Synthesis of Piperazine‐Linked Sulfonamide Derivatives and Their Inhibitory Effects on Glutathione S‐Transferase: In Vitro and In Silico Approach

In this study, a series of novel sulfonamide derivatives containing the piperazine moiety was synthesized via the Povarov reaction. Subsequently, these compounds were characterized using ¹H NMR, ¹³C NMR, IR spectroscopy, and mass spectroscopy analysis to determine their structural integrity. The inhibitory effects of these sulfonamide derivatives on the glutathione S-transferase pi 1 (GSTP1-1) enzyme were evaluated, with ethacrynic acid (INN) serving as a standard inhibitor for comparison. The half-maximal inhibitory concentration (IC₅₀) values for secondary amine and synthesized piperazine-linked sulfonamide derivatives (PLSDs) were determined to range from 0.33 to 0.86 µM, indicating significant inhibitory potential. Lineweaver-Burk plots were constructed for each inhibitor, and the inhibition constant (Ki) values were calculated, ranging from 1.443 ± 0.562 to 4.192 ± 0.125 µM. Molecular docking simulations further supported the experimental findings, revealing binding energies between -5.9 and -9.2 kcal/mol, suggesting strong interactions between the sulfonamide derivatives and the GSTP1-1 active site. Molecular dynamics (MDs) studies were performed to further investigate the interaction, orientation, and conformation of the PLSDs over the active site of GSTP1-1. In silico drug-likeness analysis and ADMET predictions of the PLSDs demonstrated that PLSDs showed drug-likeness and had a satisfactory ADMET profile. The structural insights gained from this study offer valuable guidance for the rational design of more potent GSTP1-1 inhibitors, emphasizing the relevance of these scaffolds for future therapeutic developments aimed at targeting GSTP1-1 enzymes.