Demethylase inhibitors

Burton PM, Swinney DC, Heller R, Dunlap B, Chiou M, et al. 1995. Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity. Biochem Pharmacol 50 529-544. 

The fungicides are very versatile in the contol of fungi that have become resistant to the demethylase inhibitor (DMI) fungicides described later. They have surprisingly low mammalian toxicity, but as with many other respiratory poisons, they show some toxicity to fish and other aquatic organisms. They may also be toxic to earthworms. In fungi they inhibit spore germination. The structures show the natural products strobilurin B and azoxystrobin, which has been marketed since 1996. 

The fungicides that inhibit fungal CYP51 are often called demethylase inhibitor (DMI) fungicides, but the group is chemically very diverse. A DMI... 

A last example to note before moving onto describing the diversity of microbial CYPs and their importance, is provided by the azole antifungal compounds. First developed for agriculture, where they are known as DMI compounds (demethylase inhibitors), these compounds have become central to antifungal therapy in the clinic... 

Figure 2. Later stages of the pathway of ergosterol biosynthesis (center) and locations of C-14 demethylase inhibitor action in most fungi (B) and certain yeasts (A).

In addition to blocking the demethylation of 24-methylene dihydrolanosterol at C-14, there are several other alterations of lipid metabolism in fungi treated with C-14 demethylase inhibitors. These include 1) an increase in free fatty acids, linoleic acid, and in some cases major saturated fatty acids, and 2) a decrease in oleic acid (8,22,38,39,42,47,48). The increase in free fatty acids has been attriilTted To" an imbalance between the synthesis and degradation of acyl lipids (36), and appears to be associated with changes in sterol content ra tFTer than an alternate action of the inhibitors since it also occurs in a mutant of l. maydis deficient in C-14 demethylase (46). This increase seems to occur subsequent to detectable changes in sterol metabolism and is not considered to be a major initial factor in the growth inhibitory activity of the inhibitors. The increase in free fatty acids does not occur in all cases (42,50). The decrease in oleic acid, which is accompanied by an increase in linoleic and in some cases linolenic acid, is particularly pronounced in, but not restricted to, the polar lipid... 

Sterol 14-Demethylase Inhibitors for TTypznosomaL cruzi Infections... 

Table 1. In vitro activity of sterol 14-demethylase inhibitors against , cruzi (epimastigotes or intracellular amastigotes) ...

Sterol 14-Demethylase Inhibitors Tiypanosoma cruzi libations... 

Table 3. Activity of sterol 14-demethylase inhibitors in mouse models ofJ. cruzi infection ... 

The current clinical studies have not established a dear role for using either ketooonazole or itraconazole for treatment of patients with Chagas disease, althou it is possible that there may be a marginal therapeutic benefit with itraconazole. Based on the encouraging data with newer azole drugs in animal modds (dearly with superior activity than ketoconazole or itraconazole), one has to be hopefid that aditional dinical smdies will be performed with more aaive sterol l4-demethylase inhibitors in the near future. 

Can a Better Sterol 14-Demethylase Inhibitor Be Developed against T. cruzR... 

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