In the wake of the escalating development of resistance to currently available drugs, blocking the vital MEP pathway for isoprenoid biosynthesis in pathogens such as Plasmodia or Mycobacteria offers interesting prospects for inhibiting their growth. Although the natural product retro-hydroxamate fosmidomycin and its homologue FR900098 potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the MEP pathway, their in vivo activity is compromised due to poor absorption and a suboptimal pharmacokinetic profile. In an effort to facilitate cellular uptake, we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of FR900098. 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, as well as activity against P. falciparum. X-ray structures of the parasite Dxr-inhibitor complexes show that analogues with a three- or four-carbon linker lead to the displacement of a key tryptophan residue, and the aromatic group of the ligand lies between the tryptophan and the methyl group on the hydroxamate. The most promising new Dxr inhibitors are highly potent inhibitors of Plasmodium falciparum in vitro growth.

β-Substituted fosmidomycin analogs targeting 1-deoxy-d-xylulose-5-phosphate reductoisomerase: Synthesis, structural biology, and antimalarial properties

250th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.