Malaria causes significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are threatened by emerging resistance to pyrethroid insecticides.  With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors.  Our in vitro assay studies have shown that trifluoromethyl ketones (TFKs) potently inhibit acetylcholinesterase of the malaria mosquito Anopheles gambiae (AgAChE); previous X-ray studies demonstrated covalent adducts of TFKs with the catalytic serine of mouse and Torpedo californica enzymes (PDB ID 2H9Y and 1HBJ respectively).  However, these potent TFK inhibitors have low contact toxicity against An. gambiae.  In an attempt to improve the mosquito toxicity of these compounds, we prepared potential prodrugs with generic formula 1 -5  below (n = 3).  In addition, because difluoro- and monofluoroketones are known to inhibit carboxylesterases and serine/cysteine proteases, we explored the insecticidal activity of the difluoro- and monofluoroketone analogs and their potential prodrugs (1 -5 , n = 2 and 1 respectively).  To date, several compounds have been prepared that show excellent contact toxicity (comparable to propoxur) to susceptible G3 strain An. gambiae.  These compounds have similar toxicities to resistant Akron strain An. gambiae, which exhibit >130-fold resistance to propoxur.  Studies on the possible mechanism of action of these compounds will be reported. 

Fluorinated methylketone prodrugs: Potential new insecticides against <i>An. gambiae</i>

248th National Meeting (2014)

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Fluorinated methylketone prodrugs: Potential new insecticides against An. gambiae