Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors

Eur J Med Chem. 2009 Apr;44(4):1650-63. doi: 10.1016/j.ejmech.2008.09.024. Epub 2008 Sep 30.

Abstract

The structure-activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC(50)=1.3 microM) with good potency against the K103R mutant (EC(50)=4.8 microM). Docking simulations helped to rationalize the SARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • HIV-1 / physiology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Nucleosides / chemistry
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiocarbamates / chemical synthesis
  • Thiocarbamates / chemistry*
  • Thiocarbamates / pharmacology*

Substances

  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Thiocarbamates
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase