The deployment of insecticide-treated bednets (ITNs) has significantly decreased malaria mortality in sub-Saharan Africa.  However, emerging pyrethroid-resistant strains of An. gambiae threaten to reduce the effectiveness of this form of vector control, and have motivated the development of new contact mosquitocides that do not target the voltage-gated sodium ion channel. We have focused on the development of aromatic and heteroaromatic carbamate and carboxamide inhibitors of acetylcholinesterase (AChE) as potential replacements for the pyrethroids currently used to treat ITNs. We will show how structural modification can dramatically affect insecticidal activity against WT and carbamate-resistant An. gambiae, and enzyme inhibition potencies.  Carbamate resistance in An. gambiae is known to stem in part from a G119S mutation in the oxyanion hole of AChE. The high toxicity of some compounds to carbamate-resistant An. gambiae can be rationalized in terms of steric complementarity to the reduced volume of the G119S active site.  However, in other cases, contrary to intuition, increased steric bulk improves toxicity to carbamate-resistant An. gambiae.  Possible explanations, including metabolic activation, will be discussed.

Serendipity and rational design in the development of resistance-breaking anticholinesterase insecticides for the malaria mosquito, <i>Anopheles gambiae</i>

248th National Meeting (2014)

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Serendipity and rational design in the development of resistance-breaking anticholinesterase insecticides for the malaria mosquito, Anopheles gambiae