Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors.
Bioorg Chem
; 80: 245-252, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-29966870
Multi-target-directed ligands (MTDLs) centered on ß-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11â¯nM) and BACE-1 inhibition (IC50 value of 18.3â¯nM) in comparison to donepezil (IC50 values of 6.21 and 194â¯nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetilcolinesterasa
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Diseño de Fármacos
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Inhibidores de la Colinesterasa
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Ácido Aspártico Endopeptidasas
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Secretasas de la Proteína Precursora del Amiloide
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Donepezilo
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Estados Unidos