Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.
Bioorg Med Chem
; 13(24): 6588-97, 2005 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-16230018
ABSTRACT
A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Acetilcolinesterasa
/
Tacrina
/
Inhibidores de la Colinesterasa
/
Indanos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2005
Tipo del documento:
Article
País de afiliación:
España