Synthesis and biological evaluation of new citrate-based siderophores as potential probes for the mechanism of iron uptake in mycobacteria

    Authors

    H. Y. Guo; S. A. Naser; G. Ghobrial;O. Phanstiel

    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    PARATUBERCULOSIS; TUBERCULOSIS; ANALOGS; SMEGMATIS; DISEASE; AGENTS; AVIUM; Chemistry, Medicinal

    Abstract

    Several iron chelators containing alpha,beta-unsaturated hydroxamic acid motifs appended to a citric acid platform were synthesized. Mycobacterium paratuberculosis was then challenged to grow in the presence of a panel of siderophores (mycobactin J, deferrioxamine B, acinetoferrin, and nannochelin A) and the new synthetic agents. Of the structures tested, those containing the trans 2-octenoyl motif were preferred over those with trans cinnamoyl groups. In addition, derivatives containing longer tether lengths between the iron binding ligands (C5) were more efficacious and led to higher growth index values. Perhaps most remarkable was the finding that at 2.4 muM a trans 2-octenoylated, citrate-containing imide 6 was nearly 5-fold more effective in stimulating growth than the native chelator, mycobactin J. In this regard, new structural elements were identified (e.g., an imide motif or 2-octenoyl side chain), whose presence stimulated mycobacterial growth.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    45

    Issue/Number

    10

    Publication Date

    1-1-2002

    Document Type

    Article

    Language

    English

    First Page

    2056

    Last Page

    2063

    WOS Identifier

    WOS:000175488900012

    ISSN

    0022-2623

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