New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors

J Med Chem. 2009 Jun 25;52(12):3636-43. doi: 10.1021/jm801438e.

Abstract

Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Binding Sites
  • Cell Line
  • Cell Survival / drug effects
  • Cell Transformation, Viral / drug effects
  • Computer Simulation
  • Crystallography, X-Ray
  • HIV / drug effects
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Humans
  • Microbial Sensitivity Tests
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase