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.

Creators(s): 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
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:20 Jan 2021 20:40
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URI:https://strathprints.strath.ac.uk/id/eprint/43583
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