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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease
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Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease

机译：新型O-碳酰胺二胺衍生物的设计，合成及生物学评价为用于治疗阿尔茨海默病的多目标针对配体

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摘要

A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 mu M 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 mu M), and could inhibit (58.2%) and disaggregate (43.3%) selfmediated Ad aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AICI(3)-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by A beta(1-40). PET-CT imaging demonstrated that [C-11]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：一种新型系列O型氨基甲酰基ferulamide衍生物的是由多目标定向配体（MTDLs）策略设计的，该衍生物的合成和评价，以治疗阿尔茨海默氏病（AD）。体外生物学评价，结果证实化合物4F是最好的伪不可逆转hBChE（人丁酰胆碱酯酶）抑制剂0.97亩的IC 50值M 4F是一个有效的选择性MAO-B（单胺氧化酶B）抑制剂（IC 50 = 5.3微米） ，并能抑制（58.2％）和分类（43.3％）selfmediated广告聚集。 4F还可以减少病理性tau蛋白和APP清除的水平，并显示在LO2细胞广泛的安全范围内的肝毒性。体内研究表明，4F上AICI（3）介导的斑马鱼表现出令人着迷的运动障碍恢复率和响应效率，并表现出对引起的Aβ（1-40）血管损伤显著保护作用。 PET-CT成像显示，[C-11] 4F显示出高BBB渗透（特别是可以达到给海马和大脑的纹状体）和过静脉推注后快速脑摄取。此外，复合4F能改善东莨菪碱引起的认知障碍。此外，在4f的体外代谢还研究，并提出了在大鼠肝脏微粒体代谢3种代谢物，代谢物4在人类肝微粒体，和4组的代谢物在大鼠肠道菌群，对于临床前研究提供先前的数据。因此，这些结果暗示，化合物4F是一个先进的多功能代理和值得进一步临床前研究对轻度到服务阿尔茨海默氏病。 （c）2020 Elsevier Masson SAS。版权所有。

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