# Quinazolinones as Bioisosteres of Naphthoquinones: A Path to Potent HsDHODH Inhibitors with Optimized Properties

## TL;DR

Researchers developed quinazolinone compounds that inhibit a key enzyme in virus replication, showing promise for antiviral therapies against SARS-CoV-2.

## Contribution

Quinazolinones are introduced as bioisosteres of naphthoquinones, offering improved potency and selectivity for HsDHODH inhibition.

## Key findings

- Compound 10c inhibited HsDHODH with an IC50 of 25 μM.
- Compound 10e showed high potency (IC50 = 0.59 μM) and antiviral activity (EC50 = 0.15 μM) against SARS-CoV-2.
- Quinazolinones demonstrated improved selectivity over naphthoquinone analogs but had solubility challenges.

## Abstract

Human dihydroorotate dehydrogenase (HsDHODH) 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 HsDHODH inhibition (up to 60% at 250 μM), with compound 10c having an IC50 of 25 μM. Using computational
modeling, we optimized second-generation derivatives, with 10e showing the highest potency (IC50 = 0.59 ± 0.03
μM) and significant antiviral activity against SARS-CoV-2 (EC50 = 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 HsDHODH.