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

Gang Cheng, Stephen P. Muench, Ying Zhou, Gustavo A. Afanador, Ernest J. Mui, Alina Fomovska, Bo Shiun Lai, Sean T. Prigge, Stuart Woods, Craig W. Roberts, Mark R. Hickman, Patty J. Lee, Susan E. Leed, Jennifer M. Auschwitz, David W. Rice, Rima McLeod

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2035-2043
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • ADMET
  • TgENR
  • Toxoplasma
  • Triclosan

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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