Discovery and Optimization of Novel Carbazole‐Based Ferroptosis Inhibitors

Ferroptosis is an iron‐dependent form of regulated cell death that plays a critical role in the pathogenesis of multiple human diseases, making it an attractive target for therapeutic strategy. In this study, the FerrBERT model was employed to screen a small‐molecule library, leading to the identification of 3‐amino‐9‐ethylcarbazole as a potent inhibitor of RSL3‐induced ferroptosis in HT22 mouse hippocampal neuronal cells (EC 50 = 65.2 nM). Using this scaffold as a starting point, 50 derivatives were designed, synthesized, and systematically evaluated for their structure–activity relationships (SARs). Among them, compound C4 exhibited a remarkable enhancement in inhibitory potency, showing an approximately 8.4‐fold improvement over the lead compound while maintaining low cytotoxicity (EC 50 = 7.77 nM; CC 50 = 5.97 µM; SI = 768). Mechanistic studies further revealed that C4 selectively suppresses ferroptosis through an antioxidant‐mediated pathway. Collectively, these findings identified C4 as a highly potent ferroptosis inhibitor with significant potential for the development of therapeutics targeting ferroptosis‐related neurological disorders.