Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

Eur J Med Chem. 2018 Jul 15:155:754-763. doi: 10.1016/j.ejmech.2018.06.033. Epub 2018 Jun 18.

Abstract

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.

Keywords: Antimycobacterial drugs; Drug design; Iron; Siderophores; Tuberculosis; Virtual screening.

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Lyases / antagonists & inhibitors*
  • Lyases / metabolism
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Structure-Activity Relationship

Substances

  • Antitubercular Agents
  • Enzyme Inhibitors
  • Lyases
  • salicylate synthetase