Malaria is a global scourge. Over three billion people are at risk of infection by the malaria parasites Plasmodium falciparum and Plasmodium vivax, which cause an estimated one million deaths annually. For many in sub-Saharan Africa, especially children, insecticide treated nets (ITNs) provide the only means of defense against An. gambiae, the mosquito vector of the parasites. Currently, pyrethroid insecticides (sodium channel modulators) are applied to ITNs, but continuous use of these ITNs has led to the emergence of pyrethroid-resistant strains of An. gambiae. To better manage resistance and thus provide better protection against transmission of the parasite, it is desirable to develop a new class of ITNs that possess a different mechanism of action. Currently available contact-toxic acetylcholinesterase (AChE) inhibitors (carbamates, organophosphates) possess very little selectivity for inhibition of An. gambiae AChE (AgAChE) vs. human AChE (hAChE), and are thus considered unsafe for deployment on ITNs. We have therefore undertaken several strategies to prepare highly AgAChE-selective AChE inhibitors. Redesign of an FDA-approved drug for Alzheimer’s disease led to two potent inhibitors of AgAChE (< 10 nM) and greater than 700-fold selectivity against hAChE. Aryl methylcarbamates were also reinvestigated to identify structural elements that confer high levels of selectivity for AgAChE-selective. Two distinct sub-classes of aryl methylcarbamates were identified that posess high selectivities for AgAChE (100-9,000-fold) while retaining good contact toxicity against wild-type An. gambiae. Protein modeling studies of ligand interactions with AgAChE shed insight on molecular basis for the observed selectivities.
Acknowledgement. This work was funded by grants from the FNIH/Bill & Melinda Gates Foundation, through the Grand Challenges in Global Health Initiative (GCGH-1497), and from the National Institutes of Health (1R01 AI082581-01).