Title

Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials

Authors

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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