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

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.

Citation

Xie-Huang Sheng, Li-Cong Han, Ao Gong, Xiang-Shuai Meng, Xin-Hui Wang, Lin-Song Teng, Xiao-Han Sun, Kuo-Chen Xu, Zhao-Hua Liu, Ting Wang, Jian-Ping Ma, Lei Zhang. Discovery of Novel Ortho-Aminophenol Derivatives Targeting Lipid Peroxidation with Potent Antiferroptotic Activities. Journal of medicinal chemistry. 2024 Jun 13;67(11):9536-9551

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PMID: 38822802

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