Keith Dumont Wing

A novel oxadiazine insecticide is bioactivated in lepidopteran larvae

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.

The discovery of indoxacarb: oxadiazines as a new class of pyrazoline-type insecticides†

The evolution of the insecticidal pyrazoline moiety that was originally discovered in 1972 has led to the discovery of a new crop insecticide, indoxacarb, which is the first commercialized pyrazoline-type sodium-channel blocker. Both monocyclic and fused-tricyclic pyrazolines and pyridazines, as well as structurally related semicarbazones were examined prior to the discovery of analogous tricyclic oxadiazines which had similarly high activity as well as favorable environmental dissipation rates and low toxicity to non-target organisms. The eventual leading candidate, DPX-JW062, was originally obtained as a racemic molecule, but a chiral synthesis was developed which produces material that is 50% ee in the insecticidal (+)-S-enantiomer (DPX-MP062, indoxacarb).