Zolpidem (N,N-Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide) is a well-known drug for the treatment of sleeping disorders. Recent literature reports on positive effects of zolpidem therapy on improving renal damage after cisplatin and on reducing akinesia without sleep induction. This has been ascribed to the antioxidant and neuroprotective capacity of this molecule, and tentatively explained according to a generic structural similarity between zolpidem and melatonin. In this work, we investigate in silico the antioxidant potential of zolpidem as scavenger of five ROSs, acting via hydrogen atom transfer (HAT) mechanism; computational methodologies based on density functional theory are employed. For completeness, the analysis is extended to six metabolites. Thermodynamic and kinetic results disclose that indeed zolpidem is an efficient radical scavenger, similarly to melatonin and Trolox, supporting the biomedical evidence that the antioxidant potential of zolpidem therapy may have a beneficial effect against oxidative injury, which is emerging as an important etiopathogenesis in numerous severe diseases, including psychiatric disorders.
Keywords: Antioxidant activity; DFT calculations; DFT, Density Functional Theory; HAT, Hydrogen Atom Transfer (mechanism); M06-2X, Minnesota Hybrid functional with 54% Hartree-Fock exchange; NBO, Natural Bond Orbitals; NPA, Natural Population Analysis; Oxidative stress; PC, Product Complex; Psychiatric disorders; RAF, Radical Adduct Formation (mechanism); RC, Reactant Complex; ROS, Reactive Oxygen Species; Radical scavenging; SMD, Solvation Model based on Density; TS, Transition State; Zolpidem.