Discovery of α-hexyl cinnamaldehyde and its derivatives as novel larvicides against Aedes albopictus

Mosquitoes are the vectors of numerous diseases such as malaria, Dengue and Zika. Controlling mosquito vectors is essential for preventing and managing diseases transmitted by mosquitoes. Larvicides target larvae within their breeding habitats before they mature into adult mosquitoes and disperse. In this study, using α-hexyl cinnamaldehyde (HCA) as a lead compound, three series of derivatives comprising a total of 78 compounds were designed and synthesized. The larvicidal activities of these compounds against Aedes albopictus were evaluated, resulting in the identification of ten promising compounds. Among them, furan-3-ylmethyl cinnamate (compound 2v) and (E)-allyl 3-(4-chlorophenyl)acrylate (compound 4c) exhibited the lowest LC₅₀ values (8.0 ppm and 7.2 ppm respectively). In a 96-h acute toxicity assay conducted on zebrafish, 2v showed no or very low toxicity with an LC₅₀ higher than 100 ppm. To elucidate their mode of action, morphological and histopathologic analyses were performed, and the effects of the compounds on the acetylcholinesterase (AChE) and phosphatase activities were evaluated. Results suggested that the active HCA derivatives induce injury to intestinal epithelial cells by inhibiting phosphatase activity, ultimately resulting in the mortality of mosquito larvae.