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), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). 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 σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.
Keywords:
Alzheimer’s disease; Multi-target-directed ligands; human cholinesterases; human lipoxygenase-5; human β-secretase; neurodegenerative diseases; neurogenesis; sigma receptors.
MeSH terms
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Arachidonate 5-Lipoxygenase / metabolism
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Aspartic Acid Endopeptidases / metabolism
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Butyrylcholinesterase / metabolism
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Flavonoids / chemistry
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Flavonoids / pharmacology*
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Humans
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Male
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Methylamines / chemistry
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Methylamines / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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Monoamine Oxidase / metabolism
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Nerve Regeneration / drug effects*
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
Substances
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Enzyme Inhibitors
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Flavonoids
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Methylamines
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Neuroprotective Agents
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Arachidonate 5-Lipoxygenase
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ALOX5 protein, human
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Monoamine Oxidase
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Acetylcholinesterase
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Butyrylcholinesterase
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
Grants and funding
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 – NRF24AD-CM 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. MEV 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).