Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

Bioorg Med Chem Lett. 2013 Apr 1;23(7):2035-43. doi: 10.1016/j.bmcl.2013.02.019. Epub 2013 Feb 13.

Abstract

Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Toxoplasma / enzymology*
  • Triclosan / chemical synthesis
  • Triclosan / chemistry
  • Triclosan / pharmacology*

Substances

  • Triclosan
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)