Isosteric ring exchange: Design and synthesis of phenylpyrazole derivatives with insecticidal activity

The development of novel phenylpyrazole insecticides is essential for managing pest resistance. Nicofluprole, a phenylpyrazole insecticide, serves as a valuable lead compound for structural optimization due to its insecticidal activity. In this study, a series of phenylpyrazole derivatives was designed and synthesized via an isosteric ring exchange strategy, in which the 2-chloropyridine ring of nicofluprole was replaced with substituted phenyl rings. The corresponding compounds exhibited good insecticidal activity against Plutella xylostella , and compounds 9q and 9r showed LC 50 values of 0.49 and 0.20 mg/L, respectively. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents on the phenyl ring were associated with enhanced insecticidal activity. Density functional theory (DFT) calculations and molecular docking studies were conducted to investigate the electronic properties and potential binding modes of representative compounds. The results provide mechanistic insight into how ring replacement and phenyl substitution modulate insecticidal activity within the phenylpyrazole scaffold. • Phenylpyrazole derivatives were designed by isosteric replacement of the pyridine ring in nicofluprole. • Compounds 9q and 9r showed insecticidal activity against Plutella xylostella comparable to fipronil. • DFT calculations and molecular docking provided structural context for the observed activity.