Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline.

ABSTRACT: The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC₉₀) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of

SUBMITTER: Blaser A 

PROVIDER: S-EPMC6467542 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature