Design and Synthesis of 1,4‐Diformyl‐Piperazine Ferrostatin‐1 Derivatives as Novel Ferroptosis Inhibitors

ABSTRACT The present study focuses on the design and synthesis of novel 1,4‐diformyl‐piperazine‐based ferrostatin‐1 (Fer‐1) derivatives, and their evaluation against ferroptosis activity. The synthesized compounds demonstrated significant anti‐ferroptosis activity in human umbilical vascular endothelial cells (HUVECs), with Compound 24 showing the highest potency. Mechanistic studies revealed that Compound 24 effectively reduced intracellular reactive oxygen species (ROS) levels, mitigated mitochondrial damage, and enhanced glutathione peroxidase 4 (GPX4) expression. Additionally, Compound 24 exhibited improved solubility and plasma stability compared to control compounds, Fer‐1 and JHL‐12. These findings suggest that 1,4‐diformyl‐piperazine‐based Fer‐1 derivatives hold promise as therapeutic agents for ferroptosis‐associated cardiovascular diseases.