Development of naringenin-O-carbamate derivatives as multi-target-directed liagnds for the treatment of Alzheimer's disease

  • Bioorg Med Chem Lett. 2022 Mar 15;60:128574. doi: 10.1016/j.bmcl.2022.128574.
Jing Mi  1 ,  Ying He  1 ,  Jing Yang  1 ,  Yi Zhou  1 ,  Gaofeng Zhu  2 ,  Anguo Wu  3 ,  Wenmin Liu  4 ,  Zhipei Sang  5
Affiliations
  • 1. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
  • 2. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, China.
  • 3. Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Southwest Medical University, Luzhou 646000, China. Electronic address: [email protected].
  • 4. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: [email protected].
  • 5. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: [email protected].
PMID: 35065231 DOI: 10.1016/j.bmcl.2022.128574
Abstract

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC50 = 9.7 μM) inhibitor. In addition, compound 3c significantly inhibited self-induced Aβ1-42 aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu2+-mediated Aβ1-42 aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood-brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD.

Keywords
Alzheimer’s disease; Blood-brain barrier penetration; Multi-function agents; Naringenin-O-carbamate derivatives.
Products