Design and Synthesis of Novel Chalcogen-1,2,4-triazoles as Lead-like Glutathione Peroxidase-Mimetic Antioxidants

High Resolution Image Download MS PowerPoint Slide Reactive oxygen species (ROS) play essential roles in cellular signaling; however, their dysregulation leads to oxidative stress associated with several chronic diseases. Organoselenium compounds, particularly selenocyanates, exhibit glutathione peroxidase (GPx)-mimetic activity, while the 1,2,4-triazole scaffold is a privileged pharmacophore in medicinal chemistry. In this work, a series of 15 new selenium- and sulfur-cyanides containing 1,2,4-triazole hybrids was designed, synthesized, and evaluated as potential GPx-mimetic antioxidants. The compounds were prepared via a three-step synthetic route and characterized by NMR spectroscopy and high-resolution mass spectrometry. GPx-like activity was assessed using a UV-based assay and supported by density functional theory (DFT) calculations and in silico ADME/Tox analyses. The synthetic approach afforded the target compounds in moderate to excellent yields (37–91%), with several selenium-containing derivatives displaying GPx-like activities up to 3.2-fold higher than the standard. Computational studies revealed correlations between enhanced activity, favorable electronic properties, and drug-like profiles, highlighting chalcogen–triazole hybrids as promising enzyme-mimetic antioxidants.