Home
Up
Narrow spectrum quinolones
Fluoroquinolones
Second generation fluoroquinolones
2-pyridones
Quinolone hybrids

Quinolones

Nalidixic acid (Figure 1) was the first representative of a family of compounds that share several structural features. These agents are generically known as quinolones, although they encompass a variety of molecular types, depending on the arrangement of nitrogen atoms within the heterocyclic structure.

Among the earlier quinolones are two showing marginally improved antibacterial activity: flumequine (which bears a fluorine atom at C-6 position) and pipemidic acid (with a piperazine substituent at C-7). During the 1980s a new series of quinolones were synthesized in which these two functional groups were inserted in the new structures. These compounds, of which ciprofloxacin (Fig. 1) is a key example, exhibit considerably enhanced activity. In some subsequent derivatives, piperazine was replaced by other substituents, and members of this family are now generally referred to as fluoroquinolones. Although flumequine is strictly a fluoroquinolone, the term is usually restricted to compounds that exhibit superior intrinsic activity.

Figure 1. Chemical structure of nalidixic acid and ciprofloxacin

Further attempts to improve the pharmacological and antimicrobial properties of these compounds have led to the appearance of a new group of fluoroquinolones, so that these agents can now be loosely categorized into three types plus a new family of compounds: the 2-pyridones, that have the nitrogen aton shifted from position 4 to position 2 (Table 1).

Table 1. Categories of quinolone antibacterials

Narrow spectrum quinolones Fluoroquinolones Second generation quinolones 2-pyridones
Acrosoxacin Ciprofloxacin Clinafloxacin  
Cinoxacin Enoxacin Gatifloxacin  
Flumequine Fleroxacin Gemifloxacin  
Nalidixic acid Levofloxacin Moxifloxacin  
Oxolinic acid Lomefloxacin Pazufloxacin  
Pipemidic acid Norfloxacin Sparfloxacin  
Piromidic acid Ofloxacin Tosufloxacin  
  Pefloxacin Trovafloxacin  
  Rufloxacin    

All antibacterial quinolones act against the enzymes involved in maintaining the integrity of the supercoiled DNA helix during replication and transcription. Two enzymes are affected: DNA gyrase and topoisomerase IV. These drugs have a dual site of action but diffferential affinity in Gram positive and negative strains.. In Gram-negatives the main target is DNA gyrase, with topoisomerase IV as a secondary site, while in Staphylococcus aureus and other Gram-positive cocci, the situation is reversed. Relative affinity for the two sites has has been proposed as the reason for differential activity, especially among some of the newer quinolone derivatives.

Quinolones are generally well tolerated, but rashes and gastrointestinal disturbances may occur; photophobia and various non-specific neurological complaints have also been reported. These compounds affect the deposition of cartilage in experimental animals, and should not be used in children and pregnant women. Several promising fluoroquinolones have had to be withdrawn or have been restricted in their use because of unexpected toxicity, in particular QTc prolongation.
 

     Hit Counter

 

Send mail to stefano.biondi@innovativesolution.it with questions or comments about this web site.
Copyright 2010 Innovative Solution di Biondi Stefano