Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents

Eur J Med Chem. 2016 Oct 21:122:723-730. doi: 10.1016/j.ejmech.2016.07.009. Epub 2016 Jul 9.

Abstract

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.

Keywords: BM212; Drug repurposing; MmpL3 inhibitor; Rimonabant; Sila analogue; Tuberculosis.

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / toxicity
  • Drug Repositioning*
  • Hep G2 Cells
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Mycobacterium tuberculosis / drug effects
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Piperidines / toxicity
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Pyrazoles / toxicity
  • Rimonabant
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Piperidines
  • Pyrazoles
  • Rimonabant