Avaliação da atividade gastroprotetora do composto 1-(4- clorofenil) -3-(1,3,4-tiodiazol-2-il) tioureia (MS06)

Abstract

Peptic ulcer is the term used to refer to damage to the protective barrier of the mucous layer of the esophagus, stomach or duodenum. It has a heterogeneous etiology and treatment involves pharmacological measures that have been related to adverse effects and recurrence. Therefore,the present study aimed to investigate the gastroprotective activity of the compound 1-(4-chlorophenyl) -3-(1,3,4-thiodiazol-2-yl) thiourea (MS06). In vivo, the acute toxicity of MS06 and its gastroprotective potential against ulcer models induced by ethanol and non-steroidal anti-inflammatory drugs (NSAID) were evaluated. Subsequently, possible mechanisms related to the responses were evaluated: antisecretory, involvement of prostaglandins (PG's) and ATP-dependent potassium channels (KATP) and, additionally, in vitro, the antispasmodic effect of the compound in isolated stomach fundus strips. In silico, the mechanisms were investigated through the molecular coupling of MS06 with target structures involved in the regulation of gastric acid secretion and cytoprotection: H+/K+-ATPase coupled with vonoprazan (PDB ID:5YLU), H2 receptor coupled with famotidine (PDB ID: 7UL3), M3 receptor coupled withs pecific antagonist (PDB ID: 5ZHP), and EP2 receptor coupled with the evatanepag (PDB ID:7CX4). The stability of the complexes formed was analyzed using molecular dynamics calculations. As a result, MS06 presented low toxicity, with a 50% lethal dose (DL50) between 2000 and 5000 mg.kg. In the ulcer protocol caused by ethanol, MS06 (12.5, 25 and 50 mg.kg) inhibited the appearance of ulcerated areas by 76, 84 and 86%, respectively, when compared to the negative control (Tween 80 5 %). As there was no statistical difference, the dose of 12.5 mg.kg was used in subsequent trials. In gastric ulcers caused by NSAIDs (Piroxicam), the compound inhibited the ulcerative lesion index (ILU) by 49.33%. No pylorus ligation protocol achieved a significant reduction, mainly in volume along with an increase in the pH of gastric contents. Pre-treatment with misoprostol or glibenclamide significantly reversed the gastroprotection exerted by MS06, reducing the participation of PG's and KATP in the compound's mechanism. In vitro, at a concentration of 100 M, MS06 significantly inhibited the contractile response of 1 μM CCh, decreasing antispasmodic activity. In the molecular anchoring of MS06, there was a greater layer of coating by the M3 receptor. Molecular dynamics simulations demonstrated greater stability in the complexes formed with the H+/K+-ATPase and EP2 receptor. These initial studies demonstrated that MS06 has gastroprotective potential, which may be related to an association of mechanisms.