Synthesis, antioxidant activity, DFT simulations, molecular docking studies of Schiff base derivatives containing 2-(2-hydrazinyl) thiazole moiety

Abstract

In this study, Schiff base derivatives 5a-5f containing 2-(2-hydrazinyl) thiazole moiety were synthesized and confirmed with spectral analysis (¹H NMR, ¹³C NMR, IR, MS). The antioxidant activity was evaluated using DPPH free radical scavenging assay. Compound 5c (IC₅₀ = 21.71 ± 2.64), 5d (IC₅₀ = 22.59 ± 4.26) demonstrated good antioxidant activity. Density functional theory (DFT) calculations were performed to analyze the optimized geometric structures, including natural bond orbital (NBO) analysis, frontier molecular orbital (FMO) analysis, and molecular electrostatic potential (MEP) analysis. The most credible transition observed in compound 5a was π (C21-C22) → π*(C23-C24), with highest stabilization energy of 22.67 kcal/mol. Compounds 5a-5f exhibited strong interactions and favorable binding energies. The binding affinity of Compounds 5a-5f ranged from -5.42 to -6.37 kcal/mol. The binding affinity of compound 5a was -6.31 kcal/mol. Molecular docking studies elucidated that compounds 5a-5f showed a certain binding ability to human antioxidant enzyme receptor 3MNG, supporting the experimental antioxidant activity results. Compound 5a demonstrated the most active antioxidant property. Two hydrogen bonds were found, as N13-H14…GLU27:O (GLU27, 2.15 Å), ASN24:H…S18 (ASN24, 2.33 Å). Compounds 5a-5f adhered to Lipinski's Rule of Five. Compounds 5a, 5b, and 5d demonstrated relative higher Drug-Likeness values. These results will shed light on design, preparation of new Schiff base antioxidants and provide important information for optimizing the chemical structures of antioxidants with higher anti-oxidative properties.