New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties

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).