Multicomponent reaction for the synthesis of novel nicotinonitrile analogues bearing imidazole or triazole moieties: Synthesis, antioxidant activity, molecular docking, and ADMET studies

The study is aimed to synthesize, characterize and evaluate antioxidant activity of novel highly functionalized nicotinonitrile analogues bearing imidazole or triazole moieties. The targeted compounds were synthesized via one-pot four component reaction and characterized by elemental and spectrometric analyses. The newly 16-synthesized compounds were assessed as antioxidant agents using the total antioxidant capacity assay. The experimental results indicated that four out of sixteen compounds exhibited the most antioxidant effect with 38.81 and 18.66 mg AAE/g considering ascorbic acid equivalent. The molecular docking screening on the novel potential compounds, further supported by ADMET/drug-likeness screening was conducted. The outcomes of the docking simulations revealed that compounds 4e, 4f, 4g, and 6h are considered safe and non-toxic. These 4 compounds exhibited significant affinity, as evidenced by binding energies of -11.9, -10.9, -11.2, and -11.60 kcal/mol, respectively, with the active site of human cytochrome P450. Additionally, these compounds showed significant binding energies with NAD(P)H Oxidase of -9.90, -9.50, -9.90, and -9.50 kcal/mol, respectively. These interactions involved diverse types of molecular interactions and demonstrated favorable binding energies, indicating the potential of these compounds to modulate antioxidant enzymes and demonstrate promising antioxidant effects. The in-silico ADMET profiles of compounds 4e, 4f, 4g, and 6h indicated their adherence to the Lipinski rules, subsequently, they could be potential orally bioavailable drug-like molecules.