6-Aminoquinolones: a new class of quinolone antibacterials?

A series of quinolone- and 1,8-naphthyridone-3-carboxylic acids, designed by previous QSAR studies and characterized by an amino group at the C-6 position instead of the usual fluorine atom, were synthesized for the first time and evaluated for in vitro antibacterial activity. All of the synthesized compounds maintain good activity against Gram-negative bacteria (Pseudomonas aeruginosa excluded), and those compounds having a thiomorpholine group as the C-7 substituent also have good activity against Gram-positive bacteria. Some aspects of structure-activity relationships associated with the C-1, C-5, C-7, and C-8 substituents are also discussed. Derivatives 18g and 38g displayed the best activity with geometric mean MICs of 0.45 and 0.66-0.76 micrograms/mL against Gram-negative and Gram-positive bacteria, respectively. This antimicrobial activity reflects their ability to inhibit bacterial DNA-gyrase. The results of this study show that, while the C-6 fluorine is still the preferred substituent, good activity can still be obtained by replacing it with an amino group.