Oxazole-Based Ferroptosis Inhibitors with Promising Properties to Treat Central Nervous System Diseases

Ferroptosis plays a crucial role in the onset and progression of various diseases, including neurodegenerative disorders. Therefore, ferroptosis inhibitors capable of crossing the blood-brain barrier have significant therapeutic potential. The most effective ferroptosis inhibitors to date are lipophilic radical trapping antioxidants (RTAs), which prevent lipid peroxidation in membranes. Several generations of ferrostatins have been developed, with UAMC-3203 showing high efficacy in animal models and enhanced properties compared to ferrostatin-1. To further improve its pharmacokinetic profile, drug-likeness, and permeability, we modified UAMC-3203 by reducing the molecule’s size and decreasing its polarity. This was achieved by replacing the sulfonamide group first with amide groups and then with isosteric oxazoles. In this study, we present the design, synthesis, and biological evaluation of a novel series of oxazole-based RTAs, which demonstrate high potency, excellent oral bioavailability, and elevated concentrations in brain tissue.