Abstract
A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Amyloid beta-Peptides / chemistry
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Animals
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Azoles / chemical synthesis*
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Azoles / metabolism
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Azoles / pharmacology*
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Azoles / toxicity
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Butyrylcholinesterase / metabolism
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Chemistry Techniques, Synthetic
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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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Cholinesterase Inhibitors / toxicity
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Donepezil
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Electrophorus
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Glutathione Peroxidase / metabolism
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Humans
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Indans / chemical synthesis*
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Indans / metabolism
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Indans / pharmacology*
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Indans / toxicity
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Isoindoles
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Kinetics
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Ligands
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Mice
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Molecular Docking Simulation
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Molecular Targeted Therapy*
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Organoselenium Compounds / chemical synthesis*
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Organoselenium Compounds / metabolism
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Organoselenium Compounds / pharmacology*
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Organoselenium Compounds / toxicity
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Peptide Fragments / chemistry
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Peroxynitrous Acid / metabolism
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Piperidines / chemical synthesis*
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Piperidines / metabolism
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Piperidines / pharmacology*
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Piperidines / toxicity
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Protein Multimerization / drug effects
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Protein Structure, Secondary
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Thioredoxin-Disulfide Reductase / metabolism
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Toxicity Tests, Acute
Substances
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Amyloid beta-Peptides
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Azoles
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Cholinesterase Inhibitors
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Indans
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Isoindoles
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Ligands
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Organoselenium Compounds
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Peptide Fragments
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Piperidines
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amyloid beta-protein (1-40)
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Peroxynitrous Acid
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ebselen
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Donepezil
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Glutathione Peroxidase
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Thioredoxin-Disulfide Reductase
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Acetylcholinesterase
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Butyrylcholinesterase