Synthesis and Insecticidal Activity of Novel Pyrethroids Based on Aryloxypyridinyl Ethanone Plug-in Molecules.

Pyrethroids continue to play a vital role as pesticides for the management of agricultural and public health pests. Despite decades of application, their benefits still highlight substantial potential for further development, although addressing key concerns remains a complex challenge. This article presents a straightforward synthesis of four novel series of pyrethroids that incorporate pyridine heterocycles. These compounds leverage aryloxypyridinyl ethanone scaffolds, which were previously developed by our research group and serve as plug-in molecules. Notably, compound 4-1 exhibited remarkable activity against both mosquitoes and aphids, designating it as a promising lead compound for further exploration of species selectivity. Our findings indicate that substituting the α-cyano group in the benzyl alcohol moiety with a methyl group significantly influences pyrethroid activity. While this substitution typically results in reduced activity, the introduction of a pyridyl group effectively mitigates this decline. Interestingly, this structural modification appears to be essential for enhancing species selectivity. Additionally, optimizing the synergistic interaction between chrysanthemic acid and chrysanthemic alcohol moieties represents another critical strategy for advancing novel pyrethroid development. Our research also reinforces two established principles of structure-activity relationships: (1) a phenoxy group positioned at the meta-position on the pyridine ring enhances activity, and (2) substituents on the benzene ring exert no significant effect on activity. Molecular docking studies provide detailed structural insights that corroborate these conclusions at the receptor level.