Visible light-promoted, catalyst-free synthesis of isoniazid azomethines: In vitro antioxidant activity, molecular docking, ADME and toxicity prediction

Green synthesis of biologically active molecules is essential for environmental sustainability, resource efficiency, reduced environmental impact, and compliance with regulations. It ensures a safer working environment, and fosters innovation in sustainable chemistry practices. In this context, we introduce an electron donor-acceptor (EDA)-mediated visible light-promoted, catalyst-free (VLCF) scalable synthesis of isoniazid azomethines. This synthesis encompasses the drug salizide and its analogues, which were subsequently evaluated for their antioxidant activities. Isoniazid azomethines 3e demonstrated superior activity compared to salizide and ascorbic acid, with an IC₅₀ of 0.078 mg/mL in the hydrogen peroxide antioxidant assay. Specifically, 3e exhibited greater antioxidant properties (79.02 %) than isoniazid azomethine 3b (75.82 %), isoniazid azomethine 3d (62.2 %), isoniazid azomethine 3c (59.86 %), and isoniazid azomethine 3a (54.62 %). In the superoxide dismutase antioxidant assay, 3e was also identified as the most active, with a SOD activity level of 650 U/mg of protein, surpassing other compounds (3a-d) with SOD activity levels of 330, 560, 350, and 420 U/mg of protein, respectively. Molecular docking against horseradish peroxidase (1W4Y) showed compound 3e with the best binding energy (-6.561 kcal/mol), forming key hydrogen bonds (Asn135, Pro139) and a π-cation interaction with Arg38. These interactions suggest 3e may effectively inhibit hydrogen peroxide catalysis. The in silico assessment of the physicochemical properties, pharmacokinetics, and toxicology of synthesized compounds suggests that these compounds exhibit promising ADMET characteristics, with no identified toxicological concerns.