Multiple factors, such as increased intestinal barrier permeability, upregulation of iNOS/NO expression and decreased H2S synthesis are involved in the pathogenesis of inflammation. The purpose of this investigation was to explore the role of 4-thiazolidinone-based derivatives as a novel donors of H2S in promoting the resolution of inflammation in small intestine. In the present study, we investigated the effect of novel 4-thiazolidinone derivatives (compounds Les-5054 and Les-5055) on various intestinal events occurring in association with stress-induced gastrointestinal damage. It was observed an intensification of lipid peroxidation, myeloperoxidase activity, accompanied by increase of iNOS activity, NO production and decrease of H2S content in rats with water-immersion stress group. In animals treated with compounds Les-5054 and Les-5055 the reduction of the activity of iNOS, myeloperoxidase, intensity of lipid peroxidation and increased generation of H2S were revealed. 4-thiazolidinone-based derivatives increased small intestine mucosal activity of anti-oxidative enzymes SOD and catalase in rats subjected to stress. The compound Les-5054 showed significant efficacious effect and antioxidant properties compared to compound Les-5055.