In vivo potent BM635 analogue with improved drug-like properties

Eur J Med Chem. 2018 Feb 10:145:539-550. doi: 10.1016/j.ejmech.2017.12.075. Epub 2017 Dec 27.

Abstract

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.

Keywords: Anti-mycobacterials; Drug discovery; MmpL3; Pyrroles; Tuberculosis.

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Hep G2 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy*

Substances

  • Antitubercular Agents
  • BM635 compound
  • Pyrroles