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

• 2,6-bis(2-aminophenylthio)pyridine was synthesized and identified by X-ray diffraction method. • Four new Schiff bases derived from 2,6-bis(2-aminophenylthio)pyridine were synthesized and characterized by spectrophotometric method. • Glutathione reductases inhibitory activities of all compounds were evaluated. • IFD docking analysis of the new Schiff bases was carried out for hGR (PDB:1GRA) • ADME/T properties of the compounds were predicted by Qikprop program. 2,6-bis(2-aminophenylthio)pyridine was synthesized and identified by x-ray diffraction method. Its new Schiff bases (H 2 L 1 , H 2 L 2 , L 3 and L 4 ) were synthesized and characterized by elemental analysis, FT-IR, LC-MS, 1 H NMR and 13 C 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 µM and 15.89 µM, respectively. H 2 L 1 , H 2 L 2 and L 3 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 IC 50 value of H 2 L 1 , H 2 L 2 and L 3 . 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 L 4 -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).