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Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral ribonuclease H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α–hydroxytropolone compounds can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochemical RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity analysis of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.Efficacy of α-hydroxytropolones against HBV is diminished by bulky substitutions on the troponoid ring.Carbonyl, lactone, or sulfone groups at R2 on the troponoid ring enhance activity against HBV.No cell-specific cytotoxicity was found among cells of hepatic, kidney, or stellate-cell origin.Cytotoxicity of the troponoids correlated with a hydroxyl in the α position on the troponoid ring and overall lipophilicity.