Desenho, síntese e avaliação antiulcerogênica de um novo derivado tiazol-ureia e seus bioisosteros

Abstract

Gastric ulcer is a lesion in the mucosal epithelium, in which it is caused by the excessive secretion of hydrochloric acid and the enzyme pepsin, mainly in the stomach, with a prevalence of 14% of the world population. That said, this work aims to synthesize famotidine-derived candidates capable of acting in the fight against stomach ulcers with minimal side effects. In this sense, the technique of drug development was used from pharmacophoric groups with established antiulcerogenic activity (thiazole and thiourea), as well as carrying out molecular modifications in the prototype compound MS01 based on the Topliss decision tree. After defining the development strategy, the synthesis by the conventional method of four compounds took place, as well as physicochemical characterization and structural elucidation using infrared spectrometry, nuclear magnetic resonance of carbon and hydrogen. The spectroscopic analysis, in addition to allowing the structural elucidation, also suggested that the compounds present tautomeric behavior in urea. Then, the evaluation of the acute toxicity in vivo of the prototype compounds was carried out using the dose of 2000mg/kg, and the results showed that no significant changes occurred. The main pharmacokinetic predictions in silico were also performed, which corroborate the in vivo studies. After ensuring safety, pharmacological screening of gastroprotective activity in vivo with ethanol-induced ulcer was performed, using Lansoprazole 30mg/Kg as a positive control and testing four different doses of the prototype compound MS01 (12.5 mg/Kg; 25 mg/kg). Kg; 50 mg/Kg and 100 mg/Kg) in order to identify the most promising dose. The results of this trial showed that MS01 had inhibition of ulcer formation at a dose of 12.5mg/Kg and had antiulcerogenic activity statistically equivalent to Lansoprazole at a dose of 25mg/Kg. The next step was to determine the possible mechanism of action of this compound, using in silico molecular anchoring tools, in which the interaction with the main antiulcerogenic pathways was verified: proton pump and type 2 histaminergic receptor. silico showed that the synthesized compounds, not only the MS01 prototype, can act in both pathways, since it presented ΔG binding energy ranging between -6.79 and -7.46 for the proton pump target and between -6.49 and -7.84 for the histaminergic receptor. Therefore, it was possible in this work to synthesize, elucidate four new compounds through infrared, carbon and hydrogen magnetic resonance techniques, as well as establish that the prototype compound MS01 presents promising gastroprotective activity in vivo, being able to act in the proton pump and histaminergic pathway.