First triclosan-based macrocyclic inhibitors of InhA enzyme

Bioorg Chem. 2020 Jan:95:103498. doi: 10.1016/j.bioorg.2019.103498. Epub 2019 Dec 6.

Abstract

Two macrocyclic derivatives based on the triclosan frame were designed and synthesized as inhibitors of Mycobacterium tuberculosis InhA enzyme. One of the two molecules M02 displayed promising inhibitory activity against InhA enzyme with an IC50 of 4.7 μM. Molecular docking studies of these two compounds were performed and confirmed that M02 was more efficient as inhibitor of InhA activity. These molecules are the first macrocyclic direct inhibitors of InhA enzyme able to bind into the substrate pocket. Furthermore, these biaryl ether compounds exhibited antitubercular activities comparable to that of triclosan against M. tuberculosis H37Rv strain.

Keywords: Enoyl-ACP-reductase; InhA; Macrocycle; Marchantin analogue; Mycobacterium tuberculosis; Triclosan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Structure-Activity Relationship
  • Triclosan / chemical synthesis
  • Triclosan / chemistry
  • Triclosan / pharmacology*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Macrocyclic Compounds
  • Triclosan
  • Oxidoreductases
  • InhA protein, Mycobacterium