Synthesis, structure–activity relationship analysis and kinetics study of reductive derivatives of flavonoids as Helicobacter pylori urease inhibitors

In a continuing study for discovering urease inhibitors based on flavonoids, nineteen reductive derivatives of flavonoids were synthesized and evaluated against Helicobacter pylori urease. Analysis of structure–activity relationship disclosed that 4-deoxy analogues are more potent than other reductive products. Out of them, 4′,7,8-trihydroxyl-2-isoflavene (13) was found to be the most active with IC50 of 0.85 μM, being over 20-fold more potent than the commercial available urease inhibitor, acetohydroxamic acid (AHA). Kinetics study revealed that 13 is a competitive inhibitor of H. pylori urease with a Ki value of 0.641 μM, which is well matched with the results of molecular docking. Biological evaluation and mechanism study of 13 suggest that it is a good candidate for discovering novel anti-gastritis and anti-gastric ulcer agent.

4′,7,8-Trihydroxyl-2-isoflavene (13), derived from 4′,7,8-trihydroxylisoflavone is a potent Helicobacter pylori urease inhibitor with IC50 of 0.85 μM, and it is a pure competitive inhibitor with a Ki value of 0.641 μM.Figure optionsDownload as PowerPoint slideHighlights
► Efficient methods were developed to access to 3-flavene and 2-isoflavene.
► 4-Deoxyflavonoids were determined as H. pylori urease inhibitors.
►  The most active inhibitor showed IC50 over 20-fold lower than that of acetohydroxamic acid.
► Docking model and kinetic studies revealed a competitive inhibition mechanism.