Design, Synthesis, and Evaluation of Orally Available Clioquinol-Moracin M Hybrids as Multitarget-Directed Ligands for Cognitive Improvement in a Rat Model of Neurodegeneration in Alzheimer鈥檚 Disease

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• 作者：Zhiren Wang ; Yali Wang ; Bo Wang ; Wenrui Li ; Ling Huang ; Xingshu Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8616-8637
• 全文大小：1166K
• ISSN：1520-4804

文摘

A novel series of clioquinol-moracin hybrids were designed and synthesized by fusing the pharmacophores of clioquinol and moracin M, and their activities as multitarget-directed ligands against Alzheimer鈥檚 disease were evaluated. Biological activity results demonstrated that these hybrids possessed significant inhibitory activities against phosphodiesterase 4D (PDE4D) and A尾 aggregation as well as remarkable antioxidant effects and excellent blood鈥揵rain barrier permeability. The optimal compound, 18d (WBQ5187), exhibited excellent PDE4D inhibitory potency (IC₅₀ = 0.32 渭M), significant antioxidant effects, appropriate biometal chelating functions, and interesting properties that modulated self- and metal-induced A尾 aggregation. Two-dimensional NMR studies revealed that 18d had significant interactions with A尾_1鈥?2 at the R5, H6, H14, Q15, and F20 residues. Furthermore, this typical hybrid possessed preeminent neuroprotective effects against inflammation in microglial cells. Most importantly, oral administration of 18d路HCl demonstrated marked improvements in cognitive and spatial memory in a rat model of Alzheimer鈥檚 disease and protected hippocampal neurons from necrosis.