title: Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin.
abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, 751 24, Uppsala, Sweden.
authors.forename: Sanjeewani
authors.initials: S
authors.lastname: Sooriyaarachchi
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Gent University, Ottergemsesteenweg 460, 9000, Gent, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Chofor
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Gent University, Ottergemsesteenweg 460, 9000, Gent, Belgium.
authors.forename: Martijn D P
authors.initials: MD
authors.lastname: Risseeuw
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, 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, 5000, Namur, Belgium.
authors.forename: Jenny
authors.initials: J
authors.lastname: Pouyez
authors.affiliation: Department of Chemistry, George Washington University, Washington, DC, 20052, USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
authors.forename: Louis
authors.identifier: 0000-0002-2324-9509
authors.initials: L
authors.lastname: Maes
authors.affiliation: Department of Chemistry, University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, 751 24, Uppsala, Sweden.
authors.forename: T Alwyn
authors.initials: TA
authors.lastname: Jones
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Gent University, Ottergemsesteenweg 460, 9000, Gent, Belgium. serge.vancalenbergh@ugent.be.
authors.forename: Serge
authors.identifier: 0000-0002-4201-1264
authors.initials: S
authors.lastname: Van Calenbergh
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, 751 24, Uppsala, Sweden. sherry.mowbray@icm.uu.se.
authors.forename: Sherry L
authors.identifier: 0000-0002-0732-6367
authors.initials: SL
authors.lastname: Mowbray
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005578:Fosfomycin; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases
keywords: antibiotics; antiprotozoal agents; oxidoreductases; structural biology; structure-activity relationships