Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2-ligand: Structure-activity studies and biological evaluation

Eur J Med Chem. 2017 Sep 8:137:30-44. doi: 10.1016/j.ejmech.2017.05.024. Epub 2017 May 8.

Abstract

The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2'-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2'-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).

Keywords: Design; Enzyme; HIV-1 protease; Inhibitors; P2 ligand.

MeSH terms

  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Amines / chemistry
  • Amines / pharmacology*
  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Furans / chemistry
  • Furans / pharmacology*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Mice
  • Molecular Structure
  • Rabbits
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Amines
  • Furans
  • HIV Protease Inhibitors
  • Ligands
  • tetrahydrofuran
  • acetamide
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1