Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors
Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors
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DOI：
10.1016/j.bmc.2009.12.035
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发表时间：
2010-02-01
影响因子：
3.5
通讯作者：
Li, Xingshu
中科院分区：
文献类型：
--
作者：
Huang, Ling;Shi, Anding;Li, Xingshu
针对乙酰胆碱酯酶(AChE)的双重活性部位，设计、合成了一系列新的黄连素类化合物，并对其作为乙酰胆碱酯酶抑制剂进行了评价。大多数衍生物在亚微摩尔范围内抑制AChE。化合物8c通过4碳间隔区与苯酚偶联，对AChE的抑制作用最强。对AChE和BuChE的动力学研究表明，这些黄连素衍生物存在混合竞争结合模式。分子模拟研究证实，这些杂化化合物既针对AChE的催化活性中心(CAS)，也针对其外周阴离子中心(PAS)。这是黄连素作为先导分子与AChE抑制活性相关的第一个报告。(C)2009爱思唯尔有限公司。保留所有权利。
By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule. (C) 2009 Elsevier Ltd. All rights reserved.