Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation.
Chem Biol Drug Des
; 103(4): e14529, 2024 Apr.
Article
in En
| MEDLINE
| ID: mdl-38670598
ABSTRACT
With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and ß-amyloid (Aß) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu2+ ions), antioxidation, self-induced, Cu2+-induced, and AChE-induced Aß aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10-8 M magnitude) and BuChE (10-7 M magnitude) and showed the best inhibition on AChE-induced Aß aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acetylcholinesterase
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Flavonoids
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Butyrylcholinesterase
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Blood-Brain Barrier
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Drug Design
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Cholinesterase Inhibitors
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Amyloid beta-Peptides
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Reactive Oxygen Species
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Caenorhabditis elegans
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Alzheimer Disease
Limits:
Animals
/
Humans
Language:
En
Journal:
Chem Biol Drug Des
Journal subject:
BIOQUIMICA
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FARMACIA
/
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Publication country:
ENGLAND
/
ESCOCIA
/
GB
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GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM