Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants

J Med Chem. 2009 Feb 12;52(3):840-51. doi: 10.1021/jm801330n.


The role played by stereochemistry in the C2-substituent (left part) on the S-DABO scaffold for anti-HIV-1 activity has been investigated for the first time. A series of S-DABO analogues, where the double bond in the C2-substituent is replaced by an enantiopure isosteric cyclopropyl moiety, has been synthesized, leading to the identification of a potent lead compound endowed with picomolar activity against RT (wt) and nanomolar activity against selected drug-resistant mutants. Molecular modeling calculation, enzymatic studies, and surface plasmon resonance experiments allowed us to rationalize the biological behavior of the synthesized compounds, which act as mixed-type inhibitors of HIV-1 RT K103N, with a preferential association to the enzyme-substrate complex. Taken together, our data show that the right combination of stereochemistry on the left and right parts (C6-substituent) of the S-DABO scaffold plays a key role in the inhibition of both wild-type and drug-resistant enzymes, especially the K103N mutant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Computer Simulation
  • Drug Design
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism*
  • Humans
  • Kinetics
  • Models, Molecular
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Stereoisomerism
  • Sulfides / chemical synthesis*
  • Sulfides / pharmacology*
  • Surface Plasmon Resonance


  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • Sulfides
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase