Discovery of 2-vinyl-10H-phenothiazine derivatives as a class of ferroptosis inhibitors with minimal human Ether-a-go-go related gene (hERG) activity for the treatment of DOX-induced cardiomyopathy

• Published in: Bioorganic & medicinal chemistry letters Vol. 74; p. 128911
• Main Authors: You, Jing, Yang, Wei, Ma, Ronggang, Xia, Anjie, Zhang, Guo, Fang, Zhen, Guo, Nihong, Yang, Shengyong, Li, Linli
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15-10-2022
• Subjects: 2-vinyl-10H-phenothiazine derivatives; DOX-induced cardiomyopathy; Ferroptosis inhibitor; hERG inhibition; Structure-activity relationship; hERG inhibition; DOX-induced cardiomyopathy; Structure-activity relationship; 2-vinyl-10H-phenothiazine derivatives; Ferroptosis inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128911

[Display omitted]
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.