Nano Route, DFT, MEP, and SAR of Pyran-Functionalized Pyrimidinone Hybrids as Potent Larvicides Against Culex Pipiens; Biochemical and Antioxidant Assessments

Abstract

In this study, the starting material of the pyran-functionalized pyrimidinone scaffold was synthesized using nanoscience-based techniques. Larvicidal screening was conducted on 3rd larvae of Culex pipiens, the primary vector of West Nile virus according to standard protocols at various concentration levels. Among the synthesized library, derivative 11 emerged as the most potent candidate, displaying the strongest insecticidal power with the lowest LC50 values of 103.19 µg/mL after 24 h and 76.29 µg/mL after 48 h, as well as LC90 values of 248.92 µg/ mL after 24 h and 195.75 µg/mL after 48 h. Biochemical assays revealed that larvae treated with the most potent derivative, 11, showed a notable decrease in important enzymatic activity in comparison to the control. Specifically, the most potent derivative, 11, inhibited AChE activity by approximately 50% and significantly suppressed both α- and β-esterase levels at the LC50 concentration. The study found that treated larvae showed major decreases in both protease and phosphatase digestive enzymes, which resulted in metabolic and digestive process disruptions. The assays revealed that whereas antioxidant enzyme activity declined, lipid peroxidation and total protein carbonyl content increased, which indicated severe oxidative stress and cell damage. The synthesized compounds exhibited promising antioxidant activity, with compound 11 showing the highest radical scavenging potential among the tested derivatives (IC₅₀ = 4.30 µg/mL), approaching the activity of the reference standard ascorbic acid (IC₅₀ = 3.98 µg/mL). Computational DFT studies showed that the synthesized derivatives have moderate electronic stability, with compound 11 displaying the smallest HOMO-LUMO gap and highest softness. The most reactive sites were identified by Fukui, MEP, and Mulliken studies. According to findings, the synthesized compounds are promising bioactive candidates for developing effective multiple roles.