title: Novel structures derived from 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazole as anti-Helicobacter pylori agents, Part 2.
abstract: 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.
authors.affiliation: Department of Chemistry, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carcanague
authors.forename: Youe-Kong
authors.initials: YK
authors.lastname: Shue
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wuonola
authors.forename: Maria
authors.initials: M
authors.lastname: Uria-Nickelsen
authors.forename: Camil
authors.initials: C
authors.lastname: Joubran
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Abedi
authors.forename: Jeanette
authors.initials: J
authors.lastname: Jones
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Kühler
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D005260:Female; D016480:Helicobacter pylori / Q000187:drug effects*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; C011591:2-((2-(4-pyridyl)methyl)thio)benzimidazole