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.
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 .
© 2019 Elsevier Masson SAS
- 3-Hydroxypyrimidine-2,4-dione (HPD)
- Human immunodeficiency virus (HIV)
- Reverse transcriptase (RT)
- RNase H
PubMed: MeSH publication types
- Journal Article