Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches

Eur J Med Chem. 2015 Mar 6:92:754-65. doi: 10.1016/j.ejmech.2015.01.042. Epub 2015 Jan 22.

Abstract

In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure-activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.

Keywords: Biological activity; HIV-1 RT; Molecular simulations; Physicochemical properties; Structure-based drug design; Triazolopyrimidines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Nitrogen / chemistry*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • 7-(mesityloxy)-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4-yl)-(1,2,4)triazolo(1,5-a)pyrimidin-5-amine
  • Anti-HIV Agents
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 2-Ring
  • Reverse Transcriptase Inhibitors
  • Sulfones
  • HIV Reverse Transcriptase
  • Nitrogen