Estrada Valencia, MartínHerrera Arozamena, ClaraPérez, ConcepciónViña Castelao, María DoloresMorales García, José A.Pérez Castillo, AnaRamos, EvaRomero, AlejandroLaurini, ErikPrici, SabrinaRodríguez Franco, María Isabel2020-04-062020-04-062019Martín Estrada-Valencia, Clara Herrera-Arozamena, Concepción Pérez, Dolores Viña, José A. Morales-García, Ana Pérez-Castillo, Eva Ramos, Alejandro Romero, Erik Laurini, Sabrina Pricl & María Isabel Rodríguez-Franco (2019). New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer's disease endowed with neurogenic properties, Journal of Enzyme Inhibition and Medicinal Chemistry, 34:1, 712-7271475-6366http://hdl.handle.net/10347/21198The 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), b-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (r1R/r2R). 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 r1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.eng© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedhttps://creativecommons.org/licenses/by/4.0/Multi-target-directed ligandsNeurogenesisSigma receptorsHuman b-secretaseHuman lipoxygenase-5Human cholinesterasesAlzheimer’s diseaseNeurodegenerative diseasesjournal article10.1080/14756366.2019.15811841475-6374open access