Cinnamic acid amides from Tribulus terrestris displaying uncompetitive alpha-glucosidase inhibition

Abstract

The alpha-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of alpha-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1-3) were ascertained to be active components against alpha-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of alpha-glucosidase (IC50 = 0.42 mu M). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for alpha-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both K-m, and V-max, and K-ik/K-iv, ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An alpha, beta-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for alpha-aglucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to pi-pi interaction as well as hydrogen bond interaction between enzyme and inhibitors. (C) 2016 Elsevier Masson SAS. All rights reserved.