Cation–π and π–π stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids

Scaffold varied quaternized quinine and cinchonidine alkaloid derivatives were evaluated for their selective butyrylcholinesterase (BChE) inhibitory potential. Ki values were between 0.4–260.5 μM (non-competitive inhibition) while corresponding Kivalues to acetylcholinesterase (AChE) ranged from 7.0–400 μM exhibiting a 250-fold selectivity for BChE.Docking arrangements (GOLD, PLANT) revealed that the extended aromatic moieties and the quaternized nitrogen of the inhibitors were responsible for specific π–π stacking and π–cation interactions with the choline binding site and the peripheral anionic site of BChE’s active site.

Research highlights► Quaternized quinine and cinchonidine derivatives bind selectively to BChE. ► For eight derivatives, Ki values for BChE range between 0.4–260.5 μM. ► Due to extended π–π stacking and π–cation interactions a 250 fold enhancement of binding to BChE when compared to AChE can be achieved. ► Inhibition measurements could be supported by molecular modeling studies.