Exploration of N‐(6‐Indazolyl) benzenesulfonamide Derivatives as Potential Antioxidants and Antimicrobial Agents: Integrating Synthesis, In Silico Docking, and Bioactivity Profiling

Abstract

AbstractA new series of N‐(1‐(2‐chloropyrimidin‐4‐yl)‐1H‐indazol‐5‐yl) benzenesulfonamide derivatives (4 a–i) and N‐(1‐(2‐chloropyrimidin‐4‐yl)‐6‐ethoxy‐1H‐indazol‐5‐yl) benzenesulfonamide derivatives (5 a–i) was synthesized via reduction of 1‐(2‐halopyrimidin‐4‐yl)‐5‐nitro‐1H‐indazole (3) with SnCl2 followed by reaction with various aryl sulphonyl chlorides in pyridine. The structures were confirmed using IR, 1H‐NMR, 13C‐NMR, and mass spectral methods. Compounds 4 a–i and 5 a–i were evaluated for antifungal and antibacterial activities against Gram‐negative and Gram‐positive bacteria. They also exhibited antioxidant potential in DPPH (IC50=0.094‐0.467 μmol/ml) and ABTS assays (IC50=0.101–0.496 μmol/ml). Remarkably, N‐(1‐(2‐chloropyrimidin‐4‐yl)‐1H‐indazol‐5‐yl)‐2‐nitrobenzenesulfonamide displayed the highest antibacterial activity, while N‐(1‐(2‐chloropyrimidin‐4‐yl)‐1H‐indazol‐5‐yl)‐4‐methoxybenzenesulfonamide showed excellent antifungal potential. Compound N‐(1‐(2‐chloropyrimidin‐4‐yl)‐1H‐indazol‐5‐yl)‐2‐nitrobenzenesulfonamide exhibited the most significant antioxidant activity. In this study, molecular dynamics simulations were utilized to rigorously examine the stability of ligand‐protein complexes, demonstrating a consistent and robust binding of the most potent compound within the target proteins′ binding sites. Computational assessments were further employed to predict the drug‐likeness and ADMET properties of the synthesized compounds. The results unequivocally confirmed the remarkable antioxidant and antimicrobial potential of all derivatives, a finding substantiated by comprehensive molecular docking analyses that revealed intricate interactions involving hydrogen bonds, electrostatic forces, and hydrophobic contacts. These findings collectively provide invaluable insights into the complex molecular structure and receptor target site dynamics, laying a strong foundation for the development of novel active antioxidant and antimicrobial agents with promising pharmaceutical implications.