Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors (II)

J Med Chem. 2015 May 14;58(9):4029-38. doi: 10.1021/acs.jmedchem.5b00358. Epub 2015 Apr 30.

Abstract

A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. Very high affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. Crystal structure analysis was conducted on a number of PI analogues in complex with HIV-1 protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacology
  • Crystallography, X-Ray
  • Darunavir
  • Drug Resistance, Viral
  • Furans / chemical synthesis
  • Furans / chemistry*
  • Furans / pharmacology
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Acetamides
  • Furans
  • HIV Protease Inhibitors
  • Ligands
  • Sulfonamides
  • Darunavir

Associated data

  • PDB/5AGZ
  • PDB/5AH6
  • PDB/5AH7
  • PDB/5AH8
  • PDB/5AH9
  • PDB/5AHA
  • PDB/5AHB
  • PDB/5AHC