Abstract
In this study, a series of naringenin-O-alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC50 values of 0.91 μM and 0.57 μM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aβ1-42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aβ1-40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu2+-induced Aβ1-42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.
Keywords:
Alzheimer’s disease; multifunctional agents; naringenin-O-alkylamine derivatives; scopolamine-induced mice memory impairment.
MeSH terms
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Amines / chemical synthesis
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Amines / chemistry
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Amines / pharmacology*
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / metabolism
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Animals
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Antioxidants / chemical synthesis
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Antioxidants / chemistry
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Antioxidants / pharmacology*
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Butyrylcholinesterase / metabolism
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Cell Line
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Cell Survival / drug effects
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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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Dose-Response Relationship, Drug
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Drug Development
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Flavanones / chemical synthesis
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Flavanones / chemistry
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Flavanones / pharmacology*
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Humans
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Mice
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Protein Aggregates / drug effects
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Rats
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Structure-Activity Relationship
Substances
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Amines
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Amyloid beta-Peptides
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Antioxidants
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Cholinesterase Inhibitors
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Flavanones
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Neuroprotective Agents
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Protein Aggregates
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Acetylcholinesterase
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Butyrylcholinesterase
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naringenin
Grants and funding
This work was supported by funding from the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University (Grant number FAMP202107K); Guizhou Science and Technology Platform Talents (QKHRCPT[2019]5627). And the Special Project of Nanyang Normal University (2022QN003 and 2020ZX015).