Tacrine-香豆素和 Tacrine-7-氯喹啉硫脲连接物：胆碱酯酶抑制特性、动力学研究、分子对接和血脑屏障渗透性测定。
Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier.
机构信息
Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P.J. Safarik University, Moyzesova 11, SK-041 67 Kosice, Slovakia.
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
出版信息
Curr Alzheimer Res. 2018;15(12):1096-1105. doi: 10.2174/1567205015666180711110750.
BACKGROUND
The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets.
METHODS
All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively.
RESULTS
In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier.
CONCLUSION
Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.
背景
设计新的杂合双结合位点乙酰胆碱酯酶抑制剂是开发具有扩展药理学特性的新型抗胆碱酯酶药物的主要目标导向。多靶点化合物通常通过将两个或更多已知能够与所选分子靶标相互作用的药效团组合在一个杂合分子中来设计。
方法
所有化合物均测试其对人 AChE/BChE 的抑制活性。采用 Ellman 法测定抑制动力学和 IC50 值。为了预测新型化合物的被动血脑渗透，对平行人工膜渗透测定法进行了修改。进行对接研究以预测新杂合物与 hAChE/hBChE 的结合模式。
结果
在这项研究中，我们描述了一系列他克林-香豆素和他克林-喹啉化合物的设计、合成和评价，这些化合物被发现具有潜在的抑制 ChE 和穿透血脑屏障的作用。
结论
他克林-喹啉杂合体 7a 对 hBChE 的活性最高（IC50 = 0.97 µmol），7d 对 hAChE 的活性最高（IC50 = 0.32 µmol）。动力学和分子建模研究表明，7d 是一种混合型 AChE 抑制剂（Ki = 1.69 µmol），7a 是一种混合型 BChE 抑制剂（Ki = 1.09 µmol）。此外，杂合体 5d 和 7c 可以穿透中枢神经系统。
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