Synthesis, in vivo evaluation, and in silico molecular docking of benzo[h]quinoline derivatives as potential Culex pipiens L. larvicides.

A new series of benzo[h]quinoline-containing heterocycles was synthesized via reactions of benzo[h]quinolinyl-2(3H)-furanone with some nitrogen bidentate nucleophiles, leading to the formation of pyridazinone, pyrrolinone, benzimidazole, and benzoxazinone derivatives. The synthesized compounds were evaluated for their insecticidal activity against Culex pipiens L. larvae. Among these, pyridazinone 3 demonstrated the highest insecticidal activity with an LC50 value of 1.4 µg/mL (3.40 µM), significantly outperforming the reference insecticide chlorpyrifos. Molecular docking studies were conducted to explore the potential interactions between these compounds and key mosquito neuroreceptors, such as acetylcholinesterase (AChE), nicotinic acetylcholine receptors (nAChR), and the alpha subunit of voltage-gated sodium channels (VGSC). The docking results indicated strong binding affinities, suggesting that these derivatives could disrupt the normal functions of these neuroreceptors, contributing to their insecticidal activity. Additionally, molecular dynamics (MD) simulations were performed to assess the stability and binding interactions of compound 3 with AChE which revealed stable and strong interactions with key residues in the enzyme's active site, such as Trp212, Asp200, and Ile198, leading to reduced conformational flexibility and enhanced binding stability. These findings were further supported by MM-GBSA binding free energy calculations, which aligned with the compound's observed high inhibitory potency. The structure-activity relationship (SAR) analysis demonstrated that specific structural modifications, especially those involving pyridazinone and benzoxazinone frameworks, had a significant impact on the insecticidal potency of the derivatives. Additionally, ADME profiling indicated favorable pharmacokinetic properties, supporting the potential of these compounds as effective larvicides. This study presents novel insights into the synthesis and insecticidal potential of benzo[h]quinoline derivatives, which could contribute to developing more effective and sustainable solutions for controlling mosquito populations, especially amidst growing concerns of insecticide resistance in disease vectors.