Anticholinesterase insecticides are generally considered to have poor selectivity at the target site, due to absolute conservation of the catalytic site residues across different species. In the malaria mosquito, Anopheles gambiae, the ace-1 gene codes for acetylcholinesterase (AChE). Classical inhibitors of this enzyme (e.g., carbamates and organophosphates) display little selectivity for enzyme inhibition, typically < 4-fold, compared to human. Recent studies in our laboratories identified carbamates having 100- to 1000-fold selectivity for malaria mosquito AChE compared to human AChE. These compounds also have reduced activity against other non-target vertebrates, honeybee, and certain agricultural pests. Molecular modeling efforts suggest that the mosquito enzyme is able to accommodate aryl carbamates with bulky substituents due to flexibility in the position of Trp84. These new molecules have unprecedented potential as leads to safe, effective mosquitocides in the fight against malaria.

Molecular interactions of highly selective carbamates with acetylcholinesterase of the malaria mosquito, <i>Anopheles gambiae</i>

239th National Meeting (2010)

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Molecular interactions of highly selective carbamates with acetylcholinesterase of the malaria mosquito, Anopheles gambiae