Fungicides, inhibiting ergosterol

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). 

Mechanism of Action An antifungal agent that inhibits ergosterol synthesis. Therapeutic Effect Destroys cytoplasmic membrane integrity of fungi. Fungicidal. Pharmacokinetics Low systemic absorption. Absorbed and distributed in each layer... 

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. 

Naftifine is representative of the allylamine drugs that inhibit squalene-2,3-epoxidase and thus inhibit ergosterol biosynthesis. The drug has broad-spectrum fungicidal activity. Naftifine... 

Semisynthetic y0-lactam antibiotics with a 1,2,4-triazolyl substituent have been prepared and are in clinical use. However, the most important application of 1,2,4-triazoles is as biocides. 3-Amino-1,2,4-triazole (amitrole, amizol) is an unselective herbicide. Triadimenol 4 is one of the most effective fungicides. Its configuration IS, 2R) is essential for its action [162]. The 1,2,4-triazole fungicides inhibit the biosynthesis of ergosterol in fungi. 

Triazoles have been applied as biocides. 3-Amino-l,2,4-triazole (amitrole, ami-zole) is an unselective herbicide. Triadimenol (28) is a very effective fungicide, its absolute configuration 1S,2J is essential for its activity [518]. The fungicides of the 1,2,3-triazole type inhibit ergosterol biosynthesis in fungi. 

Mecfianism of Action An imidazole derivative that inhibits synthesis of ergosterol (vital component of fungal cell formation), damaging cell membrane. TAerapeMtIc Effect Fungistatic may be fungicidal, depending on concentration. 

The principle action of the DMI fungicides is to inhibit the action of the cytochrome 450-dependent removal of the 14a-methyl group from 24-methylene dihydrolanosterol. The resulting accumulation of the substrate 24-methylene dihydrolanosterol, obtusifoliol and 14a-methyl-fecosterol, together with the consequent reduction in ergosterol synthesis, disrupts the normal functioning of cell membranes and was thought to be the basis of DMI activity. 

In research for new fungicides and antimycotics, one has to look for a concept for pathogen-specific inhibitors. This means that inhibition of sterol synthesis should not take place at any common step the aim is to only inhibit pathogen-specific steps in biosynthesis. The reason for this is to minimize the risk of human toxicity. If one compares the biosynthesis of mammalian cholesterol to that of ergosterol, the main sterol of pathogenic fungi, it becomes obvious that there are at least four pathogen-specific steps to be inhibited. 

Sterol biosynthesis inhibiting insecticides. The earliest examples of sterol biosynthesis inhibitors were triadimefon, imazalil, and triarimol. These compounds act by blocking the C14 alpha demethylation step in ergosterol biosynthesis [54], Further work in this area has resulted in numerous fungicides, a number of them containing aromatic fluorine, perfluoroalkyl ethers, and the trifluoromethylphenyl group (Fig. 11). In this section, we will discuss the trifluoromethylphenyl sterol biosynthesis inhibitors, such as triflumizole and fluotrimazole. 

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