Halogenated N-Benzylbenzisoselenazolones Efficiently Inhibit Helicobacter pylori Ureolysis In Vitro.

Inspired by the recognized activity of Ebselen against urease, we optimized the structure of 1,2-benzisoselenazol-3(2H)-one to provide potent inhibitors of ureolysis in Helicobacter pylori cells. To achieve this goal, we combined the elongation of the N-substituent of Ebselen from phenyl to benzyl with halogenation of the aromatic fragment. The modifications implemented provided compounds with activities that were several times better compared to that of the lead compound. In particular, 3-fluoro-4-trifluoromethyl and 2-chloro-5-fluoro derivatives of N-benzyl-1,2-benzisoselenazol-3(2H)-one achieved a remarkable antiureolytic effect in live H. pylori cells (IC50 < 100 nM) that outperformed the data reported so far. This activity was reflected in the antiurease potential measured for the Sporosarcina pasteurii model enzyme, with the highest affinity observed for 2-chloro-5-fluoro and 2,4-dichloro derivatives (K i < 0.6 nM). The best inhibitor demonstrated considerable antibacterial properties on a multidrug-resistant clinical H. pylori isolate in additive combination with clarithromycin (MIC = 0.073 μg/mL).