Novel Tacrine–Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography

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• 作者：Xiaoming Zha ; Doriano Lamba ; Lili Zhang ; Yinghan Lou ; Changxu Xu ; Di Kang ; Li Chen ; Yungen Xu ; Luyong Zhang ; Angela De Simone ; Sarah Samez ; Alessandro Pesaresi ; Jure Stojan ; Manuela G. Lopez ; Javier Egea ; Vincenza Andrisano ; Manuela Bartolini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：114-131
• 全文大小：679K
• ISSN：1520-4804

文摘

Twenty-six new tacrine–benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer’s disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC₅₀ = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC₅₀ = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.