Synthesis and structure-activity studies of side chain analogues of the anti-tubercular agent, Q203

Eur J Med Chem. 2017 Jan 5;125:807-815. doi: 10.1016/j.ejmech.2016.09.082. Epub 2016 Sep 28.

Abstract

The anti-tubercular activity of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo [1,2-a]pyridine-3-carboxamide (Q203) is modified by varying its side chain. In this study, we synthesized Q203 analogues with different side chains and studied their effects on anti-tubercular activity. Many analogues showed good potency against M. tuberculosis replicating in liquid broth culture medium (extracellular activity) regardless of chain length and conformational changes. However, a polar character in the side chain region was unfavorable for anti-tubercular activity. The analogues, 25, 28, 35, and 36, displayed excellent activity against M. tuberculosis replicating inside macrophages (intracellular activity) and promising pharmacokinetic (PK) properties with high drug exposure level and long half-life.

Keywords: Imidazo[1,2-a]pyridine-3-carboxamide (IPA); Pharmacokinetics; Q203; Structure-activity relationship (SAR); Tuberculosis.

MeSH terms

  • Animals
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology
  • Cells, Cultured
  • Half-Life
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Macrophages / microbiology
  • Mycobacterium tuberculosis / drug effects
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Imidazoles
  • Piperidines
  • Pyridines
  • telacebec