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The use of N-aryl amide derivatives as spatially acting insecticides remains relatively unexplored. To expand this knowledge, we synthesized eighty-nine N-aryl amide analogues and screened them for mortality against an insecticide-susceptible strain of Aedes aegypti mosquitoes, Orlando (OR), using a vapor exposure glass tube assay. Of the screened compounds, twenty-two produced >92% mortality at 24 h and warranted further investigation to determine LC50 values. Fifteen of these analogues had LC50 values within 2 orders of magnitude of transfluthrin, and of significant interest, N-(2,6-dichloro-4-(trifluoromethyl)phenyl)-2,2,3,3,3-pentafluoropropanamide (compound 70) was nearly as potent as transfluthrin and exhibited greater toxicity than metofluthrin when screened against OR A. aegypti. Compounds exhibiting potent toxicity against OR A. aegypti or whose structure-activity relationship potentially offered beneficial insights into structure optimization were screened against the insecticide-resistant, Puerto Rico (PR), strain of A. Aegypti, and it was discovered that not only did these N-arylamides typically show little resistance, some such as N-(2,6-dichloropyridin-4-yl)-2,2,3,3,4,4,4-heptafluorobutanamide (compound 36) and 2,2,3,3,4,4,4-heptafluoro-N-(3,4,5-trifluorophenyl)butanamide (compound 40) were actually more potent against the PR mosquitoes. Due to this promising insecticidal activity, five compounds were administered orally to mice to determine acute oral rodent toxicity. All five compounds were found to have mouse oral toxicity LD50 values well above the minimum safe level as set by the Innovative Vector Control Consortium (50 mg/kg). In addition to the promising biological activity documented here, we report the structure-activity relationship analysis used to guide the derivatization approach taken and to further inform future efforts in the development of N-arylamides as potential resistance-breaking, spatially acting insecticides.

A total of 115 aryl amides were synthesized and screened for vapor repellency against the Orlando (OR) strain of Aedes aegypti mosquitoes. Of these compounds, 29 had 1 h repellency EC50 values comparable to or better than N,N-diethyl-meta-toluamide (DEET, 1 h EC50 value of 35 μg/cm2), with 2,2,3,3,3-pentafluoro-N-(4-fluorophenyl)propenamide (53) and 2,2,3,3,4,4,4-heptafluoro-N-(3,4,5-trifluorophenyl)butanamide (101) exhibiting the most potent EC50 values of 4.5 and 2.9 μg/cm2, respectively. The cross-resistance of select, highly potent, derivatives against the pyrethroid-resistant Puerto Rico (PR) strain of A. aegypti was also investigated, and little to no resistance was observed. When synergized with 1R-trans-permethrinic acid (TFA), compound 101 had a 1 h EC50 value 6 times lower than metofluthrin against OR and 40 times lower against PR mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for compounds 69 and 101, and both exhibited LD50 values of >2000 mg/kg. The structure-activity relationship analysis, which guided the synthesis of these derivatives, is given, and key trends are highlighted to inform future analogue design.

The metabolic fate of metofluthrin [2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (E,Z)-(1R,3R)-2,2-dimethyl-3-(prop-1-enyl)cyclopropanecarboxylate] separately labeled with (14)C at the carbonyl carbon and the α-position of the 4-methoxymethylbenzyl ring was studied in cabbage ( Brassica oleracea ). An acetonitrile solution of (14)C-metofluthrin at 431 g ai ha(-1) was once applied topically to cabbage leaves at head-forming stage, and the plants were grown for up to 14 days. Each isomer of metofluthrin applied onto the leaf surface rapidly volatilized into the air and was scarcely translocated to the untreated portion. On the leaf surface, metofluthrin was primarily degraded through ozonolysis of the propenyl side chain to produce the secondary ozonide, which further decomposed to the corresponding aldehyde and carboxylic acid derivatives. In the leaf tissues, the 1R-trans-Z isomer was mainly metabolized to its dihydrodiol derivative probably via an epoxy intermediate followed by saccharide conjugation in parallel with the ester cleavage, whereas no specific metabolite was dominant for the 1R-trans-E isomer. Isomerization of metofluthrin at the cyclopropyl ring was negligible for both isomers. In this study, the chemical structure of each secondary ozonide derivative was fully elucidated by the various modes of liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy together with cochromatography with the synthetic standard, and their cis/trans configuration was examined by the nuclear Overhauser effect (NOE) difference NMR spectrum.