Widespread use of pyrethroids for vector control has led to the emergence of pyrethroid-resistant mosquitoes. This resistance necessitates further research into the development of new repellents and insecticides in the pursuit of resistance breaking activities. Accordingly, we explored the modification of existing pyrethroids to identify structural motifs which might not be affected by the active site mutations eliciting pyrethroid-resistance. Because synthetic pyrethroids essentially always contain activity-specific and -dependent chiral centers, we chose to focus our efforts on exploring the alkoxy moiety of the ester obtained from the esterification of trans-permethrinic and trans-chrysanthemic acid, which we showed in previous studies to have repellent and/or repellent synergism activities. To this end, we synthesized and screened 26 compounds for spatially-acting repellency and insecticidal activity against the pyrethroid-susceptible, Orlando (OR), and pyrethroid-resistant, Puerto Rico (PR), strains of Aedes aegypti mosquito. Screening was completed utilizing a high-throughput benchtop glass tube assay developed in our laboratory. If sufficient repellency or toxicity was observed at our screening concentration of 100 µg/cm2 and 10 µg/cm2, EC50 or LC50 values were obtained. The compounds screened include a mixture of branched, unbranched, aliphatic, halogenated, cyclic, non-cyclic, and heteroatom-containing esters. Trends indicate that n-propyl, n-butyl, n-pentyl, cyclobutyl- and cyclopental-substituents exhibit promising repellent and insecticidal activity with minimal resistance. While this activity is not nearly as potent as observed with transfluthrin, further derivatization of these functional groups offer a promising route to future synthesis. Preliminary testing showed that these compounds can be synergistic as repellents with certain phenyl amide and other materials.

Structural exploration of novel pyrethroid esters for repellent and insecticidal activity

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ACS Fall 2022

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