Resistance-breaking insecticidal activity of new spatial insecticides against Aedes aegypti

Authors: RICHOUX, GARY - University Of Florida; YANG, LIU - University Of Florida; Norris, Edmund; 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: 7/30/2021
Publication Date: 8/13/2021
Citation: Richoux, G.M., Yang, L., Norris, E.J., Jiang, S., Linthicum, K., Bloomquist, J.R. 2021. Resistance-breaking insecticidal activity of new spatial insecticides against Aedes aegypti. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.1c01200.
DOI: https://doi.org/10.1021/acs.jafc.1c01200

Interpretive Summary: Mosquito transmitted diseases pose an ongoing threat to humans and animals across the globe. A rise in insecticide resistance among mosquitoes has led to significant drops in efficacy from many of the commercially available insecticides. This dilemma necessitates investigation into the next generation of mosquito toxicants which are highly effective against resistant strains of mosquitoes. The scope of this research focused on the synthesis and screening of a variety of N-arylamides to identify spatially-acting adulticides that can overcome resistance. Previous reported work from our group identified fluorinated phenyl amides as potent vapor-acting repellents. In a promising continuation of this work, we found that some of our synthesized derivatives of these compounds also exhibit high mosquito mortality, and select high potency derivatives exhibited little to no cross-resistance when screened against a pyrethroid-resistant strain of Ae. aegypti. We report the synthesis of, and investigation into, the spatial insecticidal activity of eighty-nine N-arylamides against the susceptible and pyrethroid-resistant strains of Ae. aegypti. We have also performed preliminary acute oral rodent toxicity screening of select compounds in an effort to identify which highly active mosquito insecticides could be safe for human use and have potential commercial applications.

Technical Abstract: The use of N-aryl amide derivatives as spatially-acting insecticides remains relatively unexplored. To expand that knowledge, we synthesized eighty-nine N-aryl amide analogues and screened them for mortality against the insecticide susceptible, Orlando (OR), strain of Aedes aegypti mosquitoes using a vapor exposure glass tube assay. Of the screened compounds, twenty-two produced > 92% mortality at twenty-four hours and warranted further investigation to determine LC50 values. Fifteen of these analogs had LC50 values within two orders of magnitude of transfluthrin and, of significant interest, compound 70 was nearly as potent as transfluthrin and exhibited greater toxicity than metofluthrin when screened against OR Ae. aegypti. Select compounds were screened against the insecticide resistant, Puerto Rico (PR), strain of Ae. aegypti and it was discovered that not only did these N-arylamides typically show little resistance, some such as compounds 36 and 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).1 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.