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

Authors: RICHOUX, GARY - University Of Florida; YANG, LIU - University Of Florida; NORRIS, EDMUND - University Of Florida; 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(47):13960-13969. https://doi.org/10.1021/acs.jafc.0c03333.
DOI: https://doi.org/10.1021/acs.jafc.0c03333

Interpretive Summary: Mosquito vectored diseases pose a serious global threat and they infect millions of people every year. One effective method for preventing these diseases is by using mosquito repellents, which provide bite protection from infected mosquitoes. We synthesized and evaluated 150 novel chemicals and screened them for their ability to provide repellency as a vapor (termed spatial repellents) against pesticide susceptible Aedes aegypti mosquitoes. Of these compounds, 29 had 1-hour repellency that was comparable to or better than DEET. Repellency of the best compounds was evaluated against pesticide-resistant Aedes aegypti mosquitoes, and little-to-no resistance was observed. When synergized with 1R-transpermethrinic acid (TFA), one compound was six-times better at repelling mosquitoes than a commercially available spatial repellent, metofluthrin, against susceptible mosquitoes and 40-times better against resistance mosquitoes. Additionally, preliminary mammalian oral toxicity was screened for two derivatives, and both exhibited low toxicity with 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.

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.