Synthesis and Mosquitocidal activity of Phenylpyrazole derivatives bearing Schiff Base moiety for reduced acute aquatic toxicity.

Aedes albopictus is not only highly aggressive but also acts as a primary vector for major arboviruses, including dengue, yellow fever, and Zika viruses, posing severe global health risks and economic burdens. To develop novel mosquitocides, this study designed and synthesized a series of phenylpyrazole Schiff base compounds based on fipronil as a lead compound. Five compounds (5e, 7e, 10e, 19e, and 21e) exhibited potent larvicidal activity against Aedes albopictus, with LC50 values of 0.547, 0.456, 0.430, 0.485, and 0.324 μg/mL, respectively. Compound 21e with the most potent insecticidal activity demonstrated significantly lower toxicity to Danio rerio compared to fipronil. The results of molecular docking revealed that the -SOCF3 group at the 4-position of the fipronil pyrazole ring formed strong hydrogen bonds with Lys-35 and halogen bonds with Glu-34 of the Danio rerio GABA(A) receptor. In contrast, the thioether substitution at the 4-position of compound 21e eliminated hydrogen bonding, significantly reducing its binding affinity and likely accounting for its markedly diminished acute toxicity to Danio rerio. These results provide valuable lead compounds for developing environmentally benign insecticides against aquatic sanitary pests, while also establishing a new research avenue for designing insecticides with selective toxicity.