title: The inhibition and selectivity of bacterial topoisomerases by BMS-284756 and its analogues.
abstract: 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 IC(50) of BMS-284756 for human topoisomerase II (hTopo II) was 3000 times higher than its IC(50) 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Infectious Diseases, Department of Microbiology, 5 Research Parkway, Wallingford, CT 06492, USA. lawrencl@bms.com
authors.forename: L E
authors.initials: LE
authors.lastname: Lawrence
authors.forename: P
authors.initials: P
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.forename: K E
authors.initials: KE
authors.lastname: Gouveia
authors.forename: A
authors.initials: A
authors.lastname: Card
authors.forename: M
authors.initials: M
authors.lastname: Casperson
authors.forename: K
authors.initials: K
authors.lastname: Denbleyker
authors.forename: J F
authors.initials: JF
authors.lastname: Barrett
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D024841:Fluoroquinolones; D006801:Humans; D007211:Indoles; D008826:Microbial Sensitivity Tests; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007211:Indoles; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C419689:garenoxacin