Novel structures derived from 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazole as anti-Helicobacter pylori agents, Part 1.
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.
Kühler
Thomas C
TC
Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden. thomas.kuhler@mpa.se
Swanson
Marianne
M
Christenson
Beritte
B
Klintenberg
Ann-Charlotte
AC
Lamm
Bo
B
Fägerhag
Jonas
J
Gatti
Roberto
R
Olwegård-Halvarsson
Maria
M
Shcherbuchin
Vladimir
V
Elebring
Thomas
T
Sjöström
Jan-Erik
JE
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
D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; C011591:2-((2-(4-pyridyl)methyl)thio)benzimidazole