2. Academic Validation
  3. Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers

Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers

  • J Med Chem. 2024 Jul 25;67(14):11712-11731. doi: 10.1021/acs.jmedchem.4c00211.
Yang Lu 1 2,  Zexu Shen 1,  Yaping Xu 2,  Haoran Lin 1,  Liteng Shen 2,  Yizhen Jin 2,  Yu Guo 2,  Jialiang Lu 2,  Linjie Li 2,  Yuxin Zhuang 2,  Yuheng Jin 2,  Weihao Zhuang 2,  Wenhai Huang 3 4,  Xiaowu Dong 1 2 5 6,  Haibin Dai 1,  Jinxin Che 2 5 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 2 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Hangzhou Medical College, Hangzhou 310013, PR China.
  • 4 School of Pharmacy, Hangzhou Medical College, Hangzhou 310013, China.
  • 5 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, China.
  • 6 National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China.
PMID: 38996382 DOI: 10.1021/acs.jmedchem.4c00211
Abstract

Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in Ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in Ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent Ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel Ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and Ferroptosis inhibitors, providing a foundation for research and insights into novel Ferroptosis inhibitor development.

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