Structural descriptors and antioxidant activity markers of 4-[4-(2-aminoetoxy)benzyl]aniline

The release of reactive oxygen species accompanying oxidative stress is one of the most important damaging mechanisms during brain ischemia. Despite some failures in clinical trials, antioxidant therapy remains one of the best strategies for neuroprotection. Thyroid hormone signaling pathways can control redox status; however,the antioxidant effects of their bioactive metabolites are still less well known, especially for thyronamines.

The chemical species distribution at different pH values for 4-[4-(2-aminoethoxy)benzyl]aniline (Т0АМ thyronamine synthetic analogue) was estimated with the Marvin Protonation Plugin. The 2-{4-[(4-Aminophenyl)methyl]phenoxy}ethan-1-aminium cation is the main species in the pH 6.6-7.4 range. Molecular modeling of the structure and an evaluation of some structural descriptors were performed for the 2-{4-[(4-aminophenyl)methyl]phenoxy}ethan-1-aminium cation. A combination of the PM6-DH2 and B3LYP/6-31G(d,p) levels of theory was used to investigate the intramolecular dynamics of the considered protonated thyronamine.

Some aspects of the antioxidant activity of 4-[4-(2-aminoethoxy)benzyl]aniline in the model of acute cerebral ischemia were experimentally studied and discussed. In a rat brain hemisphere ischemia model, ligation of the internal carotid artery through the administration of a synthetic analogue of the thyronamine T0AM was associated with significant changes in redox markers: a lower level of malondialdehyde in the ischemic hemisphere (p = 0.022) and increased activity of glutathione peroxidase (p = 0.004) and superoxide dismutase levels (p = 0.042) in the ischemic hemisphere. Also, in an FeCl₃ model of local brain infarction, the administration of a T0AM analog was associated with a significant increase in neuroglobin level in the intact hemisphere (p = 0.02), which is a cytoprotective factor. It was revealed that the Т0АМ thyronamine analogue could control redox status in acute brain ischemia. Further experimental studies are needed to evaluate its neuroprotective potential.

Keywords: thyronamines; protonation; intramolecular dynamics; DFT calculations; ischemic stroke; oxidative stress; lipid peroxidation.