Title
Synthesis and bioactivity of <tex>$\beta$</tex>-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase Synthesis and bioactivity of <tex>$\beta$</tex>-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Biology
Pharmacology. Therapy
Human medicine
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
58(2015) :7 , p. 2988-3001
ISSN
0022-2623
ISI
000353091300006
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/6068c5/285ea3ee.pdf
E-info
https://repository.uantwerpen.be/docman/iruaauth/c055a9/d109877.pdf
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