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Phosphonodiamidate prodrugs of N-alkoxy analogs of a fosmidomycin surrogate as antimalarial and antitubercular agents |
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| Authors: | Charlotte Courtens Martijn Risseeuw Guy Caljon Paul Cos Anandi Martin Serge Van Calenbergh |
| Affiliation: | 1. Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium;2. Laboratory for Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610 Wilrijk, Belgium;3. Medical Microbiology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Avenue Hippocrate 55, B-1200 Woluwe-Saint-Lambert, Belgium |
| Abstract: | A series of N-alkoxy analogs of a l-leucine ethyl ester phosphonodiamidate prodrug of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. These compounds originate by merging a previously reported successful phosphonate derivatisation with favorable modifications of the hydroxamate moiety. None of the synthesized compounds showed enhanced activity against either P. falciparum or M. tuberculosis in comparison with the parent free hydroxamate analog. |
| Keywords: | AA amino acid ACT artemisinin-based combination therapy DCM dichloromethane DMAPP dimethylallyl pyrophosphate DXP DXR 1-deoxyxylulose 5-phosphate reductoisomerase EDC triethylamine GlpT glycerol-3-phosphate transporter HOBt hydroxybenzotriazole HRMS high-resolution mass spectrometry MDR multidrug-resistant MEP methylerythritolphosphate MIC minimal inhibitory concentration MOA mechanism of action MVA mevalonate NADPH nicotinamide adenine dinucleotide phosphate NMP non-mevalonate pathway PK pharmacokinetic POM pivaloyloxymethyl SD standard deviation SI selectivity index TB tuberculosis TDR totally drug-resistant TFA trifluoroacetic acid THF tetrahydrofuran WHO world health organization XDR extensively drug-resistant Fosmidomycin Prodrugs Non-mevalonate pathway Isoprenoid biosynthesis Malaria Tuberculosis |
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