α-Glucosidase inhibitory activities of phenolic acid amides with l-amino acid moiety

Abstract

α-Glucosidase inhibitors can effectively control postprandial hyperglycemia. In this study, a series of phenolic acids with the L-amino acid moiety were synthesized and their inhibitory activities against α-glucosidase from Saccharomyces cerevisiae (EC 3.2.1.20) were evaluated. The results suggested that all these compounds showed strong α-glucosidase inhibitory activities. In particular, N-(4-hydroxyl-phenylpropenoyl)-L-alanine (c2) and N-(4-hydroxyl-phenylpropenoyl)-L-methionine (c8) exhibited much higher potency (IC₅₀ values 0.04 mM) than the positive control, acarbose (IC₅₀ values 1.70 mM). Three-dimensional quantitative structure–activity relationship (3D-QSAR) model for comparative molecular field analysis (CoMFA) was generated and the result showed that bulk groups and high electron density groups on the amino acid residues were a benefit to their activities. Moreover, the substituents with low electron density and little steric hindrance on the para position of the benzene ring were helpful in improving the activities. Kinetic analysis indicated that compound (c2) acted as a mixed-type inhibitor with a K_i value of 0.0124 mM. Docking analysis showed that they could bind to α-glucosidase at the catalytic site via hydrogen bonds and a π–π stacking.