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;