3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations

J Med Chem. 2016 Mar 24;59(6):2648-59. doi: 10.1021/acs.jmedchem.5b01879. Epub 2016 Mar 8.

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without significantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology*
  • Catalytic Domain / drug effects
  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / drug effects
  • HIV-1 / drug effects
  • Humans
  • Models, Molecular
  • Polymerase Chain Reaction
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis
  • Uracil / pharmacology

Substances

  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Uracil
  • HIV Reverse Transcriptase
  • DNA-Directed RNA Polymerases
  • Ribonuclease H, Human Immunodeficiency Virus