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

European Journal of Medicinal Chemistry
Martín Estrada ValenciaMaría Isabel Rodríguez-Franco

Abstract

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) 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 σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.

Citations

Apr 4, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anaïs BarréVincent Levacher
Dec 20, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Martín Estrada-ValenciaMaría Isabel Rodríguez-Franco
Sep 4, 2020·Oxidative Medicine and Cellular Longevity·Mayara Dos Santos MaiaFrancisco Jaime B Mendonça-Junior
Jun 3, 2021·International Journal of Molecular Sciences·Héctor Torres-GómezBernhard Wünsch
Jul 3, 2021·International Journal of Molecular Sciences·Francesca Serena AbatematteoCarmen Abate
Dec 7, 2018·ACS Chemical Neuroscience·Huan Wang, Haiyan Zhang
Apr 22, 2021·CNS & Neurological Disorders Drug Targets·Himanshi Varshney, Yasir Hasan Siddique

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