Α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties.

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.
Authors	Mourad Chioua, David Sucunza, Elena Soriano, Dimitra Hadjipavlou-Litina, Alberto Alcázar, Irene Ayuso, María Jesús Oset-Gasque, María Pilar González, Leticia Monjas, María Isabel Rodríguez-Franco, José Marco-Contelles, Abdelouahid Samadi
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 1 Pg. 153-68 (Jan 12 2012) ISSN: 1520-4804 [Electronic] United States
PMID	22126405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Anti-Inflammatory Agents, Non-Steroidal Antioxidants Free Radical Scavengers Lipoxygenase Inhibitors N-((2-chloro-6-methylquinolin-3-yl)methylene)-1-phenylmethanamine oxide N-((2-chloro-6-methylquinolin-3-yl)methylene)-2-methylpropan-2-amine oxide Neuroprotective Agents Nitric Oxide Donors Nitrogen Oxides Oximes Quinolines nitrones Superoxides Hydroxyl Radical
Topics	Animals Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology) Antioxidants (chemical synthesis, chemistry, pharmacology) Blood-Brain Barrier (metabolism) Cell Hypoxia Cell Survival (drug effects) Cells, Cultured Cerebral Cortex (cytology) Edema (drug therapy) Female Free Radical Scavengers (chemical synthesis, chemistry, pharmacology) Hydroxyl Radical (metabolism) Lipid Peroxidation (drug effects) Lipoxygenase Inhibitors (chemical synthesis, chemistry, pharmacology) Male Necrosis Neurons (cytology, drug effects) Neuroprotective Agents (chemical synthesis, chemistry, pharmacology) Nitric Oxide Donors (chemical synthesis, chemistry, pharmacology) Nitrogen Oxides (chemical synthesis, chemistry, pharmacology) Oximes (chemical synthesis, chemistry, pharmacology) Permeability Quinolines (chemical synthesis, chemistry, pharmacology) Rats Rats, Inbred F344 Rats, Sprague-Dawley Stereoisomerism Stroke (drug therapy) Structure-Activity Relationship Superoxides (metabolism)

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