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

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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
DOIs	https://doi.org/10.1016/j.bmcl.2013.02.019
Publication status	Published - 1 Apr 2013

Keywords

triclosan
toxoplasma
ADMET

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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

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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.",

keywords = "triclosan, toxoplasma, ADMET",

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",

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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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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.

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KW - toxoplasma

KW - ADMET

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M3 - Article

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SN - 0960-894X

VL - 23

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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

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