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Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease

AuthorsEstrada Valencia. Martín; Herrera-Arozamena, Clara; Andrés, L. de; Pérez, Concepción; Morales-García, José A. ; Pérez-Castillo, Ana; Ramos, Eva; Romero, Alejandro ; Viña, Dolores; Yáñez, Matilde; Laurini, E.; Pricl, Sabrina; Rodríguez-Franco, María Isabel
KeywordsDonepezil-flavonoid hybrids
Human monoamine oxidases
Human 5-lipoxygenase
Human acetylcholinesterase
Sigma receptors
Issue Date2018
CitationEuropean Journal of Medicinal Chemistry 156: 534-553 (2018)
AbstractIn this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in sigma1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and sigma-1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.
Publisher version (URL)https://doi.org/10.1016/j.ejmech.2018.07.026
Identifiersdoi: 10.1016/j.ejmech.20168.07.026
issn: 0223-5234
e-issn: 1768-3254
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