Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

Jane B. Laursen, John Nielsen, Torsten Haack, Srinivas Pusuluri, Sunil David, Rajalakshmi Balakrishna, Yibin Zeng, Zhunkun Ma, Timothy B. Doyle, Lester A. Mitscher

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3 Scopus citations


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 (US)
Pages (from-to)663-681
Number of pages19
JournalCombinatorial Chemistry and High Throughput Screening
Issue number9
StatePublished - Nov 2006


  • Antimicrobial
  • Ketodihydronicotinic acid derivatives
  • Multiple parallel synthesis


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