Abstract

Reducing Aedes aegypti population using natural or synthetic insecticides remains one of the main strategies for controlling diseases such as dengue, Zika or Chikungunya, as this mosquito is their primary vector. Traditionally, some organic compounds -mainly carbamates or organophosphates derivatives- have been employed for this purpose. These insecticides act as irreversible inhibitors of the acetylcholinesterase enzyme (AChE), which results in high nonspecific toxicity. Moreover, the eventual development of resistance highlights the need to explore new alternatives. In this study a series of sixteen (16) new N-arylmethyl-1,2,3,4-tetrahydroquinoline derivatives containing an N-arylmethylpiperidine scaffold inspired by the structure of donepezil structure, were designed and synthesized, using a mild and efficient methodology via cationic Povarov reaction. This approach enabled access to the N-arylmethyl tetrahydroquinoline core with good to high yields (61–94 %). The biological activity of these compounds was then evaluated through insecticidal activity and acetylcholinesterase inhibition assays, as indicators of their potential as insecticidal agents. In preliminary insecticidal activity assay, compounds 4d, 4e, 4f and 4j were identified as the most active, with LC50 of 42, 21, 88 and 65 ?g/mL after 24 h of treatment. Enzymatic assays showed that compounds 4a, 4e and 4 m exhibited the highest inhibitory activity, with IC50 values of 8.32 ± 0.32, 16.43 ± 1.13, and 13.23 ± 1.42 ?M, respectively. Among them, compound 4e emerged as the most promising candidate. Finally, silico studies, including molecular dynamics simulations and binding free energy calculations, revealed the stability and strong binding interactions of the three most active compounds (4a, 4e, and 4 m) against A. aegypti AChE. © 2025 The Authors