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 (EC50 = 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 (EC50 = 7.77 nM; CC50 = 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.