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.
Gang Cheng  1 ,  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
Affiliations
  • 1. Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
PMID: 23453069 DOI: 10.1016/j.bmcl.2013.02.019
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.

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