Synthesis, in vitro α-glucosidase inhibitory activity and molecular dynamics simulation of some new coumarin-fused 4H-pyran derivatives as potential anti-diabetic agents

Abstract

Some new coumarin-fused 4H-pyran derivatives were synthesized and assessed against yeast α-glucosidase enzyme. All of the synthesized compounds showed significant inhibitory activity towards the enzyme with IC50 values in range of 30.05 ± 0.5–274.3 ± 1.0 μM in comparison with acarbose, as a standard agent (IC50 = 750.0 μM). Among them, 4-(4-(4-bromobenzyloxy)-3-methoxyphenyl)-2-amino -4,5-dihydro-5-oxopyrano[3,2-c]chromene-3-carbonitrile (compound 6e) indicated the most potent inhibitory activity. The kinetic study of the compound 6e revealed that this compound inhibited α-glucosidase in a competitive pattern. Homology modeling was utilized to determine 3D structure of the α-glucoside enzyme. Afterwards, the molecular docking and dynamic simulation studies confirmed successful placement of the compound 6e in the active site of α-glucosidase. Besides, the R- and S- enantiomers of the compound 6e showed significant interactions with the catalytic triad residues (Asp214, Glu276, Asp349). The results of in silico prediction study for ADME also indicated that these coumarin-fused 4H-pyran derivatives have acceptable pharmacokinetic and potential therapeutic benefits for the future treatment of type 2 diabetes mellitus (T2DM).