Design, synthesis, and evaluation of novel triazole-based carbohydrazide derivatives with notable antioxidant activity: an integrated experimental and DFT study

A series of novel heterocyclic compounds based on 5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carbohydrazide were designed, synthesized, and evaluated for antioxidant activity. The synthesized derivatives included phthalimide (NA-1, NA-2), cyanoacetamide (NA-3), pyridine-based (NA-4), and hydrazonoyl cyanide (NA-5 to NA-8) analogs. Structural confirmation was achieved through IR, NMR (1H and 13C), and MS analyses. Antioxidant activity was assessed using the DPPH radical-scavenging assay, with ascorbic acid as a reference. Compounds NA-2 (IC50 = 0.072 ± 0.272 mg/mL), NA-5 (IC50 = 0.029 ± 0.135 mg/mL), and NA-6 (IC50 = 0.096 ± 0.085 mg/mL) showed notable activity. DFT calculations suggested favorable electronic properties and hydrogen-bonding potential, supporting their antioxidant behavior. In silico pharmacokinetic analysis (SwissADME) showed acceptable drug-likeness with limited violations in some analogs with Lipinski’s rule of five, indicating acceptable drug-likeness. Bioavailability scores were generally 0.55, except NA-7 (0.11).