2. Academic Validation
  3. Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease

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

  • Eur J Med Chem. 2020 May 15;194:112265. doi: 10.1016/j.ejmech.2020.112265.
Zhipei Sang 1,  Keren Wang 2,  Ping Bai 3,  Anguo Wu 4,  Jian Shi 2,  Wenmin Liu 2,  Gaofeng Zhu 5,  Yiling Wang 4,  Yu Lan 6,  Zude Chen 6,  Yiyang Zhao 2,  Zhanpin Qiao 2,  Changning Wang 7,  Zhenghuai Tan 8
Affiliations

Affiliations

  • 1 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China. Electronic address: [email protected].
  • 2 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
  • 3 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA; Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, 473061, China.
  • 4 Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Southwest Medical University, Luzhou, 646000, China.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.
  • 6 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
  • 7 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. Electronic address: [email protected].
  • 8 Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 32240904 DOI: 10.1016/j.ejmech.2020.112265
Abstract

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.

Keywords

Alzheimer’s disease; Metabolism in vitro; Multi-function agents; O-carbamoyl ferulamide derivatives; PET-CT imaging; Scopolamine-induced cognitive impairment; Zebrafish AD.

Figures
Products