title: Structure-activity relationship of 2-[[(2-pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy.
abstract: A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 microg/mL. The structure-activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]-3-methyl-2-pyridyl)methyl]thio]-1H-be nzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felismodel (125 micromol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.
authors.affiliation: Department of Medicinal Chemistry, Astra Hässle AB, 431 83 Mölndal, Sweden. thomas.kuhler@arcb.us.astra.com
authors.forename: T C
authors.initials: TC
authors.lastname: Kühler
authors.forename: M
authors.initials: M
authors.lastname: Swanson
authors.forename: V
authors.initials: V
authors.lastname: Shcherbuchin
authors.forename: H
authors.initials: H
authors.lastname: Larsson
authors.forename: B
authors.initials: B
authors.lastname: Mellgârd
authors.forename: J E
authors.initials: JE
authors.lastname: Sjöström
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D016481:Helicobacter Infections / Q000188:drug therapy / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines