Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV-1 RNase H inhibitors.
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 biologic evaluation of a novel series of galloyl derivatives with HIV-1 RNase H inhibitory activity. Most of them showed IC50 s 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-1BH10 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.
Gao, P; Wang, X; Sun, L; Cheng, X; Poongavanam, V; Kongsted, J; Álvarez, M; Luczkowiak, J; Pannecouque, C; De Clercq, E; Lee, K-H; Chen, C-H; Liu, H; Menéndez-Arias, L; Liu, X; Zhan, P
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