X

Space-filling Model

Carbon = Hydrogen M = Oxygen = Fluorine = Nitrogen

Year of discovery: ca.1986 (Bayer Corporation); Year of introduction: 1988; Drug category: Fluoroquinolone/broad-spectrum antibiotic; Main uses: For the treatment of bacterial infections of the urinary and respiratory tract, sexually-transmitted diseases, anthrax; Other brand names: Ciproxin, Ciprobay; Related drugs: Norfloxacin (Noroxin), Levofloxacin (Levaquin), Gatifloxacin (Tequin).

Ciprofloxacin, a very widely used broad-spectrum antibiotic, is a non-natural, totally synthetic compound based on the quinolone ring system (shown in red above). The antimicrobial activity of quinolones was discovered more than 50 years ago, as a result of the finding that certain intermediates used for the synthesis of the antimalarial drug resochin were antibacterial. After testing a large number of synthetic analogs, a highly active compound, nalidixic acid, was discovered in 1962. It was found to be orally active and especially effective in the treatment of urinary tract infections.

Original Lead

Compound n N ch,

Nalidixic acid

Original Lead

Compound ch3

Nalidixic acid

Levofloxacin (Levaquin™)

Levofloxacin (Levaquin™)

Subsequently, a fluorine derivative, norfloxacin, was discovered that had fewer side effects and a much broader spectrum of activity than nalidixic acid. It was introduced into clinical use in the early 1980s. A further modified fluoroquinolone analog of norfloxacin, ciprofloxacin, was discovered in 1986 by Bayer and later marketed as Cipro. Ciprofloxacin proved to be especially effective against Gram-negative bacteria in low doses. The third-generation quinolone, levofloxacin, has also come into widespread use because of greater potency.

Fluoroquinolone antibiotics are orally active, well-tolerated and especially useful for the treatment of infections of the urinary and respiratory tracts, including sexually transmitted diseases. Because they distribute into the cerebrospinal fluid, fluoroquinolones effectively treat meningitis.1 Ciprofloxacin is successful against many bacteria which are resistant to (3-lactams, tetracyclines, and aminoglycosides, as well as in the treatment and prevention of anthrax.

Fluoroquinolones act by preventing the replication and repair of bacterial DNA and RNA. This is achieved by the inhibition of the enzyme DNA gyrase (topoisomerase II), which is responsible for the supercoiling of the DNA double helix. During replication, the double helix of the DNA molecule is unwound to allow the synthesis of RNA chains. However, during this process a number of supercoils are formed ahead of the enzyme RNA polymerase. DNA gyrase relaxes these supercoils and allows the replication to continue. The X-ray image of a nalidixic acid-DNA complex is shown below.2 By binding to the DNA gyrase complex, quinolone antibiotics disrupt DNA replication.

1. Profiles Drug Subst., Excip. Ret. Meth. 2004, 31. 209-214;

2. Nucleic Acids Res. 2005, 33. 4838 (2BQ2); Refs. p. 175

H-BONDING BETWEEN C:G BASE PAIR

NALIDIXIC ACID

1. Profiles Drug Subst., Excip. Ret. Meth. 2004, 31. 209-214;

2. Nucleic Acids Res. 2005, 33. 4838 (2BQ2); Refs. p. 175

NALIDIXIC ACID

NALIDIXIC ACID

H-BONDING BETWEEN C:G BASE PAIR

NALIDIXIC ACID

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