{"doi":"10.3390/ijms262010239","title":"Discovery of N-Hydroxypyridinedione-Based Inhibitors of HBV RNase H: Design, Synthesis, and Extended SAR Studies","abstract":"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 (−) 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 μM, while the 50% cytotoxic concentration (CC50) values ranged from 15 to 100 μM, 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.","journal":"International Journal of Molecular Sciences","year":2025,"id":547847,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":943492,"name":"Vasiliki Pardali","orcid":null,"position":1,"is_corresponding":false},{"id":1441074,"name":"Holly M. Walden","orcid":null,"position":2,"is_corresponding":false},{"id":1441075,"name":"Dimitrios Perivolaris","orcid":null,"position":3,"is_corresponding":false},{"id":1089835,"name":"Dimitrios Moianos","orcid":"0000-0001-8843-0950","position":4,"is_corresponding":false},{"id":164422,"name":"Maria Makri","orcid":null,"position":5,"is_corresponding":false},{"id":1440622,"name":"Antonios Drakopoulos","orcid":"0000-0001-9178-7213","position":6,"is_corresponding":false},{"id":942894,"name":"Erofili Giannakopoulou","orcid":"0000-0003-2564-6628","position":7,"is_corresponding":false},{"id":760154,"name":"Razia Tajwar","orcid":null,"position":8,"is_corresponding":false},{"id":714850,"name":"Molly E. Woodson","orcid":null,"position":9,"is_corresponding":false},{"id":321543,"name":"John E. Tavis","orcid":"0000-0002-8711-4240","position":10,"is_corresponding":false},{"id":942895,"name":"Grigoris Zoidis","orcid":"0000-0002-9442-5186","position":11,"is_corresponding":false},{"id":1441073,"name":"Dea Chotzalli","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41155527","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}