ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
Department of Toxicology and Military Pharmacy, University of Defence, Trebesska 1575, 500 05 Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Bioorg Chem. 2020 Jul;100:103928. doi: 10.1016/j.bioorg.2020.103928. Epub 2020 May 17.
A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with ICvalue of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.
设计、合成了一系列与石蒜科生物碱（AA）海曼他明相关的新型芳香酯（1a-1m），并特别强调了它们在治疗神经退行性疾病方面的体外测试。一些合成化合物显示出有希望的乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制谱。11-O-（3-硝基苯甲酰基）海曼他明（1j）对人乙酰胆碱酯酶（hAChE）的抑制作用显著，IC值为 4.0±0.3µM。最强的人丁酰胆碱酯酶（hBuChE）抑制剂是 1-O-（2-甲氧基苯甲酰基）海曼他明（1g），IC 值为 3.3±0.4µM。此外，11-O-（2-氯苯甲酰基）海曼他明（1m）能够以剂量依赖的方式抑制两种酶。通过酶动力学分析与计算机模拟实验相结合，对 hAChE 和 hBuChE 的抑制模式进行了详细检查，后者阐明了 1j-、1m-hAChE 和 1g-、1m-hBuChE 复合物中的关键相互作用。应用平行人工膜渗透测定法（PAMPA）研究了血脑屏障（BBB）的通透性，以预测化合物在中枢神经系统中的可用性。
