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

Ferroptosis plays an important role in the occurrence
and development
of many diseases, including neurodegenerative diseases. Thus, ferroptosis
inhibitors able to cross the blood-brain barrier may have therapeutic
potential. The best ferroptosis inhibitors so far are lipophilic radical
trapping antioxidants (RTAs) that block lipid peroxidation in membranes.
Several generations of ferrostatins have been synthesized, among which UAMC-3203 showed high potency in animal models with improved
properties compared to ferrostatin-1. To further improve its pharmacokinetics
properties, drug-likeness, and permeability, we modified UAMC-3203 by decreasing the size of the molecule and reducing its polarity
by replacing the sulfonamide first by amide groups and subsequently
by isosteric oxazoles. Herein, we present the design, synthesis, and
biological evaluation of a novel series of oxazole RTAs with high
potency, excellent oral bioavailability, and high concentrations in
brain tissue.