2. Academic Validation
  3. Design, synthesis, and activity evaluation of C-8 arylated luteolin derivatives as influenza endonuclease inhibitors

Design, synthesis, and activity evaluation of C-8 arylated luteolin derivatives as influenza endonuclease inhibitors

  • Bioorg Med Chem Lett. 2025 Jun 1:121:130178. doi: 10.1016/j.bmcl.2025.130178.
Artem Tsalyy 1,  Michal Kráľ 2,  Róbert Reiberger 3,  Pavel Majer 1,  Jan Konvalinka 4,  Milan Kožíšek 5,  Aleš Machara 6
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 1660, 121 08 Prague 2, Czech Republic.
  • 3 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague 2, Czech Republic.
  • 4 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague 2, Czech Republic.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic. Electronic address: milan.kozisek@uochb.cas.cz.
  • 6 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic. Electronic address: ales.machara@uochb.cas.cz.
PMID: 40064244 DOI: 10.1016/j.bmcl.2025.130178
Abstract

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.

Keywords

Endonuclease; Flavonoid; Influenza; Inhibitors; RNA polymerase.

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