Structure-based bioisosterism design, synthesis and biological evaluation of novel 1,2,4-triazin-6-ylthioacetamides as potent HIV-1 NNRTIs

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7155-62. doi: 10.1016/j.bmcl.2012.09.062. Epub 2012 Oct 2.


The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating novel chemical entities of increased potency. Previous investigations in our laboratory resulted in the discovery of several novel series of arylazolylthioacetanilides as potent NNRTIs. In this study, based on the structure-based bioisosterism strategy, novel 1,2,4-triazin-6-yl thioacetamide derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. Among them, the most promising compound was 8b15 with double-digit nanomolar activity against wild-type HIV-1 (EC(50)=0.018±0.007 μM) and moderate activity against the double mutant strain RES056 (EC(50)=3.3±0.1 μM), which indicated that 1,2,4-triazin-6-yl thioacetamide can be used as a novel scaffold to develop a new class of potent NNRTIs active against both wild-type and drug-resistant HIV-1 strains. In addition, preliminary structure-activity relationship (SAR) and molecular modeling results are also briefly discussed, which provide some useful information for the further design of novel NNRTIs.

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
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thioglycolates / chemical synthesis*
  • Thioglycolates / chemistry*
  • Thioglycolates / pharmacology
  • Triazines / chemical synthesis*
  • Triazines / chemistry*
  • Triazines / pharmacology


  • Reverse Transcriptase Inhibitors
  • Thioglycolates
  • Triazines
  • 1,2,4-triazine
  • HIV Reverse Transcriptase