Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 2)

ChemMedChem. 2006 Dec;1(12):1379-90. doi: 10.1002/cmdc.200600122.


Arylthio isopropyl pyridinylmethylpyrrolemethanols (AThPs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site (NNBS) of this enzyme. Docking experiments of the potent inhibitors 4k (IC(50) = 0.24 microM, SI = 167) and 5e (IC(50) = 0.11 microM, SI > 1667) of wild-type RT prompted the synthesis and biological evaluation of novel AThP derivatives featuring a number of polar groups in position 3 of the pyrrole ring and larger and more hydrophobic alicyclic substituents in place of the isopropyl group at position 4. Among the compounds synthesized and tested in cell-based assays against HIV-1 infected cells, 19b was the most active, with EC(50) = 0.007 microM, CC(50) = 114.5 microm, and SI = 16357. This compound and its precursor 18b retained interesting activities against clinically relevant drug-resistant RT forms carrying K103N, Y181I, and L100I mutations. Docking calculations of 10, 14, 18b, and 19b were also performed to investigate their binding mode into the RT NNBS and to rationalize both structure-activity relationship and resistance data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • Humans
  • Ligands
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Ligands
  • Pyrroles
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase