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Further Exploration of Antimicrobial Ketodihydronicotinic Acid Derivatives by Multiple Parallel Syntheses

[ Vol. 9 , Issue. 9 ]

Author(s):

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 )

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.

Keywords:

Antimicrobial, ketodihydronicotinic acid derivatives, multiple parallel synthesis

Affiliation:

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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