Knutsson_2018_J.Med.Chem_61_10545

Reference

Title : Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency - Knutsson_2018_J.Med.Chem_61_10545
Author(s) : Knutsson S , Engdahl C , Kumari R , Forsgren N , Lindgren C , Kindahl T , Kitur S , Wachira L , Kamau L , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 61 :10545 , 2018
Abstract : 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.
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PubMedID: 30339371
Gene_locus related to this paper: mouse-ACHE

Related information

Gene_locus related to this paper: mouse-ACHE

Citations formats

Knutsson S, Engdahl C, Kumari R, Forsgren N, Lindgren C, Kindahl T, Kitur S, Wachira L, Kamau L, Ekstrom F, Linusson A (2018)
Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
Journal of Medicinal Chemistry 61 :10545

Knutsson S, Engdahl C, Kumari R, Forsgren N, Lindgren C, Kindahl T, Kitur S, Wachira L, Kamau L, Ekstrom F, Linusson A (2018)
Journal of Medicinal Chemistry 61 :10545