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Alzheimer’s disease (AD) is a neurodegenerative illness characterized by a progressive loss of neurons in specific areas, such as forebrain, neocortex and subcortical cholinergic projections from nucleus basalis of Meynert. Loss of cholinergic neurons entails low levels of acetylcholine (ACh); this diminished amount of neurotransmitter is responsible for the disruption in the neuronal transmission between the cells involved in learning and memory processes. This interruption in neuronal communication is the origin of the cognitive symptoms of AD such as memory loss, incapacity to learn, to reason, to make judgments and failure to communicate. Understanding of disruption in cholinergic system led to acetylcholinesterase (AChE) as the first target in the search of therapeutic agents to treat AD. Acetylcholinesterase inhibitors (AChEi) were the first class of drugs successfully used in the symptomatic treatment of this disease. However, despite the improvement in cognitive and behavioral impairments in patients treated with AChEi’s, this kind of drugs is not able to stop the neurodegeneration. Explaining the origin of cognitive symptoms is not enough to understand the real cause of neurodegeneration in AD. Nowadays, beta-amyloid peptide (Aβ) is considered the initiating substance in the process leading to neuronal death. Insoluble Aβ fibrils are the main constituent of the senile plaques, which are considered the toxic element triggering the cascade of cellular responses that finally produce degeneration and death of neurons. Some of these events are neuro-inflammation, production of reactive oxygen species (ROS) and tau protein hyper phosphorylation...

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid–DBMA hybrids (1–13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer’s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ R/σ R). After a funnel-type screening, 6,7-dimethoxychromone–DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration., The authors gratefully acknowledge the following financial supports: Spanish Ministry of Science, Innovation and Universities (grants SAF2015-64948-C2-1-R and RTI2018-093955-B-C21 to MIRF; grant SAF2017-85199-P to APC), Spanish National Research Council (CSIC, grant PIE-201580E109 to MIRF), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 – NRF24ADCM to MIRF), Consellería de Cultura, Educación e Ordenación Universitaria de Galicia, and the European Regional Development Fund (ERDF) (accreditation 2016–2019, ED431G/05 to DV). EL and SP gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research. and CH-A also thank their PhD fellowships from Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS, Colombia) and Spanish Ministry of Education (MEC, grant FPU16/01704), respectively. JAM-G is a fellow from the Biomedical Research Networking Centre on Neurodegenerative Diseases (CIBERNED, Spain).

In 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., Financial supports from the Spanish Ministry of Economy, Industry, and Competitiveness (MEICOM, grant SAF2015-64948-C2- 1-R to MIRF; grant SAF2014-52940-R to APC), Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109 to MIRF), and Dirección General de Investigación e Innovación de la Comunidad de Madrid (DGII-CM, grant B2017/BMD-3827, acronym NRF24AD-CM to MIRF) are gratefully acknowledged. DV thanks financial support from the Consellería de Cultura, Educación e Ordenación Universitaria, Centro Singular de Investigación de Galicia and the European Regional Development Fund (ERDF) (accreditation 2016e2019, ED431G/05). MEV and CH-A thank their Ph.D. fellowships from COLCIENCIAS (Colombia) and MEC (FPU16/ 01704, Spain), respectively