Sustainable Synthesis and Medicinal Profiling of Azo‐Anchored Imidazo[4,5‐ <i>b</i> ]Indole Scaffolds: DFT Studies, Electrochemical Sensing, and Pharmacokinetic Evaluation

The synthesis of azo-anchored imidazo[4,5-b]indoles represents a promising advancement in therapeutic and sensor technologies, offering significant potential in biomedical applications. This study presents a sustainable, high-yield approach grounded in green chemistry, employing minimal catalyst loading for ecological compatibility. The methodology involves condensing para-amino-functionalized azo benzene, aryl aldehydes, indoline-2,3-dione, and ammonium acetate using L-proline as a catalyst under ultrasonic irradiation at room temperature. The electrochemical characterization via. Cyclic voltammetry (CV) on a TiO₂.SiO₂-HMS/GCE electrode revealed enhanced electrocatalytic performance, with the effective surface area increasing from 0.031 cm² to 0.087 cm². Optimal activity was achieved at pH 6.54 with CTAB, providing a detection range of 1.0 × 10^-6 M to 5.0 × 10^-6 M, a detection limit of 1.50 × 10^-7 M, and a correlation coefficient of 0.992, indicative of irreversible reactions. Remarkably, DFT studies at the B3LYP/6-311 G level provided qualitative insights into the favorable electronic properties via. HOMO-LUMO analysis. Molecular docking predicted that compound 5(f) may interact favorably with the SARS-CoV-2 spike protein, showing better docking scores than Chloroquine and Hydroxychloroquine. Molecular dynamics (MD) simulations further confirmed the stability and persistence of these protein-ligand interactions over time. This prediction is further supported by its favorable pharmacokinetic profile and measurable in vitro cytotoxicity against HEK-293 cells, aligning computational findings with biological activity. This study highlights the dual functionality of these derivatives in sensor and therapeutic domains, adhering to green chemistry principles.