6-Arylthio-3-hydroxypyrimidine-2,4-diones potently inhibited HIV reverse transcriptase-associated RNase H with antiviral activity

Lei Wang, Jing Tang, Andrew D. Huber, Mary C. Casey, Karen A. Kirby, Daniel J. Wilson, Jayakanth Kankanala, Jiashu Xie, Michael A. Parniak, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current drugs. Although a few chemotypes have been reported to inhibit HIV RNase H in biochemical assays, their general lack of significant antiviral activity in cell culture necessitates continued efforts in identifying highly potent RNase H inhibitors to confer antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-arylthio subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays these new analogues inhibited RT RNase H in single-digit nanomolar range without inhibiting RT polymerase (pol) at concentrations up to 10 μM, amounting to exceptional biochemical inhibitory selectivity. Many analogues also inhibited integrase strand transfer (INST) activity in low to sub micromolar range. More importantly, most analogues inhibited HIV in low micromolar range without cytotoxicity. In the end, compound 13j (RNase H IC50 = 0.005 μM; RT pol IC50 = 10 μM; INST IC50 = 4.0 μM; antiviral EC50 = 7.7 μM; CC50 > 100 μM) represents the best analogues within this series. These results characterize the new 6-arylthio-HPD subtype as a promising scaffold for HIV RNase H inhibitor discovery.

Original languageEnglish (US)
Pages (from-to)652-665
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Aug 5 2018

Bibliographical note

Funding 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 .

Publisher Copyright:
© 2018 Elsevier Masson SAS


  • 3-Hydroxypyrimidine-2,4-dione (HPD)
  • Human immunodeficiency virus (HIV)
  • Inhibitors
  • Integrase strand transfer
  • RNase H
  • Structure-activity-relationship (SAR)

PubMed: MeSH publication types

  • Journal Article


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