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

doi:10.1016/j.bmcl.2013.02.019

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 journal › Article › peer-review

21 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 language	English
Pages (from-to)	2035-2043
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	7
Early online date	12 Feb 2013
DOIs	https://doi.org/10.1016/j.bmcl.2013.02.019
Publication status	Published - 1 Apr 2013
Externally published	Yes

Keywords

TgENR
triclosan
ADMET
Toxoplasma

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10.1016/j.bmcl.2013.02.019

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Cheng, G., Muench, S. P., Zhou, Y., Afanador, G. A., Mui, E. J., Fomovska, A., Lai, B. S., Prigge, S. T., Woods, S., Roberts, C. W., Hickman, M. R., Lee, P. J., Leed, S. E., Auschwitz, J. M., Rice, D. W., & McLeod, R. (2013). Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase. Bioorganic and Medicinal Chemistry Letters, 23(7), 2035-2043. https://doi.org/10.1016/j.bmcl.2013.02.019

@article{ab18cb2d15fc472eb96773426644d06c,

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

abstract = "Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan{\textquoteright}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.",

keywords = "TgENR, triclosan, ADMET, Toxoplasma",

author = "Gang Cheng and Muench, \{Stephen P.\} and Ying Zhou and Afanador, \{Gustavo A.\} and Mui, \{Ernest J.\} and Alina Fomovska and Lai, \{Bo Shiun\} and Prigge, \{Sean T.\} and Stuart Woods 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 Rima McLeod",

year = "2013",

month = apr,

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doi = "10.1016/j.bmcl.2013.02.019",

language = "English",

volume = "23",

pages = "2035--2043",

journal = "Bioorganic and Medicinal Chemistry Letters",

number = "7",

}

Cheng, G, Muench, SP, Zhou, Y, Afanador, GA, Mui, EJ, Fomovska, A, Lai, BS, Prigge, ST, Woods, S, Roberts, CW, Hickman, MR, Lee, PJ, Leed, SE, Auschwitz, JM, Rice, DW & McLeod, R 2013, 'Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 7, pp. 2035-2043. https://doi.org/10.1016/j.bmcl.2013.02.019

TY - JOUR

T1 - Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

AU - Cheng, Gang

AU - Muench, Stephen P.

AU - Zhou, Ying

AU - Afanador, Gustavo A.

AU - Mui, Ernest J.

AU - Fomovska, Alina

AU - Lai, Bo Shiun

AU - Prigge, Sean T.

AU - Woods, Stuart

AU - Roberts, Craig W.

AU - Hickman, Mark R.

AU - Lee, Patty J.

AU - Leed, Susan E.

AU - Auschwitz, Jennifer M.

AU - Rice, David W.

AU - McLeod, Rima

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

KW - TgENR

KW - triclosan

KW - ADMET

KW - Toxoplasma

UR - https://www.scopus.com/pages/publications/84875231794

U2 - 10.1016/j.bmcl.2013.02.019

DO - 10.1016/j.bmcl.2013.02.019

M3 - Article

VL - 23

SP - 2035

EP - 2043

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 7

ER -

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

Abstract

Keywords

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