New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold

Eur J Med Chem. 2016 Apr 13:112:252-257. doi: 10.1016/j.ejmech.2016.02.008. Epub 2016 Feb 8.

Abstract

Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.

Keywords: InhA; Inhibitors; Synthesis; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium tuberculosis / chemistry
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / metabolism
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Oxidoreductases / metabolism
  • Pyrans / chemistry*
  • Pyrans / pharmacology*
  • Structure-Activity Relationship
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Pyrans
  • Oxidoreductases
  • InhA protein, Mycobacterium