Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly

Bioorg Med Chem Lett. 2011 Jan 1;21(1):398-404. doi: 10.1016/j.bmcl.2010.10.131. Epub 2010 Oct 31.

Abstract

The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / chemistry*
  • Benzodiazepinones / pharmacology
  • Capsid Proteins / antagonists & inhibitors*
  • Capsid Proteins / metabolism
  • Drug Evaluation, Preclinical
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • Humans
  • Imidazoles / chemistry
  • Pyrazoles / chemistry
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Benzodiazepinones
  • Capsid Proteins
  • Imidazoles
  • Pyrazoles
  • Reverse Transcriptase Inhibitors
  • pyrazole
  • imidazole
  • HIV Reverse Transcriptase