Design, larvicidal activity and toxicological assessment of piperine-based amide derivatives against Aedes aegypti (Diptera: Culicidae).
TL;DR
Tetrahydropiperine emerges as a promising scaffold for the development of selective, safe, and effective larvicidal agents by integrating in silico molecular docking and experimental bioassays, and that its saturation enhances larvicidal selectivity while reducing systemic toxicity.
Abstract
The increasing resistance of Aedes aegypti L. to conventional larvicides has intensified the search for novel bioactive compounds through molecular design. This study explores the larvicidal efficacy and toxicological profiles of piperine and its saturated analog, tetrahydropiperine, by integrating in silico molecular docking and experimental bioassays. Both compounds were subjected to docking studies using as target enzymes human and insect acetylcholinesterases (PDB: 4EY6 and 6XYU) and the juvenile hormone-binding protein (PDB: 5V13). Tetrahydropiperine exhibited higher binding affinities, with binding energies of -9.36 kcal.mol-1 (4EY6), -9.32 kcal.mol-1 (6XYU), and -10.60 kcal.mol-1 (5V13), compared to piperine, which showed energies of -9.56, -10.83, and -10.49 kcal.mol-1, respectively. In larvicidal bioassays, tetrahydropiperine demonstrated greater activity, with an LC50 of 54.5 μΜ, whereas piperine showed an LC50 of 78.8 μΜ after 24 hours of exposure. Toxicological evaluation in Swiss mice revealed that tetrahydropiperine, at 300 mg.kg-1, caused no significant adverse effects, while piperine induced mortality and behavioral alterations at doses above 50 mg.kg-1. These results suggest that the unsaturation in piperine side chain may act as a toxicophoric moiety, and that its saturation enhances larvicidal selectivity while reducing systemic toxicity. Tetrahydropiperine thus emerges as a promising scaffold for the development of selective, safe, and effective larvicidal agents.