Design, synthesis, and activity evaluation of C-8 arylated luteolin derivatives as influenza endonuclease inhibitors
Language English Country England, Great Britain Media print-electronic
Document type Journal Article
PubMed
40064244
DOI
10.1016/j.bmcl.2025.130178
PII: S0960-894X(25)00087-3
Knihovny.cz E-resources
- Keywords
- Endonuclease, Flavonoid, Influenza, Inhibitors, RNA polymerase,
- MeSH
- Antiviral Agents * pharmacology chemical synthesis chemistry MeSH
- Endonucleases * antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Luteolin * pharmacology chemical synthesis chemistry MeSH
- Molecular Structure MeSH
- Drug Design * MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antiviral Agents * MeSH
- Endonucleases * MeSH
- Enzyme Inhibitors * MeSH
- Luteolin * MeSH
The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.
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