Saperconazole: A selective inhibitor of the cytochrome P‐450‐dependent ergosterol synthesis in Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes

Abstract

Summary The N‐1‐substituted triazole antifungal, saperconazole, is a potent inhibitor of ergosterol synthesis in Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes. Fifty % inhibition is already achieved at nanomolar concentrations. The saperconazole‐induced inhibition of ergosterol synthesis coincides with an accumulation of 14‐methylated sterols, such as 24‐methylenedihydrolanosterol, lanosterol, obtusifoliol, 14α‐methylfecosterol, 14α‐methylergosta‐8,24(28)‐dien‐3,β‐6α‐diol and 14α‐methylergosta‐5,7,22,24(28)‐tetraenol. This indicates that saperconazole interferes with the cytochrome P‐450 (P‐450)‐dependent 14α‐demethylation of lanosterol and/or 24‐methylenedihydrolanosterol. Saperconazole forms stable drug‐P‐450‐complexes by binding via its free triazole nitrogen to the heme iron and via its N‐1 substituent to the apoprotein moiety. The triazole derivative is a highly selective inhibitor of the 14α‐demethylase in fungal cells. It is a poor inhibitor of the 14α‐demethylation of lanosterol in rat and human liver cells. Saperconazole is, at concentrations as high as 10 µM, devoid of effects on the P‐450‐dependent cholesterol side‐chain cleavage and 11β‐hydroxylase, 17,20‐lyase, 21‐hydroxylase and aromatase. Saperconazole does not interfere with the 2α, 6α‐, 6β‐ and 7α‐hydroxylations of testosterone in microsomes from male rat liver. At high concentrations (> 5 µM) an inhibition of the 16β‐+hydroxylations is seen.

The Novel Azole R126638 Is a Selective Inhibitor of Ergosterol Synthesis in Candida albicans , Trichophyton spp., and Microsporum canis

“…The pellets were homogenized and saponified, and the nonsaponifiable lipids were extracted as described above for C. albicans. The total radioactivity in the extracts was determined by liquid scintillation counting (22).…”

“…14 C]acetate in human hepatoma cells (HepG2) were studied as described previously (22). Cholesterol and its precursors were separated by thin-layer chromatography on precoated silica gel plates (no.…”

“…The conversion of [ 3 H]androstenedione to estrone by aromatase in human placental microsomes was carried out as described previously (22).…”

Transcription factor Efg1 contributes to the tolerance of Candida albicans biofilms against antifungal agents in vitro and in vivo

“…drug efflux pumps), (ii) altered growth rate or metabolic rate of biofilm cells, (iii) drug binding to the extracellular matrix, (iv) changes in membrane composition or (v) higher antioxidative capacities (Seneviratne et al, 2008). Azoles inhibit the 14a-demethylation of lanosterol, resulting in decreased ergosterol levels and the accumulation of toxic sterol intermediates (Kelly et al, 1997;Vanden Bossche et al, 1990). In contrast to fluconazole, miconazole is a fungicidal azole with fungicidal activity against Candida biofilms (Lamfon et al, 2004;Vandenbosch et al, 2010).…”

Synthesis and in vitro and in vivo Antifungal Activity of the Hydroxy Metabolites of Saperconazole

“…[46,47] Itraconazole and saperconazole have been reported as potent inhibitors of ergosterol biosynthesis in A. fumigatus and C. albicans. [14,46,48,49] In order to identify the mode of action of the novel triazoles, a study was designed to examine the interaction of compounds 1-8 with ergosterol biosynthesis in fungal cells. The results obtained with these compounds were compared with itraconazole and saperconazole as internal references in the same experiment.…”