S0223-5234(14)01144-1
DOI:
10.1016/j.ejmech.2014.12.035
Reference:
EJMECH 7595
To appear in:
15 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.
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N N
N
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S
NH
O2N
H3C
N
S
N
H
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1,3,4-thiadiazole
S
N N
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OH
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H
N
N N
NH
S
C4H9
HO
N
H
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Cl
N N
N
O
N N
O
H
N
CH3
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National Center for Natural Products Research (NCNPR), School of Pharmacy, University
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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,
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hyperlipidemia.
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the in depth analysis of the thiadiazoles with respect to their medicinal significance.
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1. Introduction
It has been observed that the compounds containing five-membered heterocyclicring
display
exceptional
chemical
behaviour
and
broad
spectrum
of
versatile
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Figure 1
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This review highlights the thiadiazoles on the basis of their therapeutic potential,
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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
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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
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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
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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
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Scheme 2
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and
3-hydrazino-4-amino-1,2,4-triazoline-5(1)-
Schemes 3, 4 & 5
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1-benzyl-1-(1,3,4-thiadiazole-2-yl) hydrazine
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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
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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
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Scheme 8
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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
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Scheme 10
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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
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[16].
Scheme 13
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Scheme 15
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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
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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
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corresponding semicarbazones. The Hurd-Mori procedure has been used in this synthesis[22].
Scheme 19
simple filtration[23].
Scheme 20
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1,3,4-thiadiazoles in high yields (Scheme 20). In most cases the final product is obtained by
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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
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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
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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-
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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-
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diamino-1,3,4-Thiadiazole.
Scheme 27
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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
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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)
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comparison
tetrahydropyrazine-1
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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
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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
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Indole-3-carboxylic acid[38] on treatment with aryl orheteroaryl hydrazides yieldedthe N,N/diacylhydrazines, which on further treatment with Lawessonsreagent resulted in the
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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
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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
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Polyethylene glycol (PEG)as an inexpensive and nontoxic medium is the reason for the
success of this reaction [40].
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Scheme 35
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Scheme 38
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Scheme 39
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40) and evaluated their antibacterial activity against Staphylococcus aureus, Escherichia coli
and Pseudomonas aeruginosa using ofloxacin as the standard drug.
Scheme 40
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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,
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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
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(recultured) bacterial strains by serial plate dilution method. The compounds exhibited
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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
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[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
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Muralikrishna et al [54] have synthesizedpyrrolyl/pyrazolylarylaminosulfonylmethyl1,3,4thiadiazoles and screened them for their antimicrobialactivity against Pseudomonas
aeruginosa
usingchloramphenicol
as
standard
drug
and
against
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aureusand E. coli.
Scheme 50
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50) by Zamaniet al [55]and further screened for their antimicrobial activity against S.
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Scheme 51
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and
(Scheme
2-[2-(452)were
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found to be the most active with MIC of 3.2 and 3.5 mM respectively against MTB.
Scheme 52
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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
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synthesized
the
different
thiadiazoles,[5-(5-Methyl-1H-imidazol-4-yl)-
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sulfadiazine.
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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
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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
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).
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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.
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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
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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
(Scheme
64)and
screened
them
for
their
antiproliferative activity in four human cell lines i.e. SW707 (rectal), HCV29T (bladder),
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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
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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
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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)-
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synthesized
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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
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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.
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Scheme 74
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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
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Scheme 76
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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-
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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
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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
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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
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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
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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
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andataxia[102].
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
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sulfone
linked
pyrazolyl
oxadiazoles
and
thiadiazolesfrom
Z-
Scheme 83
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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.
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Scheme 84
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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.
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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
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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
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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
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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
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[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
molecules,
4-(5-([1,4-bipiperidin]-1-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-
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4. Conclusion
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Scheme 91
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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
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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
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Bornemeier, R.D. Dyer, J. Med. Chem. 42 (1999)1161-1169.
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PT
840.
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Med.Chem.43 (2008) 808-815.
SC
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AN
U
[51] R.S. Lamani, N.S. Shetty, R.R. Kamble, I.A.M. Khazi, Eur. J. Med. Chem. 44 (2008)
2828-2833.
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Wagawade, Bioorg. Med. Chem.16 (2008) 276-283.
TE
D
[55] K. Zamani, K. Faghihi, T. Tofighi, M.R. Shariatzadeh, Turk J. Chem. 28 (2004) 95-100.
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Negahbani, F. Siavoshi, M. Omrani, E. Alipour, M. Vosooghi, A. Shafiee, A.
Foroumadi, Arch. Pharm. 344 (2011) 178-183.
EP
AC
C
[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.
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Bioorg. Med. Chem.15 (2007) 5738-5751.
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[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.
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Eur. J. Med. Chem. 45 (2010) 5006-5111.
(2009) 63-69.
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AN
U
[71] M.X. Wei, L. Feng, X.Q. Li, X.Z. Zhou, Z.H. Shao, Eur. J. Med. Chem. 44 (2009) 33403344.
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Rollas.Marm.Pharma. J. 14 (2010) 84-90.
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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.
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AC
C
(2010) 158-164.
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10 (2002) 2893-2898.
ACCEPTED MANUSCRIPT
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J. Med. Chem. 47 (2004) 2337-2347.
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(2002)312-320
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[88] B.S. Avvaru, J.M. Wagner, A. Maresca, A. Scozzafava, A.H. Robbins, C. T. Supuran,
SC
[89] M.K. Abdel-Hamid, A.A. Abdel-Hafez, N.A. El-Koussi, N.M. Mahfouz, A. Innocenti,
M
AN
U
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D
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AC
C
190-193.
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122 (1994) 33-43.
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Dodgson, S.O. Nortey, B.E. Marianoff, Epilepsia. 35 (1994) 450-460.
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(1999) 38-43.
24
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[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.
SC
M
AN
U
2602-2608.
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(2009) 4648-4653.
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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
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EP
AC
C
25
ACCEPTED MANUSCRIPT
Figure captions:
Figure 1: Isomers of Thiadiazoles.
AC
C
EP
TE
D
M
AN
U
SC
RI
PT
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
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
HO
CHO
NaOCl / KI
N N
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
R2
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
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
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
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
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
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
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
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
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
AC
C
H2N N
H
HO
HO
OH
N R
H
OH
H
N
N N
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
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
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
H2N
N N
HN
SAr
M
AN
U
O
C Cl
SC
N N
H2N
Cl
R2
R2
SAr
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
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
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
ACCEPTED MANUSCRIPT
HN NCl
HCl
AC
C
EP
TE
D
M
AN
U
SC
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
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
AC
C
EP
TE
D
M
AN
U
SC
thiadiazoles.