Novel indole-based sulfonate and sulfamate derivatives as potent and selective urease inhibitors targeting Helicobacter pylori: a promising therapeutic strategy

Helicobacter pylori (H. pylori) infection is strongly associated with peptic ulcer and gastric cancer, compounded by the growing prevalence of antibiotic resistance. Current antibiotic eradication therapies often lead to gut dysbiosis and treatment failure, highlighting the urgent need for targeted, alternative therapies. In this study, a novel series of indole-based heterocycles bearing sulfonate or sulfamate functionalities was designed, synthesized, and evaluated as potential urease inhibitors. Several derivatives exhibited potent urease inhibition using a cell-free urease assay, with compound 1n emerging as the most active inhibitor (IC₅₀ = 0.23 ± 0.33 µM), approximately 100-fold more potent than thiourea (IC₅₀ = 23.2 ± 11.0 µM). Antibacterial screening confirmed significant activity against H. pylori, particularly for compounds 1k (MIC < 1.5 µM) and 1 h (MIC = 2.31 ± 1.15 µM), both of which also demonstrated direct and significant inhibition of H. pylori urease in vitro. These compounds displayed remarkable selectivity, showing no inhibitory effect on E. coli and six Lactobacillus strains, suggesting a beneficial role in maintaining gut microflora unlike conventional antibiotic therapy. Furthermore, cytotoxicity assays on human gastric epithelial (AGS) and dermal fibroblast (F180) cells confirmed minimal toxicity, while Caco-2 permeability studies indicated low systemic absorption, suggesting localized gastrointestinal activity. Molecular docking revealed strong interactions of 1 h and 1k within the H. pylori urease active site. In silico ADMET analysis predicted low CNS toxicity, moderate CYP450 inhibition, and absence of PAINS alerts. Overall, these findings identify promising lead molecules for the development of potent, selective, and safer urease inhibitors against H. pylori.