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Review
. 2020 Sep 20;25(18):4309.
doi: 10.3390/molecules25184309.

Cytotoxic Properties of 1,3,4-Thiadiazole Derivatives-A Review

Sara Janowska  1 , Agata Paneth  1 , Monika Wujec  1
Affiliations
Review

Cytotoxic Properties of 1,3,4-Thiadiazole Derivatives-A Review

Sara Janowska et al. Molecules. .

Abstract

During recent years, small molecules containing five-member heterocyclic moieties have become the subject of considerable growing interest for designing new antitumor agents. One of them is 1,3,4-thiadiazole. This study is an attempt to collect the 1,3,4-thiadiazole and its derivatives, which can be considered as potential anticancer agents, reported in the literature in the last ten years.

Keywords: anticancer activity; cytotoxicity; thiadiazole.

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Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
The structure of bis-sulfonamide (1).
Figure 2
Figure 2
The structures of dihydrazone derivatives (2–6).
Figure 3
Figure 3
The structures of S-chlorobenzofuro[3,2-d]pyrimidine-1,3,4-thiadiazole (7–13).
Figure 4
Figure 4
The structures of compounds 14 and 15.
Figure 5
Figure 5
The structures of novel fluorinated pyrazol[3,4-d]pyrimidine with a 1,3,4-thiadiazole heterocyclic ring (16–17) Table S1.
Figure 6
Figure 6
The structure of N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-yl)cinnamamide (18).
Figure 7
Figure 7
The structures of compounds 19 and 20.
Figure 8
Figure 8
The structure of N-(4-acetyl-5-(4-hydroxyphenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)-acetamide (21).
Figure 9
Figure 9
The structure of (E)-3-(4-methoxyphenyl)-N-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)acrylamide (22).
Figure 10
Figure 10
The structure of 2-(4-chlorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (23).
Figure 11
Figure 11
The structure of 2-(4-fluorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (24).
Figure 12
Figure 12
The structures of 2-(3-chlorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acetamide (25) and 2-(4-chlorophenyl)-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acetamide (26).
Figure 13
Figure 13
The structure of ethyl 2-(4-(2,3-dimethyl-1-phenyl-5-oxo-pyrazol-4-yl)thiazol-2-ylimino)-3-(4-nitrophenyl)-1,3,4-thiadiazole-5-carboxylate (27).
Figure 14
Figure 14
The structures of the most active compounds 28 and 29.
Figure 15
Figure 15
The structure of 4-[(5-amino-1,3,4-thiadiazol-2-ylthio)methyl]-N-(4-tert-butylphenyl) benzamide (30).
Figure 16
Figure 16
The structure of N-(5-(3-methoxybenzylthio)-1,3,4-thiadiazol-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (31) (Table S1).
Figure 17
Figure 17
The structures of 2-[[1-(5-methyl-1-phenyl-5-substituted-1H-pyrazol-4-yl)-ethylidene]hydrazono]-3-phenyl-2,3-dihydro-1,3,4-thiadiazoles (32–34).
Figure 18
Figure 18
The structures of N-(5-(4-methoxybenzylthio)-1,3,4-thiadiazol-2-yl)-2-(3-methoxyphenyl)acetamide (35) and N-(5-(2-fluorobenzylthio)-1,3,4-thiadiazol-2-yl)-2-(3-methoxyphenyl)acetamide (36).
Figure 19
Figure 19
The structure of 2-(N-benzyl-amine)-[5-(2,5-dimethoxy-phenyl)-1,3,4-thiadiazole (37).
Figure 20
Figure 20
The structures of 5-(9-chloro-6,7-dihydro-5H-benzo[7]annulen-8-yl)-2-(N-phenylamino)-1,3,4-thiadiazole (38) and 5-(9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)-2-(N-phenylamino)-1,3,4-thiadiazole (39).
Figure 21
Figure 21
The structures of compounds (40–42).
Figure 22
Figure 22
The structure of 4-chlorobenzyl-(2-amino-1,3,4-thiadiazol-5-yl)disulfide (43) (Table S1).
Figure 23
Figure 23
The structure of ethyl 2-((5-(4-methoxybenzamido)-1,3,4-thiadiazol-2-yl)thio)acetate (44).
Figure 24
Figure 24
The structure of 2,6-bis[4-(5-phenylamino-1,3,4-thiadiazol-2-yl)-1H-pyrazol-3-yl]pyridine (45).
Figure 25
Figure 25
The structures of diethyl 4,4’-(biphenyl-4,4’-diyl)bis(5-((thiophen-2-ylmethylene)hydrazono)-4,5-dihydro-1,3,4-thiadiazole2-carboxylate (46) and diethyl 4,4’-(biphenyl-4,4’-diyl)bis(5-((furan-2-ylmethylene)hydrazono)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate) (47).
Figure 26
Figure 26
The structures of diethyl4,4’-(biphenyl-4,4’-diyl)bis(5-((1-(furan-2-yl)ethylidene)hydrazono)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate) (48) and diethyl 4,4’-(biphenyl-4,4’-diyl)bis(5-((1-(pyridin-3-yl)ethylidene)hydrazono)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate) (49).
Figure 27
Figure 27
The structures of the most active imidazole–thiadiazole derivatives (50–54).
Figure 28
Figure 28
The structure of N’-(1-(1H-indol-3-yl)ethylidene)-2-(5-R-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoaceto-hydrazide (55–57).
Figure 29
Figure 29
The structure 4-(4-fluorophenyl)-N-(5-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)-1,3,4-thiadiazol-2-yl)-1-thia-4-azaspiro[4.5]decan-3-imine (58) (Table S1).
Figure 30
Figure 30
The structure of N-(5-(β-D-galactopyranosylthio)-1,3,4-thiadiazol-2-yl)dodecanamide (59).
Figure 31
Figure 31
The structures of N-(5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl)adamantane-1-carboxamide (60) and N-(5-(2,3-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl)adamantane-1-carboxamide (61).
Figure 32
Figure 32
The structure of N-(5-{[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]sulfanyl}-1,2,4-thiadiazol-2-yl)-4-nitrobenzamide (62) (Table S1).
Figure 33
Figure 33
The structure of 2-(3-fluorophenyl)-N-(5-sulfanyl-1,3,4-thiadiazol-2-yl)acetamide (63) (Table S1).
Figure 34
Figure 34
The structure of thiadiazole–benzofuran hybrids (64).
Figure 35
Figure 35
The structure of thiadiazole–furochromene hybrids (65).
Figure 36
Figure 36
The structure of diphenyl(4-hydroxy-3-methoxyphenyl)(5-methyl-1,3,4-thiadiazol-2-ylamino)methylphosphonate (66).
Figure 37
Figure 37
The structures of 2-amine-5-(4-R-phenyl)-1,3,4-thiadiazole (67–69).
Figure 38
Figure 38
The structure of N-(5-nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (70).
Figure 39
Figure 39
The structure of {(3-(5-amino-1,3,4-thiadiazol-2-yl)-1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)quinoline-4(1H)-one)} (71).
Figure 40
Figure 40
The structure of 2-amino-5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazole (72).
Figure 41
Figure 41
The structures of 5-fluorouracil derivatives (73–76).
Figure 42
Figure 42
The structure of 4-(5-acetyl-3-p-tolyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (77).
Figure 43
Figure 43
The structures of 2-(R1-disulfanyl)-5-[(R2-phenylcarbamoyl)-methylthio]-1,3,4-thiadiazole (78–83).
Figure 44
Figure 44
The structures of 2-(iso/n-butyldisulfanyl)-5-[4-(4-R-phenylcarbamoyl)-benzylthio]-1,3,4-thiadiazole (84–86) (Table S1).
Figure 45
Figure 45
The structures of 2-[bis(2-chloroethyl)amino]-N-[5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetohydrazide (87) and 2-[bis(2-chloroethyl)amino]-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)acetohydrazide (88).
Figure 46
Figure 46
The structure of [5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl]-(3,4,5-trimethoxybenzylidene)amine (89).
Figure 47
Figure 47
The structure of N-[5-({[1-phenyl-5-(thiophen-2-yl)-1H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3,4-thiadiazol-2-yl}thiophene-2-carboxyamide (90).
Figure 48
Figure 48
The structure of most active compounds: ethyl 5-((-(3-(1-(4-bromophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-4-(4-tolyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (91) and 1-(5-((-(3-(1-(4-bromophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-4-(4-chlorophenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one (92).
Figure 49
Figure 49
The structure of most active 2-amino-5-phenyl-substituted 1,3,4-thiadiazole (93–95).
Figure 50
Figure 50
The structures of 2-((5-((5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl)amino)-1,3,4-thiadiazol-2-yl)thio)-1-phenylethan-1-one (96), 1-[5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl]-3-phenyl-5-(2-phenylhydrazono)-2-thioxo-dihydro-pyrimidine-4,6(1H,5H)-dione (97) and 5-benzylidene-1-[5-(3,5-dinitrophenyl)-1,3,4-thiadiazol-2-yl]-3-phenyl-2-thioxo-dihydro-pyrimidine-4,6(1H,5H)-dione (98).
Figure 51
Figure 51
The structure of N-((5-(((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)methyl)benzamide (99).
Figure 52
Figure 52
The structure of new derivatives of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (100).
Figure 53
Figure 53
The structures of 3,6-bis-(cyclopyopyl-C3/C3-fluoroquinolone)substituents-triazolo[2,1-b][1,3,4]thiadiazoles (101–103).
Figure 54
Figure 54
The structure of (S)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole-3-[1-cyclopropyl-6-fluoro-7-piperazin-1-yl-quinolin-4(1H)-one]-6-[1,8-(2,1-oxy-propyl)-6-fluoro-7-(4-methylpiperazin-1-yl)-quinolin-4(1H)-one] (104).
Figure 55
Figure 55
The structure of 6-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-3-[2-naphthyloxy)methyl] [1,2,4]triazolo[3,4-][1,3,4]thiadiazole (105).
Figure 56
Figure 56
The structure of 6-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (106) (Table S2).
Figure 57
Figure 57
The structure of new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (107).
Figure 58
Figure 58
The structures of 3,6-diphenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (108), 6-(perfluorophenyl)-3-R-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (109) and 6-(perfluorophenyl)-3-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (110).
Figure 59
Figure 59
The structure of 6-((4-fluorobutyl)sulfanyl)-3-(5’-fluoro-2’-methoxy-(1,1’-biphenyl)-3-yl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (111).
Figure 60
Figure 60
The structure of 5-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)flurobenzonitrile (DTTF) (112).
Figure 61
Figure 61
The structure of 3-R1-6-(R2-disulfanyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (113) (Table S2).
Figure 62
Figure 62
The structure of 3,6-dialkylsubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (114).
Figure 63
Figure 63
The structures of 6-(5-methoxy-1H-indol-2-yl)-3-(((7-methoxyquinolin-4-yl)oxy)methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (115) and 3-(((7-methoxyquinolin-4-yl)oxy)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (116).
Figure 64
Figure 64
The structure of the most active compounds 3-phenyl-6-(n-butyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-thiadiazole (117), 3-(4-methylphenyl)-6-(n-butyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-thiadiazole (118), 3-(4-methylphenyl)-6-(isobutyldisulfanyl)-1,2,4-triazole-[3,4-b]-1,3,4-thiadiazole (119).
Figure 65
Figure 65
The structure of 2-(4-isopropylphenyl)-6-{[4-(4-methylpiperazin)methyl]piperidin} imidazo[2,1-b][1,3,4]thiadiazol (120).
Figure 66
Figure 66
The structure of 2-benzyl-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate (121).
Figure 67
Figure 67
The structure of 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole (122).
Figure 68
Figure 68
The structures of 2-(4-chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles (123).
Figure 69
Figure 69
The structure of 2-(4-bromophenyl)-5-hydroxy-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-one (124).
Figure 70
Figure 70
The structure of methyl 2-[2-(4-bromophenyl)-6-hydroxyimidazo[2,1-b]-1,3,4-thiadiazol-5-yl]acetate (125).
Figure 71
Figure 71
The structures of 2-bromo-N-{3-[2-(2-thienyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]phenyl}acrylamide (126), 2-bromo-N-{3-[2-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]phenyl}acrylamide (127), 2-bromo-N-{3-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]phenyl}acrylamide (128).
Figure 72
Figure 72
The structures of (E)-3-((6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-5-methoxyindolin-2-one (129), (E)-3-((2-cyclopropyl-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one (130) and (E)-5-chloro-3-((6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)indolin-2-one (131).
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