某些半刚性螺环杂环的胆碱酯酶抑制活性：POM 分析和药效团部位的晶体结构。
Cholinesterase Inhibitory Activity of Some semi-Rigid Spiro Heterocycles: POM Analyses and Crystalline Structure of Pharmacophore Site.
机构信息
LCM Laboratory, Sciences Faculty, Mohammed Premier University, Oujda 60000, Morocco.
QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
出版信息
Mini Rev Med Chem. 2018;18(8):711-716. doi: 10.2174/1389557517666170713114039.
BACKGROUND
Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD.
OBJECTIVE
our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses.
METHOD
In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 µg/mL.
RESULTS
Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits.
CONCLUSIONS
Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%.
背景
胆碱酯酶家族由两种姐妹酶组成；乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE），它们水解乙酰胆碱。由于阿尔茨海默病（AD）患者的乙酰胆碱缺乏，胆碱酯酶抑制剂目前是治疗 AD 的最常用药物。
目的
本文旨在研究 5 种具有螺环骨架的已知化合物（2-6）对 AChE 和 BChE 的抑制潜力，采用 ELISA 微孔板检测法。除了它们的 ChE 抑制作用外，还计算了它们的物理化学性质。此外，本工作旨在研究生物活性基团中假设的药效团或双齿位点的电荷/几何效应对螺环化合物 2-6 抑制效率的影响，采用 Petra/Osiris/mol inspiration（POM）和 X 射线分析。
方法
在本研究中，合成了 5 种螺环骨架化合物（2-6），并在 25 µg/mL 下通过 ELISA 微量滴定板检测法体外测试了它们对 AChE 和 BChE 的抑制潜力。
结果
结果表明，测试的 5 种螺环化合物中有 3 种对一种以上的胆碱酯酶表现出超过 50%的抑制作用。化合物 5 对 AChE 的抑制率为 68.73 ± 4.73%，而化合物 6 对 BChE 的抑制率为 56.17 ± 0.83%；这两种先前合成的化合物是最活跃的化合物。
结论
我们从化合物 2-6 对两种胆碱酯酶的筛选中获得的数据表明，其中 3 种对选择性抑制 AChE 或 BChE 具有良好的潜力。螺环化合物 2、5 和 6 对 AChE 或 BChE 表现出最有效的活性，抑制率在 55-70%范围内。
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