Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase
Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase
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作为双位点乙酰胆碱酯酶抑制剂的香豆素-他克林杂化物的合成及其对丁基胆碱酯酶、Aβ聚集和β分泌酶的活性
DOI：
10.1016/j.bmc.2014.06.057
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发表时间：
2014-09-01
影响因子：
3.5
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Sun, Qi;Peng, Da-Yong;Yang, Guang-Fu
探索小分子乙酰胆碱酯酶(AChE)抑制剂以减缓乙酰胆碱(Ach)的分解是阿尔茨海默病(AD)治疗的主流方向。作为第一个被批准用于临床治疗AD的乙酰胆碱酯酶抑制剂，他克林已被广泛用作药效团来设计杂化化合物，以便将其有效的AChE抑制与其他多靶点结合起来。在本研究中，我们设计、合成了一系列新型的他克林-香豆素杂化化合物，并对其作为有效的双部位AChE抑制剂进行了评价。此外，化合物1g是最有效的候选化合物，其抗人AChE的效价(K-I=16.7 nM)比他克林(AChE的K-I=35.7 nM，BChE的K-I=8.7 nM)低约2倍。此外，一些他克林-香豆素杂交物同时显示出对Aβ聚集和β-分泌酶的抑制作用。因此，我们得出结论，他克林-香豆素杂合体是AD药物发现的一个有趣的多功能先导。(C)2014爱思唯尔有限公司。保留所有权利。
Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (K-i = 16.7 nM) against human AChE and about 2-fold lower potency (K-i = 16.1 nM) against BChE than tacrine (K-i = 35.7 nM for AChE, K-i = 8.7 nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both A beta aggregation and beta-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. (C) 2014 Elsevier Ltd. All rights reserved.