Chemical Modifications of Cinchona Alkaloids Lead to Enhanced Inhibition of Human Butyrylcholinesterase

Abstract

Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10≡)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with K_i, = 3.45±0.39 μM, and IC₅₀ BChE = 9.83±0.30 μM/human (h)BChE = 34.47±4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with K_iuc = 1.73±0.46 μM and K_ic = 0.85±0.26 μM, and IC₅₀ BChE = 0.56±0.14 μM / hBChE = 0.24±0.04. In cytotoxicity experiments, ≥80% of the cells remained viable when exposed to concentrations of up to 80 μM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE.