A Chiral Benzoquinolizine-2-carboxylic Acid Arginine Salt Active against Vancomycin-Resistant Staphylococcus aureus

Abstract

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known "floxacin". The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(-)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

Synthesis of some NH-Derivatives of ciprofloxacin as antibacterial and antifungal agents

“…A series of benzoquinolizine-2-carboxylic acid arginine salt of nadifloxacin have been synthesized and found out the excellent activity against hospital infections of multi-drug-resistance vancomycin-resistant Staphylococcus aureus (de Souza et al, 2005). Effects of skeletal modification of ciprofloxacin on antibacterial, antifungal and cytotoxic activities have been observed and described that some of its derivatives having antifungal properties (Siddiqui et al, 2007).…”

The Anti-Methicillin-Resistant Staphylococcus aureus Quinolone WCK 771 Has Potent Activity against Sequentially Selected Mutants, Has a Narrow Mutant Selection Window against Quinolone-Resistant Staphylococcus aureus , and Preferentially Targets DNA Gyrase

“…S1 in the supplementary material). For WCK 771, the cidal concentrations fall in the clinically relevant range since it achieves an unbound maximum concentration of 4 g/ml with a half-life of 6 h when it is used at the therapeutic dose in humans and has been proposed to have a PK-PD breakpoint of 2 g/ml, on the basis of the findings of in vivo studies (2,26) (Table S4 in the supplemental material). We have also established that WCK 771 effected the killing of a variety of double mutants at a CLSI-recommended starting inoculum over a concentration range of 1 to 2 g/ml (data not shown).…”

“…The IC 50 ratio of nadifloxacin (RS, Ϯ) has been reported to be the highest among all the quinolones, indicating its affinity for gyrase (33). The racemic form of nadifloxacin (RS, Ϯ) is at least half as active as that of the S(Ϫ) isomer, since the R(ϩ) isomer is devoid of significant antibacterial activity (2). Therefore, WCK 771 [the arginine salt of the active S(Ϫ) isomer of nadifloxacin] would have a lower IC 50 (approximately half) for DNA gyrase compared to those reported by Takei et al for racemic nadifloxacin (RS, Ϯ) (33).…”

Mechanisms of Drug Efflux and Strategies to Overcome Them as a Way to Control Microbial Growth

“…Antibiotics with low antibacterial effect which are analogues to antibiotics of clinical use. Three families of analogues have been patented to date: analogues of tetracyclines (Levy 1998), aminoglycosides (Nelson and Alekhsun 2004) and quinolones (De Souza et al 2002) which lower the efflux of the corresponding clinically useful antibiotics. 2.…”