Abstract
A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.
Keywords:
Anti-Alzheimer agent; Antioxidation; Aβ aggregation; Cholinesterase; Flavonoid.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Amyloid beta-Peptides / chemistry
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Animals
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Butyrylcholinesterase / chemistry
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Butyrylcholinesterase / metabolism
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Cell Death / drug effects
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Chemistry Techniques, Synthetic
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology*
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Cholinesterase Inhibitors / therapeutic use
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Dimethylamines / chemistry*
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Drug Design*
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Flavonoids / chemical synthesis*
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Flavonoids / chemistry
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Flavonoids / pharmacology*
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Flavonoids / therapeutic use
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Humans
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Hydrogen Peroxide / pharmacology
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Intracellular Space / drug effects
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Intracellular Space / metabolism
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Kinetics
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Molecular Docking Simulation
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PC12 Cells
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Peptide Fragments / chemistry
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Protein Aggregates / drug effects
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Protein Conformation
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Rats
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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Dimethylamines
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Flavonoids
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Peptide Fragments
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Protein Aggregates
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amyloid beta-protein (1-42)
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Hydrogen Peroxide
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Acetylcholinesterase
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Butyrylcholinesterase