Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency

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.