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Further Exploration of Antimicrobial Ketodihydronicotinic Acid Derivatives by Multiple Parallel Syntheses

[ Vol. 9 , Issue. 9 ]


Jane B. Laursen, John Nielsen, Torsten Haack, Srinivas Pusuluri, Sunil David, Rajalakshmi Balakrishna, Yibin Zeng, Zhunkun Ma, Timothy B. Doyle and Lester A. Mitscher   Pages 663 - 681 ( 19 )


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.


Antimicrobial, ketodihydronicotinic acid derivatives, multiple parallel synthesis


Department of Medicinal Chemistry, Chemical Methodology and Library Development Center of Excellence, Kansas University, 4010 Malott Hall, 1251 Wescoe Hall Drive,Lawrence, KS 66045-7582, USA.

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