Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels [1,2]. It is a widespread phenomenon observed in the human body. On one hand, ferroptosis plays a pivotal role in a wide array of biological processes, including development, aging, immunity, and tumor suppression [3]. On the other hand, it is closely associated with the pathogenesis of various diseases, such as acute kidney injury, liver injury, orgain ischemia/reperfusion injury (IRI), traumatic brain injury, neurodegenerative diseases [4,5]. For instance, Wang et al. [6] revealed the direct involvement of ferroptosis in cardiac ischemia-reperfusion injury and myocardial cell damage induced by the anticancer drug doxorubicin. Intriguingly, inhibitors specifically targeting ferroptosis were found to significantly reduce myocardial injury, while inhibitors of apoptosis and pyroptosis did not yield the same results. This finding underscores the potential of modulating cell death pathways exclusively associated with ferroptosis as a promising therapeutic approach for these challenging diseases that currently lack effective treatment options [7].

Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were initially discovered through high-throughput screening techniques as the first-line lipophilic inhibitors of ferroptosis. Since then, they have emerged as the most widely utilized anti-ferroptotic agents, appearing in approximately 15–20% of research papers on the subject [8]. Moreover, the ability of Fer-1 and Lip-1 to suppress cell death has become a fundamental benchmark for distinguishing ferroptosis from other forms of cell death [9,10]. However, the clinical development of these two compounds have been hampered due to their short half-life or toxicity in vivo [9]. Current efforts to discover inhibitors are primarily concentrated in two main areas. Firstly, researchers are striving to enhance the chemical stability, ADME properties, and in vivo efficacy of Fer-1 through structural modifications, such as UAMC-2418 and UAMC-3023 [[11], [12], [13]]. Concurrently, researchers are evaluating the anti-ferroptotic cell death activity within their in-house chemical library (Fig. 1A) [14,15]. Furthermore, several endogenous inhibitors, including Coenzyme Q10 (CoQ10) [[16], [17], [18]], Vitamin E [1], Vitamin K [19], Tetrahydrobipterin (BH4) [20], Hydropersulfides [21], 7-Dehydrocholesterol (7-DHC) [22] and 3-hydroxy-kynurenine (3-HK) (Fig. 1B) [23] have been identified through the study of human intrinsic defense systems against ferroptosis. However, the limited efforts directed towards the rational design and optimization of ferroptosis inhibitors to expand the scaffold space may be the primary reason for the absence of suitable inhibitors in clinical settings [24].

Here, in the pursuit of discovering innovative ferroptosis inhibitors, the scaffold of 2-amino-6-methylphenol derivatives was initially identified as a potent ferroptosis inhibitor through a combination of quantum chemistry calculations and in vitro and in vivo assays. Further optimization of this 2-amino-6-methylphenol template led to the discovery of a series of novel structures with high potency. In this report, we also describe in detail the design, syntheses and structure-activity relationship (SAR) analysis of these novel high potent ferroptosis inhibitors.