Dipartimento di Farmacia, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, Bari 70125, Italy.
Bioorg Med Chem. 2013 Jan 1;21(1):146-52. doi: 10.1016/j.bmc.2012.10.045. Epub 2012 Nov 7.
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 (IC(50) 7.6 nM) resulted in a mixed-type, thus confirming its binding at both the catalytic and peripheral binding sites of AChE.
乙酰胆碱酯酶抑制剂（AChEIs）是目前治疗阿尔茨海默病（AD）的首选药物，虽然只能对症治疗和缓解症状。多奈哌齐是 AD 治疗中使用最广泛的 AChEI 之一，作为一种双重结合部位、对乙酰胆碱酯酶（AChE）具有高选择性的可逆抑制剂，对丁酰胆碱酯酶（BChE）具有较高的选择性。通过联合的基于靶点和基于配体的方法，设计并合成了一系列符合多奈哌齐结构决定因素的香豆素烷基胺。带有可质子化的苄氨基的 6,7-二甲氧基香豆素衍生物，通过合适的连接子连接到 3 位，表现出相当好的 AChE 抑制活性和对 BChE 的高选择性。间隔基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。对最活性化合物 13（IC（50）7.6 nM）进行的抑制机制评估结果为混合型，从而证实其结合在 AChE 的催化和外周结合部位。
