Novel structure's derived from 2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazole as anti-Helicobacter pylori agents, part 2

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 (MIC90 = 0.25 mug/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 (MIC90 = > 64 mug/mL) and 18 anaerobic bacterial strains (MIC90 = > 64 mug/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.