Design, synthesis, molecular docking, and antioxidant properties of a series of new S-derivatives of ((1,2,4-triazol-3(2H)-yl)methyl)thiopyrimidines

The aim of our work is to synthesize new S-derivatives in the series of ((1,2,4-triazol-3(2H)-yl)methyl)thiopyrimidines and to study their antioxidant activity, to identify the most promising compound using molecular docking and kinetic parameters. Materials and methods. The 1H and 13C NMR spectra were recorded on a Bruker AC-500 spectrometer. LC-MS was recorded on an Agilent 1260 Infinity HPLC system equipped with a diode-array detector and proton ionization. Elemental analysis (C, H, N, S) was performed on an ELEMENTAR vario EL cube. Molecular docking was performed using the AutoDock 4.2.6 program. Free radical absorption was measured using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical assay. Results. A series of S-acyl derivatives of 4-methyl-5-((pyrimidin-2-ylthio)methyl)-4H-1,2,4-triazole-3-thiols were synthesized through alkylation and subsequent cyclization. The structure of the obtained compounds was confirmed by ¹H and ¹³C NMR spectroscopy. Antiradical activity was evaluated using the DPPH test, with compound (6) exhibiting the highest activity, surpassing ascorbic acid. Molecular docking with cytochrome c peroxidase (PDB: 2X08) confirmed strong binding interactions, highlighting the potential of these derivatives as antioxidants. Conclusions. Three compounds (1, 6, 8) exhibited higher activity than the reference drug, the natural antioxidant ascorbic acid. This high activity may be associated with the presence of pharmacophore fragments, particularly the pyrimidine skeleton and the sulfur atom linked to the 1,2,4-triazole. The IC50 for the most active compound was calculated as 4.458±1 µM, which is 27 times more effective than ascorbic acid. Molecular docking results showed that compounds 4 and 6 had the lowest binding energies, making them the most effective compounds in terms of antioxidant activity