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.