Biochemical Studies with a Novel Antifungal Agent, ICI 195,739

The rising incidence of disseminated fungal infections in compromised patients and the prolonged treatments that are necessary have highlighted the shortcomings of existing antifungal therapies. Amphotericin B is overtly toxic to the kidneys and must be given by a parenteral route, whereas ketoconazole has proved to have some toxicity related to changes in steroid hormones. Griseofulvin, although orally active, is only effective against dermatophytes. Several other antifungal compounds containing azole ring structures have been reported for both plant"' and potential human u~e'.~-but none has reached the market and has oral activity. The principal point of action of azole antifungal agents appears to be at the level of the cell membrane. It has been postulated that changes in cell membrane sterols may affect the action of membrane-bound enzymes, such as chitin synthase, and that these effects may ultimately slow cell g r ~ w t h . ~ The primary product of sterol metabolism in fungi is ergosterol; the azole antifungal agents inhibit its biosynthesis by interfering at the stage of lanosterol C14-demethylation.6 The enzyme catalyzing this reaction has been shown to be a cytochrome P-450-linked monooxygenase involving the production of formate from atmospheric oxygen.' Cytochrome P-450 is a ubiquitous hemoprotein found throughout the plant and animal kingdoms and is recognized as having an important role in the metabolism of lipids, in xenobiotic degradation in the liver, and in many other reactions? The azole antifungal agents are believed to interact with the heme by virtue of their unhindered lone-pair electrons on the ring nitrogen. There is always the potential for inhibition of important processes such as steroidogenesis in mammals because this interaction may occur with host enzymes. Therefore, a new antifungal agent should be highly selective for fungal cytochrome P-450 enzymes. Ketoconazole, the only orally active antifungal azole drug available for sale, has been reported to have effects on steroid metabolism at doses used clinically.g~'O There is a need for a new agent that has a much larger safety margin and lacks this toxicity. This communication describes the antifungal compound ICI 195,739 (2-( 2,4-difluoropheny1)1-( 3-[(Z)-44 2,2,3,3-tetrafluoropropoxy)styryl]1,2,4-triazol-l-y1)-3-( 1,2,4triazol-l-yl)propan-2-o1), a bistriazole that is orally active and has a wide spectrum