Polyphenols from the aerial parts of Lespedeza cuneata and their inhibitory effects on PTP1B and α-glucosidase: insights from in vitro and in Silico analyses.

A comprehensive phytochemical investigation of the methanol extract from the aerial parts of Lespedeza cuneata resulted in the isolation of 36 compounds, including three new C-glycosyl flavonoids (8, 9, and 11). Their structures were elucidated using HRFAB-MS, as well as 1D and 2D nuclear magnetic resonance spectroscopy, and the isolated compounds were evaluated for inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Flavonoids 1, 17, and 21 exhibited potent PTP1B inhibition (IC50 4.9-9.6 µM). Notably, compounds 17 and 25 showed strong α-glucosidase inhibition (IC50 6.0 and 5.7 µM, respectively), outperforming the reference drug acarbose. Additionally, benzofuran derivative 34 (IC50 29.2 µM) exhibited uncompetitive α-glucosidase inhibition with a Ki of 2.4 µM. Molecular docking and molecular dynamics studies indicated that compound 34 binds to an allosteric site of α-glucosidase, supporting its uncompetitive inhibition mechanism. These findings suggest that multiple constituents of L. cuneata contribute to its enzyme inhibitory activities and highlight the plant as a promising natural source of multifunctional enzyme inhibitors with potential applications in diabetes management.