New heterobimetallic ferrocenyl derivatives: Evaluation of their potential as prospective agents against trypanosomatid parasites and Mycobacterium tuberculosis

• Published in: Journal of inorganic biochemistry Vol. 187; pp. 73 - 84
• Main Authors: Rivas, Feriannys, Medeiros, Andrea, Rodríguez Arce, Esteban, Comini, Marcelo, Ribeiro, Camila M., Pavan, Fernando R., Gambino, Dinorah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2018
• Subjects: Ferrocenyl compounds; Leishmaniasis; Mycobacterium tuberculosis; Tropolone derivatives; Trypanosoma brucei; Ferrocenyl compounds; Leishmaniasis; Mycobacterium tuberculosis; Trypanosoma brucei; Tropolone derivatives
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2018.07.013

Searching for prospective agents against infectious diseases, four new ferrocenyl derivatives, [M(L)(dppf)4](PF6), with M = Pd(II) or Pt(II), dppf = 1,1′-bis(dipheny1phosphino) ferrocene and HL = tropolone (HTrop) or hinokitiol (HHino), were synthesized and characterized. Complexes and ligands were evaluated against the bloodstream form of T. brucei, L. infantum amastigotes, M. tuberculosis (MTB) sensitive strain and MTB clinical isolates. Complexes showed a significant increase of the anti-T. brucei activity with respect to the free ligands (>28- and >46-fold for Trop and 6- and 22-fold for Hino coordinated to Pt-dppf and Pd-dppf, respectively), yielding IC50 values < 5 μM. The complexes proved to be more potent than the antitrypanosomal drug Nifurtimox. The new ferrocenyl derivatives were more selective towards the parasite than the free ligands. The Pt compounds were less toxic on J774 murine macrophages (mammalian cell model), than the Pd ones, showing selectivity index values (SI = IC50 murine macrophage/IC50T. brucei) up to 23. Generation of the {M-dppf} compounds lead to a slightly positive impact on the anti-leishmanial potency. Although the ferrocenyl derivatives were more active on sensitive MTB than the free ligands (MIC90 = 9.88–14.73 μM), they showed low selectivity towards the pathogen. Related to the mechanism of action, the antiparasitic effect cannot be ascribed to an interference of the compounds with the thiol-redox homeostasis of the pathogen. Fluorescence measurements pointed at DNA as a probable target of the new compounds. [Pt(Trop)(dppf)](PF6) and [Pt(Hino)(dppf)](PF6) could be considered prospective anti-T. brucei agents that deserve further research.
Ferrocenyl compounds with tropolone co-ligands showed improved activities on Trypanosoma brucei and selectivities towards the pathogen in respect to the ligands. Compounds were active on Leishmania infantum and Mycobacterium tuberculosis but poorly selective. Interference with the thiol-redox homeostasis of T. brucei was not detected but DNA could be a target. [Display omitted]
•Heterobimetallic ferrocenyl compounds with tropolones are synthesized and characterized.•Compounds showed good activities on bloodstream Trypanosoma brucei.•Activity against T. brucei and selectivity improved in respect to the ligands.•Compounds were active on M. tuberculosis and L. infantum but low selective.•Compounds do not interfere with T. brucei thiol-redox homeostasis; DNA could be a target.