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Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-6548-6158
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2023 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 9, p. 6333-6353Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023. Vol. 66, no 9, p. 6333-6353
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-208264DOI: 10.1021/acs.jmedchem.3c00234ISI: 000979350900001PubMedID: 37094110Scopus ID: 2-s2.0-85156231351OAI: oai:DiVA.org:umu-208264DiVA, id: diva2:1758890
Funder
Swedish Research Council, 2017-00664The Kempe FoundationsAvailable from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-09-05Bibliographically approved

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Vidal-Albalat, AndreuKindahl, TomasRajeshwari, RajeshwariLindgren, CeciliaLinusson, Anna

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Journal of Medicinal Chemistry
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