Quinazolinones as Bioisosteres of Naphthoquinones: A Path to Potent <i>Hs</i> DHODH Inhibitors with Optimized Properties
Human dihydroorotate dehydrogenase (<i>Hs</i>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 quinazol-inones as bioisosteric replacements to reduce cytotoxicity and off-target effects. Through structure-based design, we synthesized quinazol-inone derivatives aimed at maintaining critical binding interactions. First-generation compounds showed moderate <i>Hs</i>DHODH inhibition (up to 60% at 250 μM), with compound <b>10c</b> having an IC<sub>50</sub> of 25 μM. Using computational modeling, we optimized second-generation derivatives, with <b>10e</b> showing the highest potency (IC<sub>50</sub> = 0.59 ± 0.03 μM) and significant antiviral activity against SARS-CoV-2 (EC<sub>50</sub> = 0.15 ± 0.03 μM). These compounds demonstrated improved selectivity compared to naphtho-quinone analogs, though challenges with aqueous solubility remain. These results highlight quinazol-inones as promising scaffolds for further development of anti-SARS-CoV-2 therapies targeting <i>Hs</i>DHODH.
Authors
- Maria Cristina Nonato (ORCID: https://orcid.org/0000-0002-4916-1505)
- Caroline S. de Freitas (ORCID: https://orcid.org/0000-0001-8100-0472)
- Thiago Moreno L. Souza (ORCID: https://orcid.org/0000-0003-2212-3899)
- Bianca Aparecida Martin (ORCID: https://orcid.org/0000-0003-1877-9801)
- Pedro Nuno Leite (ORCID: https://orcid.org/0000-0002-9016-525X)
- Renata Fonseca Vianna Lopez (ORCID: https://orcid.org/0000-0002-6448-6711)
- Thiago dos Santos (ORCID: https://orcid.org/0000-0001-7908-8604)
- Weslley Pereira da Silva (ORCID: https://orcid.org/0009-0002-4518-2373)
- Taís C. Silva (ORCID: https://orcid.org/0000-0002-0465-7291)
- Flávio da Silva Emery (ORCID: https://orcid.org/0000-0002-8652-7123)
- Josué de Moraes (ORCID: https://orcid.org/0000-0003-1766-7031)
- Carolina Horta Andrade (ORCID: https://orcid.org/0000-0003-0101-1492)
- Aline Dias da Purificação (ORCID: https://orcid.org/0000-0002-3127-7585)
- Daniel Gedder Silva (ORCID: https://orcid.org/0000-0001-8879-456X)
- Mayara Mattos (ORCID: https://orcid.org/0000-0002-6841-6999)
- Murillo V. Freitas
- Bruna Fleck Godoi (ORCID: https://orcid.org/0000-0002-5910-0511)
- Jéssica D. Bueno
Institutions
- Drugs for Neglected Diseases Initiative (CH)
- Target (United States) (US)
- Moscow Technological Institute (RU)
- Universidade Brasil (BR)
- Ono Pharmaceutical (United States) (US)
- Guarulhos University (BR)
- Mechanical Design (Czechia) (CZ)
- SUPERA Park of Innovation and Technology of Ribeirão Preto (BR)
- Institute of Informatics of the Slovak Academy of Sciences (SK)
- National Institute of Science and Technology (ID)
- Artificial Intelligence in Medicine (Canada) (CA)
- Fundação Oswaldo Cruz (BR)
- Universidade Federal de Goiás (BR)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00237
- Primary Topic
- Quinazolinone synthesis and applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00