HIV-1 protease inhibitors with a transition-state mimic comprising a tertiary alcohol: improved antiviral activity in cells

J Med Chem. 2010 Jan 28;53(2):607-15. doi: 10.1021/jm901165g.


By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohols / chemical synthesis*
  • Alcohols / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Crystallography, X-Ray
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / genetics
  • Inhibitory Concentration 50
  • Molecular Mimicry
  • Mutation, Missense


  • Alcohols
  • Antiviral Agents
  • HIV Protease Inhibitors
  • HIV Protease

Associated data

  • PDB/2WKZ
  • PDB/2WL0