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In recent times, the methods used to evaluate gastric ulcer healing worldwide have been based on visual examinations and estimating ulcer dimensions in experimental animals. In this study, the protective effect of rhodanine and 2,4-thiazolidinediones scaffolds compared to esomeprazole was investigated in an ethanol model of stomach ulcers in rats. Pretreatment with experimental treatments or esomeprazole prevented the development of ethanol-induced gastric ulcers. The severity of the lesions and injuries was significantly lower than that of vehicle (10% Tween 80) treated rats. Significant and excellent results were obtained with the compound <b>6</b> group, with inhibition percentage and ulcer area values of 97.8% and 12.8±1.1 mm², respectively. Synthesized compounds <b>2</b>, <b>7</b> and <b>8</b> exhibited inhibition percentages and ulcer areas of 94.3% and 31.2±1.1 mm², 91. 3% and 48.1±0. 8 mm², 89. 5% and 57. 6±1. 2 mm², and 89. 1% and 60.3±0. 8 mm², respectively. These biological outcomes are consistent with the docking studies in which Compounds <b>7</b> and <b>8</b> showed remarkable binding site affinities toward human H+/K+- ATPase α protein (ID: P20648), rat H+/K+- ATPase α protein (ID: P09626), and Na+/K+-ATPase crystal structure (PDB ID:2ZXE) with binding site energies of -10.7, -9.0, and -10.4 (kcal/mol) and -8.7, -8.5, and -8.0 (kcal/mol), respectively.