Identification of imidazo[1,2-a]pyridine-3-amine as a novel drug-like scaffold for efficious ferroptosis inhibition in vivo.

Ferroptosis has emerged as a promising therapeutic approach for a wide range of diseases. However, limited chemical diversity and poor drug-like profiles have hindered the development of effective ferroptosis inhibitors for clinical use. Herein, we identified drug-like imidazo[1,2-a]pyridine-3-amine derivatives as innovative ferroptosis inhibitors for injury-related diseases by drug scaffold repositioning strategy. Our findings established that the selected compounds exhibited high radical scavenging and effective membrane retention, thereby leading to significant suppression of lipid peroxidation and ferroptosis at nanomolar concentrations. Notably, compound C18, with low cytotoxicity and favorable pharmacokinetics properties, demonstrated remarkable in vivo neuroprotection against ischemic brain injury in mice. In conclusion, our investigations not only engender potent ferroptosis inhibitors with novel structural characteristics that warrant further development, but also serve as a valuable case study for drug repurposing in the discovery of additional ferroptosis inhibitors.