Chemistry

Potassium channel

Bicyclic molecule

Drug

Biochemistry

Lead compound

Organic chemistry

hERG

Tuberculosis

Biology

Biophysics

Naphthalene

Lipophilicity

Bedaquiline

Pathology

Combinatorial chemistry

Mycobacterium tuberculosis

Stereochemistry

Pharmacology

In vitro

Medicine

Bioorganic & Medicinal Chemistry

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.

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