title: Novel structures derived from 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazole as anti-Helicobacter pylori agents, Part 1.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden. thomas.kuhler@mpa.se
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Kühler
authors.forename: Marianne
authors.initials: M
authors.lastname: Swanson
authors.forename: Beritte
authors.initials: B
authors.lastname: Christenson
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Klintenberg
authors.forename: Bo
authors.initials: B
authors.lastname: Lamm
authors.forename: Jonas
authors.initials: J
authors.lastname: Fägerhag
authors.forename: Roberto
authors.initials: R
authors.lastname: Gatti
authors.forename: Maria
authors.initials: M
authors.lastname: Olwegård-Halvarsson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shcherbuchin
authors.forename: Thomas
authors.initials: T
authors.lastname: Elebring
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Sjöström
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016480:Helicobacter pylori / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; C011591:2-((2-(4-pyridyl)methyl)thio)benzimidazole