Fungicides targets

As a standard inhibitor we chose cerulenin, a secondary metabolite of Cephalosporium caeruleus, which is itself fungicidally active and is known to interfere with fatty acid biosynthesis (31 ) as well as HMG-CoA-synthase (32). Mevalonate formation on the level of HMG-CoA-synthase and HMG-CoA-reduction, however, to our knowledge is a relatively poor fungicidal target (33). Nevertheless the potency of cerulenin to interfere with early steps of terpenoid synthesis complicates interpretation. 

VIII. Discover and Develop Fungicides with New Modes of Action. The discovery of new fungicide target sites is required to compensate for the loss of products due to de-registration and resistance. 

The 2,3-oxidosqualene cyclization reaction is one of particular Interest as a fungicide target since it is quite complicated and involves more than one TS or HE intermediate. It is surprising that more Inhibitors of the enzyme catalyzing this reaction have not been synthesized. A point of interest is the unusual overlap of specificity of 1-dodecyclimidazole (Figure 2) a an inhibitor of sterol C-14 demethylation and 2,3-oxidosqualene cyclization (12.323. The simple aliphatic substituent of this Imidazole may allow the compound to act as a TS analogue of 2,3-oxldosqualene and also to bind to the sterol C-14 demethylase and interact with the heme iron. A similar overlap of specificity... 

One of the greatest challenges associated with application of S B D to all discovery processes is the production of protein and subsequent crystallization, particularly when the protein itself is membrane-bound. Many validated fungicidal targets unfortunately fall into the membrane-bound group and this has inhibited the... 

W. Knller, ed.. Target Sites of Fungicide Mction, CRC Press, Boca Raton, Fla., 1992. 

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. 

The Shikimate pathway is responsible for biosynthesis of aromatic amino acids in bacteria, fungi and plants [28], and the absence of this pathway in mammals makes it an interesting target for designing novel antibiotics, fungicides and herbicides. After the production of chorismate the pathway branches and, via specific internal pathways, the chorismate intermediate is converted to the three aromatic amino acids, in addition to a number of other aromatic compounds [29], The enzyme chorismate mutase (CM) is a key enzyme responsible for the Claisen rearrangement of chorismate to prephenate (Scheme 1-1), the first step in the branch that ultimately leads to production of tyrosine and phenylalanine. 

N-Arylmaleimides are useful reagents for trapping and characterization of nitrile oxides (see, e.g., Ref. 165). However, their cycloadducts can also be target products. Thus, a series of 3,5-diaryl-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo- 3.4-r/]isoxazoles 95 was obtained by 1,3-dipolar cycloaddition of substituted benzonitrile oxides with N-(2,6-dialkylphenyl)maleimides. Certain compounds 95 showed bactericidal and fungicidal activity (264). 

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