In the pursuit of novel insecticides with high activity and a unique mode of action on the GABA receptor, a series of phenylpyrazole esterified derivatives (PEs) were synthesized using an improved Pinner reaction with high selectivity. Lewis acid catalysis was employed in a one-step solvent-thermal method to convert the cyano group of fipronil into an ester unit. FeCl3 was found to exhibit the highest selectivity for PEs synthesis, yielding PEs at 96.4%, with the byproduct being phenylpyrazole amide (PE0) at 2.1%. Initial biological assays indicated superior insecticidal activity of the target compounds against Plutella xylostella and Mythimna separata compared to fipronil. Particularly, the smaller and shorter ester units, PE3, PE5, and PE8, demonstrated 2-2.5 times higher insecticidal activity against P. xylostella than fipronil. The higher activity of ester units compared to amide and acylhydrazone units can be attributed to the enhanced lipid solubility of PEs. Additionally, it may be due to the impact of PEs on the neurotransmitter nACh or the coordination of calcium and chloride ions with the ester's -C═O and -O- bonds, blocking the chloride ion channel. Hydrophobic parameters were confirmed by reversed-phase high-performance liquid chromatography (HPLC), indicating the enhanced lipophilicity conferred by the ester units of PEs. Molecular docking and CoMFA analysis preliminarily validated the strong interactions and structure-activity relationships between PEs and the GABA receptor and nACh receptor in P. xylostella. Furthermore, under simulated natural sunlight, PEs exhibited photodegradation capabilities, transforming back into fipronil parent fragments and enhancing their insecticidal activity. Moreover, PEs displayed excellent fluorescent properties, enabling self-detection of residues. These research findings provide new insights and directions for the development of efficient pesticides, with potential wide applications in the fields of medicine and biosensors.
Keywords: CoMFA analysis; GABA and nACh receptor inhibitor; fluorescence and self-degradability; improved Pinner reaction; molecular docking; phenylpyrazole esterified derivatives.