Scientists suggest new mode of action for pyridine alkylsulfone insecticides

A new class of insecticides, represented by pyridine alkylsulfone derivatives, has shown potent effects against several orders of insects. Highlights include Oxazosulfyl from Sumitomo Chemical and compound A2 from Syngenta.

These compounds, previously attributed to interaction with voltage-gated sodium channels, have now been shown to have a mechanism of action related primarily to inhibition of the vesicular acetylcholine transporter (VAChT), scientists have indicated.

Recent research indicates that alkylsulfone poisoning causes a reduction in the efficiency of cholinergic synaptic transmission in insects. Experiments with American cockroaches (American Periplaneta) showed a significant decrease in the afferent activity of sensory bristles. Furthermore, tests in Drosophila demonstrated a selective blockade of postsynaptic potentials dependent on cholinergic transmission. These effects are related to interference in the process of acetylcholine loading into synaptic vesicles, a function performed by VAChT.

Mode of action

VAChT is a membrane transporter that concentrates acetylcholine in vesicles, allowing its release during synaptic transmission. By inhibiting this process, alkylsulfone derivatives compromise the neuromuscular function of insects, leading to their death.

Binding tests with tritiated ligands showed the presence of a single saturable binding site in insect membrane fractions, which was identified as VAChT.

Furthermore, the correlation between insecticidal potency and the ability to displace the tritiated ligand from this site reinforces the hypothesis that this is the main basis of toxicity of the compounds.

Compared to other classes of insecticides that also act on VAChT, such as spirindolines, alkylsulfone derivatives appear to have a different binding mode, which may explain the absence of cross-resistance in some strains of Drosophila. This is significant as it allows a new approach to managing insecticide resistance, as well as expanding the chemical arsenal available for pest control.

Study conclusions

Evidence suggests that the effects of these compounds on sodium channels are less relevant to their insecticidal action than the inhibition of VAChT.

Studies have shown that oxazosulfyl stabilizes sodium channels in the inactive conformation, but with considerably less potency than that observed for inhibition of VAChT binding.

Therefore, researchers believe that this new class of compounds should be classified under a new mechanism of action group.

More information can be found at doi.org/10.1016/j.pestbp.2024.105854