A structural insight of bedaquiline for the cardiotoxicity and hepatotoxicity

Tuberculosis (Edinb). 2019 Jul:117:79-84. doi: 10.1016/j.tube.2019.06.005. Epub 2019 Jun 24.

Abstract

Bedaquiline was approved by USFDA in 2012 for pulmonary MDR-TB. The IC50 value of bedaquiline was reported to be remarkably low (25 nM), effectively inhibiting mycobacterial ATP synthase. In addition to these obvious assets of bedaquiline, the potential disadvantages of bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2) potassium channel (concurrent risk of cardiac toxicity), hepatic toxicity and possibly phospholipidosis. The current review focuses primarily on the structural part of bedaquiline for the activity-toxicity optimization. This critical analysis of the structure of bedaquiline will help medicinal chemists to synthesize the better modified analouge of bedaquiline with reduced cardiotoxicity, hepatotoxicity potential and improved pharmacokinetics.

Keywords: Bedaquiline; Cardiotoxicity; Hepatotoxicity.

Publication types

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

MeSH terms

  • Antitubercular Agents / adverse effects*
  • Antitubercular Agents / chemistry
  • Cardiotoxicity / etiology*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Diarylquinolines / adverse effects*
  • Diarylquinolines / chemistry
  • Drug Development / methods
  • Humans
  • Structure-Activity Relationship
  • Tuberculosis, Multidrug-Resistant / drug therapy

Substances

  • Antitubercular Agents
  • Diarylquinolines
  • bedaquiline