Synthetic Fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-d-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum growth in vitro.

René Chofor,Cynthia S Dowd,Martijn D P Risseeuw,Jenny Pouyez,Johan Wouters,Serge Van Calenbergh,Chinchu Johny,Robin D Couch

doi:10.3390/molecules19022571

Abstract

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.

Highlights

Up to 5 million clinical cases and a million fatalities result from malaria, an infectious disease caused by protozoa of the Plasmodium species, with P. falciparum being responsible for the most severe cases [1]
This paper aims to more systematically investigate the possibilities of replacing the retrohydroxamate group of fosmidomycin with effective alternative bidentate ligands
The synthesis of the amide derivatives 8a–i, m–q is outlined in Scheme 1

Summary

Introduction

Up to 5 million clinical cases and a million fatalities result from malaria, an infectious disease caused by protozoa of the Plasmodium species, with P. falciparum being responsible for the most severe cases [1]. Unlike Plasmodia which are endemic in the tropics, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis afflicts one-third of the world’s population annually, leading to about 2–3 million deaths [3]. The discovery that fosmidomycin (1, Figure 1) and its acetyl congener FR900098 (2), both natural products extracted from Streptomyces species inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), opened interesting opportunities for therapeutics [4,5]. Dxr is the second enzyme in the non-mevalonate pathway (NMP) for isoprenoid biosynthesis, which is absent in humans, but present in most Gram-negative and some Gram-positive bacteria (including Mtb), as well as in apicomplexan parasites (including Plasmodia) [6,7]. Fosmidomycin inhibits the Dxr-catalyzed conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2C-methyl-D-erythritol-4-phosphate (MEP), by mimicking the binding mode of DOXP to this enzyme [8,9]. SAR studies have indicated the importance of fosmidomycin’s hydroxamate moiety for chelation of a divalent metal cation (M: Mn2+ or Mg2+) present in the enzyme’s active site

Objectives

Methods

Results

Conclusion