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Noncovalent Inhibit...
Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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- Knutsson, Sofie (author)
- Umeå universitet,Kemiska institutionen
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- Engdahl, Cecilia (author)
- Umeå universitet,Kemiska institutionen
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- Kumari, Rashmi (author)
- Umeå universitet,Kemiska institutionen
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Forsgren, Nina (author)
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- Lindgren, Cecilia (author)
- Umeå universitet,Kemiska institutionen
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- Kindahl, Tomas, 1980- (author)
- Umeå universitet,Kemiska institutionen
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Kitur, Stanley (author)
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Wachira, Lucy (author)
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Kamau, Luna (author)
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Ekstöm, Fredrik (author)
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- Linusson, Anna, 1970- (author)
- Umeå universitet,Kemiska institutionen
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(creator_code:org_t)
- 2018-10-19
- 2018
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Knutsson, Sofie
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Engdahl, Cecilia
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Kumari, Rashmi
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Forsgren, Nina
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Lindgren, Cecili ...
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Kindahl, Tomas, ...
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show more...
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Kitur, Stanley
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Wachira, Lucy
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Kamau, Luna
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Ekstöm, Fredrik
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Linusson, Anna, ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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Journal of Medic ...
- By the university
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Umeå University