Abstract

The development of novel ferroptosis inhibitor reprensents a promising strategy for neurodegenerative diseases, driving the urgent need for developing therapeutic agents that can effectively modulating ferroptosis. In this study, we designed and synthesized a series of novel C2-functionalized quinazolinone derivatives. Systematic screening identified compounds 8f and 8h as selective ferroptosis inhibitor in HT-22 cell. Compound 8h exhibited superior neuroprotective activity in vitro and in zebrafish model in vivo . Preliminary mechanistic studies revealed that compound 8h exerted synergistic effects through dual activation of Steap4 and glutathione peroxidase 4 (GPX4), thereby maintaining iron metabolism homeostasis, clearing phospholipid hydroperoxides, and attenuating lipid peroxidation and reactive oxygen species accumulation. Overall, this work is the first to report the 2-benzoyl-quinazolinones scaffold as effective ferroptosis inhibitor. Compound 8h , in particular, emerges as a promising candidate warranting further development for the treatment of Parkinson’s disease (PD).