Synthesis and evaluation of 3-fluoro-2-piperazinyl-5,8,13-trihydro-5-oxoquino[1,2-a][3,1]benzoxazi ne-6-carboxylic acids as potential antibacterial agents

3-Fluoro-2-piperazinyl-5,8,13-trihydro-5-oxoquino[1,2-a][3,1]-benzoxaz zine-6-carboxylic acids were designed and synthesized as potential DNA gyrase inhibitors and antibacterial agents. The design rationale rests on the proposition made by Ohta and Koga that in order for N₁-aryl substituted quinolones to possess antibacterial activity the N₁-aryl ring should be oriented out of the plane of the quinolone ring. α-[Bis(methylthio)methylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid tert-butyl ester (6) obtained by the treatment of 2,4,5-trifluoro-β-oxobenzenepropanoic acid tert-butyl ester (5) with carbon disulfide and methyl iodide in the presence of cesium carbonate was used as a key intermediate, yielding tert-butyl 2,3-difluoro-5,8,13-trihydro-5-oxoquino[1,2-a][1,3]benzoxazine-6-carbo xylate (8) upon treatment with 2-aminobenzyl alcohol. The coupling of 8 with piperazines followed by the hydrolysis of the ester under acidic conditions afforded the desired product (3). Contrary to expectation, both compounds (3a,b) were, however, devoid of antibacterial activity, suggesting that for N₁-aryl substituted quinolones to exhibit antimicrobial activity important structural feature(s) other than the conformational requirement of the N₁-aryl ring with respect to the quinolone nucleus should also be satisfied.