Design, Synthesis, and Protective Activity against Doxorubicin-Induced Cardiotoxicity of Novel Water-Soluble Small-Molecule GPx Mimics

The clinical application of doxorubicin in cancer therapy is significantly limited by its severe cardiotoxicity, with complex mechanisms. No effective protective agents are currently available, creating an urgent clinical need. In this study, through structural optimization of ebselen, we developed a series of isoselenazolinones with improved water solubility and glutathione peroxidase (GPx)-like activity. The most promising acidic and basic derivatives, 7 and 12, exhibited a 7.0- and 10.4-fold increase in activity compared to the lead compound, alongside a 16- and 160-fold improvement in water solubility. Frontier molecular orbital theory calculation results showed a good correlation with the observed structure–activity relationships. Furthermore, compound 7 significantly protected cardiomyocytes from doxorubicin-induced injury, preventing 75% of the loss in cell viability at 20 μM. Preliminary mechanistic studies suggested that this protection is mediated by inhibiting oxidative stress and ferroptosis. This study provides a promising class of active compounds for the treatment of doxorubicin-induced cardiotoxicity.