Design and synthesis of novel anti-urease imidazothiazole derivatives with promising antibacterial activity against Helicobacter pylori

Urease enzyme is a known therapeutic drug target for treatment of Helicobacter pylori infection due to its role in settlement and growth in gastric mucosa. In this study, we designed a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold that exhibit a potent inhibitory activity of urease enzyme. The most potent compound 2c inhibited urease with an IC50 value of 2.94 +/- 0.05 mu M, which is 8-fold more potent than the thiourea positive control (IC50 = 22.3 +/- 0.031 mu M). Enzyme kinetics study showed that compound 2c is a competitive inhibitor of urease. Molecular modeling studies of the most potent inhibitors in the urease active site suggested multiple binding interactions with different amino acid residues. Phenotypic screening of the developed compounds against H. pylori delivered molecules of that possess high potency (1a, 1d, 1h, 2d, and 2f) in comparison to the positive control, acetohydroxamic acid. Additional studies to investigate the selectivity of these compounds against AGS gastric cell line and E. coli were performed. Permeability of the most promising derivatives (1a, 1d, 1h, 2d, and 2f) in Caco-2 cell line, was investigated. As a result, compound 1d presented itself as a lead drug candidate since it exhibited a promising inhibition against urease with an IC50 of 3.09 +/- 0.07 mu M, MIC value against H. pylori of 0.031 +/- 0.011 mM, and SI against AGS of 6.05. Interestingly, compound 1d did not show activity against urease-negative E. coli and exhibited a low permeability in Caco-2 cells which supports the potential use of this compound for GIT infection without systemic effect.

Automated summary

In this study, a new series of sulfonates and sulfamates bearing imidazo[2,1-b]thiazole scaffold were designed as potent inhibitors of urease enzyme. Compound 2c exhibited the highest inhibitory activity against urease, with an IC50 value of 2.94 +/- 0.05 mu M. Molecular modeling studies suggested multiple binding interactions between the most potent inhibitors and amino acid residues in the urease active site. Phenotypic screening showed that compounds 1a, 1d, 1h, 2d, and 2f had high potency against H. pylori.