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Resistance to the antiviral M2 ion\u2010channel inhibitors has largely invalidated their clinical utility. Resistance to neuraminidase inhibitors has also been observed in several influenza\u2005A virus (IAV) strains. These data have prompted research on inhibitors that target the cap\u2010snatching endonuclease activity of the polymerase acidic protein (PA). Baloxavir marboxil (Xofluza\u00ae), recently approved for clinical use, inhibits cap\u2010snatching endonuclease. Resistance to Xofluza\u00ae has been reported in both in\u2005vitro systems and in the clinic. An X\u2010ray crystallographic screening campaign of a fragment library targeting IAV endonuclease identified 5\u2010chloro\u20103\u2010hydroxypyridin\u20102(1<jats:italic>H<\/jats:italic>)\u2010one as a bimetal chelating agent at the active site. We have reported the structure\u2013activity relationships for 3\u2010hydroxypyridin\u20102(1<jats:italic>H<\/jats:italic>)\u2010ones and 3\u2010hydroxyquinolin\u20102(1<jats:italic>H<\/jats:italic>)\u2010ones 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\u2010 and 6\u2010positions of 3\u2010hydroxypyridin\u20102(1<jats:italic>H<\/jats:italic>)\u2010ones. Herein we report the structure\u2013activity relationships associated with various <jats:italic>para<\/jats:italic>\u2010substituted 5\u2010phenyl derivatives of 6\u2010(<jats:italic>p<\/jats:italic>\u2010fluorophenyl)\u20103\u2010hydroxypyridin\u20102(1<jats:italic>H<\/jats:italic>)\u2010ones and the effect of using naphthyl, benzyl, and naphthylmethyl groups as alternatives to the <jats:italic>p<\/jats:italic>\u2010fluorophenyl substituent on their activity as endonuclease inhibitors.<\/jats:p>","DOI":"10.1002\/cmdc.201900084","type":"journal-article","created":{"date-parts":[[2019,4,14]],"date-time":"2019-04-14T21:49:00Z","timestamp":1555278540000},"page":"1204-1223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Aryl and Arylalkyl Substituted 3\u2010Hydroxypyridin\u20102(1<i>H<\/i>)\u2010ones: Synthesis and Evaluation as Inhibitors of Influenza\u2005A Endonuclease"],"prefix":"10.1002","volume":"14","author":[{"given":"Hye Yeon","family":"Sagong","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey  160 Frelinghuysen Road Piscataway NJ 08854-8020 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph D.","family":"Bauman","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey  Hoes Lane Piscataway NJ 08854-5627 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aitor","family":"Nogales","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Rochester Medical Center  601 Elmwood Avenue, Box 672 Rochester NY 14642 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Mart\u00ednez\u2010Sobrido","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Rochester Medical Center  601 Elmwood Avenue, Box 672 Rochester NY 14642 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9622","authenticated-orcid":false,"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey  Hoes Lane Piscataway NJ 08854-5627 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9244-1249","authenticated-orcid":false,"given":"Edmond J.","family":"LaVoie","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey  160 Frelinghuysen Road Piscataway NJ 08854-8020 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,14]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70821-7"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03063"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-77011-1_8"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67338-2"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp058291"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1187816"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2052252515021259"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b01087"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep31500"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17419-6"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01363"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1519772113"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-27890-4"},{"key":"e_1_2_7_14_1","first-page":"00430","volume":"9","author":"Jones J. 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This intermediate was converted with NBS in acetonitrile into its 5-bromo derivative which was subsequently treated under Suzuki coupling conditions to provide the 5-(p-(5-tetrazoyl)phenyl) derivative. Removal of thetert-butoxy and MEM protecting groups using TFA in dichloromethane followed by 2\u2009nHCl in dioxane (1:1) provided the 6-(2-naphthyl)-5-(p-(5-tetrazoyl)phenyl)-3-hydroxypyridin-2(1H)-one. The compound prepared by this alternative route proved unstable and significantly decomposed in DMSO within 1\u2005h as observed by LC\u2013MS."},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0300072"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2014.12.006"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2015.11.014"},{"key":"e_1_2_7_44_1","volume-title":"Crystallography of Biological Macromolecules","author":"Arnold E.","year":"2011"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201900084","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.201900084","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/cmdc.201900084","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201900084","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:27:52Z","timestamp":1760290072000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201900084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,14]]},"references-count":45,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,6,18]]}},"alternative-id":["10.1002\/cmdc.201900084"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201900084","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,14]]},"assertion":[{"value":"2019-02-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}