Commercial insecticides and repellents are some of the most effective tools for decreasing the propagation of mosquito-vectored infectious diseases. The emergence of target site mediated resistance threatens the success of this tactic and necessitates research into the next generation of resistance-breaking chemical control agents. In our efforts to discover potential candidates, we have successfully identified multiple novel lead compounds exhibiting excellent repellency and/or toxicity while simultaneously displaying no or negative cross-resistance. Herein, we report the biological results of our ongoing investigation into lead optimization and the structure-activity relationship analysis that has rationally guided the design and synthesis of analogs. Topical applications to anesthetized mosquitos were used to screen insecticidal activity (75 compounds), and a horizontal spatial glass tube assay was used to quantify repellency and vapor-phase toxicity (116 compounds). The benchmarks used for comparison are N,N-diethyl-meta-toluamide (DEET), one of the most commonly used insect repellents, and propoxur, a carbamate insecticide approved for malaria control by the WHO. Following the synthesis and evaluation of a series of novel derivatives based on our lead compounds, we were able to identify several key features contributing to the observed toxicity and repellency. To date, we have identified a vapor-phase active derivative that is 13 times more potent than DEET. Additionally, a preliminary mouse oral toxicity study indicates that our most potent repellent exhibits an LD50 &gt;2 g/kg, well above the minimum level set by the Innovative Vector Control Consortium (&gt;50 mg/kg). Our investigation into topically applied insecticides, likewise, has provided us with very promising data. While our derivatives have not yet reached the efficacy of propoxur against wild-type mosquitos, the most active compounds are within twofold as toxic to Anopheles gambiae, and against resistant strains our derivatives are 20 to 67 times more potent. Future work will focus on further structural modification in attempts to increase the efficacy of our derivatives.

Structure-activity relationship analysis of potential new insecticides and repellents

2019 Fall National Meeting

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