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

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.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (Grants SAF2012-33304 and SAF2015-65586-R) and Universidad Camilo José Cela (NitroStroke 2015-12) to J.M.-C., the Instituto de Salud Carlos III and cofinancing by the European Development Regional Fund (FEDER) (Grants PI14/00705, PI18/0255, and RETICS RD16/0019/0006) to A.A., and the Regional Madrid Government (BIPEDD-2, Grant S2010-BMD-2457) to L.I. We thank Isquaemia Biotech SL for its financial support. A.A. thanks M. Gómez-Calcerrada for technical assistance.Peer Reviewe