Quinazolinones as Bioisosteres of Naphthoquinones: A Path to Potent Hs DHODH Inhibitors with Optimized Properties

High Resolution Image Download MS PowerPoint Slide Human dihydroorotate dehydrogenase ( Hs DHODH) is a key enzyme in pyrimidine biosynthesis and a target for antiviral therapies against RNA viruses like SARS-CoV-2. Building on prior quinone-based inhibitors, we explored quinazolinones as bioisosteric replacements to reduce cytotoxicity and off-target effects. Through structure-based design, we synthesized quinazolinone derivatives aimed at maintaining critical binding interactions. First-generation compounds showed moderate Hs DHODH inhibition (up to 60% at 250 μM), with compound 10c having an IC 50 of 25 μM. Using computational modeling, we optimized second-generation derivatives, with 10e showing the highest potency (IC 50 = 0.59 ± 0.03 μM) and significant antiviral activity against SARS-CoV-2 (EC 50 = 0.15 ± 0.03 μM). These compounds demonstrated improved selectivity compared to naphthoquinone analogs, though challenges with aqueous solubility remain. These results highlight quinazolinones as promising scaffolds for further development of anti-SARS-CoV-2 therapies targeting Hs DHODH.