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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 (US)
Pages (from-to)	2035-2043
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2013.02.019
State	Published - Apr 1 2013

Keywords

ADMET
TgENR
Toxoplasma
Triclosan

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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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

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

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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'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 = "ADMET, TgENR, Toxoplasma, Triclosan",

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",

note = "Funding Information: The authors are grateful for the financial support provided by NIAID grant U01 AI082180-0101 and the Wellcome Trust and the support of the Mann and Cornwell, Rooney-Alden, Taub, Engel and Mussilami families. SPM is funded by an MRC Career Development Fellowship ( G1000567 ). The authors also thank Alan Kozikowski for his contributions. They also thank K. Wroblewski for her assistance with statistical analyses of the in vivo data. The opinions of the authors from Walter Reed Army Institute of Research are their own and do not reflect the official views of the Department of Defense. ",

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

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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

N1 - Funding Information: The authors are grateful for the financial support provided by NIAID grant U01 AI082180-0101 and the Wellcome Trust and the support of the Mann and Cornwell, Rooney-Alden, Taub, Engel and Mussilami families. SPM is funded by an MRC Career Development Fellowship ( G1000567 ). The authors also thank Alan Kozikowski for his contributions. They also thank K. Wroblewski for her assistance with statistical analyses of the in vivo data. The opinions of the authors from Walter Reed Army Institute of Research are their own and do not reflect the official views of the Department of Defense.

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 - ADMET

KW - TgENR

KW - Toxoplasma

KW - Triclosan

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

Abstract

Keywords

ASJC Scopus subject areas

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