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| 2. |
- Knutsson, Sofie, et al.
(författare)
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N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 134, s. 415-427
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Tidskriftsartikel (refereegranskat)abstract
- Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.
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| 3. |
- Knutsson, Sofie, et al.
(författare)
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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:23, s. 10545-10557
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Vidal-Albalat, Andreu, et al.
(författare)
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Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:9, s. 6333-6353
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Tidskriftsartikel (refereegranskat)abstract
- Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.
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