Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes

Angew Chem Int Ed Engl. 2017 Oct 9;56(42):13011-13015. doi: 10.1002/anie.201707324. Epub 2017 Sep 7.


Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Keywords: CYP2C9; DprE1; anti-tubercular drugs; drug development; drug-drug interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / metabolism*
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP2C9 / chemistry
  • Cytochrome P-450 CYP2C9 / metabolism*
  • Drug Resistance, Bacterial / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Dynamics Simulation
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / metabolism*
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use
  • Tuberculosis / drug therapy
  • Tuberculosis / veterinary


  • Antitubercular Agents
  • Bacterial Proteins
  • Thiophenes
  • Cytochrome P-450 CYP2C9