Discovery of Fluconazole, a Novel Antifungal Agent

Fluconazole, 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol, is the result of a research program aimed at the development of a broad-spectrum antifungal agent active by both the oral and the intravenous routes for the treatment of superficial and systemic infections. The program began in 1978, and azole derivatives were chosen as a starting point because they were generally well tolerated and offered the advantage of a selective mode of action - inhibition of fungal sterol C-14 demethylation. Initial investigations focused on imidazole derivatives, but attention soon switched to triazole analogues because of their reduced susceptibility to metabolic activity. Polar derivatives were emphasized in an effort to facilitate the attainment of high levels in the blood and to reduce metabolic breakdown still further. This strategy resulted in a number of novel 1,3-bis-triazole-2-arylpropan-2-ol derivatives with good activity in a range of models of fungal infection. These models included systemic fungal infections in both normal and immunosuppressed animals and superficial infections in animals with normal immune function. The 2,4-difluorophenyl analogue, fluconazole, was chosen for development on the basis of an optimal combination of antifungal efficacy, pharmacokinetic characteristics, aqueous solubility, and safety profile.