Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units
| Autor: | Choi, Peter J., Sutherland, Hamish S., Tong, Amy S.T., Blaser, Adrian, Franzblau, Scott G., Cooper, Christopher B., Lotlikar, Manisha U., Upton, Anna M., Guillemont, Jerome, Motte, Magali, Queguiner, Laurence, Andries, Koen, Van den Broeck, Walter, Denny, William A., Palmer, Brian D. |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
ERG1 Potassium Channel
Bedaquiline Antitubercular Agents Administration Oral Drug development Microbial Sensitivity Tests Mycobacterium tuberculosis Article Rats Inhibitory Concentration 50 Structure-Activity Relationship Bedaquiline analogues Heterocyclic Compounds Microsomes Liver Tuberculosis Animals Humans Diarylquinolines ComputingMethodologies_COMPUTERGRAPHICS Half-Life |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters |
| ISSN: | 1464-3405 0960-894X |
| Popis: | Graphical abstract Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability. |
| Databáze: | OpenAIRE |
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