新型与 1,2,3-三唑相连的他克林-香豆素杂合体作为抗阿尔茨海默病化合物：体外和体内生物评价及对接研究。
Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer's compounds: In vitro and in vivo biological evaluation and docking study.
机构信息
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
出版信息
Bioorg Chem. 2019 Mar;83:303-316. doi: 10.1016/j.bioorg.2018.10.056. Epub 2018 Oct 28.
A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC = 27 nM) and compound 8m displayed the best anti-BChE activity (IC = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aβ which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats.
设计、合成并测试了一系列新型的与 1,2,3-三唑相连的他克林-香豆素杂合体，作为潜在的双结合位点乙酰胆碱酯酶抑制剂（ChEIs）用于治疗阿尔茨海默病（AD）。其中，化合物 8e 是最有效的抗 AChE 衍生物（IC = 27 nM），化合物 8m 表现出最好的抗 BChE 活性（IC = 6 nM），比作为参考药物的他克林和多奈哌齐活性更高。化合物 8e 还对其 BACE1 抑制活性和对暴露于 Aβ 的 PC12 细胞的神经保护活性进行了评估，结果表明活性较低。最后，通过 Morris 水迷宫任务的体内研究表明，化合物 8e 能显著逆转东莨菪碱诱导的大鼠记忆缺陷。
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