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.
Copyright © 2022 Elsevier Ltd. All rights reserved.
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