赫尔格
化学
吩噻嗪
体内
体外
程序性细胞死亡
药理学
毒性
药物发现
结构-活动关系
铅化合物
细胞凋亡
生物化学
生物物理学
钾通道
生物
生物技术
有机化学
作者
Jianxin You,Wei Yang,Ronggang Ma,Anjie Xia,Guo Zhang,Zhen Fang,Nihong Guo,Shengyong Yang,Linli Li
标识
DOI:10.1016/j.bmcl.2022.128911
摘要
Ferroptosis was an iron-dependent, nonapoptotic form of regulated cell death. In our previous study, we discovered a potent ferroptosis inhibitor with phenothiazine scaffold (1), but subsequent investigation showed that this compound had potent hERG binding affinity. Herein, we report the discovery of a series of 2-vinyl-10H-phenothiazine derivatives as new class of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the identification of compound 7j, which exhibited significantly reduced hERG inhibition (IC50 > 30 µM) while maintaining high ferroptosis inhibitory activity (EC50 = 0.001 µM on the erastin-induced HT1080 cell ferroptosis model). Further studies confirmed 7j acted as a ROS scavenger and could relieve DOX-induced cardiomyopathy. 7j also displayed favorable pharmacokinetic properties and exhibited no obvious toxicity in vivo and vitro. Overall, this study provides a promising lead compound for drug discovery targeting ferroptosis.
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