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

Abstract

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.

Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis

“…Taking into account the properties of the various fluorophores, the quinoline skeleton has attracted our great interest because of its drug-like physicochemical and photophysical properties. Previously, the quinoline derivatives have shown that the desired BBB penetrability can be applied for the development of brain imaging or neuroprotective agents (41)(42)(43)(44)(45). For example, a quinolone-based Schiff base can serve as a staining reagent for imaging metal ions (Cu 2+ and Zn 2+ ) in Aβ plaques; quinolylnitrones can be used as the potential neuroprotective agents (SI Appendix, Scheme S1).…”

“…After i.v. injection of HCP (0.5 mg/kg), in vivo imaging showed that the fluorescence intensity of the epilepsy group in the brain regions was significantly higher than that in WT healthy mice at different times (5,15,30,45, and 60 min), clearly demonstrating HCP can effectively cross the BBB and track the up-regulation of HClO in the brain. Particularly, pre/posttreatment with apigenin, the mouse brains showed reduced fluorescence signals compared to those treated with KA alone (Fig.…”

Neuroprotective Effects of Diets Containing Olive Oil and DHA/EPA in a Mouse Model of Cerebral Ischemia

“…The grip strength test is designed to assess the maximum force in the mouse’s forelimbs using a metal grid connected to a force sensor (Bioseb, Vitrolles, France). The test was performed as described previously [26,33,34] and a total of 6 trials were carried out in each test session, calculating the strength (in grams) as the mean of these trials.…”

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

“…In our current program targeted to identify new nitrones for the therapy of stroke 11 , we have already investigated nitrones derived from (hetero)aromatic aldehydes 12,13 , quinolylnitrones [14][15][16][17] , and cholesteronitrones 18 . More recently, we have designed bis-nitrones derived from alpha-phenyl-N-tert-butylnitrone (PBN) ( Fig.…”