Glutathione Peroxidase‐Mimics Organoselenium Amines: Anti‐Ferroptotic Properties and an In Silico Study of 15‐Lipoxygenase‐2

In search for better synthetic antioxidants, aminic organoselenides carrying amine and benzamide groups at ortho‐positions to the selenium atom were synthesized from alkyl halides and in situ generated sodiumselenolates as nucleophile by the sodium borohydride reduction of corresponding diselenides. The single crystal X‐ray structure of one compound showed the weak intramolecular Se×××H interactions with free amine group. The presence of Se···H interactions was confirmed using natural bond orbital (NBO) and atoms in molecules (AIM) calculations, respectively. The glutathione peroxidase enzyme (GPx)‐like antioxidant activity of all compounds was evaluated using thiophenol assay. The best antioxidant exhibited nearly 5 and 10 times greater activities than Oct2Se2 and Ph2Se2 used as references, respectively. The most active catalysts carrying a strong electron‐donating group were further investigated at different concentrations of thiol for determining the catalytic parameters. These GPx mimics have shown anti‐ferroptotic activity in a 4–OH‐tamoxifen (TAM) inducible GPx4 knockout cell line and protected cells from cell death induced by loss of GPx4 enzyme. In silico molecular docking studies showed that all antioxidants demonstrated promising Moldock scores with human 15‐lipoxygenase‐2 enzyme.