Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Fluoroquinolones (Fig. 1 ) are broad-spectrum synthetic antibiotics (effective for both Gram-negative and Gram-positive bacteria) that play an important role in treatment of serious bacterial infections, especially hospital-acquired infections and others in which resistance to older antibacterial classes is suspected. Since the discovery of nalidixic acid by George Lesher in 1962 [ 1 ], over ten thousand analogs have been synthesized from which four generations of chemotherapeutics with broad spectrum of antibacterial activities have emerged [ 2 ]. Fluoroquinolones can enter cells easily via porins and, therefore, are often used to treat intracellular pathogens. Quinolone anti-microbial agents exert their antibacterial action via inhibition of homologous type II topoisomerases, DNA gyrase, and DNA topoisomerase IV [ 3 ]. The molecular basis for the quinolone inhibition mechanism has been extensively studied. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion [ 4 ]. The position 7 is considered to be one that directly interacts with DNA gyrase [ 5 , 6 , 7 , 8 ], or topoisomerase IV. The R 7 substituent greatly influences potency, spectrum, and pharmacokinetics. A recent interesting observation is that increased bulkiness of R 7 appears to confer protection from the efflux exporter proteins of bacteria, and diminishes the likelihood of bacterial resistance in wild-type bacterial strains [ 9 , 10 , 11 ], and increases anti-anaerobic activity.