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Synthesis and antimalarial activity of amide and ester conjugates of siderophores and ozonides

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Abstract

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.

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Acknowledgements

This research was supported in part by Grant 2R01AI054193 and R37AI054193 from the National Institutes of Health (NIH) and Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana. We thank the University of Notre Dame, especially the Mass Spectrometry and Proteomics Facility (Bill Boggess, Michelle Joyce, and Nonka Sevova), which is supported by Grant CHE-0741793 from the National Science Foundation (NSF) and Viktor Krchnak for generous use of the preparative HPLC system used for the purification of the synthesized conjugates. This paper is dedicated to Prof. Gunther Winkelman in honor of his 80th birthday. We thank you for your extensive contributions to the journal as well as to the Biometals Society and the related interdisciplinary scientific community.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA

    Rohit Tiwari & Marvin J. Miller

  2. Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, 46556, USA

    Lisa Checkley & Michael T. Ferdig

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Jonathan L. Vennerstrom

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  1. Rohit Tiwari
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  2. Lisa Checkley
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Correspondence to Marvin J. Miller.

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Tiwari, R., Checkley, L., Ferdig, M.T. et al. Synthesis and antimalarial activity of amide and ester conjugates of siderophores and ozonides. Biometals 36, 315–320 (2023). https://doi.org/10.1007/s10534-022-00375-8

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