Design and synthesis of novel insecticidal 3-isothiazolols as potential antagonists of insect GABA receptors†

The ionotropic γ-aminobutyric acid (GABA) receptor (iGABAR) is an important target of agricultural insecticides. Our previous studies indicated that competitive antagonists (CAs) of iGABARs have potential to be insecticides with a novel mechanism of action, and 3-isothiazolol might be used as a basic scaffold of iGABAR CA for further structural modification. Here, we designed and synthesized a novel series of 4-(3-pyrrolidinyl/4-piperidinyl)-3-isothiazolol (5-SPI) analogs with various aromatic substituents at the 5-position of the isothiazole ring. These target 5-SPIs exhibited good insecticidal activity against Drosophila melanogaster and Spodoptera litura, especially 9j and 15g, with 100% and >85% mortality against D. Melanogaster at 100 mg L⁻¹ and with nearly 95% and >80% mortality against S. litura at 100 mg kg⁻¹ diet, respectively. Pesticide-likeness and toxicity predictions revealed that compounds 9j and 15g were well within the reasonable range of pesticide-likeness properties and may be non-toxic to honey bees and humans. Molecular docking studies indicated that the hydroxyl group of the isothiazole ring of 9j and 15g could form hydrogen bonds with R53 and S118 of the D. Melanogaster iGABAR model, respectively, and the amino group of the nitrogen heterocyclic substituent could form a hydrogen bond with E146. These interactions might be significant for the binding of target 5-SPIs with insect iGABARs. The findings of the present study might provide useful information for further designing and developing novel iGABAR-targeting insecticides.