2. Academic Validation
  3. Synthesis and biological evaluation of ferrostatin-based diamide derivatives as new ferroptosis inhibitors

Synthesis and biological evaluation of ferrostatin-based diamide derivatives as new ferroptosis inhibitors

  • Bioorg Med Chem Lett. 2024 Nov 15:113:129974. doi: 10.1016/j.bmcl.2024.129974.
Lei-Yin Zheng 1,  Nai-Yu Zhang 1,  Hui Zheng 2,  Kai-Ming Wang 1,  Juan Zhang 3,  Ning Meng 4,  Cheng-Shi Jiang 5
Affiliations

Affiliations

  • 1 School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 2 Jinan University Hospital, University of Jinan, Jinan 250022, China.
  • 3 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_zhangj@ujn.edu.cn.
  • 4 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_mengn@ujn.edu.cn.
  • 5 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_jiangcs@ujn.edu.cn.
PMID: 39332647 DOI: 10.1016/j.bmcl.2024.129974
Abstract

Ferroptosis, a distinct type of cell death caused by iron and lipid peroxidation, has been associated with several diseases, including cardiovascular disorders. Ferrostatin-1 (Fer-1) is a known Ferroptosis inhibitor, but its clinical application is limited by low efficacy and stability. In the present study, a series of Fer-1-based diamide derivatives was synthesized and evaluated to enhance Ferroptosis inhibition and in vitro metabolic stability. The synthesized compounds were tested for their protective effects against Erastin-induced injury in human vascular endothelial cells (HUVECs). Among the derivatives, compound 36 exhibited the most potent anti-ferroptosis activity with an EC50 value of 0.58 ± 0.02 µM. Remarkably, compound 36 also demonstrated superior stability in both microsomal (human and mouse) and mouse plasma assays. These findings indicated Ferroptosis inhibitor 36 as a promising hit for further developing potential therapeutic drug candidates in cardiovascular diseases.

Keywords

Cardiovascular diseases; Ferroptosis inhibitors; Ferrostatin-based diamide derivatives; HUVECs injury; Lipid peroxidation; Metabolic stability.

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