Larvicidal potential of Knoevenagel adducts against Aedes aegypti: theoretical study and in vitro validation

This study investigated the larvicidal potential of Knoevenagel adducts against Aedes aegypti larvae to develop sustainable alternatives for controlling disease vectors like dengue. Larvicidal activity of Knoevenagel adducts (1a–l) was evaluated on fourth-stage Aedes aegypti larvae. Additional analyses included nitric oxide measurement, cell profiling, toxicity assessment, molecular docking, molecular dynamics simulation, and ADMET (Absorption, Distribution, Metabolism, and Toxicity) evaluation. Compounds 1c and 1g showed high larvicidal efficacy, with LC50 values of 3.39 and 5.13 ppm. Hemolymph analysis revealed altered hemocyte composition, indicating an immune response, though nitric oxide levels remained unchanged. Molecular docking identified strong interactions between the Aedes aegypti FKBP12 enzyme (PDB: 3UQI) and Knoevenagel adducts. Compound 1g had the highest activity probability and binding affinity, while 1c showed strong interactions validated by biological assays. Molecular dynamics confirmed stable interactions of 1c and FKBP12, with both 1c and 1g displaying significant van der Waals contributions. ADMET analysis highlighted 1c as a less toxic compound, with minimal mutagenic risk, favorable pharmacokinetics, and high bioavailability. Knoevenagel adducts 1c and 1g are promising candidates for effective, selective, and environmentally friendly larvicides.