Synthesis, biological evaluation and mechanism study of 2-benzoyl-quinazolinone derivative as ferroptosis inhibitor for the treatment of Parkinson's disease.

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).