Synthesis and bioactivity of $\beta$-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia or Mycobacteria 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 hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against E. coli and M. smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

Jaar van publicatie:2015

Trefwoorden:A1 Journal article

BOF-keylabel:ja

BOF-publication weight:6

CSS-citation score:2

Auteurs:International

Authors from:Higher Education

Toegankelijkheid:Open