Scientists suggest new mechanism of action for oxazosulfyl and "compound A2"

In 2021, researchers introduced a new class of insecticides with potent activity against several insect orders. They are called pyridine alkylsulfone derivatives, with particular emphasis on oxazosulfyl (Sumitomo Chemical Company Ltd.) and compound A2 (Syngenta), these chemicals pave the way for more effective and selective solutions in combating insects that are harmful to agriculture.

Traditionally, it was believed that the action of these insecticides was linked to the interaction with the voltage-gated sodium channel (VGSC). However, recent evidence points to a mechanism of action primarily through inhibition of the vesicular acetylcholine transporter (VAChT). This discovery changes the understanding of how such substances exert their toxicity on insects.

The studies conducted revealed that alkylsulfone intoxication in insects is characterized by a reduction in the efficiency of cholinergic synaptic transmission, evidenced by the decrease in cercal afferent activity in preparations of giant neurons from the American cockroach (American Periplaneta), selective blockade of postsynaptic potentials dependent on cholinergic transmission in the giant fiber pathway Drosophila and abolition of miniature excitatory postsynaptic currents (mEPSCs) at a synapse identified in larvae of Drosophila.

Furthermore, ligand binding studies, using an exemplary tritiated compound ([3H]-A1), revealed a single saturable binding site, with a low nanomolar Kd value, in greenfly membrane fractions (Lucilia sericata), reinforcing the hypothesis of the mechanism of action via VAChT.

Interestingly, oxazosulfyl, which has previously been shown to stabilize voltage-gated sodium channels in their slow inactivated conformation, inhibits [3H]-A1 binding with approximately 5000-fold greater potency. This suggests a chemical class with a novel and highly selective mode of action for invertebrates.

The research was led by James Goodchild, Ying-Ju Chen, Judith Blythe, Lucy C. Firth, Elizabeth Hirst, Kirsty Bess a, Julia Bristow and Jenny Willis (Syngenta, Bioscience); Richard Baines and Francesca Cash (University of Manchester); Michel Muehlebach, Anke Buchholz and Sebastian Rendler (Syngenta Crop Protection AG); Fergus Earley and Andrew Crossthwaite (Syngenta, Bioscience).

More information at doi.org/10.1016/j.pestbp.2024.105854