Design and Parallel Solid-Phase Synthesis of Ring-Fused 2-Pyridinones That Target Pilus Biogenesis in Pathogenic Bacteria

Hans Emtenäs, Kristoffer Åhlin, Jerome S. Pinkner, Scott J. Hultgren, Fredrik Almqvist

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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. 19F 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.

Original languageEnglish
Pages (from-to)630-639
Number of pages10
JournalJournal of combinatorial chemistry
Volume4
Issue number6
DOIs
StatePublished - Nov 1 2002

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