Synthesis and Antibacterial Activity of a New Series of Tetracyclic Pyridone Carboxylic Acids

A series of novel tetracyclic pyridone carboxylic acids replacing the 10-position oxygen atom of 9,l-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid by imino groups (NR; R = Me, Et, c-Pr, allyl, Ph, benzyl), a sulfur atom, or a carbonyl group was prepared and evaluated for antibacterial activity and inhibitory activity on DNA gyrase isolated from E. coli KL-16. The in vitro antibacterial potency and DNA gyrase inhibitory activity were found to be in the following order: NMe ≥ O > S ≫ CO. Moreover, a methyl group was the optimal alkyl substituent at the 10-position nitrogen atom for antibacterial activity and for DNA gyrase inhibitory activity. 7-Fluoro-9,1-[(N-methylimino)methano]-8-(4-methyl-1-piperazinyl)-5-oxo-5ff-thiazolo[3,2-a]quinoline-4-carboxylic acid (10-NCH₃) showed potent in vivo antibacterial activity.