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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.

SUBMITTER: Cheng G 

PROVIDER: S-EPMC3625046 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Cheng Gang G   Muench Stephen P SP   Zhou Ying Y   Afanador Gustavo A GA   Mui Ernest J EJ   Fomovska Alina A   Lai Bo Shiun BS   Prigge Sean T ST   Woods Stuart S   Roberts Craig W CW   Hickman Mark R MR   Lee Patty J PJ   Leed Susan E SE   Auschwitz Jennifer M JM   Rice David W DW   McLeod Rima R  

Bioorganic & medicinal chemistry letters 20130213 7


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. M  ...[more]

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