Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors.

The urease enzyme, a metalloenzyme having Ni ions, is recognized in some bacteria, fungi, and plants. Particularly, it is vital to the progress of infections induced by pathogenic microbes, such as Proteus mirabilis and Helicobacter pylori. Herein, we reported the synthesis of a series of tetrahydropyrimidine derivatives and evaluated their antiurease activity. Finally, quantitative and qualitative analyses of the derivatives were performed via in silico studies. Urease inhibitory activity was determined as the reaction of H. pylori urease with different concentrations of compounds, and thiourea was used as a standard compound. Docking and dynamics methodologies were applied to study the interactions of the best compounds with the amino acids in the active site. All compounds showed good to excellent antiurease activity. The potent compounds were not cytotoxic against the HUVEC normal cell line. Based on the docking study, compound 4e with the highest urease inhibitory activity (IC  = 6.81 ± 1.42 µM) showed chelates with both Ni ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC  = 8.45 ± 1.64 μM) in comparison to thiourea (IC  = 22.03 ± 1.24 μM). The molecular docking and dynamics simulation results were correlated with the in vitro assay results. Moreover, the derivatives 4a-n followed Lipinski's rule-of-five and had drug-likeness properties.