Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties

Bioorg Med Chem. 2019 Mar 1;27(5):813-821. doi: 10.1016/j.bmc.2019.01.022. Epub 2019 Jan 23.

Abstract

We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MIC < 0.25 μM). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 μM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Keywords: Imidazo[1,2-a]pyridine-3-carboxamides; Pharmacokinetics; Structure-activity relationship; Tuberculosis; hERG K(+) channel inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / toxicity
  • Chlorocebus aethiops
  • Drug Design
  • Female
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology*
  • Imidazoles / toxicity
  • Mice, Inbred ICR
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Pyridines / toxicity
  • Structure-Activity Relationship
  • Vero Cells

Substances

  • Antitubercular Agents
  • Imidazoles
  • Pyridines