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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >N-alkylpiperidine carbamates as potential anti-Alzheimer's agents
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N-alkylpiperidine carbamates as potential anti-Alzheimer's agents

机译：N-烷基哌啶氨基甲酸酯作为潜在的抗Alzheimer的药剂

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摘要

Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 mu M), BChE (IC50 = 0.56 mu M) and MAO-B (IC50 = 26.1 mu M) inhibitor 10, dual AChE (IC50 = 2.25 mu M) and BChE (IC50 = 0.81 mu M) inhibitor 22, selective BChE (IC50 = 0.06 mu M) inhibitor 13, and selective MAO-B (IC50 = 0.18 mu M) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid beta(1-42) (A beta(1-42))-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its A beta(1-42) anti-aggregation effects. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：能够与参与阿尔茨海默病（AD）发病机制的单一或多种靶向相互作用的化合物是潜在的抗阿尔茨海默氏症的药剂。在我们的旨在开发新的抗阿尔茨海默氏菌剂，设计了一系列36种新的N-烷基哌啶氨基甲酸酯，合成和评价胆碱酯酶的抑制[乙酰胆碱酯酶（ACHE）和丁酰胆碱酯酶（BCHE）]和单胺氧化酶[单胺氧化酶A（ Mao-A和单胺氧化酶B（MAO-B）]。四种化合物非常有前途：多次疼痛（IC50 =7.31μm），BCHE（IC50 =0.56μm）和MAO-B（IC50 =26.1μm）抑制剂10，双疼痛（IC50 =2.25μm）和BCHE（IC50 =0.81μm）抑制剂22，选择性BCHE（IC50 =0.06μm）抑制剂13，以及选择性MAO-B（IC50 =0.18μm）抑制剂16。酶动力学实验结果表明，尽管结构中的氨基甲酸酯基团，化合物10,13和22是可逆的ache和/或BCHE的不计时抑制剂。BCHE复合物的分辨晶体结构与化合物13证实了非共价抑制机制。另外，N-丙基哌啶16是IRREVER MAO-B的综合和时间依赖性抑制剂，而N-苄基哌啶10是可逆的。另外，化合物10,13,16和22应该能够穿过血脑屏障，并且不是人类神经元的SH-SY5Y和肝HEPG2细胞的细胞毒性。最后，化合物10和16还防止淀粉样蛋白β（1-42）（β（1-42）） - 诱导的神经元细胞死亡。化合物16的神经保护作用可能是其β（1-42）抗聚集效应的结果。 （c）2020 Elsevier Masson SAS。版权所有。

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