Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
J Nat Prod. 2020 May 22;83(5):1359-1367. doi: 10.1021/acs.jnatprod.9b00561. Epub 2020 Apr 20.
A total of 20 derivatives (-) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (, , , , , and ) with different substitution patterns showed inhibitory potency against human serum BuChE (IC < 5 μM), highlighting the three top-ranked compounds as follows: 11--(1-naphthoyl)ambelline (), 11--(2-methylbenzoyl)ambelline (), and 11--(2-methoxybenzoyl)ambelline () with IC values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 μM, respectively. Notably, derivatives , , , and displayed selective human BuChE (BuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of BuChE.
总共合成了 20 种 crinane 型生物碱 ambelline 的衍生物（-）。这些半合成衍生物被评估为抑制乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的效力。为了预测中枢神经系统（CNS）的可用性，计算了 logBB，并且数据与从平行人工膜渗透率测定（PAMPA）获得的数据很好地相关。根据获得的结果，所有化合物都应该能够穿透血脑屏障（BBB）。总共 7 种具有不同取代模式的芳族衍生物（，，，，，和）对人血清 BuChE 显示出抑制活性（IC <5 μM），突出了以下三个排名最高的化合物：11--（1-萘甲酰基）ambelline（），11--（2-甲基苯甲酰基）ambelline（）和 11--（2-甲氧基苯甲酰基）ambelline（），IC 值分别为 0.10 ± 0.01、0.28 ± 0.02 和 0.43 ± 0.04 μM。值得注意的是，衍生物，，，和表现出选择性人 BuChE（BuChE）抑制谱，选择性指数>100。体外结果得到了计算研究的支持，这些研究预测了化合物在 BuChE 活性部位的可能结合模式。
