1. Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents
- Author
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Charlotte Courtens, Frits van Charante, Thibaut Quennesson, Martijn Risseeuw, Paul Cos, Guy Caljon, Tom Coenye, and Serge Van Calenbergh
- Subjects
Pharmacology ,Pharmacology. Therapy ,Organic Chemistry ,Organophosphonates ,General Medicine ,Mycobacterium tuberculosis ,Anti-Bacterial Agents ,Chemistry ,Antimalarials ,Drug Discovery ,Humans ,Folic Acid Antagonists ,Tuberculosis ,Prodrugs ,Malaria, Falciparum - 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.
- Published
- 2022