Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase
Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase
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DOI：
10.1016/j.bmc.2012.10.045
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发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Carotti, Angelo
中科院分区：
文献类型：
--
作者：
Catto, Marco;Pisani, Leonardo;Carotti, Angelo
乙酰胆碱酯酶抑制剂（AChEI）是目前治疗阿尔茨海默病（AD）的首选药物，尽管仅具有对症和姑息作用。多奈哌齐是AD治疗中最常用的AChEI之一，作为双结合位点的AChE可逆抑制剂，对丁酰胆碱酯酶（BChE）具有高度选择性。通过结合靶向和配体的方法，设计并制备了一系列与多奈哌齐结构决定簇相匹配的香豆素烷基胺。通过合适的连接子将可质子化的苄氨基连接到3位上的6，7-二甲氧基香豆素衍生物显示出相当好的AChE抑制活性和对BChE的高选择性。间隔子的长度和形状以及香豆素支架上的甲氧基取代基强烈影响抑制效力。对最具活性的化合物13（IC 50 7.6 nM）评估的抑制机制导致混合型，从而证实了其在AChE的催化和外周结合位点处的结合。(C)2012爱思唯尔有限公司保留所有权利。
Acetylcholinesterase inhibitors (AChEIs) are currently the drugs of choice, although only symptomatic and palliative, for the treatment of Alzheimer's disease (AD). Donepezil is one of most used AChEIs in AD therapy, acting as a dual binding site, reversible inhibitor of AChE with high selectivity over butyrylcholinesterase (BChE). Through a combined target-and ligand-based approach, a series of coumarin alkylamines matching the structural determinants of donepezil were designed and prepared. 6,7-Dimethoxycoumarin derivatives carrying a protonatable benzylamino group, linked to position 3 by suitable linkers, exhibited fairly good AChE inhibitory activity and a high selectivity over BChE. The inhibitory potency was strongly influenced by the length and shape of the spacer and by the methoxy substituents on the coumarin scaffold. The inhibition mechanism, assessed for the most active compound 13 (IC50 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE. (C) 2012 Elsevier Ltd. All rights reserved.