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

Journal Article · · ChemMedChem
 [1];  [1];  [2];  [2];  [1];  [1]
  1. Rutgers Univ., Piscataway, NJ (United States)
  2. Univ. of Rochester Medical Center, Rochester, NY (United States)
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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.

Research Organization:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE; NCRR; National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI ID:
1604190
Journal Information:
ChemMedChem, Journal Name: ChemMedChem Journal Issue: 12 Vol. 14; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

60 APPLIED LIFE SCIENCES
antiviral
endonuclease
influenza
inhibitors
pyridine-2-ones