biostudies-literatureJones TNational Institute of Allergy and Infectious DiseasesNational Institute of Neurological Disorders and StrokeNIAID NIH HHSNINDS NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS12459-12467https://www.ebi.ac.uk/biostudies/studies/S-EPMC11017374biostudies-literatureUnknown66(17)Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >296 million people worldwide, including ∼850,000 in the USA, and kills 820,000 annually worldwide. Current nucleos(t)ide analogue (NA) or pegylated interferon α therapies do not eradicate the virus and would benefit from a complementary antiviral drug. We performed a preliminary screen of 28 dispirotripiperazines against HBV, identifying 9 hits with EC₅₀ of 0.7-25 μM. Compound 11826096 displays the most potent activity and represents a promising lead for future optimization. While the mechanism of action is unknown, preliminary assays limit possible targets to activities involved in RNA accumulation, translation, capsid assembly, and/or capsid stability. In addition, we built machine learning models to determine if they were able to predict the activity of this series of compounds. The novelty of these molecules indicated they were outside of the applicability domain of these models.Journal of medicinal chemistryAntiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus.PMC11017374R01 AI122669R01 NS1021641R01NS102164R01AI122669R44 GM122196R44GM122196Riabova OBradley DPEkins SMonakhova NMakarov VLi QLane TRJones TTavis JEfalseAntiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus.Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >296 million people worldwide, including ∼850,000 in the USA, and kills 820,000 annually worldwide. Current nucleos(t)ide analogue (NA) or pegylated interferon α therapies do not eradicate the virus and would benefit from a complementary antiviral drug. We performed a preliminary screen of 28 dispirotripiperazines against HBV, identifying 9 hits with EC₅₀ of 0.7-25 μM. Compound 11826096 displays the most potent activity and represents a promising lead for future optimization. While the mechanism of action is unknown, preliminary assays limit possible targets to activities involved in RNA accumulation, translation, capsid assembly, and/or capsid stability. In addition, we built machine learning models to determine if they were able to predict the activity of this series of compounds. The novelty of these molecules indicated they were outside of the applicability domain of these models.2023-01-01T00:00:00Z2023 Sep2025-04-03T23:18:16.198Z2025-04-03T23:18:16.198ZS-EPMC110173743761124410.1021/acs.jmedchem.3c00974