Design and optimization of tricyclic phtalimide analogues as novel inhibitors of HIV-1 integrase

J Med Chem. 2005 Mar 24;48(6):1930-40. doi: 10.1021/jm049559q.

Abstract

Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Cell Line
  • HIV Integrase / chemistry
  • HIV Integrase / metabolism*
  • HIV Integrase Inhibitors / chemical synthesis*
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Models, Molecular
  • Phthalimides / chemical synthesis*
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Protein Binding
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology
  • Structure-Activity Relationship

Substances

  • 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione
  • 7-(4-chlorobenzyl)-5,9-dihydroxypyrrolo(3,4-g)quinoxaline-6,8-dione
  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Phthalimides
  • Pyrroles
  • Quinoxalines
  • HIV Integrase