Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs

Bioorg Med Chem. 2013 Nov 15;21(22):7091-100. doi: 10.1016/j.bmc.2013.09.009. Epub 2013 Sep 14.

Abstract

A series of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50=5.1-8.9 μM). Structure-activity relationship analysis indicated that N2-(3-halogenated-benzyl) analogues were more potent than N2-(unsubstituted-benzyl) analogues. The N4-substitutions contributed to the antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues.

Keywords: Drug design; HIV; Heterocycle; NNRTIs; Pyrrolothiatriazine; Reverse transcriptase; Thienothiadiazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Pyrroles / chemistry*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / pharmacology*

Substances

  • Pyrroles
  • Reverse Transcriptase Inhibitors
  • Triazines
  • HIV Reverse Transcriptase