Novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. A structure-activity relationship investigation

J Med Chem. 2005 Jun 30;48(13):4378-88. doi: 10.1021/jm050273a.

Abstract

1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is a novel family of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentration. Replacement of one phenyl ring of 1-[2-(diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole (4) with heterocyclic rings, such as 2-thienyl or 3-pyridinyl, led to novel DAMNIs with increased activity. In HIV-1 WT cell-based assay the racemic 1-{2-[alpha-(thiophen-2-yl)phenylmethoxy]ethyl}-2-methyl-5-nitroimidazole (7) (EC(50) = 0.03 microM) proved 5 times more active than compound 4. Docking experiments showed that the introduction of a chiral center would not affect the binding of both (R)-7 and (S)-7. The internal scoring function of the Autodock program calculated the same inhibition constant (K(i) = 7.9 nM) for the two enantiomers. Compounds 7 (ID(50) = 8.25 microM) were found more active than efavirenz (ID(50) = 25 microM) against the viral RT carrying the K103N mutation, suggesting for these compounds a potential use in efavirenz based anti-AIDS regimens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Cell Survival / drug effects
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Models, Molecular
  • Molecular Conformation
  • Nevirapine / chemistry
  • Nitroimidazoles / chemical synthesis*
  • Nitroimidazoles / chemistry
  • Nitroimidazoles / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Nitroimidazoles
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • HIV Reverse Transcriptase