Further Exploration of Antimicrobial Ketodihydronicotinic Acid Derivatives by Multiple Parallel Syntheses

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

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 9 , Issue 9 , 2006

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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.

Keywords: Antimicrobial, ketodihydronicotinic acid derivatives, multiple parallel synthesis

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Article Details

Year: 2006
Page: [663 - 681]
Pages: 19
DOI: 10.2174/138620706778700107
Price: $65

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