Design, characterization, DFT studies, and molecular docking of new benzofuran-pyrazol-acrylamide hybrids as insecticidal agents against Spodoptera littoralis and Tribolium castaneum

This study discusses the synthesis and structural characterization of a new series of benzofuran-pyrazole cyanoacrylamide derivatives 3a–f and 5 utilizing spectroscopic analyses involving IR, NMR, and ESI-MS spectrometry. The insecticidal activity of benzofuran-pyrazole cyanoacrylamide derivatives 3a–f and 5 against Spodoptera littoralis and Tribolium castaneum was evaluated. The benzofuran-pyrazole cyanoacrylamide derivatives on Spodoptera littoralis and Tribolium castaneum revealed that 3b, 3c, and 3a were the most effective compounds, respectively, while compounds 3d, 3e, 3f, and 5 were not lethal to S. littoralis. The LC50 values for compounds 3b, 3c, and 3a were 79.58, 106.37, and 226.17 ppm at 72 h, respectively; while in contrast, compounds 1, 3d, 3e, 3f, and 5 exhibited very low or no contact toxicity against T. castaneum. Density Functional Theory (DFT) calculations were employed to compare the E/Z stereoisomers. The E isomers of 3a, 3c, 3d, and 3e exhibited lower energy gaps, higher softness, and greater electrophilicity, with 3c.E emerging as the most reactive candidate. In contrast, compounds 3b, 3f, and 5 favored the Z configuration, showing improved orbital overlap and higher dipole moments. These findings confirm that stereochemistry strongly influences electronic structure, reactivity, and potential adsorption behavior. In addition, a computational evaluation was conducted to assess the potential of novel benzofuran-indazole hybrid compounds (3a, 3b, 3c) as insecticidal agents targeting acetylcholinesterase (AChE) from two major pests: Spodoptera litura (tobacco cutworm) and Tribolium castaneum (red flour beetle). Molecular docking revealed that all three compounds exhibited strong binding affinities (ranging from − 8.0 to − 8.8 kcal/mol) to both insect AChEs, comparable to or surpassing the positive control (carbaryl) and co-crystallized inhibitor (NAF). The binding modes involved key interactions with catalytic and peripheral anionic site residues, facilitated by hydrogen and hydrophobic bonds. Compound 3b consistently showed among the highest affinities. Subsequent molecular dynamics simulations of the 3b-AChE complexes confirmed stable binding, with minimal perturbation to protein backbone stability, maintained compactness, and persistent intermolecular hydrogen bonds. ADMET predictions indicated that the compounds generally comply with drug-likeness rules. Toxicity risks (mutagenic, tumorigenic) were predicted to be low. Overall, the in silico analyses identify these hybrid compounds, particularly 3b, as promising, stable, and specific AChE Inhibitor leads for the development of novel insecticides.