Synthesis, Biological Evaluation, and Docking Study of Rhinacanthin-Related Derivatives as α-Glucosidase Inhibitors

Abstract

This study describes the design, synthesis, and in vitro evaluation of 25 rhinacanthin-related derivatives as potential α-glucosidase inhibitors. The synthesized compounds were characterized using1H and13C NMR spectroscopy as well as mass spectrometry. Most of the synthesized compounds demonstrated significant inhibitory activity, with IC50ranging from 1.45 ± 0.04 to 31.91 ± 3.31 μM, compared to the positive control, acarbose (IC50= 836.00 ± 47.19 μM). In particular, compounds 6 and 12 exhibited the highest anti-α-glucosidase activity and acted as competitive inhibitors, with Kivalues of 14.11 and 4.14 μM, respectively. Molecular docking analysis was performed and revealed that key π–π stacking interactions with residue F300, together with hydrogen bonds involving N241, H279, E304, and R312, contributed significantly to the enhanced α-glucosidase inhibitory activity of the active compounds. These findings suggest that compounds 6 and 12 are promising candidates for developing α-glucosidase inhibitors with potential antidiabetic effects.