The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors.
Bibliographical noteFunding Information:
This research was supported by the National Institutes of Health ( AI100890 to SGS, MAP and ZW) and partially by the Center for Drug Design, University of Minnesota .
- 3-Hydroxypyrimidine-2,4-dione (HPD)
- Human immunodeficiency virus (HIV)
- Reverse transcriptase (RT)
- RNase H
PubMed: MeSH publication types
- Journal Article