Development of Phenylethynyl Anthranilic Acid-Based Dihydroorotate Dehydrogenase Inhibitors as Potential Antiviral Agents

Abstract

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in de novo py-rimidine synthesis, leading to the formation of uridine monophosphate (UMP). Afterwards, UMP is converted to other pyrimidine nucleotides needed for the biosynthesis of RNA and DNA. Large amounts of natural nucleotides are necessary during a viral infection. Blocking DHODH with small synthetic molecules should result in a depletion of pyrimidines in the nu-cleotide pool. An advantage of inhibiting essential cellular enzymes is the lower risk of re-sistance development. In combination therapy, DHODH inhibitors have the potential to en-hance the effectiveness of viral RNA polymerase-targeting nucleoside analogs by reducing the competition with cellular pyrimidine nucleotides for their incorporation into the viral RNA. Different series of DHODH inhibitors based on anthranilic acids have been developed by the group of C. MEIER, showing antiviral activity against a broad range of RNA viruses, including viruses from the families Arenaviridae, Nairoviridae, Flaviviridae and Filoviridae. This work aims to conduct an optimization campaign with selected compounds from the phe-nylethynyl anthranilic acid series, especially focusing on enzymatic stability and aqueous solubility. The newly synthesized compounds were investigated for their physicochemical properties and inhibitory potency against human DHODH (hDHODH). Furthermore, antiviral activities were assessed against several hemorrhagic fever viruses and other RNA viruses. Promising candidates for further development as therapeutic agents have emerged from this work. They are not only potent hDHODH inhibitors but also demonstrate nanomolar broad-spectrum antiviral activity in vitro and improved pharmacokinetic properties.