Abstract：
Aβ1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer\'s disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl3-induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.
摘要：
Aβ1-42和乙酰胆碱酯酶(AChE)是阿尔茨海默病(AD)的两个关键治疗靶点。本研究的目的是通过融合黄芩素和多奈哌齐的化学结构来开发抑制这两个靶标的双靶标抑制剂。其中,我们将黄芩素的结构修饰为芳基香豆素，合成了三种结构化合物，并评估了它们的生物活性。结果表明，化合物3b对AChE的抑制作用最强（IC50=0.05±0.02µM），优于多奈哌齐和黄芩素。此外,化合物3b具有较强的抑制Aβ1-42聚集和保护神经细胞的能力，它也能很好地穿透血脑屏障。使用斑马鱼行为分析仪测试，发现化合物3b可以缓解AlCl3诱导的斑马鱼幼虫运动迟缓的行为效应，对模拟AD患者的运动障碍具有一定的指导意义。总之,化合物3b有望成为治疗和缓解AD患者症状的多功能药物。
