Gnetumgams A and B: two new 2-phenylbenzofuran derivatives from the lianas of Gnetum montanum with xanthine oxidase inhibitory activity

Abstract

Gnetum montanum (“”, Gnetaceae), traditionally employed in Vietnam for the treatment of rheumatism, chronic bronchitis, menstrual disorders, and as an antidote, was investigated for xanthine oxidase (XO) inhibitory constituents. Bioassay-guided fractionation led to the isolation of five 2-phenylbenzofurans, including two previously undescribed metabolites, gnetumgam A (1) and gnetumgam B (2), along with gnetifolin M (3), gnetifolin A (4), and gnetumelin B (5). Structures were unambiguously elucidated by comprehensive spectroscopic analyses (1D/2D NMR, HR-ESI-MS) and comparison with reference data. Among these, gnetumgam B (2) and gnetifolin M (3) exhibited notable XO inhibition (IC50 = 111.7 and 113.1 µM, respectively), although less potent than the clinical agents allopurinol and febuxostat. Structure–activity relationship analysis revealed that substitution patterns on the benzyl ring and benzofuran nucleus strongly influenced activity, particularly via interactions within the molybdenum cofactor (MoCo) pocket. Molecular docking and dynamics simulations corroborated the experimental findings and underscored gnetumgam B (2) as a promising scaffold for further optimization toward next-generation XO inhibitors.