This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range. Five cinchonidine derivatives displayed 95-510 times higher inhibition selectivity to butyrylcholinesterase over acetylcholinesterase and four were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-para-bromobenzyl cinchonidinium bromide can be considered a lead for further modifications and optimizations for possible use in the treatment of neurodegenerative diseases.
Bosak A, Ramic A, Smidlehner T, Hrenar T, Primozic I, Kovarik Z (2018) Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold PLoS ONE13: e0205193
Bosak A, Ramic A, Smidlehner T, Hrenar T, Primozic I, Kovarik Z (2018) PLoS ONE13: e0205193
