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

Jing Mi; Ying He; Jing Yang; Yi Zhou; Gaofeng Zhu; Anguo Wu; Wenmin Liu; Zhipei Sang

doi:10.1016/j.bmcl.2022.128574

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. Epub 2022 Jan 19.

Authors

Jing Mi¹, Ying He¹, Jing Yang¹, Yi Zhou¹, Gaofeng Zhu², Anguo Wu³, Wenmin Liu⁴, Zhipei Sang⁵

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: wuanguo@swmu.edu.cn.
⁴ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: liuwm1969@163.com.
⁵ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: sangzhipei@126.com.

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 Aβ_1-42 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 Aβ_1-42 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Animals
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Butyrylcholinesterase / metabolism
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Cell Line
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Copper / pharmacology
Dose-Response Relationship, Drug
Drug Development
Flavanones / chemical synthesis
Flavanones / chemistry
Flavanones / pharmacology*
Humans
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Protein Aggregates / drug effects
Rats
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Carbamates
Cholinesterase Inhibitors
Flavanones
Neuroprotective Agents
Peptide Fragments
Protein Aggregates
amyloid beta-protein (1-42)
Copper
Acetylcholinesterase
Butyrylcholinesterase
naringenin