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). B...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/185467 |
| Acceso en línea: | http://hdl.handle.net/10261/185467 |
| Access Level: | acceso abierto |
| Palabra clave: | Multi-target-directed ligands Human cholinesterases Human lipoxygenase-5 Human b-secretase Alzheimer’s disease Neurodegenerative diseases Neurogenesis Sigma receptors |
| Sumario: | 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. |
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