Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria.
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria.
Molecules. 2021 Apr 3;26(7):2058. doi: 10.3390/molecules26072058.
Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood-brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.
尽管近几十年来进行了广泛而深入的研究，但仍然没有有效的治疗神经退行性疾病的方法。在此背景下，使用抑制乙酰胆碱酯酶（AChE）的药物仍然是治疗轻度至中度认知障碍的对症治疗的永恒常青树。更重要的是，由于人们的注意力转向淀粉样蛋白级联，胆碱能假说近年来有些被遗忘，但它又重新活跃起来，人们继续寻找新的、更有效的 AChE 抑制剂。我们生成了一个基于片段的库，其中包含源自一组新型 AChE 抑制剂的芳基部分和连接子。我们使用该库根据模型 GAL（结合核心）-连接子（L）-芳基片段（Ar）来设计 1220 个加兰他敏（GAL）衍生物。新设计的化合物在虚拟筛选中进行了血脑屏障（BBB）渗透性和与 AChE 结合的测试。在得分最高的前 10 种化合物中，选择了一个代表性的先导分子，并对其抗 AChE 活性和神经毒性进行了测试。结果发现，所选化合物是一种强大的无毒 AChE 抑制剂，比 GAL 活性高 68 倍，可作为进一步优化和开发的先导分子。
