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ChemMedChem

IF: 3.6
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Novel Indoline Derivatives as Ferroptosis Inhibitors: Synthesis, Biological Evaluation, and Mechanistic Investigation

Published:18 August 2025 DOI: 10.1002/cmdc.202500487 PMID: 40824902
Wen Shao, Yuanyuan Liu, Deling Jiang, Zhiyang Xing, Jiale Qiao, Man Liu, Xupeng Huang, Renyu Zhang, Yuying Fang, Wei Peng

Abstract

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.

Substances (12)

Materials
Procduct Name CAS Molecular Formula Supplier Price
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 248 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 248 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 248 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 248 suppliers $10.00-$2822.00
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00

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