2. Academic Validation
  3. Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities

Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities

  • J Med Chem. 2024 Jun 13;67(11):9536-9551. doi: 10.1021/acs.jmedchem.4c00600.
Xie-Huang Sheng 1,  Li-Cong Han 1,  Ao Gong 2,  Xiang-Shuai Meng 1,  Xin-Hui Wang 1,  Lin-Song Teng 3,  Xiao-Han Sun 1,  Kuo-Chen Xu 3,  Zhao-Hua Liu 4,  Ting Wang 5,  Jian-Ping Ma 1,  Lei Zhang 3
Affiliations

Affiliations

  • 1 College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China.
  • 2 Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan 250001, China.
  • 3 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China.
  • 4 The Model Animal Research Center, Cheeloo College of Medicine, Shandong University, Jinan 250014, China.
  • 5 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China.
PMID: 38822802 DOI: 10.1021/acs.jmedchem.4c00600
Abstract

The concept of Ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential Ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced Ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of Ferroptosis inhibitors, serving as valuable insights for future structural modifications.

Figures
Products