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

Bioorg Med Chem. 2018 May 1;26(8):1797-1809. doi: 10.1016/j.bmc.2018.02.026. Epub 2018 Feb 20.


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.

Keywords: Bedaquiline; Bedaquiline analogs; Drug development; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line, Tumor
  • Diarylquinolines / chemistry
  • Diarylquinolines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Diarylquinolines
  • Naphthalenes
  • naphthalene
  • bedaquiline