2. Academic Validation
  3. Development of naringenin-O-carbamate derivatives as multi-target-directed liagnds for the treatment of Alzheimer's disease

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

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.

Figures
Products