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 language | English (US) |
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Pages (from-to) | 663-681 |
Number of pages | 19 |
Journal | Combinatorial Chemistry and High Throughput Screening |
Volume | 9 |
Issue number | 9 |
DOIs | |
State | Published - Nov 2006 |
Keywords
- Antimicrobial
- Ketodihydronicotinic acid derivatives
- Multiple parallel synthesis