Natural Corynanthe-Type Cholinesterase Inhibitors from Malaysian Uncaria attenuata Korth.: Isolation, Characterization, In Vitro and In Silico Studies.

The Uncaria genus is notable for its therapeutic potential in treating age-related dementia, such as Alzheimer's disease. A phytochemical study of the leaves of Malaysian Uncaria attenuata Korth., afforded an undescribed natural corynanthe-type oxindole alkaloid, isovillocarine D ( 1 ) together with two known indole alkaloids, villocarine A ( 2 ) and geissoschizine methyl ether ( 3 ), and their structural identification was performed with extensive mono- and bidimensional NMR and MS spectroscopic methods. The isolated alkaloids were evaluated for their acetylcholinesterase (AChE)- and butyrylcholinesterase (BChE)-inhibitory activity. The results indicated that compound ( 2 ) was the most potent inhibitor against both AChE and BChE, with IC 50 values of 14.45 and 13.95 µM, respectively, whereas compounds ( 1 ) and ( 3 ) were selective BChE inhibitors with IC 50 values of 35.28 and 17.65 µM, respectively. In addition, molecular docking studies revealed that compound ( 2 ) interacts with the five main regions of AChE via both hydrogen and hydrophobic bonding. In contrast to AChE, the interactions of ( 2 ) with the enzymatic site of BChE are established only through hydrophobic bonding. The current finding suggests that U. attenuata could be a good source of bioactive alkaloids for treating age-related dementia.