Synthesis and antibacterial activities of novel dihydrooxazine and dihydrothiazine ring-fused tricyclic quinolonecarboxylic acids: 9-Fluoro-3-methylene-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and its 1-thia congener

A new synthetic method was developed to obtain two novel tricyclic quinolonecarboxylic acids, 9-fluoro-3-methylene-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (2) and its 1-thia congener 3. The method involves the key intermediate of an oxetane derivative and its cleavage with acids. Evaluation of the antibacterial activities showed that 2 and 3 are excellent against both Gram-positive and Gram-negative organisms in vitro, being comparable to or only slightly less effective than Ofloxacin. In experimental systemic infections in mice, compound 2 showed distinctly higher activity than Ofloxacin, especially against infection caused by Escherichia coli.