Title

Potent, plasmodium-selective farnesyltransferase inhibitors that arrest the growth of malaria parasites: Structure-activity relationships of ethylenediamine-analogue scaffolds and homology model validation

Authors

Authors

S. Fletcher; C. G. Cummings; K. Rivas; W. P. Katt; C. Horney; F. S. Buckner; D. Chakrabarti; S. M. Sebti; M. H. Gelb; W. C. Van Voorhis;A. D. Hamilton

Comments

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Abbreviated Journal Title

J. Med. Chem.

Keywords

FALCIPARUM PROTEIN FARNESYLTRANSFERASE; ANTIMALARIAL ACTIVITY; CRYSTAL-STRUCTURE; IN-VITRO; RESISTANCE; FARNESYL; DRUGS; VIVO; Chemistry, Medicinal

Abstract

New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC(50) values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED(50) values down to 55 nM. The structure-activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.

Journal Title

Journal of Medicinal Chemistry

Volume

51

Issue/Number

17

Publication Date

1-1-2008

Document Type

Article

Language

English

First Page

5176

Last Page

5197

WOS Identifier

WOS:000258979600003

ISSN

0022-2623

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