Inhibitors sterol biosynthesis

Sterols are derivatives of terpenes, within the larger chemical family of terpenoids. Such compounds are widespread and numerous in eukaryotes. Although in many cases their function is not clear, others are known to have an essential role in growth, development, metabolism and the integrity of cells. Sterols are localised in cell membranes, conferring stability and controlling permeability. 

Terbinafin resistance in Necria haematocacca may be caused by a less sensitive squalene epoxidase. The resistant biotypes have at least 10 times more squalene than the normal, and it seems that the epoxidase has less affinity to both squalene and terbinafine in the resistant mutants. Fenpropi-morph causes certain sterols to accumulate (A8,14-sterols) and some to decrease (the A5,7 analogue). Resistance seems to be caused by tolerance to these changes, rather than to less sensitive enzymes. 

Karl Heinz Kuck and Jean-Pierre Vors 

Fungicides that inhibit targets within the fungal sterol biosynthesis have been the most important group of specific fungicides world-wide for over two decades. The biochemical basis of this success is the fact that fungi have specific sterols that differ from those in plants and animals, giving the chance to develop selective inhibitors. 

Modem Crop Protection Compounds. Edited by W. Kramer and U. Sdiirmer Copyright 2007 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31496-6 

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D. Berg and M. Plempel, eds.. Sterol Biosynthesis Inhibitors—Pharmaceutical and Agrochemical Aspects, Ellis Horwood, Chichester, 1988. 

G. Haug and H. Hoffman, eds., Chemisty of Plant Protection, Hoi 1 Sterol Biosynthesis Inhibitors andMnti-Feeding Compounds, Springer-Vedag, Berlin, 1986. 

Kato, T. (1986). Sterol biosynthesis in fungi A target for broad spectrum fungicides. In Chemistry of Plant Protection No. 1 Sterol Biosynthesis Inhibitors and Anti-feeding Compounds. Berlin Springer-Verlag, 1-24. 

Chagas disease is caused by a kinetoplastid trypanosoma parasite and affects millions of people in Latin America. The disease is currently incurable. Chemotherapy is based mainly on nitrofuran and nitroimidazole compounds and sterol biosynthesis inhibitors such as ketoconazole (337). Toxicity and high doses are the major problems for these organic drugs. Urbina et al. (338, 339) have found that com-plexation of antiparasitic organic agents such as chloroquine (78)... 

D. Berg, K. H. Biichel, M. Plempel, E. Regel (1986). Antimycotic sterol biosynthesis inhibitors. Trends Pharmacol. Sci. 7 233-238. 

E.L. Mercer, Sterol Biosynthesis Inhibitors their current status and modes of action , Lipids, 1991,26, 584-597. 

Well over 100 plant pathogens have become resistant to various fungicides under field conditions. Failure of the acyl alanines, benzimidazoles, thiophanates, carboxanilides, dicarboximides, hydroxypyrimidines, some organophosphates, and most of the antibiotics has occurred. In other cases, a moderate decrease in sensitivity without a rapid loss of disease control has been observed as in the case of sterol biosynthesis inhibitors (triazoles, pyrimidines, and imidazoles) and organophosphates. The most effective approach is to use fungicides having different modes of action in combination,... 

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. 

Fig. 11. Trifluoromethyl-containing generation of sterol biosynthesis inhibitors.

In addition to the trifluoromethylphenyl sterol biosynthesis inhibitors discussed in Section 2.1.1.3, a number of fluorine phenyl-containing azoles were introduced in the years 1984 through 1993. Though these molecules share some common structural features, such as the triazole heterocycle and a 4-fluorophenyl ring in at least three of the four fungicides shown below, each also has unique chemical features. For instance, in the case of flusilazole (Punch , Nustar , Triumph , Olymp ) [164], a silicon atom is present. This represented that first time silicon... 

It was not until the late 1960s that effective systemic fungicides appeared on the market, and their development represents an important breakthrough in the field of plant chemotherapy. The major classes of systemic fungicides developed since 1966 are oxathiins, benzimidazoles, thiophanates, and pyrimidines. Other effective systemic fungicides used currently include antibiotics, morpholines, organophosphorus compounds, and most recently, the sterol biosynthesis inhibitors, e.g., triazoles. 

Scheme 4.46 Different examples of fluorinated fungicides (top) sterol biosynthesis inhibitors and (bottom) a benzamide-based compound [15—22],...

So far all mode of action studies on sterol biosynthesis inhibitors have been performed in model systems using yeasts or non-obligate fungal pathogens. 

BERGETAL. Sterol Biosynthesis Inhibitors Modes of Action... 

Vanden Bossche, H., In Sterol Biosynthesis Inhibitors Pharmaceutical and Agrochemical Aspects Berg, D., Plempel, M., Eds. Ellis Horwood, VCH-Verlagsgesellschaft London, 1988 p 79-119. 

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