In Vitro Metabolism of the N-Alkyl-N-(5-isothiazolyl)- and N-(Alkylisothiazolin-5-ylidene)phenylacetamides. Evidence of Proinsecticidal Activity

Abstract

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.