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New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents

Abstract

In the search for a more effective chemotherapy for the treatment of Chagas disease and Human African trypanosomiasis, caused by Trypanosoma cruzi and Trypanosoma brucei parasites, respectively, the use of organometallic compounds may be a promising strategy. In this work, eight new heterobimetallic compounds are described including four 5-nitrofuryl containing thiosemicarbazones as bioactive ligands (HL1-HL4) and dppf = 1,1'-bis(diphenylphosphino) ferrocene as organometallic co-ligand. Complexes of the formula [MII(L)(dppf)](PF6) with M = Pd or Pt were synthesized and fully characterized in the solid state and in solution, including the determination of the molecular structure of four of them by single crystal X-ray diffraction methods. Most compounds showed activity in the low micromolar or submicromolar range against both parasites, with the platinum compounds being more active than the palladium analogues. Activity was significantly increased by generation of the M-dppf compounds (3-24 fold increase in respect to free ligands HL for T. cruzi and up to 99 fold increase in respect to HL for T. brucei). The inclusion of the organometallic co-ligand also led to lower toxicity on mammalian cells and higher selectivity towards both parasites when compared to the free HL compounds. The complexes interact with DNA and affect the redox metabolism of the parasites. Furthermore, the most active and selective compound of the new series, showed no in vivo toxicity on zebrafish embryos.

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Publication details

The article was received on 27 Mar 2019, accepted on 13 Apr 2019 and first published on 15 Apr 2019


Article type: Paper
DOI: 10.1039/C9DT01317B
Citation: Dalton Trans., 2019, Accepted Manuscript

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    New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents

    E. Rodriguez Arce, E. Putzu, M. Lapier, J. D. Maya, C. Olea-Azar, G. Etcheverria, O. E. Piro, A. Medeiros, F. Sardi, M. Comini, G. Risi, G. Salinas, I. Correia, J. Pessoa, L. Otero and D. Gambino, Dalton Trans., 2019, Accepted Manuscript , DOI: 10.1039/C9DT01317B

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