Toxicity of highly selective carbamates towards the malaria mosquito, Anopheles gambiae

Insecticide-treated bednets (ITNs) are an important tool for the management of Anopheles gambiae, the major vector of malaria in Africa. Pyrethroids are the only insecticides approved for bednet treatments; however, widespread resistance and lack of alternative chemicals undermine the use of ITNs for mosquito control. Our research focus is to develop highly selective insecticides with high mosquito toxicity and low mammalian toxicity that might be used in parallel with current-use pyrethroids. We report the re-engineering of carbamate insecticides to increase selectivity and mitigate resistance development in An. gambiae. Based on mosquito acetylcholinesterase (AChE) protein homology modeling, we have synthesized new carbamates that are highly selective to An. gambiae AChE. Anticholinesterase activities of each carbamate were evaluated for both human and mosquito AChEs and compared to those of propoxur (WHO standard for mosquito control), and other conventional carbamate insecticides. We demonstrate novel carbamates of greater selectivity (ca. > 8000-fold) towards An. gambiae AChE, compared to 3-fold selectivity with propoxur. The new carbamates have increased potency towards mosquitoes (ca. 60-fold) than that of propoxur. We confirm both intrinsic and contact mosquito toxicity of these carbamates and demonstrate comparable toxicities to that of propoxur, and other conventional carbamates. With such high levels of selectivity, potency and toxicity, these novel carbamates provide valuable leads to developing of alternative mosquitocides for use in insecticide treated bednets and indoor residual sprays. Our findings are important in the search for new mosquito selective-insecticides and the possible use of these carbamates in malaria control programs will be discussed.