Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection

J Med Chem. 2016 Jul 14;59(13):6232-47. doi: 10.1021/acs.jmedchem.6b00415. Epub 2016 Jun 22.

Abstract

Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity at both an in vitro and in vivo level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides, we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work, we now further elaborate on the SAR of these compounds, which has led in turn to the identification of a new analog, 4,6-difluoro-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-indole-2-carboxamide (26), that shows excellent activity against drug-sensitive (MIC = 0.012 μM; SI ≥ 16000), multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, has superior ADMET properties, and shows excellent activity in the TB aerosol lung infection model. Compound 26 is also shown to work in synergy with rifampin. Because of these properties, we believe that indolecarboxamide 26 is a possible candidate for advancement to human clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Disease Models, Animal
  • Drug Design
  • Female
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Membrane Transport Proteins / metabolism
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / metabolism
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology
  • Tuberculosis, Multidrug-Resistant / drug therapy
  • Tuberculosis, Multidrug-Resistant / metabolism

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Indoles
  • Membrane Transport Proteins
  • MmpL3 protein, Mycobacterium tuberculosis