Imidazole-Thiazolidine-2,4-dione Conjugated 1,2,3-Triazole Derivatives as Tubulin Aiming Antiproliferative Agents

A new series of imidazole-thiazolidine-2,4-dione coupled 1,2,3-triazoles (VIIa-VIIm) were synthesized using Knoevengal condensation and Cu-catalyzed azide-alkyne cycloaddition as key approaches. Out of all, (Z)-3-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)ethyl)-5-((1-methyl-1H-imidazol-2-yl)methylene)thiazolidine-2,4-dione (VIId) exhibited superior activity against three human cell lines like MCF-7 (breast), A549 (lung) and HeLa (cervix) than the standard drug Nocodazole with IC50 values <1 & mu;M, while, (Z)-4-(1-(2-(5-((1-methyl-1H-imidazol-2-yl)methylene)-2,4-dioxothiazolidin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)benzonitrile (VIIf) and (Z)-5-((1-methyl-1H-imidazol-2-yl)methylene)-3-(2-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)thiazolidine-2,4-dione (VIII) displayed greater activity against MCF-7 than the Nocodazole with IC50 values 0.81 and 0.97 & mu;M respectively. The compounds (VIId), (VIIf) and (VIII) were then screened for their efficacy in inhibiting tubulin polymerization and found that compound (VIId) showed comparable activity (IC50 = 1.32 & mu;M) with the standard drug Combretastatin A-4 (CA-4) (IC50 = 1.14 & mu;M). Finally, molecular modeling studies for active compounds (VIId), (VIIf) and (VIII) on & alpha;,& beta;-tubulin (PDB ID-1SA0) were conducted and attained free energies were observed to be covenant with corresponding IC50 values.