ACCEPTED MANUSCRIPT

N N

AC
C

EP

TE
D

M
AN
U

SC

Figure 1. Isomers of Thiadiazoles

ACCEPTED MANUSCRIPT

HN NCl
HCl

AC
C

EP

TE
D

M
AN
U

SC

Figure 2. Mesoionoic systems

RI
PT

N N

ACCEPTED MANUSCRIPT

S
N N

H3 C

O
S O
NH2

Methazolamide

N
N
N N

HN

CH3

N N

CH3
CH3
N CH
3
H

H2N

Timolol

N
H3C

NO2

TE
D

Figure 3. Thiadiazole containing Drugs

EP

H3 C
N

Megazol

AC
C

CH3

N N

M
AN
U

OH

Cefazedone

Cefazolin sodium

N
S
N

HN

SC

N N

Cl

O
S O
NH2

O
N N
H3C

Acetazolamide

Cl

RI
PT

H
N

H3C

H3 C

N S
N
O

Xanomeline

ACCEPTED MANUSCRIPT

Highlights:
o Thiadiazoles are attractive pharmacological targets.
o The present review provides an overview about the synthesis and biological
properties of thiadiazoles.

RI
PT

o The present review is helpful for the researchers planning to work on

AC
C

EP

TE
D

M
AN
U

SC

thiadiazoles.