Design and parallel solid-phase synthesis of ring-fused 2-pyridinones that target pilus biogenesis in pathogenic bacteria

J Comb Chem. 2002 Nov-Dec;4(6):630-9. doi: 10.1021/cc020032d.


A new method for the solid-phase synthesis of enantiomerically enriched highly substituted ring-fused 2-pyridinones 13 has been developed. The synthesis mediates introduction of substituents at two positions in the 2-pyridinone ring in a diverse manner and is suitable for parallel synthesis. (19)F NMR spectroscopy was used as a tool to monitor each of the five steps in the reaction sequence. The optimized conditions thus obtained were then used to prepare a library of 20 2-pyridinones with high yields. The library members were chosen from a statistical multivariate design to ensure diversity and reliable data for structure-activity relationships. Screening of the library against the bacterial periplasmic chaperone PapD was performed using surface plasmon resonance. Three new 2-pyridinones with a higher affinity for the chaperone PapD than the previous best 13[10,1] were found, and important structural features could be deduced.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Combinatorial Chemistry Techniques / methods*
  • Escherichia coli / drug effects
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / antagonists & inhibitors
  • Escherichia coli Proteins / metabolism
  • Fimbriae, Bacterial / drug effects*
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / metabolism
  • Periplasmic Proteins / antagonists & inhibitors
  • Periplasmic Proteins / metabolism
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology
  • Surface Plasmon Resonance


  • Escherichia coli Proteins
  • Molecular Chaperones
  • PapD protein, E coli
  • Periplasmic Proteins
  • Pyridones