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

Cheng, Gang and Muench, Stephen P and Zhou, Ying and Afanador, Gustavo A and Mui, Ernest J and Fomovska, Alina and Lai, Bo Shiun and Prigge, Sean T and Woods, Stuart and Roberts, Craig W and Hickman, Mark R and Lee, Patty J and Leed, Susan E and Auschwitz, Jennifer M and Rice, David W and McLeod, Rima (2013) Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase. Bioorganic and Medicinal Chemistry Letters, 23 (7). pp. 2035-2043. ISSN 0960-894X

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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.

ORCID iDs

Cheng, Gang, Muench, Stephen P, Zhou, Ying, Afanador, Gustavo A, Mui, Ernest J, Fomovska, Alina, Lai, Bo Shiun, Prigge, Sean T, Woods, Stuart ORCID logoORCID: https://orcid.org/0000-0002-3798-2074, Roberts, Craig W ORCID logoORCID: https://orcid.org/0000-0002-0653-835X, Hickman, Mark R, Lee, Patty J, Leed, Susan E, Auschwitz, Jennifer M, Rice, David W and McLeod, Rima;
  • Item type:Article
    ID code:43583
    Dates:
    Date
    Event
    1 April 2013
    Published
    Notes:Copyright © 2013 Elsevier Ltd. All rights reserved.
    Keywords:triclosan, toxoplasma, ADMET, Pharmacy and materia medica, Biochemistry, Organic Chemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Molecular Biology, Clinical Biochemistry
    Subjects:Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:25 Apr 2013 10:35
    Last modified:11 Jun 2021 03:22
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/43583
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