Structure-activity relationship analysis of potential new vapor-active insect repellents

Authors: RICHOUX, GARY - University Of Florida; YANG, LIU - University Of Florida; Norris, Edmund; TSIKOLIA, MAIA - University Of Florida; JIANG, SHIYAO - University Of Florida; Linthicum, Kenneth - Ken; BLOOMQUIST, JEFFREY - University Of Florida

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/23/2020
Publication Date: 11/4/2020
Citation: Richoux, G.M., Yang, L., Norris, E.J., Tsikolia, M., Jiang, S., Linthicum, K., Bloomquist, J.R. 2020. Structure-activity relationship analysis of potential new vapor-active insect repellents. Journal of Agricultural and Food Chemistry. 68:13960-13969. https://doi.org/10.1021/acs.jafc.0c03333.
DOI: https://doi.org/10.1021/acs.jafc.0c03333

Interpretive Summary: Mosquito transmitted diseases pose a serious global threat in which millions of people are newly infected every year. One successfully employed method for interrupting disease transmission is by using mosquito repellents, which reduce disease by providing bite protection from infected mosquitoes. We investigated novel chemistries and chemical applications in a search for the next generation of active agents leading to bite protection and overcoming ever increasing resistance to synthetic pyrethroid chemicals in Aedes aegypti and other mosquitoes. When a novel synergist, 1R-transpermethrinic acid, was added to a novel spatial repellent compound the effective concentration needed to repel susceptible Aedes aegypti mosquitoes was six-times lower than a standard spatial repellent metofluthrin, and 40-times lower against resistant mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for two such compounds, and both exhibited very low toxicity.

Technical Abstract: One hundred and fifteen aryl amides were synthesized and screened for vapor repellency against the Orlando (OR) strain of Aedes aegypti mosquitoes. Of these compounds, 29 had 1-hour repellency EC50 values comparable to or better than DEET (1h EC50 = 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 lowest 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 Aedes aegypti was also investigated, and little-to-no resistance was observed. When synergized with 1R-transpermethrinic acid (TFA), compound 101 had a 1-hour EC50 six-times lower than metofluthrin against OR and 40-times lower against PR. Additionally, preliminary mammalian oral toxicity was screened for two derivatives, and both exhibited LD50 values >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 analog design.