Quinolones: Recent Structural and Clinical Developments

Abstract

Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Since their discovery in the early 1960s, the quinolone group of antibacterials has generated considerable clinical and scientific interest. Two major groups of compounds have been developed from the basic molecule: quinolones and naphthyridones. The 4-pyridone-3-carboxylic acid associated with a 5, 6-fused aromatic ring is the common chemical feature of bactericidal quinolones. In the resulting bicyclic ring, the 1-, 5-, 6-, 7-, and 8-positions are the major targets of chemical variation. Manipulations of the basic molecule, including replacing hydrogen with fluorine at position 6, substituting a cyclic amine residue at position 7 and adding new residues at position 1 of the quinolone ring, have led to improved breadth and potency of antibacterial activity and pharmacokinetics. One of the most significant developments has been the improved anti-Gram-positive activity of the newer compounds, such as moxifloxacin and garenoxacin. However, some of these structural changes have been found to correlate with specific adverse effects: the addition of fluorine or chlorine at position 8 being associated with photoreactivity, e.g. sparfloxacin; and the substitution of an amine or a methyl group at position 5 having a potential role in QTc prolongation, e.g. sparfloxacin and grepafloxacin. The clinical utility of this expanding class of antimicrobial agents, and the lower propensity for the development of resistance with the newer quinolones will need to be continually monitored in the changing therapeutic environment. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but introduction of the new quinolones has created a new and exciting era in antimicrobial chemotherapy.