Design, Synthesis, Molecular Modeling, and Evaluation of Larvicidal Efficacy of Novel Dihydropyrano[2,3-c]Pyrazole Derivatives Against Culex pipiens L. larvae (Diptera: Culicidae)

Mosquitoes play a pivotal role in the transmission of numerous infectious diseases. Despite the proven efficacy of conventional insecticides in controlling mosquito populations, their extensive and prolonged use induced resistance mechanisms, leading to adverse consequences for both public health and ecological systems, necessitating the development of novel, promising agents. Herein, a series of 12 novel synthesized dihydropyrano[2,3-c] pyrazole derivatives were evaluated for their larvicidal effectiveness against Culex pipiens. Among the tested compounds, derivatives 10, 6, 12, 8, 4, and 3 exhibited the highest larvicidal potency, with median lethal concentration (LC₅₀) values of 0.0196, 0.0227, 0.0234, 0.0241, 0.0254, and 0.0264 ppm, respectively, each significantly lower than the reference insecticide acetamiprid 20% SP LC₅₀, 0.0272 ppm. Treatment with the most potent derivatives significantly prolonged the larval stage and subsequently reduced both pupation and adult emergence percentages. Biochemical analyses revealed the significant reductions in vital metabolic constituents as well as in detoxification enzymes, including total proteins, lipids, acetylcholine esterase (AChE), glutathione S-transferase (GST), and general esterases. In silico molecular docking analyses confirmed strong binding affinities of the active compounds within the catalytic pocket of AChE. The enhanced larvicidal potential stems from the compound’s ability to establish extensive molecular interactions, including hydrogen bonding, π-π stacking with critical aromatic residues, and electrostatic contacts within the enzyme active sites, effectively blocking acetylcholine hydrolysis and leading to neurotoxic accumulation that causes paralysis and death. Structure–activity relationship of these newly synthesized compounds yields promising insights and supports their potential in the development of innovative mosquito control strategies.