New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties
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Title: | New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties |
Author: | Estrada Valencia, Martín Herrera Arozamena, Clara Pérez, Concepción Viña Castelao, María Dolores Morales García, José A. Pérez Castillo, Ana Ramos, Eva Romero, Alejandro Laurini, Erik Prici, Sabrina Rodríguez Franco, María Isabel |
Affiliation: | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
Subject: | Multi-target-directed ligands | Neurogenesis | Sigma receptors | Human b-secretase | Human lipoxygenase-5 | Human cholinesterases | Alzheimer’s disease | Neurodegenerative diseases | |
Date of Issue: | 2019 |
Publisher: | Taylor & Francis |
Citation: | Martín 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, 712-727 |
Abstract: | 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), 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. |
Publisher version: | https://doi.org/10.1080/14756366.2019.1581184 |
URI: | http://hdl.handle.net/10347/21198 |
DOI: | 10.1080/14756366.2019.1581184 |
ISSN: | 1475-6366 |
E-ISSN: | 1475-6374 |
Rights: | © 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 cited |
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Except where otherwise noted, this item's license is described as © 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 cited