Design, synthesis, and insecticidal activity of iminopyridazine derivatives containing 3-hydroxyisoxazole

Abstract

γ-aminobutyric acid (GABA) is crucial for the function and regulation of neurons, and its receptor is an important target for insecticides. Muscimol is a 3-hydroxyisoxazole bioisostere of GABA and a selective agonist of the GABA receptor (GABAR). This property makes it of great importance in the study of insecticides based on GABARs. In our previous study, it was found that the modification at the 4-position of the muscimol isoxazole ring could induce an antagonistic effect on insect GABARs. In addition, gabazine, as a typical mammalian ionotropic GABAR competitive antagonist, also showed moderate antagonistic effects on insect GABARs. Herein, the muscimol moiety was introduced into the structure of gabazine based on a scaffold hybridization strategy, and we designed and synthesized a series of iminopyridazine derivatives containing a 3-hydroxyisoxazole scaffold. These compounds exhibited insecticidal activity against Drosophila melanogaster and Plutella xylostella. Among them, compounds 11q and 11x showed the best activities, with the 48 h mortalities of 96% and 91% against D. melanogaster at 200 mg L⁻¹, respectively, and the 48 h mortalities of 93% and 97% against P. xylostella at 300 mg L⁻¹, respectively. Molecular docking analysis showed that the two compounds bind to the GABAR in a similar conformation, forming multiple hydrogen bonds with the key amino acid residues Arg109 and Glu202. These interactions may be factors that promote the relatively good activity of both compounds 11q and 11x. The findings of this research may prove valuable in informing future studies of novel insect ionotropic GABAR antagonists.