Multicomponent synthesis, insecticidal evaluation and molecular dynamics studies of new nicotinonitrile derivatives...

Two series of indolylpyrazole-nicotinonitrile and indolyltriazole-nicotinonitrile (3-cyanopyridine) derivatives were created using one-pot multicomponent reaction. This reaction involved 3-(cyanoacetyl)indole, acetylpyrazole, or acetyltriazole, and aromatic aldehydes. These reactions were carried out in methanol with conventional heat in the presence of ammonium acetate. The structure of the new products was confirmed using elemental analysis, NMR, and infrared spectroscopy. The synthesized compounds were then tested for their insecticidal activity against two disease vectors, Musca domestica and Culex pipiens. The compounds 4a, 4e, 6a, and 6f exhibited the highest activity against Culex pipiens larvae, with LC₅₀ values of 2.6, 2.7, 3.9, and 1.9 ppm, respectively. Toxicity results against Culex pipiens adults were also evaluated. Compound 6a was identified as the most potent, with an LC₅₀ of 0.21 ppm, while compound 6e was the least powerful, with an LC₅₀ of 5.57 ppm. In the case of Musca domestica larvae, compound 4e demonstrated the highest effectiveness with an LC₅₀ of 2.1 ppm, while compound 4a was the most toxic against Musca domestica adults, with an LC₅₀ value of 0.96 ppm. These results indicate a promising approach for developing new and effective insecticides against these disease vectors. Molecular dynamics simulations and MM/GBSA calculations were employed to evaluate the binding mechanism of newly synthesized compounds against the acetylcholine receptor. Compound 4a demonstrated superior binding stability, forming a compact complex with a high binding free energy (ΔG_bind = -20.86 kcal/mol), primarily driven by strong van der Waals interactions with key residues like Cys188 and Tyr193. In silico ADMET profiling revealed that all compounds, including 4a, exhibit favorable drug-likeness and oral bioavailability. However, this promising pharmacological profile was overshadowed by universal predictions of hERG-mediated cardiotoxicity and hepatotoxicity, identifying a critical liability that precludes further development of this specific chemical series.