Novel Indoline Derivatives as Ferroptosis Inhibitors: Synthesis, Biological Evaluation, and Mechanistic Investigation

A novel series of indoline derivatives is synthesized and evaluated for their ferroptosis inhibitory activity. Among them, compound 14 exhibits potent ferroptosis inhibition in HT22 cells by acting as a novel radical-trapping antioxidant and demonstrates improved metabolic stability compared to Fer-1.

Ferroptosis, a form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various neurological disorders. Ferrostatin-1 (Fer-1), a well-known ferroptosis inhibitor, exhibits therapeutic potential but suffers from poor metabolic stability, limiting its applications. In this study, a phenotype-based screening of an in-house compound library is conducted and a novel ferroptosis inhibitor, TJC-2-1, is identified. To optimize its inhibitory activity, a series of 35 indoline derivatives are synthesized and evaluated. Among them, compound 14 exhibits the most potent inhibition against erastin-induced (EC₅₀ = 0.15 μM) and RSL3-induced (EC₅₀ = 0.15 μM) ferroptosis in HT22 mouse hippocampal cells. Mechanistic investigations reveal that compound 14 functions as a novel radical-trapping antioxidant, exhibiting lipid peroxidation scavenging capacity comparable to that of Fer-1. Remarkably, compound 14 demonstrates significantly improved microsomal metabolic stability compared to Fer-1. These findings suggest that compound 14 has the potential to serve as a lead compound for ferroptosis-related diseases.

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