Tetra-aryl cyclobutane and stilbenes from the rhizomes of Rheum undulatum and their α-glucosidase inhibitory activity: Biological evaluation, kinetic analysis, and molecular docking simulation

One achiral tetr alpha-aryl cyclobutane [rheundulin A (1)] and three stilbene glycosides [rheundulins B-D (2-4)] were isolated from the methanol extract of Rheum undulatum L., along with eight known compounds (5-12). Structural determination of the new compounds (1-4) was accomplished using comprehensive spectroscopic methods. Compound 1 represents the first example of a dimeric stilbene linked via a cyclobutane ring from the Rheum genus. All isolates were screened for their inhibition against alpha-glucosidase. Among them, stilbene derivatives (5 and 6) showed strong inhibitory effects on alpha-glucosidase with IC50 values of 0.5 and 15.4 mu M, respectively, which were significantly higher than that of the positive control, acarbose (IC50, = 126.8 mu M). Rheundulin A (1) showed moderate alpha-glucosidase inhibition with an IC50 value of 80.1 mu M. In addition, kinetic analysis and molecular docking simulation of the most active compound (5) with alpha-glucosidase were performed for the first time. Kinetic studies revealed that compound 5 competitively inhibited the active site of alpha-glucosidase (K-i = 0.40 mu M), while 6 had a mixed-type inhibitory effect against alpha-glucosidase (K-i = 15.34 mu M). Molecular docking simulations of 5 and 6 demonstrated negative-binding energies, indicating high proximity to the active site and tight binding to alpha-glucosidase enzyme.