Inhibition of sterol C14 demethylation by imidazole-containing antifungals

Pye, G.; Marriott, M. S.

doi:10.1080/00362178285380461

Cited by 40 publications

(6 citation statements)

References 10 publications

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“…The mode of action of tioconazole is unclear, but it lowered ATP concentrations in cells of C. albicans (7,203) and inhibited sterol C-14 demethylation in Candida species (231). Both of these parameters suggest direct membrane damage to the yeast cells by the drug.…”

Section: Tioconazolementioning

confidence: 99%

“…Butoconazole was superior to ketoconazole against C. parapsilosis (16). Pye and Marriott (231) determined that a butoconazole concentration of 60 nM reduced synthesis of C-4,14-desmethyl sterols (ergosterol) by 50% in cells of C. albicans. The concentrations of ketoconazole, clotrimazole, and miconazole required to produce the same effect were 50, 120, and 200 nM, respectively.…”

Section: Butoconazolementioning

confidence: 99%

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Overview of medically important antifungal azole derivatives

1988

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Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

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Section: Tioconazolementioning

confidence: 99%

Section: Butoconazolementioning

confidence: 99%

Overview of medically important antifungal azole derivatives

1988

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“…Of the three imidazoles, ketoconazole exhibited the best fit with lanosterol and would be expected to be the most potent antimycotic, which is indeed the case (21). However, ketoconazole, compared to miconazole and clotrimazole, showed relatively little structural similarity to phenobarbital and would be expected to be the weakest inhibitor of the mammalian cytochrome P-450 system.…”

Section: Discussionmentioning

confidence: 94%

Adverse reactions of imidazole antifungal agents: Computer graphic studies of cytochrome P‐450 interactions

Lewis

Rodrigues

Ioannides

et al. 1989

J. Biochem. Toxicol.

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The imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P-450 proteins. A computer graphic technique capable of predicting the interaction of these structurally-related imidazoles with fungal and mammalian cytochrome P-450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P-450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P-450, toward which the antifungal agents show highest inhibitory activity.

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“…The antifungal activity of azole derivatives such as miconazole (Vanden Bossche et al ., 1978), econazole, bifonazole, clotrimazole (Vanden Bossche, 1985, 1988), ketoconazole (Vanden Bossche et al ., 1980, 1988), enilconazole (Siegel & Ragsdale, 1978; Vanden Bossche et al ., 1987b), parconazole (Pye & Marriott, 1982), terconazole (Vanden Bossche & Marichal, 1991), itraconazole (Vanden Bossche et al ., 1986, 1987a,b, 1988) and fluconazole (Hitchcock, 1991; Hitchcock & Whittle, 1993) arises from a complex multimechanistic process initiated by the inhibition of two cytochromes P450 involved in the biosynthesis of ergosterol, namely the P450 that catalyses the 14 α ‐demethylation step encoded by ERG11 ( CYP51 ) and the Δ22‐desaturase, encoded by ERG5 ( CYP61 ) (Kelly et al ., 1997a). The sterol‐14 α ‐demethylase is the major fungal target for all azole derivatives studied so far.…”

Section: Mechanisms Of Action Of Azole Antifungal Agentsmentioning

confidence: 99%