New Schiff bases with a 2,6-bis(2-aminophenylthio)pyridine moiety acting as glutathione reductase activator and inhibitors: Synthesis and molecular docking studies

Abstract

2,6-bis(2-aminophenylthio)pyridine was synthesized and identified by x-ray diffraction method. Its new Schiff bases (H2L1, H2L2, L3 and L4) were synthesized and characterized by elemental analysis, FT-IR, LC-MS, 1H NMR and 13C NMR techniques. in vitro glutathione reductase activities of the compounds were tested on yeast and human glutathione reductase. L4 enhanced both glutathione reductase activities, resulting in AC50 values of 15.06 µM and 15.89 µM, respectively. H2L1, H2L2 and L3 were found to be the inhibitors in the range of 50.09 – 55.23 µM for yeast glutathione reductase, and in the range of 56.12–66.87 µM for human glutathione reductase. According to molecular docking analysis at the xanthine binding site in human glutathione reductase (PDB: 1XAN), 2,6-bis(2-aminophenylthio)pyridine is predicted to have antimalarial property due to having a higher XP docking score than the malaria drug Chloroquine. Also, five binding pockets at the human glutathione reductase (PDB:1GRA) were identified using Sitemap analysis for Schiff bases which are non-competitive inhibitors. IFD-Docking scores were found to correlate with experimental IC50 value of H2L1, H2L2 and L3. Based on the fact that Schiff bases have higher IFD docking scores at binding pocket-1 than at the active site, it can be predicted that Schiff bases prefer to bind to binding pocket-1 in the presence of natural substrate. The difference in glutathione reductase activities of Schiff bases was attributed to the fact that the conformation of the activator L4-human GR complex was different from that of other inhibitor Schiff bases-human glutathione reductase complexes. ADMET calculations predicted that synthesized ligands obey the Lipinski Rule (rule of five) and Jorgensen Rule (rule of three). © 2022