1. Academic Validation
  2. Inhibitory activity of catecholic phosphonic and phosphinic acids against Helicobacter pylori ureolysis

Inhibitory activity of catecholic phosphonic and phosphinic acids against Helicobacter pylori ureolysis

  • Eur J Med Chem. 2023 Sep 5;257:115528. doi: 10.1016/j.ejmech.2023.115528.
Marta Maślanka 1 Wojciech Tabor 1 Paweł Krzyżek 2 Agnieszka Grabowiecka 1 Łukasz Berlicki 1 Artur Mucha 3
Affiliations

Affiliations

  • 1 Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland.
  • 2 Department of Microbiology, Faculty of Medicine, Wrocław Medical University, Wybrzeże L. Pasteura 1, 50-367, Wrocław, Poland.
  • 3 Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland. Electronic address: artur.mucha@pwr.edu.pl.
Abstract

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 (Ki = 2.36 μM, Sporosarcinia pasteurii urease), which was reflected in the antiureolytic effect in live Helicobacter pylori cells at a submicromolar concentration (IC50 = 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.

Keywords

Antivirulence; Covalent binding; Enzyme inhibitors; Organophosphorus compounds; Substituted catechols.

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