2. Academic Validation
  3. Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents

Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114924. doi: 10.1016/j.ejmech.2022.114924.
Charlotte Courtens 1,  Frits van Charante 2,  Thibaut Quennesson 1,  Martijn Risseeuw 1,  Paul Cos 3,  Guy Caljon 3,  Tom Coenye 2,  Serge Van Calenbergh 4
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
  • 2 Laboratory of Pharmaceutical Microbiology, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
  • 3 Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610, Wilrijk, Belgium.
  • 4 Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium. Electronic address: Serge.VanCalenbergh@UGent.be.
PMID: 36399924 DOI: 10.1016/j.ejmech.2022.114924
Abstract

Fosmidomycin is a natural Antibiotic with potent IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This Enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in most bacteria, including A. baumanii and M. tuberculosis, and apicomplexan parasites, including Plasmodium parasites. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against A. baumannii and M. tuberculosis as a result of its inability to penetrate the Bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report on the expansion of the acyloxymethyl and alkoxycarbonyloxymethyl phosphonate ester prodrug series of a fosmidomycin surrogate. Prodrug promoieties were designed based on electronic, lipophilic and siderophoric properties. This investigation led to the discovery of derivatives with two-digit nanomolar and submicromolar IC50-values against P. falciparum and A. baumanii, respectively.

Keywords

ESKAPE; Fosmidomycin; Isoprenoid biosynthesis; Malaria; Prodrugs; Tuberculosis.

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