Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes

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.

Kindahl, Tomas,1980-Umeå universitet,Kemiska institutionen(Swepub:umu)toskil02 (författare)
Rajeshwari, RajeshwariUmeå universitet,Kemiska institutionen(Swepub:umu)rara0074 (författare)
Lindgren, CeciliaUmeå universitet,Kemiska institutionen(Swepub:umu)celi0013 (författare)
Forsgren, NinaCBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden (författare)
Kitur, StanleyCentre for Biotechnology Research and Development, Kenya Medical Research Institute, Nairobi, Kenya (författare)
Tengo, Laura SelaCentre for Biotechnology Research and Development, Kenya Medical Research Institute, Nairobi, Kenya (författare)
Ekström, FredrikCBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden (författare)
Kamau, LunaCentre for Biotechnology Research and Development, Kenya Medical Research Institute, Nairobi, Kenya (författare)
Linusson, Anna,1970-Umeå universitet,Kemiska institutionen(Swepub:umu)analin99 (författare)
Umeå universitetKemiska institutionen (creator_code:org_t)

Ingår i:Journal of Medicinal Chemistry: American Chemical Society (ACS)66:9, s. 6333-63530022-26231520-4804

Av författaren/redakt...: Vidal-Albalat, A ...; Kindahl, Tomas, ...; Rajeshwari, Raje ...; Lindgren, Cecili ...; Forsgren, Nina; Kitur, Stanley; visa fler...; Tengo, Laura Sel ...; Ekström, Fredrik; Kamau, Luna; Linusson, Anna, ...; visa färre...

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