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N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2017 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 134, s. 415-427Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2017. Vol. 134, s. 415-427
Nyckelord [en]
Acetylcholinesterase 1, Aedes aegypti, Anopheles gambiae, Insecticides, Thiourea, Vector control
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-134612DOI: 10.1016/j.ejmech.2017.03.050ISI: 000401677500035PubMedID: 28433681Scopus ID: 2-s2.0-85017625955OAI: oai:DiVA.org:umu-134612DiVA, id: diva2:1094343
Tillgänglig från: 2017-05-09 Skapad: 2017-05-09 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Ingår i avhandling
1. Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes: design and development of new insecticides for vector control
Öppna denna publikation i ny flik eller fönster >>Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes: design and development of new insecticides for vector control
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Acetylcholinesterase (AChE) is an essential enzyme with an evolutionary conserved function: to terminate nerve signaling by rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for insecticides. Vector control by the use of insecticide-based interventions is today the main strategy for controlling mosquito-borne diseases that affect millions of people each year. However, the efficiency of many insecticides is challenged by resistant mosquito populations, lack of selectivity and off-target toxicity of currently used compounds. New selective and resistance-breaking insecticides are needed for an efficient vector control also in the future. In the work presented in this thesis, we have combined structural biology, biochemistry and medicinal chemistry to characterize mosquito AChEs and to develop selective and resistance-breaking inhibitors of this essential enzyme from two disease-transmitting mosquitoes.We have identified small but important structural and functional differences between AChE from mosquitoes and AChE from vertebrates. The significance of these differences was emphasized by a high throughput screening campaign, which made it evident that the evolutionary distant AChEs display significant differences in their molecular recognition. These findings were exploited in the design of new inhibitors. Rationally designed and developed thiourea- and phenoxyacetamide-based non-covalent inhibitors displayed high potency on both wild type and insecticide insensitive AChE from mosquitoes. The best inhibitors showed over 100-fold stronger inhibition of mosquito than human AChE, and proved insecticide potential as they killed both adult and larvae mosquitoes.We show that mosquito and human AChE have different molecular recognition and that non-covalent selective inhibition of AChE from mosquitoes is possible. We also demonstrate that inhibitors can combine selectivity with sub-micromolar potency for insecticide resistant AChE.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2017. s. 67
Nyckelord
acetylcholinesterase, non-covalent inhibitor, vector control, insecticide, mosquito, vector-borne disease, high throughput screening, rational design
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi; datorlingvistik
Identifikatorer
urn:nbn:se:umu:diva-134625 (URN)978-91-7601-723-4 (ISBN)
Disputation
2017-06-02, KB.E3.03 (stora hörsalen), KBC-huset, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-05-12 Skapad: 2017-05-10 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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Knutsson, SofieKindahl, TomasEngdahl, CeciliaLinusson, Anna

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Knutsson, SofieKindahl, TomasEngdahl, CeciliaLinusson, Anna
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European Journal of Medicinal Chemistry
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