Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimer鈥檚 Disease Based on the Fusion of Donepezil and Ebselen

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• 作者：Zonghua Luo ; Jianfei Sheng ; Yang Sun ; Chuanjun Lu ; Jun Yan ; Anqiu Liu ; Hai-bin Luo ; Ling Huang ; Xingshu Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9089-9099
• 全文大小：437K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer鈥檚 disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC₅₀ values of 0.042 渭M for Electrophorus electricus acetylcholinesterase and 0.097 渭M for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC₅₀ = 1.586 渭M), to possess rapid H₂O₂ and peroxynitrite scavenging activity and glutathione peroxidase-like activity (谓₀ = 123.5 渭M min^鈥?), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood鈥揵rain barrier model, 7d is able to penetrate the central nervous system.