Discovery of novel benzoquinazolinones and thiazoloimidazoles, inhibitors of influenza H5N1 and H1N1 viruses, from a cell-based high-throughput screen.

Abstract

A highly reproducible and robust cell-based high-throughput screening (HTS) assay was adapted for screening of small molecules for antiviral activity against influenza virus strain A/Vietnam/1203/2004 (H5N1). The NIH Molecular Libraries Small Molecule Repository (MLSMR) Molecular Libraries Screening Centers Network (MLSCN) 100,000-compound library was screened at 50 µM. The "hit" rate (>25% inhibition of the viral cytopathic effect) from the single-dose screen was 0.32%. The hits were evaluated for their antiviral activity, cell toxicity, and selectivity in dose-response experiments. The screen yielded 5 active compounds (SI value >3). One compound showed an SI(50) value of greater than 3, 3 compounds had SI values ranging from greater than 14 to 34, and the most active compound displayed an SI value of 94. The active compounds represent 2 different classes of molecules, benzoquinazolinones and thiazoloimidazoles, which have not been previously identified as having antiviral/anti-influenza activity. These molecules were also effective against influenza A/California/04/2009 virus (H1N1) and other H1N1 and H5N1 virus strains in vitro but not H3N2 strains. Real-time qRT-PCR results reveal that these chemotypes significantly reduced M1 RNA levels as compared to the no-drug influenza-infected Madin Darby canine kidney cells.

• Authors: Joseph A Maddry, Xi Chen, Colleen B Jonsson, Subramaniam Ananthan, Judith Hobrath, Donald F Smee, James W Noah, Diana Noah, Xiaolin Xu, Fuli Jia, Clinton Maddox, Melinda I Sosa, E Lucile White, William E Severson
• Journal: Journal of biomolecular screening (J Biomol Screen) Vol. 16 Issue 1 Pg. 73-81 (Jan 2011) ISSN: 1552-454X [Electronic] United States
• PMID: 21059874 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Imidazoles
• Quinazolinones
• Small Molecule Libraries
• Thiazoles
• RNA

Topics

• Animals
• Antiviral Agents (pharmacology)
• Birds
• Cell Line
• Cytopathogenic Effect, Viral (drug effects)
• Dogs
• High-Throughput Screening Assays (methods)
• Humans
• Imidazoles (pharmacology)
• Influenza A Virus, H1N1 Subtype (drug effects)
• Influenza A Virus, H3N2 Subtype (drug effects)
• Influenza A Virus, H5N1 Subtype (drug effects)
• Influenza in Birds
• Influenza, Human
• Inhibitory Concentration 50
• Quinazolinones (pharmacology)
• RNA (metabolism)
• Small Molecule Libraries (pharmacology)
• Thiazoles (pharmacology)
• Virus Replication (drug effects)