Vol.:(0123456789) 1 3 Transition Metal Chemistry https://doi.org/10.1007/s11243-018-0277-6 Metal complex derivatives of bis(pyrazol‑1‑yl)methane ligands: synthesis, characterization and anti‑Trypanosoma cruzi activity Daniela Fonseca 1  · Carolina Páez 1  · Laura Ibarra 1  · Paola García‑Huertas 2  · Mario A. Macías 2  · Omar Triana‑Chávez 2  · John J. Hurtado 1 Received: 24 August 2018 / Accepted: 27 September 2018 © Springer Nature Switzerland AG 2018 Abstract In this work, the synthesis and characterization of seven complexes (1–7) was performed with Zn(II), Cu(II), Co(II) and Ni(II) transition metals and ligands derived from bis(3,5-dimethylpyrazol-1-yl)methane (bdmpzm) and bis(3,5-dimethyl- 4-nitro-1H-pyrazolyl)methane (L). The complexes were obtained in high yields, isolated as air-stable solids and character- ized by physicochemical and spectroscopic methods. The structures of L and complex 1 were determined by single-crystal X-ray difraction analysis. The complexes and their respective ligands were evaluated against epimastigotes of Trypanosoma cruzi strains. An increase in the activity of the complexes was observed compared to the free ligands. Greater activities were found for Co(II) complexes than for Cu(II), Ni(II) and Zn(II) complexes. Additionally, complexes 3 and 9 had little efect on erythrocytes, indicating that they are non-toxic. The results obtained in mitochondrial membrane potential analyses suggest a possible mechanism by which complex 3 has a trypanocidal efect through the induction of oxidative stress. The results could provide an interesting contribution to the further design of active complexes against T. cruzi. Introduction Chagas disease is caused by the parasite Trypanosoma cruzi and afects approximately 18 million people in Latin Amer- ica [1]. Nifurtimox (N-(3-methyl-1,1-dioxo-1,4-thiazinan- 4-yl)-1-(5-nitro)-2-furyl)methanimine) and benznidazole (N-benzyl-2-(2-nitroimidazol-1-yl)acetamide) are the only two available drugs for the treatment of Chagas, but both exhibit strong side efects. These drugs do not counteract the disease in its diverse stages, nor is treatment 100% satisfac- tory, because they generate diferent side efects and some strains of the parasite are resistant. Consequently, new azole derivatives have been designed to treat this disease [2, 3]. Various studies have focused on azole compounds, as these molecules have shown antimicrobial activity. In this context, new organic compounds and complexes containing transition metals have been synthesized and have shown trypanocidal activity, such as Pt(II), Pd(II), Ru(II), Mn(II), Ni(II), Co(II) and Cu(II) [4]. In general, the complexes have a higher anti-T. cruzi activity than the corresponding free ligands. Thus, metal complexes may have dual mechanisms of action by combining the biological properties of both “ligand and metal,” giving rise to synergistic or additive efects [5–8]. Azoles as ligands are an attractive area of research because of their multidonor ability and antiparasitic properties. They are low cost; require no special handling techniques, such as high-vacuum condi- tions or an all-glass apparatus; and can form a variety of stable complexes with various metals by varying the geometry of coordination and nuclearity. Recently, we reported the synthe- sis and characterization of a Cr(III) complex of the bdmpzm ligand, which showed high activity against T cruzi. The anti-T. cruzi activity was related to improved solubility and intermo- lecular associations with DNA [9]. Pyrazoles have a stable, planar structure due to their excess π character, which allows them to easily react as nucleophiles in aromatic electrophilic substitution reactions and enables the insertion of substitu- ents that can change the electron density of the ring [5]. The synthesis of complexes containing ligands with potential Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11243-018-0277-6) contains supplementary material, which is available to authorized users. * John J. Hurtado jj.hurtado@uniandes.edu.co 1 Departamento de Química, Universidad de los Andes, Carrera 1 No. 18A-12, Bogotá 111711, Colombia 2 Grupo Biología y Control de Enfermedades Infecciosas, Universidad de Antioquia, Medellín, Colombia