Structure-Activity Relationship Analysis of Potential New Vapor-Active Insect Repellents

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.