A novel oxadiazine insecticide is bioactivated in lepidopteran larvae

Abstract

DPX‐JW062 is a new insecticide showing strong field activity, especially on Lepidoptera. Metabolism studies in several lepidopteran larvae show that orally administered [14C]DPX‐JW062 is rapidly cleaved to a decarbomethoxyllated metabolite (DCJW), based upon HPLC and mass spectrometry identification. The metabolic conversion is correlated with appearance of neurotoxic symptoms. Tissue localization studies with fifth instar Manduca sexta larvae have shown that the fat body and especially midgut are the most active tissues in catalyzing the conversion. The enzyme(s) appears to be localized in many subcellular fractions and can be inhibited by the esterase inhibitors DFP, paraoxon, and DEF but not by the cytochrome p450–dependent monooxygenase inhibitors piperonyl butoxide and 1‐phenyl imidazole, or the glutathione S‐transferase inhibitor N‐ethyl maleimide. The enzyme thus appears to have properties like an esterase/amidase. DCJW is a highly potent blocker of sodium channels in a Manduca sexta larval motor nerve preparation in vitro. The block of compound action potentials in this preparation is voltage‐dependent, which is similar to the local anesthetic‐like action previously ascribed to dihydropyrazole insecticides. In contrast, DPX‐JW062 is weakly active in these blocking actions. We also observe a diminution of spontaneous CNS action potentials which is correlated with neurotoxic symptoms in DPX‐JW062–treated larvae. This mode of action is entirely distinct from pyrethroids, which cause prolonged membrane depolarization leading to repetitive nerve firing. In summary, DPX‐JW062 appears to be rapidly bioactivated by target insects to the potent insecticidally active sodium channel blocker, the S‐enantiomer of its decarbomethoxyllated metabolite. Arch. Insect Biochem. Physiol. 37:91–103, 1998. © 1998 Wiley‐Liss, Inc.

Genetics, cross‐resistance and synergism of indoxacarb resistance in Helicoverpa armigera (Lepidoptera: Noctuidae)

“…5 Metabolism studies in Lepidoptera have shown that indoxacarb is bioactivated by an esterase or amidase type of enzyme(s) to the active N-decarbomethoxyllated metabolite, which blocks voltage-dependent sodium channels, preventing influx of sodium into neurons and resulting in insect paralysis and death. 5,6 Indoxacarb is among the most recent compounds to be used for control of H. armigera in Australia, and resistance to indoxacarb has been monitored since it was introduced in 2002. From 2002 to 2012, field resistance was determined from traditional screening methods involving topical application of a discriminating concentration of insecticide to larvae in the F 0 generation.…”

It takes a team: reflections on insecticide discoveries, toxicological problems and enjoying the unexpected

“…18 The compound is bioactivated by insects to the potent sodium channel blocker DCJW (which stands for decarbomethoxylated DPX-JW062, or DCMP if the proinsecticide is enantiomerially enriched DPX-MP062) via an N-decarbomethoxylation enzymatic cleavage. 19,20 However, indoxacarb is broken down quite extensively by mammals and is exceptionally safe. 21 Later, another SCBI insecticide, metaflumizone, was commercialized by Nihon Noyaku, BASF and Pfizer Animal Health.…”

Whole‐cell biocatalytic of Bacillus cereus WZZ006 strain to synthesis of indoxacarb intermediate: (S)‐5‐Chloro‐1‐oxo‐2,3‐dihydro‐2‐hydroxy‐1H‐indene‐2‐carboxylic acid methyl ester

“…Chiral pesticides with specificity and environmental safety have captured continuously with wide attention in agriculture, 1,2 because of the emphasis on environmental pollution and the advocacy of green chemistry. Indoxacarb (see Figure 1 for structure), a new chiral oxadiazine pro-insecticide, 3 being converted into the active compound by removal of a CO 2 Me in the insect gut (discovered and developed by the E.I. DuPont Company), has shown to possess high activity, commercial availability, and environmental compatibility to administered to lepidopteran and hemipteran pests.…”

“…Studies have shown that the S-enantiomer of indoxacarb is active as the racemate in insects, while the R-enantiomer is inactive. 3 Therefore, the synthesis of (S)-5-chloro-1-oxo-2,3-dihydro-2-hydroxy-1H-indene-2-carboxylic acid methyl ester has sparked heated interest in the pesticide industry.…”