Estrada Valencia, MartínHerrera Arozamena, ClaraAndrés Gordo, Lucía dePérez, ConcepciónMorales García, José A.Pérez Castillo, AnaRamos, EvaRomero, AlejandroViña Castelao, María DoloresYáñez Jato, MatildeLaurini, ErikPricl, SabrinaRodríguez Franco, María Isabel2024-02-082024-02-082018Martín Estrada Valencia, Clara Herrera-Arozamena, Lucía de Andrés, Concepción Pérez, José A. Morales-García, Ana Pérez-Castillo, Eva Ramos, Alejandro Romero, Dolores Viña, Matilde Yáñez, Erik Laurini, Sabrina Pricl, María Isabel Rodríguez-Franco, Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease, European Journal of Medicinal Chemistry, Volume 156, 2018, Pages 534-553, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2018.07.026.0223-5234http://hdl.handle.net/10347/32592In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (s1R) 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 σ1R, 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 s1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHsengCC BY-NC-ND 4.0Donepezil-flavonoid hybridsNeurogenesisNeuroprotectionSigma receptorsHuman acetylcholinesteraseHuman 5-lipoxygenaseHuman monoamine oxidases3209journal article10.1016/J.EJMECH.2018.07.026open access