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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]

PMID: 23453069

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