Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5190-5196. doi: 10.1016/j.bmcl.2017.10.042. Epub 2017 Oct 20.

Abstract

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.

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

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology
  • Diarylquinolines / chemistry*
  • Diarylquinolines / pharmacokinetics
  • Diarylquinolines / pharmacology
  • ERG1 Potassium Channel / antagonists & inhibitors
  • ERG1 Potassium Channel / metabolism
  • Half-Life
  • Heterocyclic Compounds / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Microsomes, Liver / metabolism
  • Mycobacterium tuberculosis / drug effects
  • Rats
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • ERG1 Potassium Channel
  • Heterocyclic Compounds
  • bedaquiline