Phenyl substituted 4-hydroxypyridazin-3(2 H)-ones and 5-hydroxypyrimidin-4(3 H)-ones: Inhibitors of influenza a endonuclease

Hye Yeon Sagong, Joseph D. Bauman, Disha Patel, Kalyan Das, Eddy Arnold, Edmond J. Lavoie

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is attractive for the development of new agents for the treatment of influenza infection. Our earlier studies identified a series of 5- and 6-phenyl substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors of influenza endonuclease. These agents identified as bimetal chelating ligands binding to the active site of the enzyme. In the present study, several aza analogues of these phenyl substituted 3-hydroxypyridin-2(1H)-one compounds were synthesized and evaluated for their ability to inhibit the endonuclease activity. In contrast to the 4-aza analogue of 6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one, the 5-aza analogue (5-hydroxy-2-(4-fluorophenyl)pyrimidin-4(3H)-one) did exhibit significant activity as an endonuclease inhibitor. The 6-aza analogue of 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (6-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one) also retained modest activity as an inhibitor. Several varied 6-phenyl-4-hydroxypyridazin-3(2H)-ones and 2-phenyl-5-hydroxypyrimidin-4(3H)-ones were synthesized and evaluated as endonuclease inhibitors. The SAR observed for these aza analogues are consistent with those previously observed with various phenyl substituted 3-hydroxypyridin-2(1H)-ones.

Original languageEnglish (US)
Pages (from-to)8086-8098
Number of pages13
JournalJournal of medicinal chemistry
Volume57
Issue number19
DOIs
StatePublished - Oct 9 2014

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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