Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3730-3. doi: 10.1016/j.bmcl.2011.04.070. Epub 2011 Apr 24.

Abstract

A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC(50) values in the nanomolar range. An active site binding model for inhibitors 2a and 2d was suggested based upon the computational-docking results of the ligand with HIV-1 protease. This model offers molecular insights regarding ligand-binding site interactions of the hydroxyprolinamide-derived novel P2-ligand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Binding Sites
  • Darunavir
  • Drug Design
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Hydroxyproline / chemical synthesis*
  • Hydroxyproline / chemistry
  • Hydroxyproline / pharmacology
  • Inhibitory Concentration 50
  • Ligands
  • Molecular Structure
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Amides
  • HIV Protease Inhibitors
  • Ligands
  • Sulfonamides
  • Hydroxyproline
  • Darunavir