Recent Success in Fungicide Development from Antifungal Leads

Since strobilurin A and oudemansin A were found to be fungicidal metabolites in Basidiomycete fungi Strobilurus tenacellus (Anke et al. 1977) and Oudemansiella mucida (Musilek et al. 1969), respectively, a number of structurally related compounds were reported to have fungicidal activity. Each member of this family incorporates a methyl b-methoxyacrylate group linked at its a-position to a phenylpentadienyl unit, and all the compounds except strobilurin A carry either one or two additional substituents on the benzene ring that render structural complexity (Figure 1). Their mode of action on mitochondrial respiration, binding at a specific site on cytochrome b, is not shared by any other known class of fungicides (Sauter et al. 1995). The unique mode of action may not provide a chance of cross-resistance between b-methoxylacrylates and other fungicides. Although strobilurin A has excellent in vitro activity against a range of fungi, it did not show any useful in vivo activity in the greenhouse. This was due to its photochemical instability and relatively high vapor pressure, which cause it to disappear rapidly from a leaf surface. Through a series of synthetic program to solve these problems, azoxystrobin (Godwin et al. 1992) and kresoxim-methyl (Ammermann et al. 1992) were

Figure 1 Chemical structures of biofungicides in practical use and their lead compounds.

developed as commercial fungicides that overcame the problems of the lead compounds (Clough et al. 1995). Azoxystrobin has a methyl b-methoxyacrylate toxophore, like strobilurin A, whereas kresoxim-methyl has a methyl methoxyiminoacetamide structure (Figure 1). Axoxystrobin has a wide antifungal spectrum against all four taxonomic groups of fungi and strong preventative activity, including inhibition of fungal germination (Heaney and Knight 1994). Kresoxim-methyl is also a broad-spectrum fungicide with strong antifungal activity against powdery mildew and apple scab (Brunelli et al. 1996). Considering its novel mode of action and amenability for synthetic approach, strobilurins are expected to be a major fungicide in near future.

Pyrrolnitrin is another example of a microbial metabolite used as a lead compound. Pyrrolnitrin, a secondary metabolite of Pseudomonas pyrrocinia, which has a very simple structure, is thought to play a significant role in biocontrol activity of the bacterium (Arima et al. 1964). Although it showed excellent in vitro and in vivo activity in the greenhouse against B. cinerea and M. grisea, the disease-control efficacy in the fields was poor, because it rapidly decomposed when exposed to sunlight. In the extensive synthetic programs using pyrrolnitrin as a template, feniclonil (Nevill et al. 1988) and fludioxonil (Gehmann et al. 1990) were developed as seed-dressing agents against numerous fungal pathogens. The replacement of the chloro substituent in the 3-position of the pyrrole by a cyano group led to a remarkable enhancement in stability (Figure 1). Its biological activity also was optimized by appropriate substitution on the phenyl ring. Their improved photostability over pyrrolnitrin conferred the possibility as a foliar fungicide active against B. cinerea, Monilinia spp. and Sclerotinia spp. (Nyfeler and Ackermann 1992).

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