Transformation of 3-(4-methoxybenzylidine)-5-(p-tolyl)-2(3H)-furanone into new nitrogen heterocyclic candidates as insecticidal agents with in silico studies

Abstract

A series of new nitrogen-containing heterocyclic compounds derived from a 2(3H)-furanone precursor was synthesized via reactions with mono- and bidentate nucleophiles, affording pyrrolone, benzoxazinone, quinazolinone, and pyridazine frameworks. The synthesized candidates were characterized spectroscopically and evaluated for larvicidal activity against third-instar Culex pipiens larvae, revealing a wide potency range (LC₅₀ = 0.1–458.6 µg mL⁻¹). Among them, compound 4 exhibited the highest toxicity (LC₅₀ = 0.1 µg mL⁻¹), while several others showed moderate activity (LC₅₀ = 34–95 µg mL⁻¹). Molecular docking against Culex acetylcholinesterase (AChE) and the methoprene-tolerant (Met) receptor indicated that the tested compounds engage catalytically relevant residues such as HIS567 and TRP212 in AChE and HIS23 in Met, though binding energies did not consistently parallel larvicidal potency. Molecular-dynamics simulations (100 ns) supported the stability of the ligand–protein complexes and provided structural evidence for the potential accommodation of the compounds within both targets. In silico ADME predictions revealed high gastrointestinal absorption, balanced lipophilicity, and generally good BBB permeability, with only minor differences, such as the non-BBB-permeant compounds 7, 8, and 14, that may influence access to neural targets. Overall, the combined experimental and computational findings suggest that larvicidal activity arises from a multifactorial interplay between molecular recognition, transport properties, and physicochemical balance rather than docking affinity alone. These results indicate that 2(3H)-furanone-derived heterocycles may represent promising scaffolds for further investigation as dual-target larvicidal candidates. The present findings may contribute to the rational design of next-generation mosquito control agents and support ongoing efforts toward developing more effective and sustainable strategies for vector-borne disease management.