DHODH Inhibitors Based on the Vidofludimus Scaffold Containing Carboxylic Acid Bioisosteres Exert a Superior Broad-Spectrum Antiviral Activity.

Emerging and re-emerging viral infections demand the rapid development of broad-spectrum antivirals. Host-directed therapies targeting cellular metabolic pathways required for viral replication offer a promising strategy with a low risk of resistance. Dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine synthesis, is essential for the replication of many human pathogenic viruses. Several DHODH inhibitors, including vidofludimus calcium, are under clinical investigation for viral diseases, such as coronavirus disease 19 (COVID-19). We report medicinal chemistry optimization of vidofludimus, yielding more potent derivatives with improved DHODH inhibition across mammalian species and enhanced activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Optimized compounds also showed broad-spectrum antiviral activity against enveloped and nonenveloped DNA and RNA viruses and a retrovirus, with single-digit nanomolar potency and no detectable cytotoxicity. Selectivity indices exceeded 50,000, highlighting the therapeutic potential of this target. These findings identify this compound class as a promising starting point for host-directed antivirals (HDAs), as well as for pandemic preparedness and applications in other disease areas.