New Quinolylnitrones for Stroke Therapy: Antioxidant and Neuroprotective (Z)‑N-tert-Butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine Oxide as a New Lead-Compound for Ischemic Stroke Treatment

• Published in: Journal of medicinal chemistry Vol. 62; no. 4; pp. 2184 - 2201
• Main Authors: Chioua, Mourad, Martínez-Alonso, Emma, Gonzalo-Gobernado, Rafael, Ayuso, Maria I, Escobar-Peso, Alejandro, Infantes, Lourdes, Hadjipavlou-Litina, Dimitra, Montoya, Juan J, Montaner, Joan, Alcázar, Alberto, Marco-Contelles, José
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28-02-2019
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis - drug effects; Cells, Cultured; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - pharmacology; Free Radical Scavengers - therapeutic use; Imines - chemical synthesis; Imines - pharmacology; Imines - therapeutic use; Ischemic Attack, Transient - drug therapy; Lipid Peroxidation - drug effects; Male; Mice, Inbred C57BL; Neurons - drug effects; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Quinolines - chemical synthesis; Quinolines - pharmacology; Quinolines - therapeutic use; Rats, Wistar; Reactive Oxygen Species - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01987

We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen–glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN (Z)-N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)­methanimine oxide (23) was shown as a very potent neuroprotective agent. Antioxidant analysis based on the ability of QN 23 to trap different types of toxic radical oxygenated species supported and confirmed its strong neuroprotective capacity. Finally, QN 23 showed also neuroprotection induction in two in vivo models of cerebral ischemia, decreasing neuronal death and reducing infarct size, allowing us to conclude that QN 23 can be considered as new lead-compound for ischemic stroke treatment.