Abstract

The concept of multitarget-directed ligands (MTDLs) has attracted considerable interest in the development of agents against Alzheimer’s disease. Cathepsin B, a cysteine protease, and butyrylcholinesterase, a serine hydrolase, play important function in the development and progression of Alzheimer’s disease. We present herein the evaluation of 8-hydroxyquinoline-based analogues with activities against butyrylcholinesterase and β-secretase activity of cathepsin B. Furthermore, inhibition of amyloid β aggregation, chelation of copper and zinc ions coupled with antioxidative properties and safe cytotoxicity profile of (1R,2S)-N-ethyl-2-[[(8-hydroxy-5-nitroquinolin-7-yl)methyl]amino]cyclohexane-1-carboxamide suggest that this derivative is a good starting point for optimization towards an effective multifunctional ligand.

Graphic abstract

中文翻译：

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基于8-羟基喹啉的抗阿尔茨海默病多峰剂

摘要

定向多配体（MTDLs）的概念已引起人们对对抗阿尔茨海默氏病的药物的兴趣。组织蛋白酶B（一种半胱氨酸蛋白酶）和丁酰胆碱酯酶（一种丝氨酸水解酶）在阿尔茨海默氏病的发生和发展中起重要作用。我们在本文中对基于8羟基喹啉的类似物进行评估，该类似物具有对组织蛋白酶B的丁酰胆碱酯酶和β-分泌酶活性的活性。此外，淀粉样蛋白β聚集的抑制，铜和锌离子的螯合以及抗氧化特性和（1R的安全细胞毒性），2S）-N-乙基-2-[[（（8-羟基-5-硝基喹啉-7-基）甲基]氨基]环己烷-1-羧酰胺表明该衍生物是优化有效的多功能配体的良好起点。

图形摘要