SBIC ECR Symposium & Poster Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Anti-trypanosomatid activity of [M(L)(PPh3)] (M = Pd, Pt) complexes with L = coumarin-thiosemicarbazone derivatives: inclusion of a nitro group (#526)

Santiago Rostán Talasimov 1 , Esteban Rocha 2 3 , Francisca Fernández 2 3 , Gonzalo Scalese 1 4 , Mauricio Moncada-Basualto 3 , Marcelo Comini 4 , Claudio Olea-Azar 2 , Graciela Mahler 5 , Lucía Otero 1
  1. Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay
  2. Departamento de Química Analítica e Inorgánica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago de Chile, Chile
  3. Laboratorio de Química Biológica, Instituto Universitario de Investigación y Desarrollo tecnológico, UTEM, Santiago de Chile, Chile
  4. Laboratorio de Biología Redox de Tripanosomas, Institut Pasteur de Montevideo, Montevideo, Uruguay
  5. Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Unversidad de la República, Montevideo, Uruguay

In the search of new anti-trypanosomatid drugs, our group has been working on the design of coumarin-thiosemicarbazone hybrids. Different structural variations in the hybrid structure could improve their activity. Additionally, the coordination of potentially anti-trypanosomatid coumarin-thiosemicarbazone hybrids to metals (e.g. Pd(II) or Pt(II)) could also improve the anti-trypanosomal activity of the free ligands and also lower their nonspecific toxicity. Based on the above, we previously reported a family of compounds with the formula [M(L1-L4)(PPh3)] that showed low activity vs. Trypanosoma cruzi, the etiological agent of Chagas´ disease [1].
In this work, we report the synthesis and characterization of a new family of coumarin-thiosemicarbazones including a NO2 group in the coumarin moiety (H2L5-H2L8). This group was selected because it is present in the pharmacophore of Nifurtimox, a clinically approved drug for Chagas´s disease and human African trypanosomiasis. In addition, we present the preparation of two new families of complexes with the formula [M(L5-L8)(PPh3)], M = Pd, Pt. The nitro-containing ligands and their metal complexes showed an improved anti-T. cruzi activity. Furthermore, we tested both families of ligands H2L1-H2L4 and H2L1-H2L4 as well as [M(L1-L4)(PPh3)] complexes on T. brucei brucei parasite (African trypanosoma). Interestingly, the activities and selectivities were significantly higher than those vs. T. cruzi (e.g. sub-micromolar IC50 and SI up to 230, calculated as SI = IC50 macrophages / IC50 T. brucei). Further studies are in progress to determine the activity of [M(L5-L8)(PPh3)] vs. T. b. b. and to explain the differences between the observed activities in such closely related parasites.

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Figure 1. Left: prepared coumarin-thiosemicarbazone hybrids. Right: generic structure of the obtained complexes.

  1. [1] Rostán, S., Pozo-Martínez, J., Arcos, M. A., Moncada-Basualto, M., Aguilera, E., Alvarez, N., ... & Otero, L. (2024). Pt (II) and Pd (II) complexes with coumarin-thiosemicarbazone hybrid ligands and triphenylphosphine coligand as potential anti T. cruzi agents. Journal of Molecular Structure, 1313, 138711.