Fluconazole Diflucan

Structural Formula Ball-and-Stlck Model Space-filling Model

^ = Carbon = Hydrogen ^^ = Oxygen ^ = Fluorine = Nitrogen

Year of discovery: Mid 1980s (Pfizer); Year of introduction: 1990 (both oral and intravenous); Drug category: Triazole antifungal drug/Cytochrome P450 14a-demethylase inhibitor; Main uses: For the treatment and prevention of superficial and systemic fungal infections; Related drugs Clotrimazole (Lotrimin), Itraconazole (Sporanox), Voriconazole (Vfend), Posaconazole (Noxafil).

Fluconazole, a synthetic bistriazole, is a potent antifungal drug used for fungal infections, both superficial (e.g., candidiasis) and systemic (e.g., cryptococcal meningitis).

Imidazoles, the first orally active, broad-spectrum antifungal agents, were first used as antifungal agents in the early 1970s. Before the discovery of imidazole drugs (e.g., clotrimazole and miconazole, see structures below), amphotericin B was the most widely used antifungal agent (see page 160). However, the early imidazoles are effective only when used against superficial fungal infections and their oral bioavailability is poor due to their highly lipophilic nature.

Clotrimazole Miconazole X, Y = F, CI, Br

Clotrimazole Miconazole X, Y = F, CI, Br

In 1978, Pfizer began a program to find effective, safe and wide-spectrum antifungal agents that were active against both superficial and life-threatening systemic fungal infections and could be administered both orally and intravenously. The most potent antifungal imidazole at that time was ketocona-zole, the structure of which was used as the starting point for the design of analogs. A decade and thousands of compounds later, several highly active bis-1,2,4-triazole tertiary alcohols were identified. These compounds all had halogen substituents in the 2 and 4 positions of the phenyl ring (shown in green above). The most potent of the series, the 2,4-difluoro-phenyl derivative, fluconazole, was safe, water soluble and exceptionally active in humans.' The corresponding dichloro derivative (X=Y=CI) is less active and teratogenic.

Fluconazole acts by specifically inhibiting the cytochrome P450 fungal enzyme C-14a-demethylase. Oxidation of the methyl group at C-14 is one of the 20 enzymatic steps required for the biosynthetic conversion of lanosterol to ergosterol. The 14a. methyl group is one of the three methyl groups (highlighted in yellow boxes) that must be removed for the lanosterol to ergosterol transformation. Since ergosterol is a critical component of the fungal cell membrane, inhibition of ergosterol biosynthesis prevents fungal cell replication.

Fluconazole binds tightly to the iron (Fe) center of the fungal cytochrome P450 enzyme (see X-ray below).2 One of the nitrogens of fluconazole coordinates to the Fe ion. Unfortunately, triazole-resistant fungal strains have already emerged, necessitating the development of new agents and the use of antifungal combination therapy.3 A second-generation triazole, voriconazole (Vfend™, Pfizer), which is both potent and active against resistant strains, was approved for human use in 2002.

1. Contemp. Org. Synth. 1996. 3, 125-132; 2. Proc. Natl. Acad. Sci. U. s. A. 2001, 98, 3068-3073. (1EA1); 3. Drugs 2005, 65, 1461-1480; Refs. p. 178
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