The highly complex pathophysiology of Alzheimer's disease (AD) and other neurodegenerative illnesses have led to replace the traditional one-drug - one-target by the multi-target-directed ligands (MTDLs) paradigm, in which a single molecule is designed to be active against several pharmacological targets. Continuing with our interest in neuroprotective and neurogenic compounds, in this work we describe a new family of donepezil flavonoid hybrids exhibiting nanomolar affinities for the sigma-1 receptor and a combined inhibition of key enzymes in AD, such as 5-lipoxygenase, acetylcholinesterase, and monoaminoxidases. In general, they scavenge free radical species and are predicted to be brain-permeable. In phenotypic assays, new hybrids protect neuronal cells against mitochondrial oxidative stress and promote maturation of neural stem cells into a neuronal phenotype. Therefore, new donepezil - flavonoid hybrids could contribute to the protection and even, the reparation of neuronal tissues, of great therapeutic interest in AD and neurodegenerative diseases.

Resumen del trabajo presentado a la XXXVIII Reunión Anual del Grupo Español de Neurotransmisión y Neuroprotección (GENN), celebrada en Almagro (Ciudad Real) del 13 al 15 de diciembre de 2017.

Spanish Ministry of Economy and Competitiveness MINECO (grant SAF2015-64948-C2-1-R) and Spanish National Research Council CSIC (grant PIE-201580E109).

Peer Reviewed