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.