Phosphonodiamidate prodrugs of N-alkoxy analogs of a fosmidomycin surrogate as antimalarial and antitubercular agents. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: Courtens, Charlotte; Risseeuw, Martijn; Caljon, Guy; Cos, Paul; Martin, Anandi; Van Calenbergh, Serge
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 9(2019)
• Page Start: 1051
• Page End: 1053
• Publication Date: 2019-05-01
• Subjects: AA amino acid -- ACT artemisinin-based combination therapy -- DCM dichloromethane -- DMAPP dimethylallyl pyrophosphate -- DXP 1-deoxy-d-xylulose 5-phosphate -- DXR 1-deoxyxylulose 5-phosphate reductoisomerase -- EDC N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide -- Et3N 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 -- Mtb Mycobacterium tuberculosis -- 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; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.03.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of N -alkoxy analogs of al -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.