New Schiffbases 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 Schiffbases (H2L1, H2L2, L-3 and L-4) were synthesized and characterized by elemental analysis, FT-IR, LC-MS, H-1 NMR and C-13 NMR techniques. in vitro glutathione reductase activities of the compounds were tested on yeast and human glutathione reductase. L-4 enhanced both glutathione reductase activities, resulting in AC(50) values of 15.06 mu M and 15.89 mu M, respectively. H2L1, H2L2 and L-3 were found to be the inhibitors in the range of 50.09 - 55.23 mu M for yeast glutathione reductase, and in the range of 56.12-66.87 mu M 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 Schiffbases which are non-competitive inhibitors. IFD-Docking scores were found to correlate with experimental IC50 value of H2L1, H2L2 and L-3. Based on the fact that Schiffbases have higher IFD docking scores at binding pocket-1 than at the active site, it can be predicted that Schiffbases prefer to bind to binding pocket-1 in the presence of natural substrate. The difference in glutathione reductase activities of Schiffbases was attributed to the fact that the conformation of the activator L-4-human GR complex was different from that of other inhibitor Schiffbases-human glutathione reductase complexes. ADMET calculations predicted that synthesized ligands obey the Lipinski Rule (rule of five) and Jorgensen Rule (rule of three). (C) 2022 Elsevier B.V. All rights reserved.