College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
Eur J Med Chem. 2020 May 15;194:112265. doi: 10.1016/j.ejmech.2020.112265. Epub 2020 Mar 24.
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 IC value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ 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 AlCl-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ. PET-CT imaging demonstrated that [C]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.
设计了一系列新型的 O-邻苯二甲酰基阿魏酰胺衍生物，采用多靶点导向配体（MTDLs）策略，合成并评价了这些衍生物治疗阿尔茨海默病（AD）的活性。体外生物学评价表明，化合物 4f 是最好的假性不可逆 hBChE（人丁酰胆碱酯酶）抑制剂，IC 值为 0.97μM。4f 是一种有效的选择性 MAO-B（单胺氧化酶-B）抑制剂（IC = 5.3μM），能够抑制（58.2%）和解聚（43.3%）自身介导的 Aβ 聚集。4f 还可以降低病理性 tau 和 APP 的清除水平，并在 LO2 细胞上显示出广泛的安全范围的肝毒性。体内研究表明，4f 对 AlCl 介导的斑马鱼表现出迷人的运动障碍恢复率和反应效率，对 Aβ 引起的血管损伤具有显著的保护作用。PET-CT 成像表明 [C]4f 具有较高的 BBB 穿透性（尤其是可以到达大脑的海马体和纹状体），静脉推注后具有较快的脑摄取。此外，化合物 4f 可以改善东莨菪碱诱导的认知障碍。进一步研究了 4f 的体外代谢情况，在大鼠肝微粒体代谢中发现了 3 种代谢产物，在人肝微粒体中发现了 4 种代谢产物，在大鼠肠道菌群中发现了 4 种代谢产物，为临床前研究提供了前期数据。因此，这些结果表明化合物 4f 是一种先进的多功能药物，值得进一步进行针对轻度至中度阿尔茨海默病的临床前研究。
