Journal of enzyme inhibition and medicinal chemistry, 2019-01, Vol.34 (1), p.712-727
2019
Details
- Autor(en) / Beteiligte
- Titel
- New flavonoid - N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties
- Ist Teil von
- Journal of enzyme inhibition and medicinal chemistry, 2019-01, Vol.34 (1), p.712-727
- Ort / Verlag
- England: Taylor & Francis
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 1 R/σ 2 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 1 R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1475-6366eISSN: 1475-6374DOI: 10.1080/14756366.2019.1581184Titel-ID: cdi_crossref_primary_10_1080_14756366_2019_1581184
- Format
- –
- Schlagworte
- Acetylcholinesterase - metabolism, Alzheimer Disease - drug therapy, Alzheimer Disease - metabolism, Alzheimer's disease, Amyloid Precursor Protein Secretases - antagonists & inhibitors, Amyloid Precursor Protein Secretases - metabolism, Animals, Arachidonate 5-Lipoxygenase - metabolism, Aspartic Acid Endopeptidases - antagonists & inhibitors, Aspartic Acid Endopeptidases - metabolism, Blood-Brain Barrier - drug effects, Blood-Brain Barrier - metabolism, Butyrylcholinesterase - metabolism, Enzyme Inhibitors - chemical synthesis, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Flavonoids - chemistry, Flavonoids - pharmacology, human cholinesterases, human lipoxygenase-5, human β-secretase, Humans, Male, Methylamines - chemistry, Methylamines - pharmacology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, Molecular Structure, Monoamine Oxidase - metabolism, Multi-target-directed ligands, Nerve Regeneration - drug effects, neurodegenerative diseases, neurogenesis, Neuroprotective Agents - chemical synthesis, Neuroprotective Agents - chemistry, Neuroprotective Agents - pharmacology, Research Paper, sigma receptors