{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:05:52Z","timestamp":1791291952429,"version":"4.1.0"},"reference-count":33,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2015,9,16]],"date-time":"2015-09-16T00:00:00Z","timestamp":1442361600000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1021\/jm500958x","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T15:28:12Z","timestamp":1412004492000},"page":"8086-8098","source":"Crossref","is-referenced-by-count":56,"title":["Phenyl Substituted 4-Hydroxypyridazin-3(2\n                    <i>H<\/i>\n                    )-ones and 5-Hydroxypyrimidin-4(3\n                    <i>H<\/i>\n                    )-ones: Inhibitors of Influenza A Endonuclease"],"prefix":"10.1021","volume":"57","author":[{"given":"Hye Yeon","family":"Sagong","sequence":"first","affiliation":[{"name":"Rutgers, The State University of New Jersey , , , ,","place":["Piscataway, New Jersey, United States, 08854-8020"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"Bauman","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08854-5627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Patel","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08854-5627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan","family":"Das","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08854-5627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Rutgers University , , , ,","place":["Piscataway, New Jersey, United States, 08854-5627"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmond J.","family":"LaVoie","sequence":"additional","affiliation":[{"name":"Rutgers, The State University of New Jersey , , , ,","place":["Piscataway, New Jersey, United States, 08854-8020"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,9,16]]},"reference":[{"key":"2026090114552859600_cit1","first-page":"119","article-title":"Emergence and transmission of influenza A viruses resistant\nto amantadine and rimantadine","volume":"176","author":"Hayden","year":"1992","journal-title":"Curr. Top. Microbiol.\nImmunol."},{"key":"2026090114552859600_cit2","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S0140-6736(05)67338-2","article-title":"Incidence of admantane resistance\namong influenza A (H3N2) viruses isolated worldwide from 1994 to 2005:\na cause for concern","volume":"366","author":"Bright","year":"2005","journal-title":"Lancet"},{"key":"2026090114552859600_cit3","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1056\/NEJMp058291","article-title":"Oseltamivir\nResistance\u2500Disabling our Influenza Defenses","volume":"353","author":"Moscona","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"2026090114552859600_cit4","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1126\/science.1187816","article-title":"Permissive secondary mutations enable\nthe evolution of influenza oseltamivir resistance","volume":"328","author":"Bloom","year":"2010","journal-title":"Science"},{"key":"2026090114552859600_cit5","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1093\/infdis\/jiq067","article-title":"Multidrug-resistant 2009 pandemic\ninfluenza A(H1N1) viruses maintain fitness and transmissibility in\nferrets","volume":"203","author":"Memoli","year":"2011","journal-title":"J. Infect Dis."},{"key":"2026090114552859600_cit6","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nsmb.1779","article-title":"Structures\nof influenza A proteins and insights into antiviral drug targets","volume":"17","author":"Das","year":"2010","journal-title":"Nature Struct Mol. Biol."},{"key":"2026090114552859600_cit7","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/nature07120","article-title":"Crystal structure\nof the polymerase PAC\u2013PB1N complex from an avian influenza\nH5N1 virus","volume":"454","author":"He","year":"2008","journal-title":"Nature"},{"key":"2026090114552859600_cit8","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nature07720","article-title":"Crystal structure of\nan avian influenza polymerase PAN reveals an endonuclease\nactive site","volume":"458","author":"Yan","year":"2009","journal-title":"Nature"},{"key":"2026090114552859600_cit9","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/nature07745","article-title":"The cap-snatching\nendonuclease of influenza virus polymerase resides in the PA subunit","volume":"458","author":"Dias","year":"2009","journal-title":"Nature"},{"key":"2026090114552859600_cit10","doi-asserted-by":"crossref","first-page":"e1002830","DOI":"10.1371\/journal.ppat.1002830","article-title":"Structural and biochemical\nbasis for development of influenza virus inhibitors targeting the\nPA endonuclease","volume":"8","author":"DuBois","year":"2012","journal-title":"PLoS Pathog."},{"issue":"8","key":"2026090114552859600_cit11","doi-asserted-by":"publisher","first-page":"e1002831","DOI":"10.1371\/journal.ppat.1002831","article-title":"Structural Analysis of Specific Metal Chelating Inhibitor\nBinding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase","volume":"8","author":"Kowalinski","year":"2012","journal-title":"PLoS Pathogens"},{"key":"2026090114552859600_cit12","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1128\/JVI.03270-13","article-title":"The N-terminal domain of PA from bat-derived influenza-like\nvirus H17N10 has endonuclease activity","volume":"88","author":"Tefsen","year":"2013","journal-title":"J. Virol."},{"key":"2026090114552859600_cit13","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1021\/cb400400j","article-title":"Crystallographic fragment screening and structure-based\noptimization yields a new class of influenza endonuclease inhibitors","volume":"8","author":"Bauman","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2026090114552859600_cit14","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/0092-8674(81)90449-9","article-title":"A unique Cap(m7CppXm)-dependent\ninfluenza virion endonuclease cleaves capped RNAs to generate the\nprimers that initiate viral RNA transcription","volume":"23","author":"Plotch","year":"1981","journal-title":"Cell"},{"key":"2026090114552859600_cit15","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1128\/AAC.38.12.2827","article-title":"Inhibition\nof Cap (m7GpppXm)-dependent endonuclease of influenza virus\nby 4-substituted 2,4-dioxobutanoic acid compounds","volume":"38","author":"Tomassini","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090114552859600_cit16","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1128\/AAC.40.5.1304","article-title":"Anti-influenza\nvirus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors","volume":"40","author":"Hastings","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090114552859600_cit17","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1128\/AAC.40.5.1189","article-title":"A novel\nantiviral agent which inhibits the endonuclease of influenza viruses","volume":"40","author":"Tomassini","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090114552859600_cit18","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1016\/0040-4039(95)00214-W","article-title":"Total synthesis\nof flutimide, a novel endonuclease inhibitor of influenza virus","volume":"36","author":"Singh","year":"1995","journal-title":"Tetrhedron Lett."},{"key":"2026090114552859600_cit19","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1021\/mp400482a","article-title":"Metal-Chelating\n2-Hydroxyphenyl Amide Pharmacophore for Inhibition of Influenza Virus\nEndonuclease","volume":"11","author":"Carcelli","year":"2013","journal-title":"Mol. Pharmaceutics"},{"key":"2026090114552859600_cit20","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1021\/jm020334u","article-title":"Use of a pharmacophore\nmodel to discover a new class of influenza endonuclease inhibitors","volume":"46","author":"Parkes","year":"2002","journal-title":"J. Med. Chem."},{"key":"2026090114552859600_cit21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1021\/ml4003474","article-title":"Computation-guided discovery of influenza endonuclease\ninhibitors","volume":"5","author":"Chen","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"2026090114552859600_cit22","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1021\/ml4001112","article-title":"3-Hydroxyquinolin(1H)-2-ones: potential\ninhibitors of influenza A endonuclease","volume":"4","author":"Sagong","year":"2013","journal-title":"ACS\nMed. Chem. Lett."},{"key":"2026090114552859600_cit23","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1016\/j.bmc.2013.08.053","article-title":"Phenyl substituted\n3-hydroxypyridin-2(1H)-ones: potential inhibitors\nof influenza A endonuclease","volume":"21","author":"Parhi","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"2026090114552859600_cit24","unstructured":"Aronov, A.; Bandarage, U. K.; Cottrell, K.; Davies, R.; Krueger, E.; Ledeboer, M.; Ledford, B.; Le Tiran, A.; Liao, Y.; Messersmith, D.; Wang, T.; Xu, J.\n          Tetrahydrothiazolopyridine\nInhibitors of Phosphatidylinositol\n3-kinase. (Vertex Pharmaceuticals, Inc.) Patent WO\/2010\/096389, 2010."},{"key":"2026090114552859600_cit25","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/jm001124p","article-title":"Structure\u2013Activity\nRelationships of 1,4-dihydro-(1H,4H)-quinoxalin-2,3-diones as N-methyl-d-aspartate\n(glycine site) receptor antagonists.\n1. Heterocyclic substituted 5-alkyl derivatives","volume":"44","author":"Fray","year":"2001","journal-title":"J. Med. Chem."},{"key":"2026090114552859600_cit26","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1021\/jm301626p","article-title":"Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled\nreceptor 119","volume":"56","author":"Darout","year":"2013","journal-title":"J. Med. Chem."},{"key":"2026090114552859600_cit27","unstructured":"Wolkenberg, S.; Harrison, S. T.; Barrow, J. C.; Zhao, Z.; Kett, N.; Zartman, A.\n          Inhibitors of\nCatechol O-methyl Transferase and their Use in the\nTreatment of Psychotic disorders. (Merck Sharp &\nDohme Corp.) Patent WO\/2011\/109267, 2011."},{"key":"2026090114552859600_cit28","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.bmcl.2012.12.030","article-title":"SAR analysis of novel\nnon-peptide NPBWR1 (GPR7) antagonists","volume":"23","author":"Guerrero","year":"2013","journal-title":"Bioorg.\nMed. Chem. Lett."},{"key":"2026090114552859600_cit29","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1248\/cpb.35.350","article-title":"Studies on\nsyntheses and reactions of methoxypyridazines. II. Methoxylation of\n3,4,6-trichloropyridazine","volume":"35","author":"Nagashima","year":"1987","journal-title":"Chem. Pharm. Bull."},{"key":"2026090114552859600_cit30","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1021\/jm400095b","article-title":"4-Hydroxypyridazin-3(2H)-one derivatives as novel d-amino acid oxidase\ninhibitors","volume":"56","author":"Hondo","year":"2013","journal-title":"J. Med. Chem."},{"key":"2026090114552859600_cit31","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1021\/jm900128w","article-title":"Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent d-amino acid oxidase (DAAO)\ninhibitors","volume":"52","author":"Duplantier","year":"2009","journal-title":"J. Med. Chem."},{"key":"2026090114552859600_cit32","first-page":"307","article-title":"Processing of\nX-ray Diffraction Data Collected in Oscillation Mode","volume-title":"Methods in Enzymology, 276","author":"Otwinowski","year":"1997"},{"key":"2026090114552859600_cit33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based\nsystem for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm500958x","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/19\/8086\/15126210\/jm500958x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/19\/8086\/15126210\/jm500958x.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:55:38Z","timestamp":1788288938000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/19\/8086\/1436082\/Phenyl-Substituted-4-Hydroxypyridazin-3-2H-ones"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,16]]},"references-count":33,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2014,9,16]]},"published-print":{"date-parts":[[2014,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/jm500958x","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,16]]}}}