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 <b>UAMC-3203</b> 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 <b>UAMC-3203</b> 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.
Authors
- Koen Augustyns (ORCID: https://orcid.org/0000-0002-5203-4339)
- Emily Van San (ORCID: https://orcid.org/0000-0003-1429-1980)
- Greta Klejborowska (ORCID: https://orcid.org/0000-0001-9365-4238)
- Maya Berg
- Ashley M. Toye (ORCID: https://orcid.org/0000-0003-4395-9396)
- Pieter Van der Veken (ORCID: https://orcid.org/0000-0003-1208-3571)
- Behrouz Hassannia
- Camilla Scarpellini (ORCID: https://orcid.org/0000-0002-1860-6532)
- Hans De Winter
- Caroline Lanthier (ORCID: https://orcid.org/0000-0002-5814-3173)
- Tom Vanden Berghe (ORCID: https://orcid.org/0000-0002-1633-0974)
- Magali Walravens
- Karolina Musiałek
Institutions
- University of Antwerp (BE)
- Ghent University Hospital (BE)
- Ghent University (BE)
- VIB-UGent Center for Inflammation Research (BE)
- Pharmaceutical Biotechnology (Czechia) (CZ)
- Adam Mickiewicz University in Poznań (PL)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03149
- Citations
- 9
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 13.67
Funders
- European Commission
- Fonds Wetenschappelijk Onderzoek
- Fondation Charcot
- Universiteit Antwerpen
- Vlaamse regering
- Fondation contre le Cancer
- H2020 Marie Skłodowska-Curie Actions