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: [email protected].
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.