Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials

    Authors

    P. Bendale; S. Olepu; P. K. Suryadevara; V. Bulbule; K. Rivas; L. Nallan; B. Smart; K. Yokoyama; S. Ankala; P. R. Pendyala; D. Floyd; L. J. Lombardo; D. K. Williams; F. S. Buckner; D. Chakrabarti; Clmj Verlinde; W. C. Van Voorhis;M. H. Gelb

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    PLASMODIUM-FALCIPARUM; PRENYLATION; BMS-214662; RESISTANCE; BINDING; DESIGN; Chemistry, Medicinal

    Abstract

    Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the lownanomolar ran-e. This body of structure- activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    50

    Issue/Number

    19

    Publication Date

    1-1-2007

    Document Type

    Article

    Language

    English

    First Page

    4585

    Last Page

    4605

    WOS Identifier

    WOS:000249501500004

    ISSN

    0022-2623

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