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

Eur J Med Chem. 2018 Aug 5:156:652-665. doi: 10.1016/j.ejmech.2018.07.039. Epub 2018 Jul 17.

Abstract

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.

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

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Drug Design
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Models, Molecular
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Ribonuclease H, Human Immunodeficiency Virus / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • Ribonuclease H, Human Immunodeficiency Virus