Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease.
J Enzyme Inhib Med Chem
; 38(1): 100-117, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-36519319
ABSTRACT
Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood-brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Alzheimer
Tipo de estudo:
Observational_studies
Limite:
Animals
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article