In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability

    Authors

    D. Carrico; J. Ohkanda; H. Kendrick; K. Yokoyama; M. A. Blaskovich; C. J. Bucher; F. S. Buckner; W. C. Van Voorhis; D. Chakrabarti; S. L. Croft; M. H. Gelb; S. M. Sebti;A. D. Hamilton

    Comments

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    Abbreviated Journal Title

    Bioorg. Med. Chem.

    Keywords

    Plasmodium falciparum; peptidomimetic; protein farnesyltransferase; ester prodrug; PLASMODIUM-FALCIPARUM; TRYPANOSOMA-BRUCEI; MALARIA; FARNESYLATION; TRANSFERASE; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, ; Organic

    Abstract

    A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. faliparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED50 = 150nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1 %, at a dose of 50 mg kg(-1)day(-1) against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety. (C) 2004 Elsevier Ltd. All rights reserved.

    Journal Title

    Bioorganic & Medicinal Chemistry

    Volume

    12

    Issue/Number

    24

    Publication Date

    1-1-2004

    Document Type

    Article

    Language

    English

    First Page

    6517

    Last Page

    6526

    WOS Identifier

    WOS:000225523200017

    ISSN

    0968-0896

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