Acetylcholinesterase (AChE) inhibitors have been widely used to control agricultural pests, and have seen limited use in indoor residual spraying to control vectors of human disease. To date, no AChE inhibitor has been approved by WHOPES for use on insecticide treated nets (ITNs). We have discovered that select aryl methylcarbamates bearing a bulky substituent at C3 can possess good selectivity for Anopheles gambiae AChE (AgAChE) over human AChE (hAChE), and have excellent contact toxicity vs. An. gambiae. Such compounds, deployed on ITNs, could prove useful to reduce malaria transmission, and circumvent growing pyrethroid resistance. In this presentation we will review the effect of structural variation on AgAChE vs hAChE selectivity, and on contact toxicity to An. gambiae, as well as toxicity to nontarget organisms and the effect of synergists on mosquito toxicity. Subtle variation in the size and shape of the C3-substituent is found to dramatically affect AgAChE vs hAChE selectivity. Enzyme/inhibitor docking studies provide possible explanations for these findings and will be presented.
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