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

Some new coumarin-fused 4H-pyran derivatives were synthesized and assessed against yeast alpha- 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 mu M in comparison with acarbose, as a stan-dard agent (IC50 = 750.0 mu M). 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 alpha-glucosidase in a competitive pattern. Homology modeling was utilized to determine 3D structure of the alpha-glucoside en-zyme. Afterwards, the molecular docking and dynamic simulation studies confirmed successful placement of the compound 6e in the active site of alpha-glucosidase. Besides, the R -and S -enantiomers of the com-pound 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 deriva-tives have acceptable pharmacokinetic and potential therapeutic benefits for the future treatment of type 2 diabetes mellitus (T2DM).(c) 2023 Elsevier B.V. All rights reserved.

Automated summary

This study synthesized some new coumarin-fused 4H-pyran derivatives and evaluated their inhibitory activity against yeast alpha-glucosidase enzyme. All of the synthesized compounds showed significant inhibitory activity, with compound 6e exhibiting the most potent activity. Kinetic and molecular modeling studies confirmed the competitive inhibition of compound 6e against alpha-glucosidase. In silico prediction suggested that these derivatives have potential therapeutic benefits for the treatment of type 2 diabetes mellitus.