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

İngilizce (OpenAlex)

ABSTRACT 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 1 H NMR, 13 C 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 (IC 50 ) 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 (K i ) 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.