Discovery and optimization of 1,2,4-triazole derivatives as novel ferroptosis inhibitors

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid ROS accumulation, which is associated with various diseases, including acute organ injury, neurodegenerative disorders, and cancer. Pharmacological inhibition of ferroptosis has great potential for the treatment of these diseases. However, the clinical translation of many ferroptosis inhibitors is hindered by their inadequate activity or suboptimal pharmacokinetic profiles. In this study, several 1,2,4-triazole derivatives were identified as novel ferroptosis inhibitors through phenotypic screening of our in-house compound library. Among these compounds, NY-26 was found to significantly inhibit RSL3-induced ferroptosis in 786-O cells with nanomolar level (EC₅₀ = 62 nM). The antiferroptotic activity of NY-26 was further validated across multiple cell lines. Mechanistic studies revealed that NY-26 inhibits ferroptosis through its intrinsic free radical-trapping antioxidant capacity. Additional results demonstrated that the triazole derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Taken together, NY-26, tethering a novel 1,2,4-triazole scaffold, could be an effective ferroptosis inhibitor with great therapeutic potential for further investigation.