Discovery of novel benzo[b][1,4]oxazine derivatives as ferroptosis inhibitors.

Ferroptosis is a novel type of programmed cell death characterized by radical-driven lipid peroxidation accumulation, which is involved in various diseases, including acute organ injury and neurodegenerative disorders. Pharmacological inhibition of ferroptosis is a promising strategy for treating these diseases. In this study, 16 benzo[b][1,4]oxazine derivatives were synthesized and assayed for their antiferroptotic activity. NYY-6a showed significant inhibitory activity against RSL3-induced ferroptosis across various cell lines, with an EC50 value of approximately 50 nM. Mechanistic studies revealed that NYY-6a functions as a radical trapping antioxidant (RTA) with efficacy of diminishing lipid peroxidation comparable to ferrostatin-1 and liproxtatin-1. Further results demonstrated that the benzoxazine derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Therefore, NYY-6a, bearing a novel benzoxazine scaffold, may serve as a lead compound for further investigation in the treatment of ferroptosis-related pathologies.