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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 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
Early online date12 Feb 2013
DOIs
Publication statusPublished - 1 Apr 2013
Externally publishedYes

Keywords

  • TgENR
  • triclosan
  • ADMET
  • Toxoplasma

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