A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC₅₀ values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC₅₀: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu²⁺-induced Aβ _1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ _1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

中文翻译：

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合理修饰多奈哌齐作为多功能乙酰胆碱酯酶抑制剂以治疗阿尔茨海默氏病

设计，合成和评估了一系列新型多奈哌齐衍生物，作为多功能乙酰胆碱酯酶（AChE）抑制剂，用于治疗阿尔茨海默氏病（AD）。筛选结果表明，大多数化合物均表现出对AChE的有效抑制作用，IC ₅₀值在纳摩尔范围内。此外，这些衍生物显示出良好的抗氧化剂，Aβ相互作用，血脑屏障渗透性（PAMPA-BBB +）和ADMET性能（计算机模拟）。其中，图5c显示了优秀的抑制乙酰胆碱酯酶（IC ₅₀：85纳米的eeAChE，73纳米的HACHE），金属螯合，并在自感应，HACHE诱导和Cu抑制作用²⁺诱导的Aβ _1-42聚集（20μM时为18.5％，72.4％和46.3％）。动力学分析和分子建模研究表明5c可以同时与AChE的催化活性位点（CAS）和外围阴离子位点（PAS）结合。更重要的是，5c对_Aβ1-42诱导的PC12细胞损伤表现出明显的神经保护作用。此外，逐步被动回避测试显示5c可以显着逆转东pol碱所致的记忆缺陷，并且对小鼠没有肝毒性。这些结果表明5c可能是用于AD疗法的有希望的候选药物。