Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles

Publication date: Available online 20 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hamish S. Sutherland, Amy S.T. Tong, Peter J. Choi, Daniel Conole, Adrian Blaser, Scott G. Franzblau, Christopher B. Cooper, Anna M. Upton, Manisha U. Lotlikar, William A. Denny, Brian D. Palmer
Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.

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