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.

doi:10.1021/JM970165R

Paper

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.

Published Apr 29, 1998 · Thomas Kühler, Marianne Swanson, Vladimir Shcherbuchin

Journal of medicinal chemistry

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77

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1

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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.

In Vitro Study

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Study Snapshot

The antibacterial utility of 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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.

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References

Citations

Design and Synthesis of 1-(2-amino-1-(4-methoxyphenyl)ethyl) cyclohexanol Analogs as Potential Microbial Agents

The synthesized compounds exhibit good to moderate antibacterial activity against various microorganisms, but show no antifungal activity against tested fungal species.

Studies on Methylpyrazole-Substituted Benzimidazoles to Target Helicobacter pylori Infection through HpIMPDH Inhibition.

Methylpyrazole-substituted benzimidazoles show promising potential as inexpensive and bioavailable drugs to effectively treat Helicobacter pylori infection compared to current therapies.

Ultrasound Assisted MK-10 Catalyzed New Benzimidazole Bejeweled Quinoline Molecular Hybrids: Facile Synthesis, SAR, Molecular Modelling and Biological Evaluation as Free Radical Scavengers and Antiinflammatory Agents

Ultrasound-assisted MK-10 catalyzed benzimidazole bejeweled quinolines show promising antioxidant and anti-inflammatory properties, with compound 3j showing the highest antioxidant efficacy.

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