Aryl methylcarbamates: Potency and selectivity towards wild-type and carbamate-insensitive (G119S) Anopheles gambiae acetylcholinesterase, and toxicity to G3 strain An. gambiae

► Thirty four aryl methylcarbamates are examined for inhibition of AgAChE. ► Both WT and G119S carbamate-insensitive enzymes are examined. ► Recombinant enzyme results are compared to those from mosquito homogenates. ► We show that the 123 aa N-terminal domain of AgAChE does not affect inhibition. ► A predictive model for carbamate toxicity to Anopheles gambiae is presented. New carbamates that are highly selective for inhibition of Anopheles gambiae acetylcholinesterase (AChE) over the human enzyme might be useful in continuing efforts to limit malaria transmission. In this report we assessed 34 synthesized and commercial carbamates for their selectivity to inhibit the AChEs found in carbamate-susceptible (G3) and carbamate-resistant (Akron) An. gambiae, relative to human AChE. Excellent correspondence is seen between inhibition potencies measured with carbamate-susceptible mosquito homogenate and purified recombinant wild-type (WT) An. gambiae AChE (AgAChE). Similarly, excellent correspondence is seen between inhibition potencies measured with carbamate-resistant mosquito homogenate and purified recombinant G119S AgAChE, consistent with our earlier finding that the Akron strain carries the G119S mutation. Although high (100- to 500-fold) WT An. gambiae vs human selectivity is observed for several compounds, none of the carbamates tested potently inhibits the G119S mutant enzyme. Finally, we describe a predictive model for WT An. gambiae tarsal contact toxicity of the carbamates that relies on inhibition potency, molecular volume, and polar surface area.