engleski

Design, synthesis and kinetic evaluation of cinchonines and cinchonidines as selective human butyrylcholinesterase inhibitors

Studies on the impact of butyrylcholinesterase (BChE) on the symptoms and progression of cognitive impairments like Alzheimer's disease (AD) or other neurodegenerative disruptions speak in favour of selective BChE inhibitors as a new approach in future AD pharmacotherapy. Some derivatives of quinine and quinidine, present in the Cinchona species bark, have already been identified as selective BChE inhibitors with respect to acetylcholinesterase (AChE) ; therefore, further investigation of these compounds might result in promising leads for enhanced anti-AD drugs. We synthesised ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. Quaternization of quinuclidine moiety was carried out with groups diverse in size: methyl and differently meta and para substituted benzyl groups. All of the compounds were prepared in good yields, characterized by standard analytical spectroscopy methods, and were tested for their BChE and AChE inhibition potency. The inhibition potency of the compounds was defined by the dissociation constants of the enzyme−inhibitor complex (Ki). All of the tested compounds reversibly inhibited both human BChE and AChE. The compounds inhibited BChE with Ki constants in the range of 0.04-30 µM, and AChE in the range 2.5-70 µM. Five cinchonidines displayed a 95- 510 times higher inhibition selectivity to BChE over AChE, and four of them were potent BChE inhibitors with Ki constants up to 100 nM. BChE affinity toward the studied compounds depended on the size of the substituent on the nitrogen of the quinuclidinium part of the molecule and on the resonance stabilization of the substituent at the quaternized nitrogen. Based on the presented results, cinchonidine CD-(pBr) can be pointed out as a potent and selective BChE inhibitor that could be considered for further research in Alzheimer disease pharmacotherapy.

inhibition ; selectivity ; stereoselectivity ; Alzheimer's disease

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