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2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazoles (2, sulfides) exhibit antibacterial properties that are selective for Helicobacter spp., but they also have an inherent susceptibility to metabolic oxidation to furnish 2-[[(2-pyridyl)methyl]sulfinyl]-1H-benzimidazoles (1), which act as proton pump inhibitors (PPIs). We have discovered five compounds with retained antibacterial potency and selectivity in which the overall framework of the sulfides 2 could be kept intact while structural modifications were made to remove PPI activity. These compounds, 2-[((2-methyl-3-(2-(2-(2-methoxyethoxy)ethoxy)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (79), 2-[((2-methyl-3-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (80), 2-[((2-methyl-3-((2-morpholino)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (86), 2-[[[2-methyl-3-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]phenyl]methyl]thio]-1H-benzimidazole (88), and 2-[[[2-methyl-3-[2-(1,2,4-triazol-1-yl)ethylthio]phenyl]methyl]thio]-1H-benzimidazole (89), had minimum bactericidal concentrations (MBCs) of 0.5, 0.5, 1, 2, and 4 microg/mL, respectively. The reported compounds are bactericidal with MBCs within 1 order of magnitude of MBCs of clinically used antimicrobials such as clarithromycin (0.1 microg/mL) or metronidazole (2-4 microg/mL) but differ from these inasmuch that they have an extremely narrow spectrum activity and appear to be species specific.

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A parallel chemistry expansion of the 2-([3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-phenyl]sulfanyl)-1-ethanol scaffold (2) successfully provided a set of 2-([3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl]sulfanyl)ethyl carbamates with the generic structure 12, which displayed potent and selective activities against the gastric pathogen Helicobacter pylori. A prototype carbamate 12a was studied further and found to meet several significant in vitro microbiological criteria required for a novel anti-H. pylori agent. The compound displayed low minimal inhibition concentration (MIC) values against a panel of 27 different clinically relevant H. pylori strains (MIC(90) = 0.25 microg/mL), including strains resistant to either metronidazole or clarithromycin or both. Additionally, 12a was almost inactive against a wide range of commensal or pathogenic microorganisms comprising panels of 25 aerobic bacterial strains including two strains of methicillin resistant Staphylococcus aureus (MIC(90) = >64 microg/mL) and 18 anaerobic bacterial strains (MIC(90) = >64 microg/mL). The measured rate of resistance development against 12a was found to be less than 10(-9), a clinically acceptable level, and pharmacokinetic studies revealed in vivo exposure levels comparable with those established for antimicrobials currently used in H. pylori triple regimen.