Premium
Targeting an Aromatic Hotspot in Plasmodium falciparum 1‐Deoxy‐ d ‐xylulose‐5‐phosphate Reductoisomerase with β‐Arylpropyl Analogues of Fosmidomycin
Author(s) -
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.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600249
Subject(s) - stereochemistry , lipophilicity , substituent , enzyme , steric effects , plasmodium falciparum , chemistry , biosynthesis , residue (chemistry) , potency , biochemistry , biology , in vitro , malaria , immunology
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.