Non-fluorinated quinolones

Classification and structure-activity relationship

The group of quinolone derivatives is divided into two major subgroups based on their chemical structure—specifically, the presence or absence of a fluorine atom. This structural feature directly determines the spectrum of antibacterial action and the pharmacokinetics of the drugs.

Structure-activity relationship (SAR) analysis shows that maximum antibacterial efficacy is achieved with the presence of a piperazine ring (substituted or unsubstituted) at position 7 of the quinolone core, as well as a fluorine atom at position 6. Compounds lacking a fluorine atom at position 6 are classified as non-fluorinated (classic) quinolones.

The first generation of drugs in this group includes:

• Nalidixic acid (trade names: Negram, Nevigramon) is the progenitor of the group.
• Oxolinic acid (Gramurin) and pipemidic acid (Palin) are structural analogues with higher pharmacological activity compared to nalidixic acid.

Mechanism and spectrum of antibacterial action

All drugs in this group are characterized by a bactericidal type of action. Their main pharmacological target is the bacterial enzyme DNA gyrase. Inhibition of this enzyme leads to the disruption of bacterial DNA replication, which causes the death of the microbial cell.

The spectrum of activity of classic quinolones is relatively narrow and covers predominantly Gram-negative (Gr-) flora. The drugs are effective against:

• Escherichia coli (E. coli);
• Shigella and Salmonella;
• Klebsiella (including Friedländer's bacillus);
• Proteus.

Important clinical exception: non-fluorinated quinolones are completely inactive against Pseudomonas aeruginosa (Pseudomonas aeruginosa). Furthermore, a significant drawback of the entire group is the rapid development of secondary microbial resistance to the therapy.

Pharmacokinetics and Clinical Application

The progenitor of the group — nalidixic acid — is characterized by good absorption from the gastrointestinal tract when administered orally (per os). Absorption is particularly effective if the drug is taken on an empty stomach.

A key feature of the distribution of non-fluorinated quinolones is that they are unable to accumulate in body tissues (e.g., lung tissue or cerebrospinal fluid). High therapeutic concentrations are achieved exclusively in the urine. About 80% of the administered dose is excreted by the kidneys unchanged. Due to rapid elimination, the drugs require a frequent dosing regimen — 4 times a day.

Indications for use are strictly limited by their pharmacokinetics:

• Genitourinary tract infections (cystitis, pyelitis, pyelonephritis, urethritis, prostatitis);
• Prevention of infectious complications in surgical operations on the kidneys, ureters, and bladder;
• Intestinal infections.

Safety profile and adverse effects

Despite the narrow spectrum of application, first-generation drugs can cause a number of side effects from various body systems. In clinical practice, it is important to consider the following adverse reactions:

• Gastrointestinal tract: dyspeptic disorders, in rare cases bleeding is possible.
• Central nervous system: psychomotor agitation, development of convulsions.
• Sense organs: specific visual disturbances, including distortion of color perception.
• Hepatobiliary system: impaired liver function, development of cholestatic jaundice and hepatitis.
• Blood formation: hematological shifts in the form of thrombocytopenia and leukopenia.
• Skin and immune system: allergic reactions and photosensitization.

Class and exam questions

What else to study on this topic

• Structure-activity relationship (SAR) of quinolone derivatives
• First-generation fluoroquinolones: broadening the spectrum of activity
• Second-generation fluoroquinolones: levofloxacin and moxifloxacin
• Mechanisms of resistance development to DNA gyrase inhibitors
• Pharmacology of oxolinic and pipemidic acids

Other topics in the section "Antibacterial Chemotherapeutic Agents"

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