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

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 using ¹H and ¹³C NMR spectroscopy as well as mass spectrometry. Most of the synthesized compounds demonstrated significant inhibitory activity, with IC₅₀ ranging 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 K _i values 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.