Department of Chemistry, Federal University of Amazonas, Manaus, Amazonas, Brazil.
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
PLoS One. 2020 Feb 5;15(2):e0227811. doi: 10.1371/journal.pone.0227811. eCollection 2020.
Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most widespread insecticides of the neonicotinoid group. However, they produce adverse effects on the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluorinated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal increased insecticidal activity due to higher hydrophobicity and metabolic stability. We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) binding site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi, and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were prepared and characterized by NMR and mass-spectrometry. The synthesized molecules were modelled by time-dependent density functional theory and analyzed, their interaction with nAChR was investigated by molecular docking. Their insecticide activity was tested on Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neonicotinoid analogs were prepared and tested against 3rd instars larvae of A. darlingi showing high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds and suggest that their insecticidal potency is governed by specific interactions with the receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1-ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All obtained substances possessed high larvicidal activity in low concentrations in 48 hours of exposure, compared to commercial flupyradifurone. Such activity is connected to a unique binding pattern of the synthesized compounds to insect's nAChR and to their enhanced bioavailability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in question have a high potential for application as control agents for insects transmitting tropical diseases, and they will be less persistent in the environment.
致倦库蚊是巴西主要的疟疾传播媒介，具有高度的嗜人血和亲水性。吡虫啉、噻虫啉和噻虫胺是新烟碱类杀虫剂中应用最广泛的杀虫剂。然而，它们会对非靶标昆虫产生不良影响。氟啶虫酰胺已作为非氟化新烟碱类杀虫剂的替代品推向市场。含三氟乙酰基取代基的新烟碱类杀虫剂由于更高的疏水性和代谢稳定性而显示出更高的杀虫活性。我们合成了含有氟化吸电子基团的新型新烟碱类杀虫剂，并通过分子对接研究估计了它们与烟碱型乙酰胆碱受体（nAChR）结合位点的相互作用，以评估它们对致倦库蚊的杀虫活性，并评估它们的户外光降解行为。新的新烟碱类类似物被制备并通过 NMR 和质谱进行了表征。通过时间依赖的密度泛函理论对合成分子进行了建模和分析，通过分子对接研究了它们与 nAChR 的相互作用。将合成的分子在巴西马瑙斯郊区收集的按蚊幼虫上进行了杀虫活性测试。合成了 4 种新型含氟新烟碱类类似物，并对 3 龄致倦库蚊幼虫进行了测试，结果显示出很高的杀虫活性。对接研究揭示了合成化合物的结合模式，并表明其杀虫效力受与受体结合位点的特定相互作用和增强的亲脂性控制。2-氯-5-（2-三氟甲基-吡咯烷-1-基甲基）吡啶 5 在水中迅速降解，同时保持高杀虫活性。与商业氟啶虫酰胺相比，所有获得的物质在暴露 48 小时后，在低浓度下具有很高的杀虫活性。这种活性与合成化合物与昆虫 nAChR 的独特结合模式以及由于引入含氟氨基部分而提高的生物利用度有关。因此，所研究的化合物具有作为控制热带病传播昆虫的药剂的高潜力，并且它们在环境中的持久性较低。
