Ergosterol biosynthesis inhibition

The fust strongly active, broad spectrum, ergosterol biosynthesis inhibiting fungicide we prepared was 2-(2,4-dichlorophenyl)-l-(l-imidazolyl) hexane, 1, and we began a synthesis program in this area of chemistry in an attempt to obtain an... 

BarretBee, K. and G. Dixon. 1995. Ergosterol biosynthesis inhibition a target for antifungal agents. Acta Biochim. Polonica, 42, 465—479. 

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). 

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). 

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

Ergosterol, the predominant sterol in yeast cells, plays an important role in membrane fluidity, permeability and the activity of many membrane-bound enzymes. In terpene-treated cells, ergosterol synthesis was strongly inhibited, and a global upregulation of genes associated with the ergosterol biosynthesis pathway was described in response to terpene toxicity [80, 121]. 

R.I. Baloch, E.L Mercer, T.E. Wiggins and B.C. Baldwin, Inhibition of Ergosterol Biosynthesis in Saccharomyces cerevisiae and Ustilago maydis by Tridemorph, Fenpropimorph and Fenpropidin , Phytochemistry, 1984, 23, 2219-2226. 

Some saturated heterocycles also inhibit ergosterol biosynthesis, but probably at a point later in the pathway. Fenpropimorph (44) (80AGIEH84) is the most potent, superseding the older tridemorph (45). Triforine (46) (B-77MI10712) contains a piperazine ring, but the activity is believed to be associated with the 2,2,2-trichloro-l-formamidoethyl moiety rather than the heterocycle. 

The site at which triadimenol inhibits ergosterol biosynthesis is illustrated in Figure 10 and the accumulating sterol is framed. This result clearly indicates that triadimenol inhibits the cytochrome P Q-dependent oxidative removal of the C -methyl group of 24-methylenedihydrolanosterol, which is a pathogen-specific precursor of ergosterol. 

Ergosterol biosynthesis inhibitors differ in their molecular modes of action. This is especially true for the morpholine derivative tride-morph and fenpropimorph. In Pyricularia oryzae, tridemorph inhibits the A to A7 -isomerization reaction in ergosterol synthesis,... 

Schepers, H. T. A. M. 1983. Decreased sensitivity of Sphaero-theca fuliginea to fungicides which inhibit ergosterol biosynthesis. Neth. J. PI. Path. 89 185-187. 

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