Highly potent cholinesterase inhibition of geranylated xanthones from Garcinia fusca and molecular docking studies

Abstract

Three new oxygenated xanthones, fuscaxanthones L-N (1–3), and 14 known xanthones 4–17, together with the other known metabolites 18–20 were isolated from the stem barks of Garcinia fusca Pierre. Their chemical structures were determined based on NMR and MS spectroscopic data analysis, as well as single X-ray crystallography. The geranylated compounds, cowanin (13), cowagarcinone E (15), norcowanin (16) and cowanol (17) exhibited potent inhibitions against acetylcholinesterase (AChE) (IC50 0.33–1.09 μM) and butyrylcholinesterase (BChE) (IC50 0.048–1.84 μM), which were more active than the reference drug, galanthamine. Compound 15 was highly potent BChE inhibitor (IC50 0.048 μM) and was 76-fold more potent than the drug. Structure-activity relationship studies indicated that the C-2 prenyl and C-8 geranyl substituents in the tetraoxygenated scaffold are important for high activity. Molecular docking studies revealed that the leads 13 and 15–17 showed similar binding orientations on both enzymes and very well-fitted at the double binding active sites of PAS and CAS with strong hydrophobic interactions from both isoprenyl side chains. © 2020 Elsevier B.V.