Abstract In this paper, we report the synthesis and biological evaluation of picolylamide based diselenides with the aim of developing a new series of diselenides with O•••Se non-bonded interactions. The synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested against different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than classical standard i.e. diphenyl diselenide. The same compound significantly inhibited iron (Fe)-Induced thiobarbituric acid reactive species (TBARS) production in rat’s brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of non-bonding interactions on organochalcogens potency.