Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers

Ferroptosis
is a promising therapeutic target for injury-related
diseases, yet diversity in ferroptosis inhibitors remains limited.
In this study, initial structure optimization led us to focus on the
bond dissociation enthalpy (BDE) of the N–H bond and the residency
time of radical scavengers in a phospholipid bilayer, which may play
an important role in ferroptosis inhibition potency. This led to the
discovery of compound D1, exhibiting potent ferroptosis inhibition,
high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose
deprivation/reoxygenation (OGD/R) model and reduced infarct volume
in an in vivo stroke model upon intravenous treatment. Further screening
based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors
with highly polar structural characteristics. This approach bridges
the gap between free radical scavengers and ferroptosis inhibitors,
providing a foundation for research and insights into novel ferroptosis
inhibitor development.