2. Academic Validation
  3. Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors

Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors

  • Bioorg Med Chem. 2024 May 1:105:117716. doi: 10.1016/j.bmc.2024.117716.
Hua-Long Ji 1,  Yi-Fan Zhang 1,  Nai-Yu Zhang 1,  Kai-Ming Wang 1,  Ning Meng 2,  Juan Zhang 3,  Cheng-Shi Jiang 4
Affiliations

Affiliations

  • 1 School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 2 School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_mengn@ujn.edu.cn.
  • 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: bio_jiangcs@ujn.edu.cn.
PMID: 38608329 DOI: 10.1016/j.bmc.2024.117716
Abstract

In this study, a series of new formylpiperazine-derived Ferroptosis inhibitors were designed and synthesized based on the structure of a known Ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge Reactive Oxygen Species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new Ferroptosis inhibitors for the treatment of vascular diseases.

Keywords

Ferroptosis inhibitors; Ferrostatin-1; Formylpiperazine analogs; Microsomal stability; Vascular diseases.

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