A novel series of quinoline–indole derivatives were synthesized and evaluated as multitarget-directed ligands for the treatment of Alzheimer’s disease (AD). Biological evaluation revealed that the derivatives had multifunctional profiles including antioxidant effects, blood–brain barrier (BBB) penetration, biometal chelation, Aβ aggregation modulation, neurotrophic and neuroprotective properties. Moreover, several representative target derivatives demonstrated hippocampal cell proliferation in living adult mice by intracerebroventricular (icv) injection or oral administration. Further drug-like property analysis demonstrated that the optimized compound, 8d (WI-1758), had liver microsomal metabolic stability, was well tolerated (>2000 mg/kg), and had a rational pharmacokinetic profile, as well as an oral bioavailability of 14.1% and a positive log BB (−0.19) to cross the BBB in vivo. Pharmacodynamics studies demonstrated that chronic oral administration of 8d·HCl substantially ameliorated the cognitive and spatial memory deficits in APP/PS1 AD mice and noticeably reduced overall cerebral β-amyloid deposits.

中文翻译：

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口服生物利用喹啉-吲哚衍生物作为创新的多靶标定向配体的设计，合成和评估：促进成年鼠海马细胞增殖以治疗阿尔茨海默氏病

合成了一系列新颖的喹啉-吲哚衍生物，并将其评估为多靶标定向配体，用于治疗阿尔茨海默氏病（AD）。生物学评估表明，这些衍生物具有多种功能，包括抗氧化作用，血脑屏障（BBB）渗透，生物金属螯合，Aβ聚集调节，神经营养和神经保护特性。而且，几种代表性的靶衍生物通过脑室内（icv）注射或口服给药在成年成年小鼠中证明了海马细胞增殖。进一步的类药物性质分析表明，优化后的化合物8d（WI-1758），具有肝微粒体代谢稳定性，耐受性良好（> 2000 mg / kg），具有合理的药代动力学特征，口服生物利用度为14.1％，BB阳性对数（-0.19）可以通过体内的血脑屏障。药效学研究表明，长期口服8d·HCl可以明显改善APP / PS1 AD小鼠的认知和空间记忆缺陷，并显着减少总的脑β-淀粉样蛋白沉积。