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

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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
Fosmidomycin, Prodrugs, Isoprenoid biosynthesis, Malaria, Tuberculosis, ESKAPE, METHYLERYTHRITOL PHOSPHATE-PATHWAY, FR900098, SIDEROPHORE, DERIVATIVES, INHIBITION, ANALOGS, ESTERS

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Citation

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MLA
Courtens, Charlotte, et al. “Acyloxymethyl and Alkoxycarbonyloxymethyl Prodrugs of a Fosmidomycin Surrogate as Antimalarial and Antibacterial Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 245, no. 1, 2023, doi:10.1016/j.ejmech.2022.114924.
APA
Courtens, C., van Charante, F., Quennesson, T., Risseeuw, M., Cos, P., Caljon, G., … Van Calenbergh, S. (2023). Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 245(1). https://doi.org/10.1016/j.ejmech.2022.114924
Chicago author-date
Courtens, Charlotte, Frits van Charante, Thibaut Quennesson, Martijn Risseeuw, Paul Cos, Guy Caljon, Tom Coenye, and Serge Van Calenbergh. 2023. “Acyloxymethyl and Alkoxycarbonyloxymethyl Prodrugs of a Fosmidomycin Surrogate as Antimalarial and Antibacterial Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 245 (1). https://doi.org/10.1016/j.ejmech.2022.114924.
Chicago author-date (all authors)
Courtens, Charlotte, Frits van Charante, Thibaut Quennesson, Martijn Risseeuw, Paul Cos, Guy Caljon, Tom Coenye, and Serge Van Calenbergh. 2023. “Acyloxymethyl and Alkoxycarbonyloxymethyl Prodrugs of a Fosmidomycin Surrogate as Antimalarial and Antibacterial Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 245 (1). doi:10.1016/j.ejmech.2022.114924.
Vancouver
1.
Courtens C, van Charante F, Quennesson T, Risseeuw M, Cos P, Caljon G, et al. Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2023;245(1).
IEEE
[1]
C. Courtens et al., “Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 245, no. 1, 2023.
@article{01HE012S7K6B9YCARV7TP208PY,
  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.}},
  articleno    = {{114924}},
  author       = {{Courtens, Charlotte and van Charante, Frits and Quennesson, Thibaut and Risseeuw, Martijn and Cos, Paul and  Caljon, Guy and Coenye, Tom and Van Calenbergh, Serge}},
  issn         = {{0223-5234}},
  journal      = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Fosmidomycin,Prodrugs,Isoprenoid biosynthesis,Malaria,Tuberculosis,ESKAPE,METHYLERYTHRITOL PHOSPHATE-PATHWAY,FR900098,SIDEROPHORE,DERIVATIVES,INHIBITION,ANALOGS,ESTERS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{14}},
  title        = {{Acyloxymethyl and alkoxycarbonyloxymethyl prodrugs of a fosmidomycin surrogate as antimalarial and antibacterial agents}},
  url          = {{http://doi.org/10.1016/j.ejmech.2022.114924}},
  volume       = {{245}},
  year         = {{2023}},
}

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