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Discovery of Novel Ortho -Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Jun 13; Vol. 67 (11), pp. 9536-9551. Date of Electronic Publication: 2024 Jun 01. - Publication Year :
- 2024
-
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.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38822802
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00600