{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T07:43:30Z","timestamp":1770018210558,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T00:00:00Z","timestamp":1532044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2018,8,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human cytomegalovirus (HCMV) infection poses a major health threat to immunocompromised individuals. Until recently, treatment of HCMV infection has relied solely on polymerase inhibitors that have safety and resistance issues. pUL89 provides the enzymatic functions for the HCMV terminase complex in viral DNA packaging and is an attractive target for developing a new class of HCMV drugs. However, inhibitors of the endonuclease activity of the C\u2005terminus of pUL89 (pUL89\u2010C) were unknown before our recently characterized hydroxypyridonecarboxylic acid (HPCA) hit <jats:bold>7\u2009r<\/jats:bold> (1\u2010(3\u2010chloro\u20104\u2010fluorobenzyl)\u20105\u2010hydroxy\u20104\u2010oxo\u20101,4\u2010dihydropyridine\u20103\u2010carboxylic acid; numbered as <jats:bold>10\u2009k<\/jats:bold> in our previous publication: Y. Wang, L. Mao, J. Kankanala, Z. Wang, R.\u2005J. Geraghty, <jats:italic>J. Virol<\/jats:italic>. <jats:bold>2017<\/jats:bold>, <jats:italic>91<\/jats:italic>, e02152\u201016). Herein, we explored the structure\u2013activity relationship (SAR) of the HPCA chemotype mainly with regard to the N1 site through the synthesis of 35 analogues. The SAR studies, along with molecular modeling, identified a possible pharmacophore model minimally consisting of a chelating triad and a hydrophobic phenyl or biphenyl methyl substituent at N1. Lastly, our best compounds consistently inhibited pUL89\u2010C in the low micromolar range in biochemical assays and exhibited strong antiviral activity without cytotoxicity, laying a solid medicinal chemistry foundation for further HCMV drug discovery efforts targeting pUL89\u2010C.<\/jats:p>","DOI":"10.1002\/cmdc.201800283","type":"journal-article","created":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T04:14:07Z","timestamp":1530591247000},"page":"1658-1663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease"],"prefix":"10.1002","volume":"13","author":[{"given":"Jayakanth","family":"Kankanala","sequence":"first","affiliation":[{"name":"University of Minnesota Academic Health Center, Center for Drug Design, Nils Hasselmo Hall  312 Church Street SE Minneapolis MN 55455 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Minnesota Academic Health Center, Center for Drug Design, Nils Hasselmo Hall  312 Church Street SE Minneapolis MN 55455 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Geraghty","sequence":"additional","affiliation":[{"name":"University of Minnesota Academic Health Center, Center for Drug Design, Nils Hasselmo Hall  312 Church Street SE Minneapolis MN 55455 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1326-5986","authenticated-orcid":false,"given":"Zhengqiang","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Minnesota Academic Health Center, Center for Drug Design, Nils Hasselmo Hall  312 Church Street SE Minneapolis MN 55455 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,7,20]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1086\/508173"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1586\/14789450.2014.971116"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra050700"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2012.658775"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656560802678138"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00311-13"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02538-10"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110224109"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.344"},{"key":"e_1_2_7_10_1","unstructured":"Letermovir (PrevymisTM) patient information sheet Reference ID 4179078:https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/209939Orig1s000 209940Orig1s000lbl.pdf(URL accessed July 16 2018)."},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuy004"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05265-11"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.717-725.1998"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/48.6.757"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1007144107"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00465"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00440"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00040"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01879"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm1014378"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml1002162"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm070512p"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.09.054"},{"key":"e_1_2_7_24_1","first-page":"02152","volume":"91","author":"Wang Y.","year":"2017","journal-title":"J. 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