Studies on N-(6-Indazolyl) benzenesulfonamide Derivatives as Potential Anticancer Agents: Integrating Synthesis, In silico Docking, and Molecular Dynamics Simulations

Abstract

A new series of benzenesulfonamide derivatives, namely N-(1-(2-chloropyrimidin-4-yl)-1[Formula: see text]-indazol-5-yl) compounds (4a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1[Formula: see text]-indazol-5-yl) derivatives (5a-i), were synthesized. This was achieved by reducing 1-(2-halopyrimidin-4-yl)-5-nitro-1[Formula: see text]-indazole (3) with SnCl2, followed by reacting with various aryl sulphonyl chlorides in pyridine. Structural confirmation was carried out through IR, 1H-NMR, [Formula: see text]C-NMR and mass spectral methods. Anticancer activity evaluation of compounds 4a-i and 5a-i revealed that N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl)-2-nitrobenzenesulfonamide (5b) displayed exceptional efficacy. Molecular dynamics simulations were employed to rigorously assess the stability of ligand–protein complexes, highlighting a consistent and robust binding of the most potent compound within the binding sites of target proteins. The results unequivocally affirmed the remarkable anticancer activity, supported by comprehensive molecular docking analyses uncovering intricate interactions involving hydrogen bonds, electrostatic forces and hydrophobic contacts. These findings collectively offer invaluable insights into the complex molecular structure and dynamics of receptor target sites, establishing a robust foundation for the development of novel and potent anticancer agents with promising pharmaceutical implications.