1. The inhibition and selectivity of bacterial topoisomerases by BMS-284756 and its analogues
- Author
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Kenneth DenBleyker, Kristine Gouveia, Amy Card, Ping Wu, Margaret E Casperson, Laura Lawrence, John F. Barrett, and Li Fan
- Subjects
Microbiology (medical) ,Indoles ,Topoisomerase IV ,medicine.drug_class ,Stereochemistry ,education ,Microbial Sensitivity Tests ,Quinolones ,Topoisomerase-I Inhibitor ,DNA gyrase ,Anti-Infective Agents ,Moxifloxacin ,Escherichia coli ,medicine ,Humans ,Topoisomerase II Inhibitors ,Pharmacology (medical) ,Antibacterial agent ,Pharmacology ,biology ,Topoisomerase ,digestive, oral, and skin physiology ,Quinolone ,stomatognathic diseases ,DNA Topoisomerases, Type II ,Infectious Diseases ,DNA Topoisomerases, Type I ,Biochemistry ,biology.protein ,Topoisomerase I Inhibitors ,Topoisomerase-II Inhibitor ,Fluoroquinolones ,medicine.drug - 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. more...
- Published
- 2001
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