Several novel tropolone derivatives have been identified that inhibit HIV-1 RNase H function and have potential for anti-viral activity due to reduced cellular toxicity. Inhibiting RNase H function is a potential treatment for many viral infections, since RNase H function is essential for viral replication for many pathogenic retroviruses such as HIV-1 and HIV-2. Although many hydroxytropolone compounds are potent RNase H inhibitors biding at the enzymatic active site, they are limited as therapeutic candidates by their toxicity in mammalian cells. The toxicity thought to be a result of inhibition of multiple essential mammalian metalloenzymes. We reasoned that the potential beneficial application of tropolone RNase H inhibition might be of therapeutic use if the toxic effects in mammalian cell were eliminated. By selectively adding steric bulk to add new drug-enzyme contacts for the RNase H active site, a number of novel compounds, that have initially demonstrated reduced cytotoxicity, have been produced. Importantly, these novel compounds appear to retain antiviral activity essential for use as therapeutics.