{"title":"Novel Indoline Derivatives as Ferroptosis Inhibitors: Synthesis, Biological Evaluation, and Mechanistic Investigation","authors":"Wen Shao, Yuanyuan Liu, Deling Jiang, Zhiyang Xing, Jiale Qiao, Man Liu, Xupeng Huang, Renyu Zhang, Yuying Fang, Wei Peng","doi":"10.1002/cmdc.202500487","DOIUrl":null,"url":null,"abstract":"<p>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, <b>TJC-2-1</b>, is identified. To optimize its inhibitory activity, a series of 35 indoline derivatives are synthesized and evaluated. Among them, compound <b>14</b> exhibits the most potent inhibition against erastin-induced (EC<sub>50</sub> = 0.15 μM) and RSL3-induced (EC<sub>50</sub> = 0.15 μM) ferroptosis in HT22 mouse hippocampal cells. Mechanistic investigations reveal that compound <b>14</b> functions as a novel radical-trapping antioxidant, exhibiting lipid peroxidation scavenging capacity comparable to that of Fer-1. Remarkably, compound <b>14</b> demonstrates significantly improved microsomal metabolic stability compared to Fer-1. These findings suggest that compound <b>14</b> has the potential to serve as a lead compound for ferroptosis-related diseases.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 17","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202500487","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
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