Discovery and Structure-Activity Relationship Studies of Diazepine Derivatives as a New Class of Ferroptosis Inhibitors with Potent Efficacy in the Doxorubicin-Induced Cardiomyopathy Model.

Abstract

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, contributes to diverse pathological conditions. However, the clinical translation of ferroptosis inhibitors has been hampered by the limited efficacy or suboptimal pharmacokinetic profiles. Here, we report the discovery of diazepine derivatives as a new structural class of ferroptosis inhibitors. Through systematic structure-activity relationship optimization, we identifiedas the most potent analogue, demonstrating exceptional cellular potency with an ECof 0.8 nM. Mechanistically,functions as a radical-trapping antioxidant, directly halting the propagation of lipid peroxidation and thereby blocking ferroptosis. This compound also exhibits favorable drug-like pharmacokinetic properties. In vivo,provided substantial protection against doxorubicin-induced cardiomyopathy in both acute and chronic murine models, with no detectable toxicity. Together, these findings establishas a promising lead compound for the treatment of ferroptosis-related diseases, warranting further preclinical development.