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

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.