Design and Synthesis of Some New Benzimidazole-1,2,3-triazole-thiazolidine-2,4-dione Conjugates as Tubulin Polymerization Inhibitors

Objective: It is worthy to note that the benzimidazole, thiazolidine-2,4-dione and 1,2,3-triazole pharmacophores have keen role in anticancer drug discovery. In order to overcome the limitations associated with reported antimitotic compounds, our group is first time combining these three pharmacophores and revealing their in vitro anticancer and anti-mitotic activities. Methods: As a part of our efforts on the development of novel anticancer agents, in this study, we concentrated on the synthesis of benzimidazole-thiazolidine-2,4-dione-1,2,3-triazoles ( VIIa­–VIIl ) via piperidine catalyzed Knoevenagel condensation and Cu(I) catalyzed azide-alkyne cycloaddition reactions as key approaches. Then, in vitro anticancer and tubulin polymerization inhibition ( VIIa–VIIl ) were studied via IC 50 values. Finally, docking interactions of three potent compounds ( VIIg ), ( VIIh ), and ( VIIk ) towards α,β-tubulin were studied using AutoDock tools. Results and Discussion: Three compounds namely ( VIIg ), ( VIIh ), and ( VIIk ) showed better results against A549, MCF-7, and HeLa human cancer cell lines than standard drug nocodazole. In addition, compounds ( VIIg ) and ( VIIh ) have shown greater inhibitory potency with IC 50 values 0.62 and 0.31 μM respectively than standard Combretastatin A-4 (CA-4) against tubulin polymerization. Finally, in silico molecular docking studies for the compounds ( VIIg ), ( VIIh ), and ( VIIk ) with α,β-tubulin showed that they have great binding interactions with the target protein and to be specific the compound ( VIIh ) displayed highest binding energy, i.e. –9.23 kcal/mol. Conclusions: We propose that the remarkable in vitro anticancer activity of compounds ( VIIg ), ( VIIh ), and ( VIIk ), would be due to their tubulin polymerization inhibition.