INSECTICIDAL ACTION AND MITOCHONDRIAL UNCOUPLING ACTIVITY OF AC-303,630 AND RELATED HALOGENATED PYRROLES

The mode of action of the experimental insecticide/acaricide, AC-303,6 30 ethyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile); Pirate, Stalker, CAS No. [122453-73-0]), and its halogenated pyrrole analogs was studi ed. AC-303,630 caused greatly increased respiratory activity in German cockroaches but was virtually inactive as an uncoupler against isolat ed mitochondria. However, its N-dealkylated analog, AC-303,268, was a potent uncoupler with notable activity in the range of 10-100 nM again st rat, fish, and insect mitochondria. Both respiratory stimulation an d toxicity were antagonized in insects by pretreatment with the monoox ygenase inhibitor piperonyl butoxide. Structure-activity studies with a range of halogenated pyrroles also supported a relationship between uncoupling and toxicity. Based on these results it is concluded that A C-303,630 is a propesticide that is activated by the oxidative removal of the N-ethoxymethyl group. This releases a lipophilic, weakly acidi c pyrrole metabolite which exerts its toxicity through mitochondrial u ncoupling. (C) 1994 Academic Press, Inc.