{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T03:16:15Z","timestamp":1773803775113,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"USA National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AI150610"],"award-info":[{"award-number":["R01 AI150610"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"USA National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AI148362"],"award-info":[{"award-number":["R01 AI148362"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curi","award":["945380"],"award-info":[{"award-number":["945380"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis B Virus (HBV) continues to pose a significant global health challenge, with over 254 million chronic infections and current therapies being non-curative, necessitating lifelong treatment. The HBV ribonuclease H (RNase H) is essential during HBV reverse transcription by cleaving the viral pregenomic RNA after it has been copied into the (\u2212) polarity DNA strand, enabling the viral polymerase to synthesize the (+) DNA strand. Although RNase H inhibition terminates viral replication and thus viral infectiveness, its targeting as an HBV treatment is unexploited. Its catalytic site contains four carboxylates that bind to two Mg2+ ions essential for RNA hydrolysis. As part of our ongoing research on RNase H inhibitors, we developed 23 novel N-hydroxypyridinedione (HPD) analogues. Specifically, 17 HPD imines, 4 HPD oximes, 1 2,6-diamino-4-((substituted)oxy)pyrimidine 1-oxide derivative, and 1 barbituric acid analogue were designed, synthesized, and tested for their anti-HBV activity. The HPD derivatives could be docked in the RNase H active site to coordinate the two Mg2+ ions and effectively inhibited viral replication in cellular assays. The 50% effective concentration (EC50) values of these HPD compounds ranged from 0.5 to 73 \u03bcM, while the 50% cytotoxic concentration (CC50) values ranged from 15 to 100 \u03bcM, resulting in selectivity indexes (SIs) up to 112. Furthermore, the novel HPD derivatives exhibited favourable pharmacokinetic-relevant characteristics, including high cellular permeability, good aqueous solubility, and overall drug-like properties. These findings indicate that HPD imines and oximes possess substantial antiviral potency and selectivity against HBV, underscoring the potential of the HPD scaffold as a promising framework for the development of next-generation anti-HBV agents.<\/jats:p>","DOI":"10.3390\/ijms262010239","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:53:19Z","timestamp":1761058399000},"page":"10239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of N-Hydroxypyridinedione-Based Inhibitors of HBV RNase H: Design, Synthesis, and Extended SAR Studies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6843-5630","authenticated-orcid":false,"given":"Dea","family":"Chotzalli","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasiliki","family":"Pardali","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holly M.","family":"Walden","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"},{"name":"Saint Louis University Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitrios","family":"Perivolaris","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-0950","authenticated-orcid":false,"given":"Dimitrios","family":"Moianos","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Makri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-7213","authenticated-orcid":false,"given":"Antonios","family":"Drakopoulos","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, 41296 G\u00f6teborg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2564-6628","authenticated-orcid":false,"given":"Erofili","family":"Giannakopoulou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Razia","family":"Tajwar","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"},{"name":"Saint Louis University Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly E.","family":"Woodson","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"},{"name":"Saint Louis University Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-4240","authenticated-orcid":false,"given":"John E.","family":"Tavis","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"},{"name":"Saint Louis University Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-5186","authenticated-orcid":false,"given":"Grigoris","family":"Zoidis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.virol.2015.02.031","article-title":"Molecular Biology of Hepatitis B Virus Infection","volume":"479\u2013480","author":"Seeger","year":"2015","journal-title":"Virology"},{"key":"ref_2","first-page":"100925","article-title":"Alignment of Countries in the Americas with the Latest WHO Guidelines for Hepatitis B Virus (HBV) Infection: A 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