Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC₅₀ (half maximal effective concentration) value of 0.0005 μM in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations.

铁死亡是最近发现的一种新型程序性细胞死亡，已被证明与缺血性中风等多种人类疾病有关。铁死亡抑制剂有望具有治疗这些疾病的潜力。在此，我们报告了异丙嗪衍生物作为新型铁死亡抑制剂的鉴定。构效关系 (SAR) 分析发现了最有效的化合物 2-(1-(4-(4-甲基哌嗪-1-基)苯基)乙基)-10 H-吩噻嗪 ( 51) ，其显示出在erastin诱导的HT1080细胞铁死亡模型中，EC ₅₀ （半最大有效浓度）值为0.0005 μM。在MCAO（大脑中动脉闭塞）缺血性中风模型中， 51呈现出优异的治疗效果。该化合物还表现出良好的药代动力学特性，特别是良好的透过血脑屏障的能力。总体而言， 51可能是治疗铁死亡相关疾病的有前景的先导化合物，值得进一步研究。