Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2465-8. doi: 10.1016/j.bmcl.2014.04.008. Epub 2014 Apr 13.

Abstract

The design, synthesis, and biological evaluation of a series of six HIV-1 protease inhibitors incorporating isosorbide moiety as novel P2 ligands are described. All the compounds are very potent HIV-1 protease inhibitors with IC50 values in the nanomolar or picomolar ranges (0.05-0.43 nM). Molecular docking studies revealed the formation of an extensive hydrogen-bonding network between the inhibitor and the active site. Particularly, the isosorbide-derived P2 ligand is involved in strong hydrogen bonding interactions with the backbone atoms.

Keywords: Design; Drug-resistant; HIV-1 protease inhibitors; Isosorbides; P2 ligand; Synthesis.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Isosorbide / chemical synthesis
  • Isosorbide / chemistry
  • Isosorbide / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Structure-Activity Relationship

Substances

  • HIV Protease Inhibitors
  • Ligands
  • HIV Protease
  • Isosorbide