Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents

Bioorg Med Chem Lett. 2012 Jan 15;22(2):954-7. doi: 10.1016/j.bmcl.2011.12.022. Epub 2011 Dec 9.

Abstract

A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H(37)Rv by a microdilution method, with MIC values ranging from 4 to 64μg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R(2) group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.

Publication types

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

MeSH terms

  • Amines / chemistry
  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Hep G2 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium Infections / drug therapy*
  • Mycobacterium tuberculosis / drug effects*
  • Phenyl Ethers / chemical synthesis
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amines
  • Antitubercular Agents
  • Phenyl Ethers
  • phenyl ether