Three-Dimensional Quantitative Structure-Activity Relationship-Based Molecular Design through a Side Arm Strategy to...

Three-dimensional quantitative structure-activity relationship (3D-QSAR) serves as one of the most important and effective tools to guide molecular design for the development of new pesticides. According to the principle of structural splicing, only changing a small group may lead to a great increase in activity while maintaining the active center unchanged. Under the guidance of 3D-QSAR, three series of phenylpyrazole oxime fluorescent insecticides acting on the GABA receptor, namely, esters (POEs), ethers (POETs), and triazoles (POTs), were designed through a side arm strategy and synthesized by an ultrasonic bath reaction, which were fully characterized and crystal-analyzed. The preliminary bioassay results indicated that the insecticidal activities of POE and POT against Plutella xylostella were 4.2 and 2.7 times higher than that of fipronil and better than that of the isolated Mythimna separata. Through the trend of insecticidal activity, the introduction of an aryl ring and an electron-withdrawing group in the substituted functional group of the side arm can enhance the insecticidal activity. Reversed-phase HPLC also confirmed that POEs and POTs had good lipid solubility, which was beneficial to improve their fluidity in the cell membrane. Through molecular packing, molecular docking, and Hirshfeld surface, the intermolecular interaction brought by side arms of POEs, POETs, and POTs and the strong interaction with GABA receptors were preliminarily verified. Photophysical tests revealed that the introduction of the side arm expanded the conjugated system and improved its light absorption and fluorescence. Under the irradiation of simulated sunlight, it was found that they had photoself-degradation and could be retransformed into the parent fragment of phenylpyrazole, thereby improving its biological activity and reducing residues.