engleski

Cinchona-alkaloid-derived compounds as selective inhibitors of butyrylcholinesterase

Cinchona alkaloids are known natural products with multiple bioactivities Accordingly, it can be expected that compounds structurally related to Cinchona alkaloids might also possess various biological activities. To continue our work and additionally explor e Cinchona-alkaloid-derived compounds as cholinesterases inhibitors, 46 new quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines were synthesised and evaluated as human cholinesterases inhibitors Alkaloids were modified by quaternization of quinuclidine moiety of each compound with groups containing fluorine atoms Furthermore, to determine the role of the vinyl group in binding of compounds to ChEs, 10, 11- dihydrocinchonidine derivatives were prepared by transfer hydrogenation of cinchonidine using formic acid/ammonium formate as hydrogen donor All prepared compounds proved to be reversible inhibitors of human butyrylcholinesterase and acetylcholinesterase with Ki constants from nanomolar to micromolar range Cinchonidine derivatives displayed higher inhibition selectivity toward ChEs than cinchonines Three cinchonidine compounds were 84–533 times better inhibitors of butyrylcholinesterase than acetylcholinesterase Some cinchonidine derivatives were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-meta- fluorobenzylcinchonidinium bromide can be considered as a lead for further modifications and optimizations of structure to obtain a higher butyrylcholinesterase inhibition potency and selectivity To enable the better prediction and facilitate design of new and more efficient inhibitors, the most optimal regression models for the prediction of bioactivity were established and validated by extensive machine learning protocol.

Cinchona alkaloid derivatives ; cholinesterase inhibitors ; multivariate linear regression models

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