title: 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: Laboratorio de Radicales Libres y Química Computacional, Instituto de Química Orgánica General (CSIC), Juan de la Cierva, 3, 28006-Madrid, Spain.
authors: Mourad
authors: M
authors: Chioua
authors: David
authors: D
authors: Sucunza
authors: Elena
authors: E
authors: Soriano
authors: Dimitra
authors: D
authors: Hadjipavlou-Litina
authors: Alberto
authors: A
authors: Alcázar
authors: Irene
authors: I
authors: Ayuso
authors: María Jesús
authors: MJ
authors: Oset-Gasque
authors: María Pilar
authors: MP
authors: González
authors: Leticia
authors: L
authors: Monjas
authors: María Isabel
authors: MI
authors: Rodríguez-Franco
authors: José
authors: J
authors: Marco-Contelles
authors: Abdelouahid
authors: A
authors: Samadi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004487:Edema / Q000188:drug therapy; D005260:Female; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D020521:Stroke / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016166:Free Radical Scavengers; D016859:Lipoxygenase Inhibitors; C570907:N-((2-chloro-6-methylquinolin-3-yl)methylene)-1-phenylmethanamine oxide; C570908:N-((2-chloro-6-methylquinolin-3-yl)methylene)-2-methylpropan-2-amine oxide; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010091:Oximes; D011804:Quinolines; C015388:nitrones; D013481:Superoxides; D017665:Hydroxyl Radical