Ramadan Sayed K, Abou-Elmagd Wael S I, Hosni Eslam M, Kamal Mahmoud, Hashem Ahmed I, El-Helw Eman A E
Chemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt.
Chemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt.
Bioorg Chem. 2025 Jan;154:108090. doi: 10.1016/j.bioorg.2024.108090. Epub 2024 Dec 27.
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 LC 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.
通过苯并[h]喹啉基-2(3H)-呋喃酮与一些氮双齿亲核试剂的反应，合成了一系列新的含苯并[h]喹啉的杂环化合物，从而形成了哒嗪酮、吡咯啉酮、苯并咪唑和苯并恶嗪酮衍生物。对合成的化合物进行了对致倦库蚊幼虫的杀虫活性评估。其中，哒嗪酮3表现出最高的杀虫活性，LC值为1.4 µg/mL（3.40 µM），显著优于参考杀虫剂毒死蜱。进行了分子对接研究，以探索这些化合物与关键蚊子神经受体之间的潜在相互作用，如乙酰胆碱酯酶（AChE）、烟碱型乙酰胆碱受体（nAChR）和电压门控钠通道（VGSC）的α亚基。对接结果表明具有很强的结合亲和力，表明这些衍生物可能会破坏这些神经受体的正常功能，从而产生杀虫活性。此外，进行了分子动力学（MD）模拟，以评估化合物3与AChE的稳定性和结合相互作用，结果显示与酶活性位点的关键残基，如Trp212、Asp200和Ile198存在稳定且强的相互作用，导致构象灵活性降低和结合稳定性增强。MM-GBSA结合自由能计算进一步支持了这些发现，其与化合物观察到的高抑制效力一致。构效关系（SAR）分析表明，特定的结构修饰，尤其是涉及哒嗪酮和苯并恶嗪酮骨架的修饰，对衍生物的杀虫效力有显著影响。此外，ADME分析表明具有良好的药代动力学性质，支持了这些化合物作为有效杀幼虫剂的潜力。本研究为苯并[h]喹啉衍生物的合成和杀虫潜力提供了新的见解，这可能有助于开发更有效和可持续的解决方案来控制蚊子种群，特别是在病媒对杀虫剂抗性日益受到关注的情况下。
