Double prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents

Bioorg Med Chem Lett. 2019 May 15;29(10):1232-1235. doi: 10.1016/j.bmcl.2019.03.009.

Charlotte Courtens ¹, Martijn Risseeuw ¹, Guy Caljon ², Louis Maes ², Paul Cos ², Anandi Martin ³, Serge Van Calenbergh ⁴

Affiliations

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.
4 Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.

PMID: 30879839 DOI: 10.1016/j.bmcl.2019.03.009

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.

Keywords

Fosmidomycin; Isoprenoid biosynthesis; Malaria; Non-mevalonate pathway; Prodrugs; Tuberculosis.

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