Abstract
In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Animals
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Behavior, Animal / drug effects
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Binding Sites / physiology
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Biphenyl Compounds / chemistry
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Butyrylcholinesterase / metabolism*
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology
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Coumaric Acids / chemical synthesis
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Coumaric Acids / chemistry
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Coumaric Acids / pharmacology*
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Humans
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Inhibitory Concentration 50
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Kinetics
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Liver / metabolism
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Liver / pathology
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Mice, Inbred ICR
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Models, Molecular
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Nitric Oxide / metabolism
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Nitric Oxide Donors / chemical synthesis*
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Nitric Oxide Donors / chemistry
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Nitric Oxide Donors / pharmacology
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Picrates / chemistry
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Tacrine / analogs & derivatives*
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Tacrine / chemistry
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Tacrine / pharmacology
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Vasodilation / drug effects
Substances
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Biphenyl Compounds
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Cholinesterase Inhibitors
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Coumaric Acids
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Nitric Oxide Donors
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Picrates
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Nitric Oxide
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Tacrine
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1,1-diphenyl-2-picrylhydrazyl
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Butyrylcholinesterase