Pidany Filip, Kroustkova Jana, Al Mamun Abdullah, Suchankova Daniela, Brazzolotto Xavier, Nachon Florian, Chantegreil Fabien, Dolezal Rafael, Pulkrabkova Lenka, Muckova Lubica, Hrabinova Martina, Finger Vladimir, Kufa Martin, Soukup Ondrej, Jun Daniel, Jenco Jaroslav, Kunes Jiri, Novakova Lucie, Korabecny Jan, Cahlikova Lucie
Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
Institut de Recherche Biomédicale des Armées, Département de Toxicologie et Risques Chimiques, 1 Place Général Valérie André, 91220, Brétigny-sur-Orge, France.
Eur J Med Chem. 2023 Apr 5;252:115301. doi: 10.1016/j.ejmech.2023.115301. Epub 2023 Mar 22.
Butyrylcholinesterase (BChE) is one of the most frequently implicated enzymes in the advanced stage of Alzheimer's disease (AD). As part of our endeavors to develop new drug candidates for AD, we have focused on natural template structures, namely the Amaryllidaceae alkaloids carltonine A and B endowed with high BChE selectivity. Herein, we report the design, synthesis, and in vitro evaluation of 57 novel highly selective human BChE (hBChE) inhibitors. Most synthesized compounds showed hBChE inhibition potency ranging from micromolar to low nanomolar scale. Compounds that revealed BChE inhibition below 100 nM were selected for detailed biological investigation. The CNS-targeted profile of the presented compounds was confirmed theoretically by calculating the BBB score algorithm, these data were corroborated by determining the permeability in vitro using PAMPA-assay for the most active derivatives. The study highlighted compounds 87 (hBChE IC = 3.8 ± 0.2 nM) and 88 (hBChE IC = 5.7 ± 1.5 nM) as the top-ranked BChE inhibitors. Compounds revealed negligible cytotoxicity for the human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines compared to BChE inhibitory potential. A crystallographic study was performed to inspect the binding mode of compound 87, revealing essential interactions between 87 and hBChE active site. In addition, multidimensional QSAR analyses were applied to determine the relationship between chemical structures and biological activity in a dataset of designed agents. Compound 87 is a promising lead compound with potential implications for treating the late stages of AD.
丁酰胆碱酯酶（BChE）是阿尔茨海默病（AD）晚期最常涉及的酶之一。作为我们开发AD新药候选物的努力的一部分，我们专注于天然模板结构，即具有高BChE选择性的石蒜科生物碱卡尔托宁A和B。在此，我们报告了57种新型高选择性人BChE（hBChE）抑制剂的设计、合成及体外评价。大多数合成化合物对hBChE的抑制效力范围为微摩尔至低纳摩尔级别。对显示BChE抑制作用低于100 nM的化合物进行了详细的生物学研究。通过计算血脑屏障评分算法从理论上证实了所呈现化合物的中枢神经系统靶向特征，通过使用PAMPA测定法测定最具活性衍生物的体外渗透性，这些数据得到了进一步证实。该研究突出了化合物87（hBChE IC = 3.8 ± 0.2 nM）和88（hBChE IC = 5.7 ± 1.5 nM）作为排名靠前的BChE抑制剂。与BChE抑制潜力相比，这些化合物对人神经母细胞瘤（SH-SY5Y）和肝癌（HepG2）细胞系的细胞毒性可忽略不计。进行了晶体学研究以检查化合物87的结合模式，揭示了87与hBChE活性位点之间的关键相互作用。此外，应用多维QSAR分析来确定设计药物数据集中化学结构与生物活性之间的关系。化合物87是一种有前途的先导化合物，对治疗AD晚期具有潜在意义。
