Target strobilurins

With the introduction of Be 1 complex inhibitors (Chapter 13.2) in 1996, which act on the electron transport of fungi cells, the most important new compound class called strobilurins, derived from the natural compound Strobilurin A, was introduced in the reference period to the market. Chapter 13 describes the biochemistry of oxidative phosphorylation and of the related compounds and compound classes acting at different sites, reflecting the importance of these targets for the fungicide market nowadays. At the same time it became evident that resistance development, e.g., in the compound class of strobilurins must not lead necessarily to the abandonment of the marketing, research and development of such chemistry. 

From the BASF group, a first review concentrated on the discovery of BAS 490 F (kresoxim-methyl), on pharmacophore variations and on structure-activity relationships at the mitochondrial target level [7]. Another paper was focused more on biokinetic features, and their affect on final biological properties [8j. In 1999 a general review summarized the historical evolution from natural products to commercial strobilurins up to trifloxystrobin, and the international R D competition, including some dramatic patent races [9j. Additionally, strobilurins have been reviewed in Russian, Chinese and Indian journals [10-13]. 

A decisive factor is the activity of the respective active substance for its molecular target in the fungus and potentially also in non-target organisms. With strobilurins, intrinsic activity is primarily determined by the binding affinity of the active substance to the Qo site of the bci complex of the respiratory chain (see Chapter 13.1 of this volume). 

Fig. 13.2.5. Strobilurins with the kresoxim-methyl side chain and variations on the pharmacophore. Their relative activities at the target level are given below the formulas F is inversely proportional to the activity (see text).

Fig. 13.2.7. Target-level activity of a series of strobilurin oximino esters as a function of the lipophilicity of the substituents X. p/50 is the negative logarithm of the /50 value from the yeast mitochondria test. Each point represents a variant of the general structure shown.

Table 13.2.2 lists, for comparison, data for the commercialized strobilurin fungicides. The F values for mitochondrial target activity according to Eq. (1) were... 

Besides target activity, dosage transfer of a strobilurin from the point of application to the receiving bci complex of the fungal target organism and its availability at this receptor determines its activity in vivo. 

Complex III has been very successfully exploited as a target site for fungicides such as the strobilurins, fanoxadone and fenamidone [75]. However, it has only been in the last few years that insecticidal or acaricidal products have used inhibition at Complex III as a mode of action. 

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