engleski

Synthesis and evaluation of fluorinated Cinchona alkaloids as cholinesterases inhibitors

Cinchona alkaloids are natural products isolated from the bark of the Cinchona tree and the most known are quinine, quinidine, cinchonine and cinchonidine. These alkaloids and their derivatives are used in organic chemistry as chiral organocatalysts in asymmetric synthesis and as chiral agents in different chromatographic techniques. Also, they possess a wide variety of biological properties like anti-malarial, anti- inflammatory and anti-arrhythmic ones and recently they have been identified as human cholinesterase inhibitors. We synthesized seven quaternary derivatives of cinchonine and their corresponding pseudo-enantiomeric cinchonidine where the quaternization of quinuclidine nitrogen atom was achieved with differently substituted benzyl groups bearing fluorine atom(s) in different positions. All synthesized compounds reversibly inhibited the activity of both human butyrylcholinesterase and human acetylcholinesterase, with inhibition constants (Ki) in the range of 0.075-69 μM. All compounds were butyrylcholinesterase-selective inhibitors with up to 533 times higher affinity for butyrylcholinesterase compared to acetylcholinesterase. Generally, both cholinesterases were stereoselective to cinchonidines. Supported by the Croatian Science Foundation, Projects No. IP-2016-06- 3775 ADESIRE and IP-2018- 01-7683 AnalyseBChE.

cinchonidine, cinchonine, cholinesterases inhibitors

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