Synthetic fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase or Plasmodium falciparum growth in vitro

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging

Synthesis and evaluation of β-substituted fosmidomycin analogues as inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Although fosmidomycin is a remarkably safe antimalarial agent, low oral absorption, short serum half-life and malaria recrudescence preclude its use in monotherapy. The development of more lipophilic Dxr inhibitors able to passively permeate into cells with improved pharmacokinetic properties could lead to more efficacious agents. Previously, we discovered that analogue 4, featuring a 3,4-dichlorophenyl substituent in α-position of the phosphonate, surpasses fosmidomycin’s potency in inhibiting P. falciparum growth. Here we explored the introduction of aryl or aralkyl substituents at the β-position of the known hydroxamate analogue 3. We studied the effect of introducing substituents in β-position of the hydroxamate analogue 3. While direct addition of a β-aryl moiety resulted in poor P. falciparum Dxr inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzyme. 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. Several analogues emerged as highly potent inhibitors of Plasmodium falciparum in vitro growth. In some cases (e.g. for compounds 7b and 7f) good Dxr inhibitory activity failed to translate in good in vitro activity against the parasite, which may be due to inefficient uptake. Compounds 5a-e likewise failed to inhibit EcDxr and MtbDxr while 6c was optimal for inhibition of these enzymes