Synthesis of benzimidazole derivatives, biological evaluation and molecular docking studies / Nik Khairunissa Nik Abdullah Zawawi

Benzimidazoles which form a vital part of vitamin B12 are of wide interest because of their diverse biological activity and clinical application. This privileged structure has gained our interest to explore some new benzimidazole derivatives by combining with other biologically active moieties such as hydrazone, oxadiazole and thiourea. The first part of our work was to synthesize and characterize a total of 61 benzimidazole derivatives bearing different substituents such as hydrazone, oxadiazole and thiourea, by reacting benzimidazole benzoyl hydrazide and various aromatic aldehydes, aromatic acids or phenylisothiocyanates under certain conditions. The second part is to evaluate the synthesized compounds for their cytoprotective activity against cytokine-induced apoptosis in β-cells (20 compounds), α-glucosidase (43 compounds) or β-glucuronidase (18 compounds) inhibition activities. The final part is to construct a structure-activity relationship (SAR) and molecular docking studies in order to understand the mechanism of inhibition. For the first series, twenty six benzimidazole bearing hydrazone derivatives were synthesized and evaluated for cytoprotective activity against cytokine-induced apoptosis in β-cells and Baker’s yeast α-glucosidase inhibitory activities. In the presence of pro-inflammatory cytokines, compounds 208, 211 and 217 were the most potent among all the analogues, in which they increased the cellular ATP levels, inhibited caspase-3 activity, decreased nitrite production and restored GSIS in a dose-dependent manner.