Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland.
Department of Microbiology, Faculty of Medicine, Wrocław Medical University, Wybrzeże L. Pasteura 1, 50-367, Wrocław, Poland.
Eur J Med Chem. 2023 Sep 5;257:115528. doi: 10.1016/j.ejmech.2023.115528. Epub 2023 Jun 1.
Catechols have been reported to be potent covalent inhibitors of ureases, and they exhibit activity by modifying cysteine residues at the entrance to enzymatic active sites. Following these principles, we designed and synthesized novel catecholic derivatives that contained carboxylate and phosphonic/phosphinic functionalities and assumed expanded specific interactions. When studying the chemical stability of the molecules, we found that their intrinsic acidity catalyzes spontaneous esterification/hydrolysis reactions in methanol or water solutions, respectively. Regarding biological activity, the most promising compound, 2-(3,4-dihydroxyphenyl)-3-phosphonopropionic acid (15), exhibited significant anti-urease potential (K = 2.36 μM, Sporosarcinia pasteurii urease), which was reflected in the antiureolytic effect in live Helicobacter pylori cells at a submicromolar concentration (IC = 0.75 μM). As illustrated by molecular modeling, this compound was bound in the active site of urease through a set of concerted electrostatic and hydrogen bond interactions. The antiureolytic activity of catecholic phosphonic acids could be specific because these compounds were chemically inert and not cytotoxic to eukaryotic cells.
儿茶酚已被报道为强效的脲酶共价抑制剂，它们通过修饰酶活性位点入口处的半胱氨酸残基发挥作用。基于这些原理，我们设计并合成了含有羧酸根和膦酸/次膦酸官能团的新型儿茶酚衍生物，并假设它们具有扩展的特定相互作用。在研究这些分子的化学稳定性时，我们发现它们的内在酸度分别在甲醇或水溶液中催化自发的酯化/水解反应。关于生物活性，最有前途的化合物 2-(3,4-二羟基苯基)-3-膦酸丙酸（15）表现出显著的抗脲酶潜力（K=2.36 μM，巴斯德氏梭菌脲酶），这在亚微摩尔浓度下在活幽门螺杆菌细胞中表现出抗酶解作用（IC=0.75 μM）。正如分子建模所示，该化合物通过一组协同的静电和氢键相互作用结合在脲酶的活性位点中。儿茶酚膦酸的抗酶解活性可能是特异性的，因为这些化合物在化学上是惰性的，对真核细胞没有细胞毒性。
