Synthesis and biological evaluation of alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors that possess increased hydrolytic stability

J Med Chem. 2007 Oct 4;50(20):4854-67. doi: 10.1021/jm070382k. Epub 2007 Sep 6.

Abstract

Non-nucleoside inhibitors of HIV reverse transcriptase (NNRTIs), albeit not the mainstays of HIV/AIDS treatment, have become increasingly important in highly active antiretroviral therapy (HAART) due to their unique mechanism of action. Several years ago our group identified the alkenyldiarylmethanes (ADAMs) as a potent and novel class of NNRTIs; however, the most active compounds were found to be metabolically unstable. Subsequent work has led to the synthesis of 33 analogues, with improved metabolic profiles, through the replacement of labile esters with various heterocycles, nitriles, and thioesters. As a result, a number of hydrolytically stable NNRTIs were identified with anti-HIV activity in the nanomolar concentration range. Furthermore, an improved pharmacophore model has been developed based on the new ADAM series, in which a salicylic acid-derived aryl ring is oriented cis to the side chain and the aryl ring that is trans to the side chain contains a hydrogen bond acceptor site within the plane of the ring.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemical synthesis*
  • Alkenes / pharmacology
  • Alkenes / toxicity
  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / toxicity
  • Benzoates / chemical synthesis*
  • Benzoates / pharmacology
  • Benzoates / toxicity
  • Cytopathogenic Effect, Viral / drug effects
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Hydrolysis
  • Mutation
  • Nitriles / chemical synthesis
  • Nitriles / pharmacology
  • Nitriles / toxicity
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology
  • Oxadiazoles / toxicity
  • Oxazoles / chemical synthesis
  • Oxazoles / pharmacology
  • Oxazoles / toxicity
  • Rats
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Reverse Transcriptase Inhibitors / toxicity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / pharmacology
  • Tetrazoles / toxicity

Substances

  • Alkenes
  • Anti-HIV Agents
  • Benzoates
  • Nitriles
  • Oxadiazoles
  • Oxazoles
  • Reverse Transcriptase Inhibitors
  • Tetrazoles
  • HIV Reverse Transcriptase