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 journalArticle

15 Citations (Scopus)

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
Pages (from-to)2035-2043
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number7
DOIs
Publication statusPublished - 1 Apr 2013

Keywords

  • triclosan
  • toxoplasma
  • ADMET

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