Synthesis and in vitro / in silico investigation of selenotetrazole derivatives: antioxidant activity and ADME/T profile

Tetrazole-based compounds exhibit neuroprotective and antioxidant activities, and the incorporation of selenium further enhances their redox-modulating and cytoprotective properties. A series of five selenotetrazole derivatives (1–5) was designed and synthesized through a [3 + 2] cycloaddition reaction between the corresponding selenocyanates and sodium azide, affording the desired products in excellent yields. For the biological assessment, the present study employed an integrated set of in silico approaches, including pharmacokinetic and toxicity predictions (ADME/T) and molecular docking targeting pro-oxidant enzymes, combined with in vitro antioxidant evaluations. Reactive species (RS) and lipid peroxidation (TBARS) levels were quantified in the mouse brain, and antioxidant mechanisms were assessed using DPPH, ABTS, FRAP, GST-like, and SOD-like assays. In silico analyses indicated that the compounds exhibit potential to interact with xanthine oxidase and NADPH oxidase, along with a favorable ADME/T profile. The in vitro results demonstrated significant antioxidant activity, showing that the synthesized compounds protected against the induction of cerebral RS (1–5) and TBARS (2, 3 and 4). In addition, selenotetrazoles 4 and 5 exhibited electron-transfer activity in the FRAP and ABTS assays. Overall, these findings reinforce the potential of selenium-containing tetrazole scaffolds as promising candidates for the development of novel antioxidant agents targeting disorders associated with oxidative stress.