Design, Synthesis, and Biological Evaluation of New Improved Ferrostatin‐1 Derived Ferroptosis Inhibitors

Ferrostatin‐1 (Fer‐1), a first potent ferroptosis inhibitor, faces limitations in clinical use due to its low potency and metabolic instability. This study introduces a series of novel Ferrostatin‐1 analogs designed to enhance plasm stability. Our design strategy focused on the modification of the 3‐NH2 of Fer‐1 with benzenesulfonyl groups, resulting in analogs 9‐25. Biological evaluation revealed that compound 18, with an EC50 value of 0.57 µM, outperformed Fer‐1 in inhibiting ferroptosis. It reduced intracellular ferrous ion accumulation, lipid peroxidation, and restored glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels effectively. Moreover, compound 18 exhibited favorable solubility and remarkable metabolic stability in rat plasma. These results position compound 18 as a promising candidate for developing therapeutics against ferroptosis‐related diseases.