{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T08:47:44Z","timestamp":1775638064555,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T00:00:00Z","timestamp":1718841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AI150610"],"award-info":[{"award-number":["R01 AI150610"]}]},{"name":"NIH","award":["R21 AI124672"],"award-info":[{"award-number":["R21 AI124672"]}]},{"name":"NIH","award":["R01 AI150610"],"award-info":[{"award-number":["R01 AI150610"]}]},{"name":"NIH","award":["R21 AI124672"],"award-info":[{"award-number":["R21 AI124672"]}]},{"name":"Gilead \u2018ASKLEPIOS Grants Program\u2019","award":["R01 AI150610"],"award-info":[{"award-number":["R01 AI150610"]}]},{"name":"Gilead \u2018ASKLEPIOS Grants Program\u2019","award":["R21 AI124672"],"award-info":[{"award-number":["R21 AI124672"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low \u03bcM range (1.1\u20137.7 \u03bcM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure\u2013activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.<\/jats:p>","DOI":"10.3390\/molecules29122942","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T11:42:03Z","timestamp":1718883723000},"page":"2942","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["N-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-0950","authenticated-orcid":false,"given":"Dimitrios","family":"Moianos","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, 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":"Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgia-Myrto","family":"Prifti","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0052-8393","authenticated-orcid":false,"given":"Aristeidis","family":"Chiotellis","sequence":"additional","affiliation":[{"name":"Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research \u201cDemokritos\u201d, 15310 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5041-7279","authenticated-orcid":false,"given":"Alexandros","family":"Pappas","sequence":"additional","affiliation":[{"name":"Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research \u201cDemokritos\u201d, 15310 Athens, Greece"}],"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"}],"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"}],"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-5186","authenticated-orcid":false,"given":"Grigoris","family":"Zoidis","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, 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":[[2024,6,20]]},"reference":[{"key":"ref_1","unstructured":"(2024, April 07). 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