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Título

New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and β-amyloid-reducing properties

Autor Fernández-Bachiller, María Isabel ; Pérez, Concepción; Monjas, Leticia ; Rademann, Jörg; Rodríguez-Franco, María Isabel
Fecha de publicación 2012
EditorAmerican Chemical Society
Citación Journal of Medicinal Chemistry 55: 1303- 1317 (2012)
ResumenBy 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 β-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. © 2012 American Chemical Society.
URI http://hdl.handle.net/10261/93277
DOI10.1021/jm201460y
Identificadoresdoi: 10.1021/jm201460y
issn: 0022-2623
e-issn: 1520-4804
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