Aryl and Arylalkyl Substituted 3‐Hydroxypyridin‐2(1 H )‐ones: Synthesis and Evaluation as Inhibitors of Influenza A Endonuclease

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(1 H )‐one as a bimetal chelating agent at the active site. We have reported the structure–activity relationships for 3‐hydroxypyridin‐2(1 H )‐ones and 3‐hydroxyquinolin‐2(1 H )‐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(1 H )‐ones. Herein we report the structure–activity relationships associated with various para ‐substituted 5‐phenyl derivatives of 6‐( p ‐fluorophenyl)‐3‐hydroxypyridin‐2(1 H )‐ones and the effect of using naphthyl, benzyl, and naphthylmethyl groups as alternatives to the p ‐fluorophenyl substituent on their activity as endonuclease inhibitors.