Structural highlights
Function[ACES_MOUSE] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Publication Abstract from PubMedResistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of e.g. malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure-activity relationship analyses and molecular dynamics simulations of inhibitor-protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of non-covalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development. Non-covalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency.,Knutsson S, Engdahl C, Kumari R, Forsgren N, Lindgren C, Kindahl T, Kitur S, Wachira L, Kamau L, Ekstrom FJ, Linusson A J Med Chem. 2018 Oct 19. doi: 10.1021/acs.jmedchem.8b01060. PMID:30339371[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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