Chemical control has been effective in reducing malaria mortality, but insecticide-treated nets are losing efficacy due to emerging pyrethroid resistance. Thus, alternative insecticides are urgently needed. Anticholinesterase inhibitors selective for An. gambiae acetylcholinesterase could be useful additions to the malaria control arsenal if low mammalian toxicity and circumvention of existing resistance mechanisms was achieved. Over the past several years, we have explored the structural determinants of enzyme selectivity and potency of carbamates through side chain alteration and heterocycle ring replacement. Toxicity studies have evaluated in vivo mortality to An. gambiae mosquitoes of wild type G3 strain and the Akron strain possessing target site (G119S) and metabolic resistance mechanisms. All of these studies were augmented by in silico modeling of enzyme structure/ligand docking and toxicity versus physicochemical property relationships. Efforts to combine high An. gambiae/human selectivity with good contact toxicity towards WT and resistant mosquitoes will be presented.

Inhibitors targeting acetylcholinesterase with high selectivity for arthropod disease vectors

246th National Meeting (2013)

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