El-Helw_2026_Bioorg.Chem_181_110407

A new series of benzo[h]quinoline-based heterocyclic derivatives was synthesized and evaluated as larvicidal candidates against third instar Culex pipiens larvae. The prepared compounds showed concentration-dependent toxicity with clear structure-related variation across the series. Benzo[h]quinolone-triazinone hybrid 3 was the most active derivative, giving the lowest LC(50) value (142 +/- 0.2 microg/mL) and the highest toxicity index (100), and was approximately 2.1-fold more potent than chlorpyrifos under the same assay conditions. Biochemical evaluation of triazinone 3 revealed significant reductions in acetylcholinesterase activity and in total protein, carbohydrate, and lipid contents compared with untreated larvae, indicating that larval mortality was accompanied by cholinergic disturbance and depletion of metabolic reserves. Molecular docking was performed for all synthesized compounds against acetylcholinesterase (AChE) and nicotinic acetylcholine receptor (nAChR), whereas molecular dynamics simulations were applied to the bioassay-selected compound 3 and the reference systems to examine the dynamic behavior of the predicted complexes. Triazinone 3 maintained a stable AChE complex during simulation and showed persistent contacts with residues including SER250, TRP212, HIS567, PHE416, THR252, TYR258, SER327, and PHE457. In the nAChR model, the trajectory was more mobile but retained recurrent contacts involving ASP153, ASN196, SER149, LYS198, TYR200, TYR152, LYS156, and TYR94. SwissADME analysis further suggested that the activity profile was influenced by a balance between target-recognition potential and physicochemical accessibility. Overall, the findings identify benzo[h]quinoline-based heterocycles, particularly triazinone 3, as promising larvicidal scaffolds and support further optimization of this class as potential alternatives to conventional insecticides.