Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.
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 .
© 2018 Elsevier Masson SAS
- 3-Hydroxypyrimidine-2,4-dione (HPD)
- Human immunodeficiency virus (HIV)
- RNase H
- Structure-activity-relationship (SAR)
PubMed: MeSH publication types
- Journal Article