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

A. Tsalyy, M. Kráľ, R. Reiberger, P. Majer, J. Konvalinka, M. Kožíšek, A. Machara

. 2025 ; 121 (-) : 130178. [pub] 20250308

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25009269

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.

Citace poskytuje Crossref.org

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$a The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.
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$a Kráľ, Michal $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 1660, 121 08 Prague 2, Czech Republic
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$a Reiberger, Róbert $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague 2, Czech Republic
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$a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic
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$a Konvalinka, Jan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 00 Prague 2, Czech Republic
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$a Kožíšek, Milan $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 166 10 Prague 6, Czech Republic. Electronic address: milan.kozisek@uochb.cas.cz
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$a Machara, Aleš $u 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
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