Synthesis and antibacterial activities of novel oxazine and thiazine ring-fused tricyclic quinolonecarboxylic acids: 10-(Alicyclic amino)-9-fluoro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids and the corresponding 1-thia congeners

Several analogs 4 and 5 of Ofloxacin (1) which contain the oxazine and thiazine rings fused with a quinolone carboxylic acid moiety, respectively, were prepared and their in vitro and in vivo antibacterial activities were compared with those of 1 and its previously prepared 3-exo-methylene analogs 2 and 3. Unlike 1, 2, and 3, analogs 4 and 5 possess an antiaromatic oxazine and thiazine moiety and show markedly lower antibacterial activities. Alteration of their C-10 amino-substituent groups from piperazine to azetidine significantly improved the in vitro antibacterial activities, particularly in the case of the thiazine derivative 5, but not the in vivo ones. The antibacterial activities of these three types of tricyclic quinolonecarboxylic acids are briefly discussed on the basis of the molecular properties revealed by molecular orbital calculation. The molecular dipole moment was suggested to be one possible factor controlling the binding affinity of these compounds with DNA gyrase.