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 mosquitoes. Of these compounds, 29 had 1 h repellency EC values comparable to or better than ,-diethyl--toluamide (DEET, 1 h EC value of 35 μg/cm), with 2,2,3,3,3-pentafluoro--(4-fluorophenyl)propenamide () and 2,2,3,3,4,4,4-heptafluoro--(3,4,5-trifluorophenyl)butanamide () exhibiting the most potent EC values of 4.5 and 2.9 μg/cm, respectively. The cross-resistance of select, highly potent, derivatives against the pyrethroid-resistant Puerto Rico (PR) strain of was also investigated, and little to no resistance was observed. When synergized with 1--permethrinic acid (TFA), compound had a 1 h EC value 6 times lower than metofluthrin against OR and 40 times lower against PR mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for compounds and , and both exhibited LD 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.