Abstract
We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antioxidants / chemical synthesis*
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Antioxidants / chemistry
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Antioxidants / pharmacology
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Blood-Brain Barrier / metabolism*
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Cell Hypoxia
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / cytology
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Edema / drug therapy
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Female
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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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Hydroxyl Radical / metabolism
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Lipid Peroxidation / drug effects
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Lipoxygenase Inhibitors / chemical synthesis
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Lipoxygenase Inhibitors / chemistry
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Lipoxygenase Inhibitors / pharmacology
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Male
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Necrosis
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Neurons / cytology
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Neurons / drug effects
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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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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Nitrogen Oxides / chemical synthesis*
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Nitrogen Oxides / chemistry
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Nitrogen Oxides / pharmacology
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Oximes / chemical synthesis*
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Oximes / chemistry
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Oximes / pharmacology
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Permeability
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Rats
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Rats, Inbred F344
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Rats, Sprague-Dawley
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Stereoisomerism
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Stroke / drug therapy*
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Structure-Activity Relationship
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Superoxides / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antioxidants
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Free Radical Scavengers
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Lipoxygenase Inhibitors
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N-((2-chloro-6-methylquinolin-3-yl)methylene)-1-phenylmethanamine oxide
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N-((2-chloro-6-methylquinolin-3-yl)methylene)-2-methylpropan-2-amine oxide
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Neuroprotective Agents
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Nitric Oxide Donors
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Nitrogen Oxides
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Oximes
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Quinolines
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nitrones
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Superoxides
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Hydroxyl Radical