James M. Gifford

Recent advances in the chemistry of spinosyns

The spinosyns are a new class of fermentation-derived insect control agents that are effective against a variety of chewing insect pests. The successful introduction of spinosad into the agricultural marketplace represents an important milestone in the use of natural products for commercial pest control. The development of a natural product presents additional limitations relative to a synthetic material. While the latter affords some degree of control in building appropriate physical attributes such as photostability, a natural product, designed to function in a different environment, is often less suited for traditional spray applications. Despite its intrinsic photolability, spinosad is stable enough to perform under field conditions. In an effort to generate analogs with improved physical characteristics, we have developed a variety of conditions for selectively modifying different portions of the molecule, and we have discovered analogs with greater activity against a broader spectrum of pests. The inability to translate improved greenhouse activity to actual field conditions resulted in a detailed study of the effects of formulations and crystallinity on biological activity. Through this effort, measurably improved field performance of synthetic spinosyn analogs relative to the natural product have now been observed.

Neural network-based QSAR and insecticide discovery: spinetoram

Improvements in the efficacy and spectrum of the spinosyns, novel fermentation derived insecticide, has long been a goal within Dow AgroSciences. As large and complex fermentation products identifying specific modifications to the spinosyns likely to result in improved activity was a difficult process, since most modifications decreased the activity. A variety of approaches were investigated to identify new synthetic directions for the spinosyn chemistry including several explorations of the quantitative structure activity relationships (QSAR) of spinosyns, which initially were unsuccessful. However, application of artificial neural networks (ANN) to the spinosyn QSAR problem identified new directions for improved activity in the chemistry, which subsequent synthesis and testing confirmed. The ANN-based analogs coupled with other information on substitution effects resulting from spinosyn structure activity relationships lead to the discovery of spinetoram (XDE-175). Launched in late 2007, spinetoram provides both improved efficacy and an expanded spectrum while maintaining the exceptional environmental and toxicological profile already established for the spinosyn chemistry.

In vitro metabolism of the N-alkyl-N-(5-isothiazolyl)-and N-(alkylisothiazolin-5-ylidene)phenylacetamides. Evidence of proinsecticidal activity

In vitro studies have demonstrated that N-(4-chloro-3-methyl-5-isothiazolyl)-N-methyl-2-[p-((α,α,α-trifluoro-p-tolyl)oxy]phenyl]acetamide (2a) undergoes NADPH-dependent metabolism, which is catalyzed by monooxygenase enzymes, in rat liver microsomes. The primary metabolite in rat was found to arise from ring-methyl hydroxylation, while N-demethylation to give N-(4-chloro-3-methyl-5-isothiazolyl)-2-[p-[(a,a,a-trifluoro-p-tolyl)oxy]phenyl]acetamide (1) was also observed to occur, but at a slower rate. In microsomal proteins prepared from tobacco budworm midgut tissues, the reverse was observed, as 1 is the predominant metabolite, while ring-methyl hydroxylation occurs at a slower rate. The overall rate of metabolism in trout liver microsomes was found to be 50-fold slower than in rat and afforded 1 as the predominant metabolite. Metabolism studies conducted on the N-alkyl-N-(5-isothiazolyl)- and N-(alkyl-isothiazolin-5-ylidene)phenylacetamides (2 and 3) have shown that the ring-alkylated isomers 3 were converted to 1 more rapidly than isomers 2 in all three species. In general, the rate of conversion to 1, or bioactivation, increased with increasing radical or carbocation stability of the alkyl group in rat and trout liver. In tobacco budworm, however, bioactivation was highest in the ethyl and n-propyl analogues. The ratio of bioactivation in tobacco budworm to that in trout, used as a predictor of selectivity, was observed to be highest with the methyl group.