Abstract
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.
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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Alzheimer Disease / drug therapy*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid beta-Peptides / metabolism*
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Animals
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Antioxidants / chemical synthesis*
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Antioxidants / chemistry
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Antioxidants / pharmacology
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Aspartic Acid Endopeptidases / antagonists & inhibitors
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry
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Benzopyrans / pharmacology
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Blood-Brain Barrier / metabolism
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Butyrylcholinesterase / chemistry
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Catalytic Domain
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Cattle
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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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Chromones / chemical synthesis*
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Chromones / chemistry
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Chromones / pharmacology
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Free Radical Scavengers / chemical synthesis
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Free Radical Scavengers / chemistry
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Free Radical Scavengers / pharmacology
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Humans
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Membranes, Artificial
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Permeability
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Structure-Activity Relationship
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Tacrine / analogs & derivatives*
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Tacrine / chemical synthesis*
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Tacrine / chemistry
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Tacrine / pharmacology
Substances
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6-hydroxy-4-oxo-N-(10-((1,2,3,4-tetrahydroacridin-9-yl)amino)decyl)-4H-chromene-2-carboxamide
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Amyloid beta-Peptides
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Antioxidants
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Benzopyrans
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Cholinesterase Inhibitors
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Chromones
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Free Radical Scavengers
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Membranes, Artificial
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Tacrine
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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