Strobilurins pharmacophore

Kresoxim-methyl is based on the same strobilurin A lead compounds in which variations of the methoxyacrylate moiety produced the methoxyiminoacetate pharmacophore. 

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]. 

The variations in all the commercial strobilurins (Fig. 13.2.2) can be categorized according to this pattern. All possess the central linking ring - as ortho-disubstituted benzene - unchanged, but one finds five( ) different pharmacophores and nine different side-chains. 

Fluoxastrobin was announced by Bayer in 2004 [49]. It contains once more a new pharmacophore type, in which the carbonyl group of the previous ester or amide pharmacophores is now inventively replaced by an oximino moiety that, in addition, is incorporated in a six membered dihydrodioxazine ring. However, the skeleton of the remaining molecule including its side-chain closely resembles that of azoxystrobin. Like the latter, fluoxastrobin is obviously successfully designed for xylem mobility [50] and exhibits broad-spectrum activity [51]. It is also the first strobilurin marketed for seed treatment. 

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. 13.2.6. Model of the hydrogen bridge between Glu 272 (yeast protein numbering) of the bq complex and the carbonyl group of a strobilurin pharmacophore. (Adapted from Refs. [8, 60, 61].) Glyl43 indicates the area of steric repulsion between strobilurins and the resistant Glyl43Ala mutants. The torsion of the pharmacophore relative to the side chain S is adapted from the active, torsionally restricted (+)-enantiomer in Ref [65].

For synthetic organic chemists, the schemes are self-explanatory and require no detailed comment. In strobilurins, the ortho substitution pattern at the central bridging ring favors the use of easy accessible starting materials or intermediates in which a lactone-type ring is cleaved to obtain pharmacophores and side chains built up in the proper ortho connection. As already mentioned at the end of Section 13.2.3.4, the thermodynamically favored E-configuration of the differ-... 

Scheme 13.2.1. Synthesis routes to strobilurins with the oximino pharmacophores.

---