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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 23, p. 10545-10557Article in journal (Refereed) Published
Abstract [en]

Resistance 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 noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 61, no 23, p. 10545-10557
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-154812DOI: 10.1021/acs.jmedchem.8b01060ISI: 000453488200014PubMedID: 30339371OAI: oai:DiVA.org:umu-154812DiVA, id: diva2:1275830
Funder
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved

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Knutsson, SofieEngdahl, CeciliaKumari, RashmiLindgren, CeciliaKindahl, TomasLinusson, Anna

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