Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease

• Published in: European journal of medicinal chemistry Vol. 194; p. 112265
• Main Authors: Sang, Zhipei, Wang, Keren, Bai, Ping, Wu, Anguo, Shi, Jian, Liu, Wenmin, Zhu, Gaofeng, Wang, Yiling, Lan, Yu, Chen, Zude, Zhao, Yiyang, Qiao, Zhanpin, Wang, Changning, Tan, Zhenghuai
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-05-2020
• Subjects: Alzheimer’s disease; Metabolism in vitro; Multi-function agents; O-carbamoyl ferulamide derivatives; PET-CT imaging; Scopolamine-induced cognitive impairment; Zebrafish AD; Zebrafish AD; PET-CT imaging; Alzheimer’s disease; Multi-function agents; Scopolamine-induced cognitive impairment; O-carbamoyl ferulamide derivatives; Metabolism in vitro
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112265

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 Aβ1-40. 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.
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•4f was a promising multi-function agent in vitrol 4f showed fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish.•4f demonstrated significant protective effect on Aβ1-40-induced vascular injury.•PET-CT imaging revealed that [11C]4f exhibited high BBB penetration.•4f improved scopolamine-induced memory impairment.