5-(4-Pyridinyl)-3-isothiazolols as Competitive Antagonists of Insect GABA Receptors: Design, Synthesis, and a New Mechanism Leading to Insecticidal Effects

Abstract

Ionotropic γ-aminobutyric acid (GABA) receptors (iGABARs) are validated targets of drugs and insecticides. Our previous studies showed that the competitive antagonists of insect iGABARs exhibit insecticidal activities and that the 3-isothiazolol scaffold is used as a lead for developing novel iGABAR antagonists. Here, we designed a novel series of 4-aryl-5-(4-pyridinyl)-3isothiazolol (4-API) analogs that have various aromatic substituents at the 4-position. Two-electrode voltage clamp experiments showed that all synthesized 4-APIs exhibited antagonistic activity against Musca domestica and Spodoptera litura iGABARs (RDL) expressed in oocytes of Xenopus laevis at 100 μM. Of the 4-APIs, the 4-(1,1′-biphenylyl) analog was the most potent antagonist with IC 50 s of 7.1 and 9.9 μM against M. domestica and S. litura RDL receptors, respectively. This analog also showed a certain insecticidal activity against S. litura larvae, with >75% mortality at 100 μg/g diet. Molecular docking studies with a M. domestica iGABAR model indicated that the π−π stacking interactions formed between the pyridinyl ring and Y252 and between the 4-substituted aromatic group and Y107 might be important for antagonism by the 4-(1,1′-biphenylyl) analog. Our studies provide important information for designing novel iGABAR antagonists and suggest that the 4-APIs acting on iGABARs are promising insecticide leads for further studies.

Structural Diversity Design, Synthesis, and Insecticidal Activity Analysis of Ester-Containing Isoxazoline Derivatives Acting on the GABA Receptor

“…The mixture was stirred at 25 °C for 12 h. After completion of the reaction, purification using silica gel column chromatography produced target compounds 10a−q (Scheme 1). The structural characterization data ( 1 H NMR, 13 C NMR, and HRMS) can be found in the Supporting Information.…”

“…The γ-aminobutyric acid receptor (GABAR) is an important pesticide target with four distinct coupled binding sites that are associated with high selectivity and limited cross-resistance. − Currently, there are various types of chemical noncompetitive antagonists (NCAs) that target GABAR. Isoxazoline drugs with an active core skeleton of 3,5-diphenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole are the second generation of NCAs. − They kill insects by blocking the inward current of chloride ions through ionotropic GABAR (iGABAR) channels, − which disrupts the nervous system and causes hyperexcitation. Fluralaner (Figure ), a representative isoxazoline veterinary drug, is primarily used to control ectoparasites .…”

Metabolic Engineering for the Comprehensive Utilization of N,N-Dimethylformamide-Containing Wastewater

“…N , N -dimethylformamide (DMF) is an anthropogenic compound that does not occur in nature and was first synthesized in 1893 . Subsequently, DMF has been widely employed in diverse chemical, manufacturing, and pharmaceutical industries due to its excellent miscibility with most organic liquids and water. − In Asia alone, more than 300 DMF suppliers have been identified . The global DMF consumption was approximately 285,000 metric tons in 2001, with an annually increasing demand. , Following its industrial utilization, most DMF, including recovered DMF, is discarded.…”