Ghareeb_2026_Bioorg.Chem_175_109821

A series of benzo[f]quinoline-based heterocyclic compounds was synthesized through a cyanoacryloyl isothiocyanate intermediate and evaluated for larvicidal and biochemical activity against Culex pipiens and Musca domestica. Eleven derivatives were generated by reacting the intermediate 2 with various nitrogen nucleophiles, yielding pyrimidine, triazole, triazine, and other fused heterocycles. Several compounds showed strong larvicidal effects, with compounds 11, 12, and particularly compound 13 displaying higher potency than the reference insecticide chlorpyrifos, especially against Culex pipiens. Enzyme assays revealed marked inhibition of acetylcholinesterase (AChE), indicating a neurotoxic mechanism of action. Computational docking supported these findings and showed that the active compounds form stable interactions with acetylcholinesterase (AChE) models from both insect species. Notably, compound 13 showed superior performance compared to conventional organophosphate insecticides such as chlorpyrifos, azamethiphos, and quinalphos. This trend remained consistent even when tested against the resistant Anopheles gambiae AChE mutant (PDB ID: 6ARY). Molecular dynamics simulations further supported these results by confirming the stability of these interactions over time. Specifically, compound 13 maintained favorable binding throughout the entire 100-ns simulation period, indicating a robust and stable ligand-receptor association. These combined experimental and computational findings suggest that this compound series, particularly compound 13, represents a promising larvicidal candidate. The compound may provide a useful starting point for developing new agents capable of addressing resistance in vector control.