Design, synthesis, anti-urease activity, molecular docking, molecular dynamics, DFT analysis, and ADMET profiling of new barbiturate-phenylhydrazone-acetamide derivatives

In this work, a new series of barbiturate-phenylhydrazone-acetamide derivatives 5a-m has been synthesized and characterized. The design of compounds 5a-m was based on the hybridization of effective pharmacophores on urease, so these compounds were evaluated against urease in vitro and computationally and the obtained data were compared to thiourea, which is a known inhibitor into urease. Urease is an important therapeutic target in the treatment for helicobacter pylori infections. In vitro anti-urease assay on compounds 5a-m demonstrated that all these compounds, with the exception of a compound (compound 5k ), with the IC 50 range from 7.37 μM to 20.16 μM, were more potent than thiourea. The best compounds in this assay were 5a , 5i , and 5m , which demonstrated valuable results in the in silico studies. Docking study on these compounds showed that, in terms of the involved residues in the interaction modes and calculated affinity, 5a , 5i , and 5m interacted as well with the urease's active site. The stability of the compound 5a -urease complex in a physiological environment was confirmed via molecular dynamics simulations. ADMET predictions were favorable in terms of oral bioavailability, low risk of hepatotoxicity, and good pharmacokinetics.