ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Department of Toxicoloxy and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 500 05 Hradec Králové, Czech Republic.
Molecules. 2019 Apr 3;24(7):1307. doi: 10.3390/molecules24071307.
Twelve derivatives - of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11--(2-methylbenzoyl)-haemanthamine () and 11--(4-nitrobenzoyl)-haemanthamine (), revealed the most intriguing profile, both being acetylcholinesterase (AChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of AChE and BuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.
开发了 12 种β-石蒜碱型生物碱血根碱的衍生物。所有半合成衍生物均研究了其对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制潜力。此外，在活性衍生物中评估了糖原合酶激酶 3β（GSK-3β）抑制效力。为了揭示药物对中枢神经系统的可用性，我们阐明了选定衍生物穿透血脑屏障（BBB）的潜力。两种化合物，即 11--（2-甲基苯甲酰基）血根碱（）和 11--（4-硝基苯甲酰基）血根碱（），显示出最有趣的特征，它们都是在微摩尔范围内抑制乙酰胆碱酯酶（AChE）的化合物，具有 GSK-3β抑制特性，并预测可以穿透 BBB。体外数据通过详细检查化合物在 AChE 和 BuChE 的活性部位的可能结合模式得到进一步证实，这使我们能够提供负责对这些酶活性的结构决定因素。
