Rational Design, Synthesis, Docking Simulation, and ADMET Prediction of Novel Barbituric-hydrazine-phenoxy-1,2,3-triazole-acetamide Derivatives as Potent Urease Inhibitors

Urease is an important target for the treatment of Helicobacter pylori infection. In this study, several pharmacophores for the inhibition of urease were considered and coupled to design new molecules capable of acting as potent urease inhibitors. Literature review reveals that barbituric-hydrazine, phenoxy-1,2,3-triazole, and acetamide moieties are pharmacophores for urease inhibition. Therefore, in this study, the barbituric-hydrazine-phenoxy-1,2,3-triazole-acetamide scaffold was designed and twelve derivatives 9 a-l of it were synthesized and evaluated. The urease inhibition assay of these compounds revealed that all new title compounds, except for one compound, with IC50 values of 0.73 to 5.27 mu M were more potent than standard inhibitor thiourea. The most potent compound inhibited urease in a mixed-type inhibition mode and interacted as well with the urease active site. In silico drug-likeness and toxicity studies of the most potent compounds predicted that these compounds passed successfully Lipinski's rule of five and had no carcinogenicity on the rat.