4W9S

2-(4-(1H-tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3H)-one bound to influenza 2009 H1N1 endonuclease

Summary for 4W9S

• Entry DOI: 10.2210/pdb4w9s/pdb
• Related: 4LN7 4M4Q 4M5O 4M5Q 4M5R 4M5U 4MK1 4MK2 4MK5
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: cap-snatching, rna binding protein, rna binding protein-inhibitor complex, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Influenza A virus
• Cellular location: Host cytoplasm: P13166
• Total number of polymer chains: 1
• Total formula weight: 29063.49

Authors

Bauman, J.D.,Patel, D.,Das, K.,Arnold, E. (deposition date: 2014-08-27, release date: 2014-10-01, Last modification date: 2023-09-27)

Primary citation

Sagong, H.Y.,Bauman, J.D.,Patel, D.,Das, K.,Arnold, E.,LaVoie, E.J.
Phenyl Substituted 4-Hydroxypyridazin-3(2H)-ones and 5-Hydroxypyrimidin-4(3H)-ones: Inhibitors of Influenza A Endonuclease.
J.Med.Chem., 57:8086-8098, 2014

PubMed 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.

PubMed: 25225968
DOI: 10.1021/jm500958x

Experimental method

X-RAY DIFFRACTION (1.8 Å)