Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis

Research efforts have been directed to the development of oleanolic acid (OA) based alpha-glucosidase inhibitors and various OA derivatives showed improved anti-alpha-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on alpha-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 1) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-alpha-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior alpha-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-31) and OA (with IC50 values of 4.02 mu M-5.30 mu M v.s. over 10 mu M and 5.52 mu M, respectively). In addition, mechanistic studies using biochemical (kinetic assay), biophysical (circular dichroism), and computational (docking) methods revealed that OA-indole derivatives (2a and 2f) are mixed type of alpha-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with alpha-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising alpha-glucosidase inhibitors as a potential management of diabetes mellitus.