Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer’s Disease

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• 作者：Rong Sheng ; Li Tang ; Liu Jiang ; Lingjuan Hong ; Ying Shi ; Naiming Zhou ; Yongzhou Hu
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：January 20, 2016
• 年：2016
• 卷：7
• 期：1
• 页码：69-81
• 全文大小：742K
• ISSN：1948-7193

文摘

A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer’s disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H₃ receptor antagonists. Most of these new compounds displayed designed quadruple functions, H₃ receptor antagonism, Aβ aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC₅₀ values in H₃ receptor antagonism with high selectivity, efficient capability to interrupt the formation of Aβ_1–42 fibrils, good copper and iron chelating properties, and more potent 2,2′-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS^?+) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood–brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy.