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. 2014 Oct 9;57(19):8086-98.
doi: 10.1021/jm500958x. Epub 2014 Sep 29.

Phenyl Substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: Inhibitors of Influenza A Endonuclease

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Phenyl Substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: Inhibitors of Influenza A Endonuclease

Hye Yeon Sagong et al. J Med Chem. .
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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.

Figures

Figure 1
Figure 1
Structures and of 5-(p-fluorophenyl-3-hydroxypyridin-2(1H)-one (5-FPhP), 6-(p-fluorophenyl)-3-hydroxypyridin-2(1H)-one (6-FPhP), 6-(p-fluorophenyl)-3-hydroxyquinolin-2(1H)-one (6-FPhQ), and 7-(p-fluorophenyl)-3-hydroxyquinolin-2(1H)-one (7-FPhQ).
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Scheme 5
Scheme 5
Figure 2
Figure 2
Stereoview image of a crystal structure of 11 (yellow) bound to PAN(cyan) superposed with a previously published structure (PDB ID: 4M5U) of 5-(4-(1H-tetrazol-5-yl)phenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (green). Metal-coordinating bonds are depicted as black dashed lines whereas hydrogen or electrostatic bonds are depicted in blue. Electron density calculated from an omit map is contoured at 4.0σ (blue mesh).

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