Kamal Mahmoud, Hekal Mohamed H, El-Azm Fatma S M Abu, Hosni Eslam M, Ali Yasmeen M, Yahya Abdullah Alzahrani Abdullah, Rafat El-Hady
Department of Entomology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Sci Rep. 2025 Jul 31;15(1):28031. doi: 10.1038/s41598-025-13063-7.
Mosquito-borne diseases remain a significant global public health challenge. This challenge is further exacerbated by the growing resistance of disease-vector species such as Culex pipiens to conventional insecticides. In this study, we present the design, synthesis, and biological assessment of a new series of thiophene-isoquinolinone hybrids as potential larvicides. Among the synthesized compounds, derivatives 5f, 6, and 7 showed significant larvicidal effectiveness against Culex pipiens larvae, with LC₅₀ values of 0.3, 0.1, and 1.85 µg/mL, respectively. Notably, all twelve thiophene-isoquinolinone derivatives were much more toxic than the reference organophosphate insecticide chlorpyrifos (LC₅₀ = 293.8 µg/mL), demonstrating the strength of these chemical structures. Interestingly, the synthetic intermediate compound 1a, a thiophene-based half-ester, exhibited the highest activity (LC₅₀ = 0.004 µg/mL), outperforming all final derivatives despite not being fully optimized. Mechanistic bioassays showed consistent neurotoxic symptoms that suggest a disruption of cholinergic function. Molecular docking and molecular dynamics simulations supported this observation, revealing strong and specific interactions with both acetylcholinesterase (AChE) and nicotinic acetylcholine receptors (nAChRs), which points to a possible dual-target mechanism. Density Functional Theory (DFT) calculations further confirmed the favorable electronic properties and reactivity of the active compounds. The structural variety within this series, along with consistently high potency, may lower the risk of cross-resistance and aid resistance management strategies through compound rotation or combination. Overall, these findings highlight thiophene-isoquinolinone hybrids as a promising option for developing next-generation larvicides that target neurophysiological pathways in insect vectors.
蚊媒疾病仍然是一项重大的全球公共卫生挑战。疾病传播媒介物种，如致倦库蚊，对传统杀虫剂的耐药性不断增强，进一步加剧了这一挑战。在本研究中，我们展示了一系列新型噻吩 - 异喹啉酮杂化物作为潜在杀幼虫剂的设计、合成及生物学评估。在合成的化合物中，衍生物5f、6和7对致倦库蚊幼虫显示出显著的杀幼虫效果，其LC₅₀值分别为0.3、0.1和1.85 μg/mL。值得注意的是，所有十二种噻吩 - 异喹啉酮衍生物的毒性均远高于参考有机磷杀虫剂毒死蜱（LC₅₀ = 293.8 μg/mL），证明了这些化学结构的优势。有趣的是，合成中间体化合物1a，一种基于噻吩的半酯，表现出最高活性（LC₅₀ = 0.004 μg/mL），尽管尚未完全优化，但优于所有最终衍生物。机理生物测定显示出一致的神经毒性症状，表明胆碱能功能受到破坏。分子对接和分子动力学模拟支持了这一观察结果，揭示了与乙酰胆碱酯酶（AChE）和烟碱型乙酰胆碱受体（nAChRs）的强烈且特异性相互作用，这表明可能存在双靶点机制。密度泛函理论（DFT）计算进一步证实了活性化合物具有良好的电子性质和反应活性。该系列化合物的结构多样性以及始终如一的高效性，可能会降低交叉耐药的风险，并通过化合物轮换或组合辅助抗耐药管理策略。总体而言，这些发现突出了噻吩 - 异喹啉酮杂化物作为开发针对昆虫传播媒介神经生理途径的下一代杀幼虫剂的有前景的选择。
