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 α-glucosidase inhibitors and various OA derivatives showed improved anti-α-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on α-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 l) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-α-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior α-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-3l) and OA (with IC₅₀ values of 4.02 μM-5.30 μM v.s. over 10 μM and 5.52 µM, 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 α-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with α-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising α-glucosidase inhibitors as a potential management of diabetes mellitus.