Design, synthesis, biological evaluation, and molecular modeling studies of TIBO-like cyclic sulfones as non-nucleoside HIV-1 reverse transcriptase inhibitors

ChemMedChem. 2006 Jan;1(1):82-95. doi: 10.1002/cmdc.200500020.


TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell-based assays (EC50=0.07 microM, CC50>200 microM, SI>2857). It was twofold less potent than R82913, but more selective. An X-ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1-3 were proven to target HIV-1 RT. In fact, representative derivatives inhibited recombinant HIV-1 RT in vitro at concentrations similar to those active in cell-based assays. 3D QSAR studies and docking simulations were developed on TIBO- and TBO-like sulfone derivatives to rationalize their anti-HIV-1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor-based alignment by docking of TIBO- and TBO-like derivatives into the NNBS of RT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Quantitative Structure-Activity Relationship
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Sulfones / chemistry*
  • Sulfones / pharmacology*


  • Reverse Transcriptase Inhibitors
  • Sulfones
  • HIV Reverse Transcriptase