Zhang Chao, Du Qiao-Yi, Chen Lang-Di, Wu Wen-Hao, Liao Si-Yan, Yu Li-Hong, Liang Xin-Tong
School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, PR China.
Eur J Med Chem. 2016 Jun 30;116:200-209. doi: 10.1016/j.ejmech.2016.03.077. Epub 2016 Mar 29.
A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aβ aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.
设计、合成并评估了一系列苯甲酸酯（或苯乙酸酯或肉桂酸酯）-他克林杂合物（7a-o）作为多效抗阿尔茨海默病候选药物。筛选结果表明，它们中的大多数表现出显著的抑制胆碱酯酶的能力，对乙酰胆碱酯酶（AChE）相对于丁酰胆碱酯酶（BuChE）具有一定的选择性，并且对自身诱导的β-淀粉样蛋白（Aβ）聚集具有强效抑制作用。所有生物活性的IC50值均在纳摩尔范围内。特别是，化合物7c表现出最大的抑制AChE的能力，IC50值为5.63 nM，并且具有最高的选择性，BuChE/AChE值的比率为64.6。此外，它还表现出对Aβ聚集的强效抑制作用，IC50值为51.81 nM。Lineweaver-Burk图和分子模拟研究表明，化合物7c靶向胆碱酯酶的催化活性位点（CAS）和外周活性位点（PAS）。构效关系分析表明，通过乙酰基与他克林相连的芳环的电子密度在确定抑制活性方面起着重要作用。
