Design, Synthesis and Biological Evaluation of Novel Galloyl Derivatives as HIV‐1 RNase H Inhibitors

A series of galloyl derivatives was designed and synthesized as anti‐HIV‐1 RNase H inhibitors, the most potent compound of which showed an IC₅₀ of 0.72 ± 0.07 μM, 2.8 times more potent than β‐thujaplicinol. SAR studies and molecular modeling analysis provided helpful insight for further optimization of selected compounds.

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT)‐associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis and biological evaluation of a novel series of galloyl derivatives with HIV‐1 RNase H inhibitory activity. Most of them showed IC₅₀s at sub to low micromolar concentrations in enzymatic assays. The most potent compound was II‐25 that showed an IC₅₀ of 0.72 ± 0.07 μM in RNase H inhibition assays carried out with the HIV‐1_BH10 RT. II‐25 was 2.8 times more potent than β‐thujaplicinol in these assays. Interestingly, II‐25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure‐activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.

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