DeepSAT-guided discovery of triterpenoid galloyl and hexahydroxydiphenoyl esters from Castanopsis megaphylla Hu with α-glucosidase inhibitory activity.

Triterpenoid ellagitannins serve as characteristic chemotaxonomic markers for Castanopsis species and exhibit potent α-glucosidase inhibitory activity. However, systematic phytochemical investigations targeting these compounds have not yet been performed on Castanopsis megaphylla Hu, an endemic subtropical tree native to Southwest China. An HSQC-DeepSAT prediction workflow was utilized for targeted isolation of fifteen triterpenoid ellagitannin derivatives (megaphyllanins A-O, 1-15) from this plant. This collection comprises five unreported galloyl triterpenoid esters (1-4, 12), nine unreported triterpenoid ellagitannins (5-11, 13, 15), and one known triterpenoid ellagitannin (14) obtained from natural sources for the first time. All isolated compounds exhibited significant inhibitory activity against α-glucosidase. Compounds 10, 14 and 15 exhibited superior activity (IC50: 7.41-11.32 μM) compared with acarbose (IC50 = 1698.67 μM). Enzymatic kinetics confirmed compound 15 as a mixed-type inhibitor, and molecular docking binding energies (-6.19, -7.15, -7.35 kcal/mol) matched their activity order. The three highly active compounds are promising acarbose alternatives. This study provides material and theoretical support for developing natural hypoglycemic agents and medicinal exploitation of C. megaphylla.