tetano
Editor, Senior Moderator
ChemMedChem. 2019 Apr 14. doi: 10.1002/cmdc.201900084. [Epub ahead of print]
[h=1]Aryl and arylalkyl substituted 3-hydroxypyridin(1H)-2-ones: Synthesis and evaluation as inhibitors of influenza A endonuclease.[/h] LaVoie EJ[SUP]1[/SUP], Sagong HY[SUP]2[/SUP], Bauman JD[SUP]3[/SUP], Nogales A[SUP]4[/SUP], Mart?nez-Sobrido L[SUP]4[/SUP], Arnold E[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 strains. These data have prompted research on inhibitors that target the cap-snatching endonuclease activity of PA. Xofluza, baloxavir marboxil, recently approved for clinical use, inhibits cap-snatching endonuclease. Resistance to Xofluza has been reported in both in vitro systems and in the clinic. A X-ray crystallographic screening campaign of a fragment library targeting the IAV endonuclease enzyme identified 5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating ligand 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 metal modes associated with inhibition of this enzyme that are influenced by the presence of substituents on the phenyl groups at the 5- and 6-positions of 3-hydroxypyridin(1H)-2-ones. We report herein on the structure-activity relationships associated with various para-substituted 5-phenyl derivatives of 6-(p-fluorophenyl)-3-hydroxypyridin (1H)-2-one and the effect of using naphthyl, benzyl, and napthylmethyl groups as alternatives to the p-fluorophenyl substituent on their activity as endonuclease inhibitors.
? 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[h=4]KEYWORDS:[/h] Antiviral Endonuclease Influenza Inhibitors Pyridin-2-ones
PMID: 30983160 DOI: 10.1002/cmdc.201900084
[h=1]Aryl and arylalkyl substituted 3-hydroxypyridin(1H)-2-ones: Synthesis and evaluation as inhibitors of influenza A endonuclease.[/h] LaVoie EJ[SUP]1[/SUP], Sagong HY[SUP]2[/SUP], Bauman JD[SUP]3[/SUP], Nogales A[SUP]4[/SUP], Mart?nez-Sobrido L[SUP]4[/SUP], Arnold E[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 strains. These data have prompted research on inhibitors that target the cap-snatching endonuclease activity of PA. Xofluza, baloxavir marboxil, recently approved for clinical use, inhibits cap-snatching endonuclease. Resistance to Xofluza has been reported in both in vitro systems and in the clinic. A X-ray crystallographic screening campaign of a fragment library targeting the IAV endonuclease enzyme identified 5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating ligand 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 metal modes associated with inhibition of this enzyme that are influenced by the presence of substituents on the phenyl groups at the 5- and 6-positions of 3-hydroxypyridin(1H)-2-ones. We report herein on the structure-activity relationships associated with various para-substituted 5-phenyl derivatives of 6-(p-fluorophenyl)-3-hydroxypyridin (1H)-2-one and the effect of using naphthyl, benzyl, and napthylmethyl groups as alternatives to the p-fluorophenyl substituent on their activity as endonuclease inhibitors.
? 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[h=4]KEYWORDS:[/h] Antiviral Endonuclease Influenza Inhibitors Pyridin-2-ones
PMID: 30983160 DOI: 10.1002/cmdc.201900084