Inhibition sterol biosynthesis

Mechanism of Action. Voriconazole inhibits sterol biosynthesis in fungal cell membranes.53 That is, this drug acts like fluconazole and similar agents to impair membrane synthesis, which results in membrane integrity loss and death of the fungal cell. 

High serum cholesterol levels are an important risk factor for coronary heart disease and an effective way of reducing serum cholesterol is to inhibit sterol biosynthesis. The "statins" work by inhibiting 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), a major regulatory enzyme in the cholesterol biosynthetic pathway which catalyses the rate-limiting conversion of HMG CoA to mevalonic acid. 

Many fungicides [15] act by inhibiting sterol biosynthesis. More specifically, they block the C-14a demethylation step in ergosterol biosynthesis [16]. In many of these compounds (Flutriafol [17], Flusilazole [18], Triflumizole [19], Fluotri-... 

The specificity of the inhibition by mevinolin through its high affinity for HlK-CoA reductase may also serve as a model to develop highly effective and specific artificial biocides and to stinulate research in this topic. For example, citrinin, another antibiotic having a bicyclic structure produced by Pentctllium citrinum has been shown to inhibit sterol biosynthesis (143) at the site of acetoacetyl-CoA thiolase (EC 2.3.2.9) and HMG-CoA... 

This synthetic allylamine derivative inhibits the enzyme squalene epoxidase at an early stage in fungal sterol biosynthesis. Acting as a structural analogue of squalene, naffidine causes the accumulation of this unsaturated hydrocarbon, and a decrease in ergosterol in the fungal cell membrane. 

Imibenconazole is a triazole fungicide exhibiting direct cell membrane destruction as well as sterol biosynthesis inhibition for controlling major diseases of fruits, vegetables, cereals, ornamentals and turf. 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

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). 

Morpholines such as tridemorph (9.112) attack sterol biosynthesis via A -reductase enzyme inhibition and are valuable agricultural fungicides. 

B.C. Baldwin and A.J. Corran, Inhibition of Sterol Biosynthesis application to the agrochemical industry , in Antifungal Agents. Discovery and Mode of Action , eds. G.K. Dixon, L.G. Copping and D.W. Hollomon, BIOS Scientific Publishers Ltd., Oxford, 1995, pp. 59-68. 

HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35-3) that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. 

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. 

Siegel, M. R. 1981. Sterol-inhibiting fungicides Effects on sterol biosynthesis and sites of action. Plant Disease 65 986-989. 

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