The suppression of ferroptosis is emerging as a promising therapeutic strategy for effectively treating a wide range of diseases, including neurodegenerative disorders, organ ischemia-reperfusion injury, and inflammatory conditions. However, the clinical utility of ferroptosis inhibitors is significantly impeded by the limited availability of rational drug designs. In our previous study, we successfully unraveled the efficacy of ferrostatin-1 (Fer-1) attributed to the synergistic effect of its ortho-diamine (-NH) moiety. In this study, we present the discovery of the ortho-hydroxyl-amino moiety as a novel scaffold for ferroptosis inhibitors, employing quantum chemistry as well as in vitro and in vivo assays. 2-amino-6-methylphenol derivatives demonstrated remarkable inhibition of RSL3-induced ferroptosis, exhibiting EC₅₀ values ranging from 25 nM to 207 nM. These compounds do not appear to modulate iron homeostasis or lipid reactive oxygen species (ROS) generation pathways. Nevertheless, they effectively prevent the accumulation of lipid peroxides in living cells. Furthermore, compound 13 exhibits good in vivo activities as it effectively protect mice from kidney ischemia-reperfusion injury. In summary, compound 13 has been identified as a potent ferroptosis inhibitor, warranting further investigation as a promising lead compound.

抑制铁死亡正在成为一种有前景的治疗策略，可有效治疗多种疾病，包括神经退行性疾病、器官缺血再灌注损伤和炎症性疾病。然而，合理药物设计的可用性有限，严重阻碍了铁死亡抑制剂的临床应用。在我们之前的研究中，我们成功地揭示了 Ferrostatin-1 (Fer-1) 的功效归因于其邻二胺 (-NH)部分的协同作用。在这项研究中，我们利用量子化学以及体外和体内测定，发现了邻羟基氨基部分作为铁死亡抑制剂的新型支架。 2-氨基-6-甲基苯酚衍生物表现出对 RSL3 诱导的铁死亡的显着抑制作用，EC ₅₀值范围为 25 nM 至 207 nM。这些化合物似乎不会调节铁稳态或脂质活性氧 (ROS) 生成途径。然而，它们有效地防止活细胞中脂质过氧化物的积累。此外，化合物13表现出良好的体内活性，可有效保护小鼠免受肾缺血再灌注损伤。总之，化合物13已被确定为有效的铁死亡抑制剂，值得作为有前途的先导化合物进行进一步研究。