Publication
Title
Synthesis and bioactivity of -substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase
Author
Abstract
Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia or Mycobacteria growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the longer compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against E. coli and M. smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.
Language
English
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Publication
Washington, D.C. : 2015
ISSN
0022-2623
Volume/pages
58:7(2015), p. 2988-3001
ISI
000353091300006
Full text (Publisher's DOI)
Full text (open access)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 29.04.2015
Last edited 16.07.2017
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