Megastigmane sesquiterpenoids from the leaves of Gaultheria fragrantissima and their bioactivity evaluation.

Ten megastigmane sesquiterpenoids (1-10), including five previously undescribed ones, named megafragrines A-E (1-5), were isolated from the leaves of Gaultheria fragrantissima Wall. Their structures were determined by spectrometric and spectroscopic data analyses, including HRESIMS, NMR, IR, and UV, as well as NMR and ECD calculations. Megafragrine A (1) is the third example of a 6,9:9,13-di-epoxymegastigmane sesquiterpenoid bearing a unique 8,12-dioxatricyclo[7.2.1.01,6]dodecane core, and megafragrine B (2) represents the first 6,9-epoxymegastigmane sesquiterpenoid containing a ketal functionality. This is the first report of megastigmane sesquiterpenoids from G. fragrantissima. Ten megastigmane sesquiterpenoids (1-10) were evaluated for their NO release, NLRP3 inflammasome, α-glucosidase, and protein disulfide isomerase (PDI) inhibitory activities. Six megastigmane sesquiterpenoids (1-3, 5, 8, and 10) exhibited weak PDI inhibitory activities by binding to the b domain of PDI, rather than the b' domain like isoquercetin. The preliminary structure-activity relationship analyses and AutoDock-based molecular docking analyses provide valuable hints for the rational design of PDI inhibitors based on megastigmane sesquiterpenoids.