Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 8, Issue 10, Pages 1019-1024Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00196
Keywords
Bedaquiline; diarylquinoline; tuberculosis; ATP synthase; hERG; lipophilicity
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Funding
- Bill and Melinda Gates Foundation
- U.S. Agency for International Development (USAID)
- U.K. Department for International Development (DFID)
- Directorate General for International Cooperation of The Netherlands (DGIS)
- Irish Aid
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Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6 -substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
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