Development of coumarin tagged 1,2,3-triazole derivatives targeting α-glucosidase inhibition: Synthetic modification, biological evaluation, kinetic and in silico studies

Abstract

Coumarin derivatives have been demonstrated as promising anti-diabetic compounds through α-glucosidase inhibition. This is a ubiquitous brush border membrane-bound enzyme and an effective curative target for the treatment of diabetes. A novel series of compounds namely N-aryl-2-(4-(((2-oxo-2H-chromen-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide 8a-p were synthesized conveniently. Furthermore, the α-glucosidase inhibition potential of synthesized compounds was investigated, and based on the obtained data, all derivatives showed excellent inhibitory effect against α-glucosidase compared to standard antidiabetic drug acarbose. Among them, compounds 8d and 8j were represented to be the most potent ones with IC50s = 6.4 ± 0.1 and 3.5 ± 0.1, respectively. Kinetic enzymatic assays investigated that compound 8j was a competitive inhibitor of the enzyme, and further studies represented a Ki value of 2.2 µM for compound 8j. Moreover, the binding energy for compound 8j was obtained -8.30 kcal/mol in the molecular docking study. The structural dynamics incurred by the most potent compound have been investigated through the RMSD and RMSF studies. Underlining their physicochemical parameters, they have promising drug-like properties.