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 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC₅₀ = 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 AlCl₃-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ_1-40. PET-CT imaging demonstrated that [¹¹C]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.

通过多目标定向配体（MTDLs）策略设计了一系列新的O-氨基甲酰基阿魏酰胺衍生物，合成并评估了这些衍生物用于治疗阿尔茨海默氏病（AD）。体外生物学评估表明，化合物4f是最佳的假不可逆h BChE（人丁酰胆碱酯酶）抑制剂，IC ₅₀值为0.97μM4f是有效的选择性MAO-B（单胺氧化酶B）抑制剂（IC ₅₀  = 5.3μM ），以及能抑制（58.2％）和集计（43.3％）的自介导的β聚集。4楼还可以降低病理性tau和APP清除水平，并且对LO2细胞显示出广泛的安全肝毒性。的体内研究显示，4F展示引人入胜的运动障碍恢复率和上的AlCl响应效率₃介导的斑马鱼，并表现出显著保护作用引起的血管损伤β _1-40。PET-CT成像显示[ ¹¹ C] 4f表现出较高的BBB渗透性（特别是可以到达海马体和大脑纹状体），静脉推注后脑吸收迅速。此外，化合物4f可以改善东pol碱引起的认知障碍。此外，还研究了4f的体外代谢，并显示了大鼠肝微粒体代谢中的3种代谢物，人肝微粒体中4种代谢物和大鼠肠道菌群中4种代谢物，为临床前研究提供了以前的数据。因此，这些结果表明化合物4f是一种先进的多功能药物，值得针对轻度服务的阿尔茨海默氏病进行进一步的临床前研究。