To date, deployment of public health mosquitocides targeting acetylcholinesterase (AChE) has been limited to indoor residual spraying, due in part to concerns of human toxicity. With the goal of developing a new active ingredient suitable for insecticide-treated nets we have investigated a number of AChE inhibitor pharmacophores. Aryl methylcarbamates featuring a gamma-branch in the 2-substituent (1-3) have high selectivity for inhibition of WT mosquito (An. gambiae) AChE over human AChE. Pyrazol-4-yl methylcarbamates 4 bearing an alpha-branched substituent (4) have excellent contact toxicity to both WT (G3) and “carbamate-resistant” G119S-AChE carrying An. gambiae (Akron). In the hope that high An. gambaie vs human AChE inhibition selectivity and low cross-resistance could be combined in one structure, we prepared pyrazol-4-yl methylcarbamates bearing beta- and gamma-branched substituents (5 and 6 respectively). The effects of these structural modification on target engagement and contact mosquito selectivity will be reported. We will also report unexpected findings on the role of the N-alkyl groups on mosquito contact toxicity of 2,3-disubstituted aryl carbamates (cf. 7a, 7b).

Lessons learned in the search for mosquitocidal AChE inhibitors having both target selectivity and resistance-breaking properties

254th National Meeting (2017)

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