Design and parallel solid-phase synthesis of ring-fused 2-pyridinones that target pilus biogenesis in pathogenic bacteria.
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.
Emtenäs
Hans
H
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Ahlin
Kristoffer
K
Pinkner
Jerome S
JS
Hultgren
Scott J
SJ
Almqvist
Fredrik
F
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000187:drug effects*; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism; D033903:Periplasmic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D020349:Surface Plasmon Resonance
D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; C084330:PapD protein, E coli; D033903:Periplasmic Proteins; D011728:Pyridones