Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

Eur J Med Chem. 2017 Dec 1:141:149-161. doi: 10.1016/j.ejmech.2017.09.054. Epub 2017 Sep 28.

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC50 = 0.04 μM) with decent antiviral potency (EC50 = 7.4 μM) and no cytotoxicity (CC50 > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC50 = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.

Keywords: Human immunodeficiency virus (HIV); Integrase strand transfer; Molecular modeling and crystallography; N-Hydroxy thienopyrimidine-2,4-diones; RNase H; RT-Polymerase.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV / drug effects*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Ribonuclease H, Human Immunodeficiency Virus / metabolism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • 5-(4-chlorophenyl)-3-hydroxythieno(2,3-d)pyrimidine-2,4(1H,3H)-dione
  • Antiviral Agents
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • Thiophenes
  • HIV Reverse Transcriptase
  • Ribonuclease H, Human Immunodeficiency Virus