New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation
New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation
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DOI：
10.1080/14756366.2016.1220377
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发表时间：
2016-01-01
影响因子：
5.6
通讯作者：
Scipione, Luigi
中科院分区：
文献类型：
--
作者：
De Vita, Daniela;Pandolfi, Fabiana;Scipione, Luigi
合成了一系列含有N，N-二苄氨基的N，N-二甲基氨基甲酸酯类化合物，并对其抑制乙酰胆碱酯酶(AChE)的能力进行了测试。活性最强的化合物4和8在50亩M处的抑制率分别为85%和69%。在此基础上，提出了一些基本的构效关系规律：6个亚甲基的烷基连接基团是氨基甲酰基和二苄基氨基之间的最佳间隔基；二苄氨基上芳环上的引电子取代基降低了抑制能力。化合物4对AChE有缓慢的抑制作用，化合物4对AChE的时间依赖性抑制实验和MALDI-TOF MS分析表明，化合物4对AChE的抑制作用不是由于酶的氨甲酰化作用所致。相反，化合物4可以作为AChE的慢结合抑制剂，这可能是因为化合物4的直链具有较高的构象自由度。
A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mu M, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.