Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb, Croatia.
Faculty of Science, Horvatovac 102A, University of Zagreb, Zagreb, Croatia.
PLoS One. 2018 Oct 5;13(10):e0205193. doi: 10.1371/journal.pone.0205193. eCollection 2018.
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.
本文描述了基于金鸡纳生物碱的合成和抗胆碱酯酶活性；十种金鸡纳碱的季铵衍生物及其相应的伪对映异构体辛可宁碱。每个化合物的 quinuclidine 部分的季铵化是用不同大小的基团进行的：甲基、苄基和不同的间位和对位取代的苄基。所有制备的化合物可逆地抑制人丁酰胆碱酯酶和乙酰胆碱酯酶，Ki 常数在纳摩尔到微摩尔范围内。五种辛可宁碱衍生物对丁酰胆碱酯酶的抑制选择性比乙酰胆碱酯酶高 95-510 倍，有四种是有效的丁酰胆碱酯酶抑制剂，Ki 常数高达 100 nM，其中 N-对溴苄基辛可宁溴化物可以被认为是进一步修饰和优化的先导化合物，以用于治疗神经退行性疾病。
