| Autor: |
Kuhler, T. C., Swanson, M., Christenson, B., Klintenberg, A.-C., Lamm, B., Fagerhag, J., Gatti, R., Olwegard-Halvarsson, M., Shcherbuchin, V., Elebring, T., Sjostrom, J.-E. |
| Zdroj: |
Journal of Medicinal Chemistry; September 2002, Vol. 45 Issue: 19 p4282-4299, 18p |
| Abstrakt: |
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 μg/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 μg/mL) or metronidazole (2−4 μg/mL) but differ from these inasmuch that they have an extremely narrow spectrum activity and appear to be species specific. |
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