Nitrones, Old Fellows for New Therapies in Ischemic Stroke

Quinolinyl Nitrone RP19 Induces Neuroprotection after Transient Brain Ischemia

“…Further mechanism of action studies are needed to justify, along with the known radical trapping activity, the biological activity found. In this context, a first in silico prediction of targets for this and other related compounds was reported by our group . In the particular study of RP19, a potential modulation of the metabotropic glutamate receptor 1 (mGluR1) was found, which is a target for excitotoxicity (an ischemic injury inducer) reduction .…”

“…In this context, a first in silico prediction of targets for this and other related compounds was reported by our group . In the particular study of RP19, a potential modulation of the metabotropic glutamate receptor 1 (mGluR1) was found, which is a target for excitotoxicity (an ischemic injury inducer) reduction . This finding may support the neuroprotective effect of RP19 in OGD-exposed neurons not only when it was administered at the onset of recovery, when free radicals are induced, but also when it was administered later, during recovery after ischemia.…”

5-Aryl-2-(3,5-dialkyl-4-hydroxyphenyl)-4,4-dimethyl-4H-imidazole 3-Oxides and Their Redox Species: How Antioxidant Activity of 1-Hydroxy-2,5-dihydro-1H-imidazoles Correlates with the Stability of Hybrid Phenoxyl–Nitroxides

“…Indeed, the observed hfs constants of the methyl protons are double the hfs constant of the nitrogen nuclei of nitroxide groups. When the substituents at C-3,5 of the phenoxyl ring are replaced with tertiary alkyl groups (compounds 22b-d, g-i, l-n), the hfs constants of the methine hydrogen atom of the cyclohexyl or isopropyl substituent decrease 3.5-fold in comparison with those for methyl-substituted analogs and, therefore, they become 2-to 3-fold less than the hfs constant of the nitrogen nucleus of the nitroxide part and 1.5-fold less than hfs constants of phenoxyl protons H 2,6 . This is due to the presence of several conformational isomers of these radicals with different spin density distributions, which exist in equilibrium in their diluted solutions, and therefore the observed spectra are a superposition of the spectra of these conformers.…”

“…High antioxidant activity of nitrones bearing aliphatic, aromatic, heterocyclic, or heteroatom substituents allows the consideration of them as effective therapeutic agents against oxidative stress that occurs under critical pathological conditions in the human body, e.g., myocardial infarction or stroke [ 6 ]. One of the first nitrones to be used as a neuroprotector reducing ischemic hippocampal damage in animals was N - tert -butyl-α-phenylnitrone (PBN) 1a [ 7 ].…”

Recent Advances on Nitrones Design for Stroke Treatment

“…Thus, the purpose of this review, to make it new and attractive for interested readers of the Journal, is to gather and discuss some of the most important recently reported nitrones and show critically their pharmacology from the perspective of the neuroprotection to prevent neurons death after stroke and reperfusion . This means obviously a selection of nitrones that I have restricted to the tetramethylpyrazine nitrones TBN, TN-2, and CT-011 (Figure ) developed at University College of Pharmacy (Guangzhou, China), and to nitrone QN23 (Figure ), selected among the quinolylnitrones discovered at the Institute of General Organic Chemistry (CSIC, Spain), mainly due to the fact that they are easily available and show strong antioxidant and pharmacological properties that made them promising agents for stroke clinical developments. Finally, a last section has been included to show the potential therapeutic profile of some pharmacologically relevant nitrones, such as cholesteronitrones, PBN analogues, hybrid Trolox-nitrones, and bis-nitrones such as stilbazulenyl nitrone .…”