Acorafloxacin

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G^- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.

Quinolones are potent antimicrobial agents with a basic chemical structure of bicyclic ring. Fluorine atom at position C-6 and various substitutions on the basic quinolone structure yielded fluoroquinolones, namely norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin and numerous other agents. The target molecules of quinolones and fluoroquinolones are bacterial gyrase and topoisomerase IV enzymes. Broad-spectrum and excellent tissue penetration make fluoroquinolones potent agents but their toxic side effects and increasing number of resistant pathogens set limits on their use. This review focuses on recent advances concerning quinolones and fluoroquinolones, we will be summarising chemical structure, mode of action, pharmacokinetic properties and toxicity. We will be describing fluoroquinolones introduced in clinical trials, namely avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and non-fluorinated nemonoxacin. These agents have been proved to have enhanced antibacterial effect even against ciprofloxacin resistant pathogens, and found to be well tolerated in both oral and parenteral administrations. These features are going to make them potential antimicrobial agents in the future.