Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

Jane B. Laursen, Janne Nielsen, T. Haack, S. Pusuluri, S. David, R. Balakrishna, Y.B. Zeng, Z.K. Ma, T.B. Doyle, L.A. Mitscher

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.
Original languageEnglish
JournalCombinatorial Chemistry & High Throughput Screening
Volume9
Issue number9
Pages (from-to)663-681
ISSN1386-2073
DOIs
Publication statusPublished - 2006

Keywords

  • multiple parallel synthesis
  • ketodihydronicotinic acid derivatives
  • antimicrobial

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