2. Academic Validation
  3. Modular Design of Mitochondrion-Targeted Iron Chelators Allows Highly Selective Antiparasitic Activity against Trypanosomes and Apicomplexan Parasites

Modular Design of Mitochondrion-Targeted Iron Chelators Allows Highly Selective Antiparasitic Activity against Trypanosomes and Apicomplexan Parasites

  • ACS Infect Dis. 2026 Jan 9;12(1):119-127. doi: 10.1021/acsinfecdis.5c00548.
Ronald Malych 1,  Yann Bordat 2,  Kristýna Klanicová 3,  Dominik Arbon 1,  Farnaz Zahedifard 1,  Anna Šipková 1,  Eliška Drncová 1,  Viktoriya Levytska 4,  Jan Mach 1,  Laura Plutowski-Wrobel 5,  Marta Machado 5 6,  Jan Štursa 7,  Jaroslav Truksa 8,  Markus Ganter 5,  Daniel Sojka 4,  Martin Zoltner 1,  Sébastien Besteiro 2,  Lukáš Werner 7,  Robert Sutak 1
Affiliations

Affiliations

  • 1 Department of Parasitology, Faculty of Science, Charles University, BIOCEV, Vestec 25250, Czech Republic.
  • 2 LPHI, University of Montpellier, CNRS, INSERM, Montpellier 34095, France.
  • 3 Department of Organic Chemistry, Faculty of Science, Charles University, Prague 25250, Czech Republic.
  • 4 Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, BC CAS, Branišovská 1160/31, České Budějovice 37005, Czech Republic.
  • 5 Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg 69120, Germany.
  • 6 Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal.
  • 7 Laboratory of Clinical Pathophysiology, Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 140 21, Czech Republic.
  • 8 Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec 25250, Czech Republic.
PMID: 41428959 DOI: 10.1021/acsinfecdis.5c00548
Abstract

Parasitic protozoa exhibit a high demand for iron, with mitochondrial iron metabolism representing a vulnerable target for chemotherapeutic intervention. We recently demonstrated that mitochondrial targeting of the iron chelator deferoxamine (DFO) via triphenylphosphonium (TPP) conjugation enhances its antiparasitic efficacy. To expand upon this strategy, mitochondrially targeted derivatives of DFO and deferasirox (DFX) were synthesized and evaluated for their activity against important human parasites. The DFX derivative mitoDFX was effective against Trypanosoma spp. and Toxoplasma gondii with remarkable selectivity. The fact that mitoDFX is a promising Anticancer agent, which is likely safe to use in the context of human health, highlights the potential for drug repurposing in parasitology. Structure-activity relationship (SAR) studies and iron distribution analyses in trypanosomes revealed that mitochondrial targeting of the compounds, rather than iron chelation per se, is the main driver of the antiparasitic effects, underscoring the critical role of phosphonium salts in bioactivity.

Keywords

Toxoplasma; Trypanosoma; antiparasitic agents; drug repurposing; iron chelators; mitochondrion.

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