Synthesis of new 1,2,3-triazole analogues of metronidazole and their identification as α-glucosidase inhibitors
摘要
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 IC50 values ranging from 64 to 447 µM. Amid them, compounds 44 and 43 showed the most significant inhibition (IC50 = 64 ± 1.17 and 67 ± 0.64 µM, respectively) followed by compounds 54 and 55 (IC50 = 73 ± 0.39 and 78 ± 1.34 µM, respectively). Kinetics studies showed active compounds as non-competitive as well as mixed type of inhibition with Ki ranging between 67.59 and 85.59 µM. 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.