Comparative in vitro and in vivo activities of six new monofluoroquinolone and difluoroquinolone 3-carboxylic acids with a 7-azetidin ring substituent

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Abstract
E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 are new monofluorinated or difluorinated quinolone agents that are chemically characterized by the presence of an azetidin ring, with different C'-3 substituents, at position 7 of the molecular structure. The MICs of the difluorinated compounds E-4501, E-4474, and E-4441 for 90% of isolates were 0.06 to 1, 0.06 to 1, and 0.12 to 1 microgram/ml, respectively, against gram-positive organisms (staphylococci, streptococci, and Enterococcus faecalis); 0.0015 to 0.12, 0.015 to 0.12, and 0.03 to 0.12 microgram/ml, respectively, against members of the family Enterobacteriaceae except Providencia spp.; and 1, 1, and 2 micrograms/ml, respectively, against Pseudomonas aeruginosa. E-4501, E-4474, and E-4441 inhibited all anaerobic bacteria at concentrations of 1, 2, and 4 micrograms/ml, respectively. Difluorinated compounds were significantly more active than the corresponding monofluorinated analogs E-4502, E-4500, and E-4480 against aerobic and facultatively anaerobic organisms, as well as against anaerobes. Considering monofluorinated and difluorinated compounds, activity in moderate ascending order was observed in quinolones containing an amine and a methyl group (E-4441 and E-4480), an amine group (E-4474 and E-4500), and a methylamine group (E-4501 and E-4502) in the C'-3 position of the azetidin ring. E-4501, E-4474, and E-4441 were more active than norfloxacin and DR-3355 [S-(-)-ofloxacin], had activities comparable to or slightly lower than that of ciprofloxacin against gram-negative bacteria, and were more active than all the reference quinolones against gram-positive organisms and anaerobes. E-4502 and E-4501, which were used to determine the effect of pH, were less active in acidic medium. In general, E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 activities were not affected or increased in medium containing serum but decreased in the presence of 10 mM Mg2+ or in human urine at pH 5.5. The protective effect of E-4501, E-4474, and E-4441 after oral administration against systemic infections with Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa in mice was greater than that of ciprofloxacin.