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

Abstract

The urease enzyme, a metalloenzyme having Ni 2+ 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 50 = 6.81 ± 1.42 µM) showed chelates with both Ni 2+ ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC 50 = 8.45 ± 1.64 μM) in comparison to thiourea (IC 50 = 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.

Synthesis, Biological Activity Evaluation, Docking and Molecular Dynamics Studies of New Triazole‐Tetrahydropyrimidinone(thione) Hybrid Scaffolds as Urease Inhibitors

“…All of these interactions limited the flexibility of the flap region to reduce the enzymatic activity. [27,34] The distance between the carbonyl group and the Ni 2 + ions are 2.05 Å and 2.78 Å, respectively, suggesting a strong interaction between the ligand and the enzyme. Furthermore, sulfur atom in X interacted with His322, THPM ring and ester moiety in R1 made hydrophobic interactions with Ala169, Arg338, His248, Asp362 and Gly279.…”

“…The observed results are nearby in agreement with the described literature on anti-urease activity. [27] According to the reported urease inhibitors, [16,27,28] current hybrids revealed a moderate to good activity.…”

“…[30 -32] Validation of molecular docking was done precisely similar to our previous article. [27] According to molecular docking studies, hybrids 9a -g were bonded to the urease enzyme through the hydrophobic interactions and hydrogen bonds with the main active site amino acid residues. One of the interesting strategies for the design and optimization of drug candidates is the integration of computational and experimental approaches.…”

“…Interacting of compounds with the two Ni 2 + ions in the urease active site plays a main role in the enzyme inhibitory activity. [27,33] This compound formed a hydrogen bond between the amine of Arg338 residue and the oxygen atom of ester moiety (R1), a hydrogen bond between the amine of His221 and the oxygen atom of carbonyl in ester (R1) and a hydrogen bond between the oxygen atom of carbonyl of Met366 and NH of triazole ring of compound 9c. All of these interactions limited the flexibility of the flap region to reduce the enzymatic activity.…”

“…[26,17,19,20,8] Furthermore, recently, our research group has reported 1,2,3,4-THPM derivatives A and metronidazole-1,2,3-triazole derivatives B with high inhibitory activity against urease (Figure 2). [27,28] Therefore, in our continuous effort to introduce new urease inhibitors, we attached benzyl 1,2,3-triazole moiety to 1,2,3,4-THPM derivatives to design 1,2,3-triazole-1,2,3,4-THPM hybrids 9a -g as a new urease inhibitor (Figure 2). Given this, we synthesized these hybrids with varying substituted and evaluated them for urease inhibitory activity in vitro.…”