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 IC 50 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 IC 50 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.

Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold

“…This observation is in accordance with results by Nawaz et al [ 22 ], where cinchonine quaternized with anthracene was about a 110 times more potent inhibitor than cinchonine without a substituent. The inhibition potency of CD-Met toward human BChE determined here is similar to that for equine BChE determined previously [ 23 ]. The K s values derived from the kinetics of inhibition were very close to BChE’s previously determined Michaelis-Menten constant ( K M ) [ 7 ], which implies binding of the tested compounds to the catalytic site of BChE.…”

“…Furthermore, these alkaloids are bioactive and are used in treating malaria and fever, while some also possess analgesic, anti-inflammatory and antiarrhythmic properties [ 21 ]. Recently, some cinchonine and cinchonidines were proven to be up to 100 times more potent inhibitors for equine BChE than human AChE, while anthracene/benzyl modified cinchonidine has been identified as selective BChE inhibitors with a BChE/AChE selectivity ratio of 250 [ 22 , 23 ]. In addition, a high affinity for binding to the active site of BChE was determined for some Cinchona oxime compounds studied as reactivators of OP-inhibited human BChE [ 24 ].…”

New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds

“…The oximes inhibited both cholinesterases in micromolar range but showed a strong preference for binding to hBChE. This confirmed previous studies on similar compounds [ 13 , 14 ] but also indicated that the addition of the oxime moiety did not influence their ability to bind to the cholinesterases active site. Moreover, the evaluated dissociation inhibition constants ( K i ) were higher than those published for pyridinium oximes and hAChE [ 22 , 23 , 24 ], and were 10–100-fold lower for pyridinium and imidazolium oximes and hBChE [ 17 , 25 ].…”

“…This paper reports on the synthesis of three derivatives of Cinchona oxime compounds. Some derivatives of cinchonidine have been identified as inhibitors of cholinesterases fitting their active site [ 13 , 14 ]. Therefore, we found them interesting for oxime moiety addition and their evaluation as reactivators of human AChE (hAChE) and BChE (hBChE) inhibited by OPs.…”

Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

“…Many studies have demonstrated that compounds based on a quinoline structure are potent inhibitors of both cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) [2,3]. As their primary structural motive, these compounds have tacrine or quinidine moiety [4][5][6][7][8][9]. Furthermore, anticholinesterase activity has been confirmed for antimalarial drugs chloroquine, hydroxychloroquine and primaquine [10][11][12].…”