Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites

    Authors

    M. P. Glenn; S. Y. Chang; C. Horney; K. Rivas; K. Yokoyama; E. E. Pusateri; S. Fletcher; C. G. Cummings; F. S. Buckner; P. R. Pendyala; D. Chakrabarti; S. M. Sebti; M. Gelb; W. C. Van Voorhis;A. D. Hamilton

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    PROTEIN FARNESYLTRANSFERASE; ANTIMALARIAL-DRUGS; FALCIPARUM; DISCOVERY; FARNESYL; CELLS; Chemistry, Medicinal

    Abstract

    Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    49

    Issue/Number

    19

    Publication Date

    1-1-2006

    Document Type

    Article

    Language

    English

    First Page

    5710

    Last Page

    5727

    WOS Identifier

    WOS:000240495600008

    ISSN

    0022-2623

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