Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Arch Pharm (Weinheim). 2022 Oct;355(10):e2200158. doi: 10.1002/ardp.202200158. Epub 2022 Jul 14.
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.
脲酶是一种含有 Ni 离子的金属酶，在一些细菌、真菌和植物中被发现。特别是，它对由致病性微生物引起的感染的进展至关重要，如奇异变形杆菌和幽门螺杆菌。在此，我们报道了一系列四氢嘧啶衍生物的合成，并评估了它们的抗脲酶活性。最后，通过计算机模拟研究对衍生物进行了定量和定性分析。脲酶抑制活性是通过 H. pylori 脲酶与不同浓度化合物的反应来确定的，硫脲用作标准化合物。对接和动力学方法被应用于研究最佳化合物与活性部位氨基酸的相互作用。所有化合物均表现出良好至优异的抗脲酶活性。在对 HUVEC 正常细胞系的检测中，强活性化合物无细胞毒性。基于对接研究，具有最高脲酶抑制活性（IC = 6.81 ± 1.42 µM）的化合物 4e 与脲酶活性部位的两个 Ni 离子形成螯合物。此外，与硫脲（IC = 22.03 ± 1.24 μM）相比，化合物 4f 表现出非常好的抑制活性（IC = 8.45 ± 1.64 μM）。分子对接和动力学模拟结果与体外测定结果相关。此外，衍生物 4a-n 遵循 Lipinski 的五规则，具有类药性。
