Differences between Heliothis virescens and rat metabolism of a methoxy-carbonyl group in insecticidal semi-carbazone compounds
Russell Eldridge, firstname.lastname@example.org, Leo B. Dungan, email@example.com, David M. Roush, firstname.lastname@example.org, Daniel H. Cohen2, Ellen M. Crawford3, and Louis V. LaFrance4. (1) FMC Corporation, P.O. Box 8, Princeton, NJ, (2) Fort Dodge Animal Health, P.O. Box 5366, Princeton, NJ, (3) Merck Research Laboratories, P.O. Box 2000, Rahway, NJ, (4) Glaxo Smith Kline, 1250 South Collegeville Rd, Collegeville, PA
We have synthesized a number of semi-carbazone compounds that are active against specific lepidopteran pests. One compound, FMC 275956 shows foliar LC50 activity of 3.2 ppm against tobacco budworm (Heliothis virescens), 106 ppm against cabbage looper (Tricoplusia ni), and 3.3 ppm on beet armyworm (Spodoptera exigua). It is also highly toxic to mammals, with an acute oral LD50 of <50 mg/kg in rats. Addition of a methoxy-carbonyl safening group in the urea portion of the molecule resulted in FMC 275968. This compound showed decreased mammalian oral toxicity (>500 mg/kg in rats), without greatly altering the insect activity (LC50: 4 ppm tobacco budworm, 50 ppm cabbage looper, 10 ppm beet armyworm). Through comparative in vitro metabolism studies, we determined that tobacco budworm metabolic enzymes remove the methoxy-carbonyl group more readily than do the rat enzymes. Removal of the safening group results in a potent toxin in insects, but the inability of rats to carry out the same metabolic reaction results in low acute toxicity for the parent compound. HPLC-MS analysis of tissue extracts showed that TBW larvae are able to remove the methoxy-carbonyl group in vivo. Addition of the methoxy-carbonyl group also reduced rat toxicity in a number of other semi-carbazone analogs.
Species 1: Lepidoptera Noctuidae Heliothisvirescens (tobacco budworm) Species 2: Lepidoptera Noctuidae Tricoplusiani (cabbage looper) Species 3: Lepidoptera Noctuidae Spodopteraexigua (beet armyworm) Keywords: metabolism, insecticide