Repurposing of 8-Hydroxyquinoline-Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors.
ChemMedChem
; 17(5): e202100694, 2022 03 04.
Article
em En
| MEDLINE
| ID: mdl-34994078
ABSTRACT
A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened inâ
vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35â
µM and 50â
nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20â
µM. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3 , histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Butirilcolinesterase
/
Catepsina B
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2022
Tipo de documento:
Article