Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors.
Bioorg Med Chem Lett
; 28(17): 2910-2913, 2018 09 15.
Article
em En
| MEDLINE
| ID: mdl-30017317
ABSTRACT
A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7â¯nM) and BACE-1 inhibition (IC50 value of 13.1â¯nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Inibidores da Colinesterase
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Ácido Aspártico Endopeptidases
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Secretases da Proteína Precursora do Amiloide
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Donepezila
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article