Wide variations in the antibacterial potency and spectrum of quinolones are presumably attributable, in part, to their variable potency against the molecular targets, DNA gyrase and topoisomerase IV. In addition, susceptibility of quinolones to resistance development via known point mutations in the target genes gyrA and parC / grlA varies depending on the effective affinities of the compounds toward the mutated targets. Using a medicinal chemistry approach, a series of 8-methoxy, Non-Fluorinated Quinolones (NFQs), with fluorine in the R6 position of the traditional fluoroquinolones replaced with hydrogen, were designed to retain potency against DNA gyrase and / or topoisomerase IV with point mutations in the serine-aspartate / glutamate hotspots. This resulted in compounds with antibacterial activity against a broad-spectrum of bacterial species, including multidrug-resistant gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pn eumoniae (PRSP). The efficacy of the NFQs was also demonstrated in a murine septicemia model. Furthermore, the design of the NFQs resulted in lower acute intravenous (IV) toxicity and clastogenicity relative to their 6-fluorinated counterparts. Use of the non-fluorinated quinolone nucleus allowed exploration of new structure-activity space and generation of a series of NFQs with unique combinations of affinities toward the wild type and mutated forms of the molecular targets.
Keywords: Non-Fluorinated Quinolones (NFQs), Antibacterials, Quinolone Resistance, Enzyme Inhibition, DNA Gyrase, Nalidixic Acid, Ciprofloxacin, Moxifloxacin
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