New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and ß-amyloid-reducing properties.
J Med Chem
; 55(3): 1303-17, 2012 Feb 09.
Article
en En
| MEDLINE
| ID: mdl-22243648
ABSTRACT
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and ß-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Tacrina
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Benzopiranos
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Inhibidores de la Colinesterasa
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Péptidos beta-Amiloides
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Cromonas
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Enfermedad de Alzheimer
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Antioxidantes
Idioma:
En
Revista:
J Med Chem
Año:
2012
Tipo del documento:
Article
País de afiliación:
España