Synthesis of new 1,2,3-triazole analogues of metronidazole and their identification as α-glucosidase inhibitors

Abstract α -Glucosidase inhibitors are considered as significant clinical targets for the treatment of type-2 diabetes. As, marketed drugs exhibit adverse effects; there is an outmost need to find safe, and effective inhibitors of α -glucosidase enzyme. Taking into account the significance of α -glucosidase inhibition, metronidazole was functionalized into its corresponding new seventeen 1,2,3-triazole analogues with drug repurposing perspective. For this, Click chemistry protocol (cycloaddition reaction) was used, commencing from metronidazole azide (as dipole molecule) and substituted N -propargyl- N -benzyl aniline (as dipolarophile). The precursor molecules (metronidazole azide and N -propargyl- N -benzyl anilines) in-turn were obtained after steps including mesylation/azidation and reductive amination/propargylation strategies, respectively. Comparatively, all the synthesized 1,2,3-triazole compounds showed better in vitro α -glucosidase inhibition than the standard drug acarbose, with the IC 50 values ranging from 64 to 447 µ M. Amid them, compounds 44 and 43 showed the most significant inhibition (IC 50 = 64 ± 1.17 and 67 ± 0.64 µ M, respectively) followed by compounds 54 and 55 (IC 50 = 73 ± 0.39 and 78 ± 1.34 µ M, respectively). Kinetics studies showed active compounds as non-competitive as well as mixed type of inhibition with K i ranging between 67.59 and 85.59 µ M. Also, in silico studies revealed that all compounds formed interactions with the residues of the enzyme. Moreover, all the compounds were non-toxic against normal cell line and showed a favorable ADME profile. In the final account, new 1,2,3-triazole analogues of metronidazole could be identified as good and safe leads for α -glucosidase inhibition.