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
  • 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.
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