Affinity ultrafiltration based metabolomic profiling directed discovery novel butyrylcholinesterase inhibitors from Uncaria sessilifructus.

The butyrylcholinesterase (BChE) is an attractive target for treating Alzheimer's disease. In this study, we report the discovery of five new monoterpene indole alkaloids (MIAs) along with three known analogues from Uncaria sessilifructus Roxb. as BChE inhibitors using affinity ultrafiltration based metabolomic profiling directed isolation strategy. Their structures were well identified through comprehensive spectroscopic and chiroptical analyses. Compounds 1-2 featured unique glycosidic linkages with 1,3-dioxane structure. All the compounds exhibited BChE inhibitory bioactivity without any cytotoxic effects. Enzymatic kinetic and molecular docking analyses of compounds 1 and 6 demonstrated their inhibiting mechanisms and binding patterns to BChE. These findings provide a valuable workflow for efficiently screening ligands that bind to proteins, and scientific recognition in the discovery of BChE inhibitors for treating neurodegenerative disorders.