Synthesis and Evaluation of Novel Ebselen Derivatives as Urease Inhibitors for Combating Helicobacter pylori Infections

Abstract

The development of novel inhibitors targeting urease that affects the colonization of Helicobacter pylori (H. pylori) is a promising strategy to address the growing challenge of antibiotic resistance. In this study, a novel urease covalent inhibitor, XBP2 (IC₅₀ = 0.14 ± 0.01 μM and MIC = 8 μg/mL), was identified through structure-based design using Ebselen as a template. XBP2 binds to a newly identified site, forming stable dipole interaction with residues ASP223 and HIS322, which enhances both stability and inhibitory activity against urease. It exhibits potent in vitro antibacterial activity, reducing cell apoptosis rates and significantly decreasing the fluorescence intensity of ROS and γH2AX in GES-1 cells infected with H. pylori. In the mouse gastritis model infected with H. pylori, XBP2 exhibits significant gastric mucosal protective effects. High-dose XBP2 (50 mg/kg) effectively prevented pathological changes such as bleeding and hyperplasia. Furthermore, acute toxicity test revealed that XBP2 does not display any detectable toxicity. These findings not only expand the structural diversity of Ebselen derivatives but also provide valuable insights for developing targeted therapies for eradicating H. pylori.