title: Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. 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 hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.
authors.affiliation: †Laboratory for Medicinal Chemistry (FFW), Universiteit Gent, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Chofor
authors.affiliation: ‡Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Sanjeewani
authors.initials: S
authors.lastname: Sooriyaarachchi
authors.affiliation: †Laboratory for Medicinal Chemistry (FFW), Universiteit Gent, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
authors.forename: Martijn D P
authors.initials: MD
authors.lastname: Risseeuw
authors.affiliation: ‡Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Terese
authors.initials: T
authors.lastname: Bergfors
authors.affiliation: §Department of Chemistry, University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium.
authors.forename: Jenny
authors.initials: J
authors.lastname: Pouyez
authors.affiliation: ∥Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States.
authors.forename: Chinchu
authors.initials: C
authors.lastname: Johny
authors.affiliation: ∥Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Haymond
authors.affiliation: ⊥Laboratory of Pharmaceutical Microbiology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Annelien
authors.initials: A
authors.lastname: Everaert
authors.affiliation: #Department of Chemistry, George Washington University, Washington, D.C. 20052, United States.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
authors.affiliation: ¶Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: ⊥Laboratory of Pharmaceutical Microbiology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Coenye
authors.affiliation: ∇Evenor Consulting Ltd., The New Barn, Mill Lane, Eastry, Kent CT13 0JW, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Alex
authors.affiliation: ∥Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Couch
authors.affiliation: ‡Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: T Alwyn
authors.initials: TA
authors.lastname: Jones
authors.affiliation: §Department of Chemistry, University of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.affiliation: ‡Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.affiliation: †Laboratory for Medicinal Chemistry (FFW), Universiteit Gent, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases