Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
Introduction
The phosphonic acid derivatives Fosmidomycin 1 and its N-acetyl analogue FR900098 are active inhibitors of the Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme [1] − an established antimalarial target [2]. The therapeutic value of these compounds is, however, limited by their rapid in vivo clearance and the recrudescence associated with their use [3,4] and attention has turned to the development of novel analogues. Brücher et al. [5] have reported the preparation of promising ligands 2 (Fig. 1), which exhibit high inhibitory potency against PfDXR. In addition to a ‘reversed’ arrangement of the hydroxamate moiety, these compounds contain an α-phenyl substituent capable of occupying the hydrophobic pocket adjacent to the PfDXR active-site.
Our own research has focussed on developing ligands which exploit such hydrophobic binding opportunities [[6], [7], [8]] and, more particularly, on phosphoramidic acid derivatives 3 in which the hydrophobic aryl group is attached to nitrogen rather than to a tetrahedral sp3 carbon (as in compound 2), thus obviating chirality issues. Although the phosphonic acid moiety is expected to bind to the PfDXR phosphate binding-site, phosphonate esters have, in fact, been shown to be effective PfDXR inhibitors [5]. The use of ester derivatives as pro-drugs would be expected not only to delay exposure of the phosphoramidic acid moiety to premature decomposition, but also to decrease the overall polarity of the ligands, possibly mitigating the unacceptably rapid clearance exhibited by fosmidomycin itself. Recent reports [9,10] reflect the potential of aryl and dialkyl phosphoramidate pro-drugs as hepatitis C virus inhibitors. In this communication, we now report on our attempts to access the N-aryl compounds 3 and the eventual synthesis of a range of N-benzylated phosphoramidate ester derivatives 4 as “reverse” fosmidomycin analogues.
Section snippets
Results and discussion
In designing the synthesis of the N-aryl phosphoramidic acid analogues (3), compound 5 was identified as a critical intermediate and several approaches to this compound were explored (Scheme 1). In Approach I, ethyl 3-bromopropanoate 7, obtained by acid-catalysed esterification of 3-bromopropanoic acid 6 [[11], [12], [13]] (Scheme 1), was reacted with aniline and NaH in dry THF to furnish compound 8 which contains the desired bimethylene linking group and the functionality needed to generate
General methods
NMR spectra were recorded on Bruker 300, 400 or 600 MHz spectrometers in CDCl3, DMSO‑d6 or CD3OD, and were calibrated using solvent signals. Melting points were measured using a hot-stage apparatus and are uncorrected. High-resolution mass spectra (HRMS) were recorded on a Waters API Q-TOF Ultima spectrometer (University of Stellenbosch, Stellenbosch, South Africa). NMR spectra, bioassay protocols and results and computer modelling methods are provided in the Supporting Information.
Reaction of benzylamine derivatives with diethyl chlorophosphate
A mixture of
Acknowledgements
The authors thank Rhodes University and the South African Medical Research Council (SAMRC) for generous financial support. This research project was funded by the SAMRC with funds from National Treasury under its Economic Competitiveness and Support Package.
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