Double prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents. Issue 10 (15th May 2019)

• Record Type: Journal Article
• Authors: Courtens, Charlotte; Risseeuw, Martijn; Caljon, Guy; Maes, Louis; Cos, Paul; Martin, Anandi; Van Calenbergh, Serge
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 10(2019)
• Page Start: 1232
• Page End: 1235
• Publication Date: 2019-05-15
• Subjects: AIDS acquired immunodeficiency syndrome -- DCM dichloromethane -- DMF dimethylformamide -- DXR 1-deoxyxylulose 5-phosphate reductoisomerase -- EDC N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide -- Et3N triethylamine -- HIV human immunodeficiency virus -- 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 -- PK pharmacokinetic -- POM pivaloyloxymethyl -- TB tuberculosis -- TFA trifluoroacetic acid -- THF tetrahydrofuran -- TMSBr trimethylsilyl bromide -- WHO world health organization; Fosmidomycin -- Prodrugs -- Non-mevalonate pathway -- Isoprenoid biosynthesis -- Malaria -- Tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.03.009
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis . A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N -benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC50 value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.