Synthesis and Insecticidal Evaluation of Chiral Neonicotinoids Analogs: The Laurel Wilt Case.

Xyleborus sp beetles are types of ambrosia beetles invasive to the United States and recently also to Mexico. The beetle can carry a fungus responsible for the Laurel Wilt, a vascular lethal disease that can host over 300 tree species, including redbay and avocado. This problem has a great economic and environmental impact. Indeed, synthetic chemists have recently attempted to develop new neonicotinoids. This is also due to severe drug resistance to "classic" insecticides. In this research, a series of neonicotinoids analogs were synthesized, characterized, and evaluated against Xyleborus sp. Most of the target compounds showed good to excellent insecticidal activity. Generally, the cyclic compounds also showed better activity in comparison with open-chain compounds. Compounds R-13, 23, S-29, and 43 showed a mortality percent of up to 73% after 12 h of exposure. These results highlight the enantioenriched compounds with absolute R configuration. The docking results correlated with experimental data which showed both cation-π interactions in relation to the aromatic ring and hydrogen bonds between the search cavity 3C79 and the novel molecules. The results suggest that these sorts of interactions are responsible for high insecticidal activity.

Synthesis, crystal structure, and biological evaluation of a novel eight-membered dinitration neonicotinoid analogues.

In the studies on dihydroxy intermediate synthesis, a serendipitous reaction of introducing nitro group from nitromethylene has been observed. Instead of expected dihydroxy compounds, dinitration structures with nitromethylene analogues were prepared under mild conditions by using a metal-free catalyst B(OH)3. In this reaction, the extra nitro group was suggested to be from starting material. Bioassays indicated that compound 3a showed good insecticidal activities against cowpea aphid (Aphis craccivora) and armyworm (Mythimna separata), with LC50 values were 4.9 mg/L and 7.1 mg/L, respectively.

l-Proline as a Valuable Scaffold for the Synthesis of Novel Enantiopure Neonicotinoids Analogs.

In this research, six neonicotinoid analogs derived from l-proline were synthesized, characterized, and evaluated as insecticides against Xyleborus affinis. Most of the target compounds showed good to excellent insecticidal activity. To the best of our knowledge, this is the first report dealing with the use of enantiopure l-proline to get neonicotinoids. These results highlighted the compound 9 as an excellent candidate used as the lead chiral insecticide for future development. Additionally, molecular docking with the receptor and compound 9 was carried out to gain insight into its high activity when compared to dinotefuran. Finally, the neurotoxic evaluation of compound 9 showed lower toxicity than the classic neonicotinoid dinotefuran.

Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae.

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.

Total synthesis of 13 C2 ,15 N-imidacloprid with three stable isotopes in the pyridine ring.

Imidacloprid (IC) is an important crop-protecting insecticide worldwide and commonly used for seed treatment. However, only few data are available on human toxicity of IC. Having in view the metabolic studies at low doses in humans and residue analysis of IC in food and consumer products, we elaborated the synthesis and prepared 13 C2 ,15 N-IC with three stable isotopes of the "heavy" atoms in positions 1, 2, and 3 of the pyridine ring. By using readily available and affordable starting materials, 15 NH4 Cl and 13 C4 -acetic anhydride, the target compound has been prepared in eight steps with an overall yield of 13%.

Isoxazole-containing neonicotinoids: Design, synthesis, and insecticidal evaluation.

A series of novel isoxazole-containing neonicotinoids were synthesized from nitromethylene analogues and aromatic aldehydes in the presence of l-proline/K2CO3. Bioassays indicated that several synthesized compounds showed 40-70% mortality against brown planthopper (Nilaparvata lugens) under the concentration of 4mgL-1, higher than that of imidacloprid (20%). Against cowpea aphid (Aphis craccivora), the best activity of title compounds reached 90% at the concentration of 20mgL-1.