Abstract
A number of 1,2,3,4-tetrahydrochromeno[3,2-c]pyridin-10-one derivatives have been synthesized and screened against different targets involved in the onset and progression of Alzheimer's disease (AD), such as acetyl- and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of β-amyloid (Aβ) and reactive oxygen species (ROS) production. Derivatives 1 c, 3 b, 4 and 5 a showed multifaceted profiles of promising anti-AD features and returned well-balanced multitargeting inhibitory activities. Moreover, compound 1 f, a potent and selective human MAO B inhibitor (IC50 =0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ1-42 and pro-oxidant insult. Furthermore, structure-activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage.
Keywords:
Alzheimer's disease; inhibitors; medicinal chemistry; multitarget-directed ligands; tetrahydrochromenopyridinone.
© 2020 Wiley-VCH GmbH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / metabolism
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Alzheimer Disease / enzymology*
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Amyloid beta-Peptides / pharmacology
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Animals
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Butyrylcholinesterase / metabolism
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Cell Line, Tumor
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Cholinesterase Inhibitors / chemical synthesis
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Cholinesterase Inhibitors / metabolism
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Cholinesterase Inhibitors / pharmacology*
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Chromones / chemical synthesis
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Chromones / metabolism
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Chromones / pharmacology*
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Horses
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Humans
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Ligands
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Molecular Docking Simulation
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Molecular Structure
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Monoamine Oxidase / metabolism
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Monoamine Oxidase Inhibitors / chemical synthesis
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Monoamine Oxidase Inhibitors / metabolism
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Monoamine Oxidase Inhibitors / pharmacology*
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / pharmacology
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Protein Binding
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Pyridines / chemical synthesis
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Pyridines / metabolism
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Pyridines / pharmacology*
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Reactive Oxygen Species / metabolism
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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Chromones
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Ligands
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Monoamine Oxidase Inhibitors
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Neuroprotective Agents
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Peptide Fragments
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Pyridines
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Reactive Oxygen Species
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amyloid beta-protein (1-42)
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Monoamine Oxidase
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Acetylcholinesterase
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Butyrylcholinesterase