Biosynthesis ergosterol

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

EBI fungicides Ergosterol biosynthesis inhibitors used as fungicides. 

Terbinafme (Fig. 5.171), a member ofthe allylamine class ofantimycotics, is an inhibitor of the enzyme squalene epoxidase in fungal ergosterol biosynthesis. Terbinafme is orally active, is fungicidal and is effective against a broad range of dermatophytes and yeasts. It can also be used topically as a cream. 

Hata S, T Nishino, H Katsuki, Y Aoyama, Y Yoshida (1983) Two species of cytochrome P-450 involved in ergosterol biosynthesis in yeast. Biochem Biophys Res Comm 116 162-166. 

Synthesis-Directing Structure-Activity Relationships of Some Fungicides Inhibiting Ergosterol Biosynthesis... 

Although termed "SI" or "EBI" compounds, the latter referring to ergosterol biosythesis inhibitors, these compounds do not all inhibit ergosterol biosynthesis at the same metabolic site (Fig. 2). For instance, the fungicide tridemorph, unlike most EBI compounds, does not inhibit demethylation at C-14 but rather it apparently prevents the A A isomerization resulting in the accumulation of A containing sterols in treated cells (3). 

The schematic presentation of ergosterol biosynthesis and EBI sites of inhibition is available in references (Siegel [5] Kato [6]) and only that segment directly related to the interests of this report will be presented here (Figure 4). 

The antifungal flucytosine (5-fluorocytosine) is an inhibitor of the sterol C-14 demethylase. This latter is an enzyme involved in ergosterol biosynthesis, an element of the fungal wall. It is marketed as an antifungal, while the nucleoside derivatives of 5-fluorocytosine emtricitabine, elvucitabin, and FdCyd (287220)) are used for treatment of viral infection and cancer (Figure 8.6). 

Ergosterol biosynthesis inhibitors via 14a-demethylase enzyme inhibition... 

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