{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:38:16Z","timestamp":1780076296417,"version":"3.54.0"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R01 AI150610"],"award-info":[{"award-number":["R01 AI150610"]}]},{"name":"Gilead Sciences","award":["ASKLEPIOS"],"award-info":[{"award-number":["ASKLEPIOS"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,1,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              We previously reported\n              <jats:italic>N<\/jats:italic>\n              -hydroxypyridinedione (HPD) compounds with mid-nanomolar efficacy and selectivity indexes around 300 against hepatitis B virus (HBV) replication. However, they lack pharmacological evaluation. Here, we report\n              <jats:italic>in vitro<\/jats:italic>\n              anti-HBV efficacy, cytotoxicity, and pharmacological characterization of 29 novel HPDs within seven subgroups. The best two compounds had EC\n              <jats:sub>50<\/jats:sub>\n              s of 61 and 190 nM and selectivity indexes of 526 and 1,071. Compounds with one halogen on the major R group were most effective and compounds with large ether R groups were most cytotoxic. Compounds were not cytotoxic in primary human hepatocytes. All compounds were freely soluble in pHs reflecting plasma (7.4) and the gastrointestinal tract (5 and 6.5). Almost all highly soluble compounds were passively permeable at pH 5.0 and 7.4. Only 2 of 11 compounds tested were likely to be effluxed by p-glycoprotein. The most potent HPDs inhibited HBV replication over human ribonuclease H1 activity by 10-fold. Four of 19 compounds inhibited CYP2D6 &gt;50%, but their CYP2D6 IC\n              <jats:sub>50<\/jats:sub>\n              s were &gt;8\u00d7 higher than their anti-HBV EC\n              <jats:sub>50<\/jats:sub>\n              . No compound substantially inhibited CYP3A4. Thirteen of 15 compounds had human microsomal half-lives &gt;30 min with medium to low rates of intrinsic clearance. Eleven of 12 compounds bound plasma proteins by \u226580%; however, effects against HBV replication for only one would likely be physiologically relevant. These results identify two lead candidate HPDs with pharmacological characteristics resembling commercially available drugs that are suitable for\n              <jats:italic>in vivo<\/jats:italic>\n              pharmacological and efficacy studies.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01455-24","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T14:02:51Z","timestamp":1732716171000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Efficacy and\n            <i>in vitro<\/i>\n            pharmacological assessment of novel\n            <i>N<\/i>\n            -hydroxypyridinediones as hepatitis B virus ribonuclease H inhibitors"],"prefix":"10.1128","volume":"69","author":[{"given":"Molly E.","family":"Woodson","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine","place":["St. Louis, USA"]},{"name":"Institute for Drug and Biotherapeutic Innovation, St. Louis University","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly F.","family":"Walden","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine","place":["St. Louis, USA"]},{"name":"Institute for Drug and Biotherapeutic Innovation, St. Louis University","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Abdul","family":"Mottaleb","sequence":"additional","affiliation":[{"name":"Institute for Drug and Biotherapeutic Innovation, St. Louis University","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Moianos","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Pardali","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-5186","authenticated-orcid":true,"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","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-4240","authenticated-orcid":true,"given":"John E.","family":"Tavis","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, St. Louis University School of Medicine","place":["St. Louis, USA"]},{"name":"Institute for Drug and Biotherapeutic Innovation, St. Louis University","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"WHO. 2024. 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