Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase

被引：95

作者：

Catto, Marco ^{[1
]}

Pisani, Leonardo ^{[1
]}

Leonetti, Francesco ^{[1
]}

Nicolotti, Orazio ^{[1
]}

Pesce, Paolo ^{[1
]}

Stefanachi, Angela ^{[1
]}

Cellamare, Saverio ^{[1
]}

Carotti, Angelo ^{[1
]}

机构：

[1] Univ Bari Aldo Moro, Dipartimento Farm, I-70125 Bari, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 01期

关键词：

Alzheimer's disease; Coumarin derivatives; Acetylcholinesterase; Dual binding site inhibitors; Selective cholinesterase inhibition; ALZHEIMERS-DISEASE; CHOLINESTERASE-INHIBITORS; MONOAMINE OXIDASES; ACHE INHIBITORS; HIGHLY POTENT; DERIVATIVES; HYPOTHESIS; STRATEGY; LIGANDS; DRUGS;

D O I：

10.1016/j.bmc.2012.10.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：146 / 152

页数：7

共 30 条

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