Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with β-Arylpropyl Analogues of Fosmidomycin

• Published in: ChemMedChem 2016-09, Vol.11 (18), p.2024-2036
• Main Authors: Sooriyaarachchi, Sanjeewani, Chofor, René, Risseeuw, Martijn D. P., Bergfors, Terese, Pouyez, Jenny, Dowd, Cynthia S., Maes, Louis, Wouters, Johan, Jones, T. Alwyn, Van Calenbergh, Serge, Mowbray, Sherry L.
• Format: Article
• Language: English
• Subjects: Aldose-Ketose Isomerases - antagonists & inhibitors; Aldose-Ketose Isomerases - metabolism; antibiotics; antiprotozoal agents; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fosfomycin - analogs & derivatives; Fosfomycin - chemical synthesis; Fosfomycin - chemistry; Fosfomycin - pharmacology; Models, Molecular; Molecular Structure; oxidoreductases; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; structural biology; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201600249

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. Meta is better: X‐ray structures show that arylpropyl substituents on β‐phenylpropyl hydroxamate analogues of fosmidomycin displace a key tryptophan residue of the active site flap of Dxr, which then becomes largely disordered. For both meta‐ and para‐substituted compounds, smaller substituents are associated with better potency; meta‐substituted compounds such as 6 f are usually better inhibitors, similar to the unsubstituted lead compound 5 d.