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

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c03149

Authors: Camilla Scarpellini, Greta Klejborowska, Caroline Lanthier, Ariane Toye, Karolina Musiałek, Emily Van San, Magali Walravens, Maya Berg, Behrouz Hassannia, Pieter Van der Veken, Hans De Winter, Tom Vanden Berghe, Koen Augustyns

Institutions: University of Antwerp, Adam Mickiewicz University in Poznań, Vlaams Instituut voor Biotechnologie, Ghent University, VIB-UGent Center for Inflammation Research

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: European Commission, Fonds Wetenschappelijk Onderzoek, Fondation Charcot, Universiteit Antwerpen, Vlaamse regering, Fondation contre le Cancer, H2020 Marie Skłodowska-Curie Actions

Awards: Integrated Training in Dry Eye Disease Drug Development (IT-DED3), Ferroptosis monitoring and targeting in lung ischemia-reperfusion injury from mice to human., G2584703641, Blocking ischemia reperfusion injury during dynamic preservation of organ grafts using lead ferroptosis inhibitors, G3640898913, G3900982171, G402061679, G434337789, G443164402, G5085580681, Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds, G5207582180, Cell Death Regulation and Role in Infection and Inflammatory Diseases (CD-INFLADIS)., G6072363096, G6484125622, G8019628334, Integrated Training in Dry Eye Disease Drug Development (IT-DED3), G8729894435, G8980775851

OpenAlex ID: W4407201006

FWCI: 10.94

Cites: 52

Cited by: 18

Related to: 10