Seasonal influenza infections are associated with an estimated 250-500 000 
deaths annually. Resistance to the antiviral M2 ion-channel inhibitors has 
largely invalidated their clinical utility. Resistance to neuraminidase 
inhibitors has also been observed in several influenza A virus (IAV) strains. 
These data have prompted research on inhibitors that target the cap-snatching 
endonuclease activity of the polymerase acidic protein (PA). Baloxavir marboxil 
(Xofluza®), recently approved for clinical use, inhibits cap-snatching 
endonuclease. Resistance to Xofluza® has been reported in both in vitro systems 
and in the clinic. An X-ray crystallographic screening campaign of a fragment 
library targeting IAV endonuclease identified 
5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating agent at the active 
site. We have reported the structure-activity relationships for 
3-hydroxypyridin-2(1H)-ones and 3-hydroxyquinolin-2(1H)-ones as endonuclease 
inhibitors. These studies identified two distinct binding modes associated with 
inhibition of this enzyme that are influenced by the presence of substituents at 
the 5- and 6-positions of 3-hydroxypyridin-2(1H)-ones. Herein we report the 
structure-activity relationships associated with various para-substituted 
5-phenyl derivatives of 6-(p-fluorophenyl)-3-hydroxypyridin-2(1H)-ones and the 
effect of using naphthyl, benzyl, and naphthylmethyl groups as alternatives to 
the p-fluorophenyl substituent on their activity as endonuclease inhibitors.