Inhibition of urease results in Helicobacter pylori growth arrest in the stomach, promoting urease as promising targets for gastrointestinal ulcer therapy. Twenty hybrid derivatives of flavonoid scaffold and hydroxamic acid, β-hydroxy-β-phenylpropionylhydroxamic acids, were therefore synthesized and evaluated against H.ápylori urease. Biological evaluation of these compounds showed improved urease inhibition exhibiting micromolar to mid-nanomolar IC₅₀ values. Most importantly, 3-(3-chlorophenyl)-3-hydroxypropionyl-hydroxamic acid (6g) exhibited high potency with IC₅₀ of 0.083á▒á0.004áμM and K_i of 0.014á▒á0.003áμM, indicating that 6g is an excellent candidate to develop novel antiulcer agent. A mixture of competitive and uncompetitive mechanism was putatively proposed to understand the inconsistency between the crystallographic and kinetic studies for the first time, which is supported by our molecular docking studies.