The widespread deployment of insecticide-treated bednets (ITNs) in sub-Saharan Africa has led to a dramatic decline in malaria mortality. However, wide-spread and growing resistance of Anopheles gambiae mosquitoes to the pyrethroid class of voltage-gated Na⁺ channel modulators used on these nets jeopardizes this achievement, and has prompted the search for suitable insecticidal AChE inhibitors to replace pyrethroids. Such compounds would have three favorable characteristics:  excellent contact toxicity towards susceptible adult An. gambiae, good contact toxicity to those that bear the G119S resistance mutation of AChE, and very weak inhibition of human AChE.¹ We will review our work on the development of aromatic and heterocyclic core methyl and dimethylcarbamate AChE inhibitors,² and including both enzymatic inhibition potencies and mosquito contact toxicities.  Finally, the inhibition selectivities of particular compounds will be rationalized in the context of our recently obtained high resolution X-ray structures of G119S An. gambiae AChE.³

Keywords: mosquito; malaria; carbamate; resistance; G119S