"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.
Bioorg Med Chem
; 42: 116269, 2021 07 15.
Article
em En
| MEDLINE
| ID: mdl-34130217
ABSTRACT
Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetilcolinesterase
/
Butirilcolinesterase
/
Inibidores da Colinesterase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2021
Tipo de documento:
Article