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Journal of Antimicrobial Chemotherapy (2001) 48, 195-201
© 2001 The British Society for Antimicrobial Chemotherapy

The inhibition and selectivity of bacterial topoisomerases by BMS-284756 and its analogues

Laura E. Lawrencea,*, Ping Wua, Li Fana, Kristine E. Gouveiab, Amy Carda, Margaret Caspersona, Kenneth Denbleykera and John F. Barretta

a Bristol-Myers Squibb Pharmaceutical Research Institute, Infectious Diseases, Department of Microbiology, 5 Research Parkway, Wallingford, CT 06492; b Oregon Health Science University, Portland, OR, USA

Analogues of BMS-284756, a novel des-F(6)-quinolone, were synthesized and evaluated in order to determine the effects of modification of substituents on in vitro target inhibition. BMS-340281 (stereoisomer of BMS-284756), BMS-340280 (C-6 fluorinated analogue of BMS-284756), BMS-340278 (C-8-H derivative), BMS-433366 (C-8 methoxy analogue) and fluoroquinolone comparators were evaluated for antibacterial activity. The MICs of BMS-284756 were generally found to be within two-fold of the MICs of BMS-284756 analogues against a panel of Gram-positive and -negative organisms. BMS-284756 had MICs of 0.03–0.125 mg/L against Streptococcus pneumoniae strains with GyrA and ParC mutations, and was the most active quinolone. BMS-284756 and its analogues had similar activity compared with ciprofloxacin and moxifloxacin against topoisomerase IV decatenation, but were three times more active than levofloxacin. The IC50 of BMS-284756 for human topoisomerase II (hTopo II) was 3000 times higher than its IC50 for DNA gyrase, and no whole-cell cytotoxicity was noted. Two analogues, BMS-340280 and BMS-340278, demonstrated moderate inhibition against hTopo II and cytotoxicity in the cellular assay. BMS-284756 demonstrated greater Gram-positive antibacterial activity and similar inhibition of targets compared with other fluoroquinolones, and more favourable selectivity compared with the other BMS-284756 analogues.

* Corresponding author. Tel: +1-203-677-6547; Fax: +1-203-677-6771; E-mail: lawrencl{at}bms.com


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