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Journal of Inorganic Biochemistry 138 (2014) 3946

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Journal of Inorganic Biochemistry

journal homepage: www.elsevier.com/locate/jinorgbio

Lanthanide complexes containing 5-methyl-1,2,4-triazolo[1,5-a]

pyrimidin-7(4H)-one and their therapeutic potential to ght
leishmaniasis and Chagas disease
Ana B. Caballero a,, Antonio Rodrguez-Diguez a, Juan M. Salas a, Manuel Snchez-Moreno b, Clotilde Marn b,
Inmaculada Ramrez-Macas b, Noelia Santamara-Daz a, Ramn Gutirrez-Snchez c
a
b
c

Departamento de Qumica Inorgnica, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spain
Departamento de Parasitologa, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spain
Departamento de Estadstica, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spain

a r t i c l e

i n f o

Article history:
Received 15 January 2014
Received in revised form 25 April 2014
Accepted 28 April 2014
Available online 6 May 2014
Keywords:
Triazolopyrimidine
Antiparasitic
Leishmania
Trypanosoma

a b s t r a c t
In the last years, numerous and signicant advances in lanthanide coordination chemistry have been achieved.
The unique chemical nature of these metal ions which is conferred by their f-electrons has led to a wide range
of coordination compounds with interesting structural, physical and also biological properties. Consequently,
lanthanide complexes have found applications mainly in catalysis, gas adsorption, photochemistry and as
diagnostic tools. However, research on their therapeutic potential and the understanding of their mechanism
of action is still taking its rst steps, and there is a distinct lack of research in the parasitology eld. In the present
work, we describe the synthesis and physical properties of seven new lanthanide complexes with the
anionic form of the bioactive ligand 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO), namely
[Ln(mtpO)3(H2O)6]9H2O (Ln = La(III), Nd(III), Eu(III), Gd(III), Tb(III), Dy(III) and Er(III)). In addition, results
on the in vitro antiproliferative activity against Leishmania spp. and Trypanosoma cruzi are described. The high
activity of the new compounds against parasite proliferation and their low cytotoxicity against reference host
cell lines show a great potential of this type of compounds to become a new generation of highly effective and
non-toxic antiparasitic agents to ght the so considered neglected diseases leishmaniasis and Chagas disease.
2014 Elsevier Inc. All rights reserved.

1. Introduction
In the last decades, triazolopyrimidine derivatives have been
the subject of chemical and biological studies due to their interesting
pharmacology including antipyretic, analgesic, antiinammatory, herbicidal, fungicidal, antitumoral and leishmanicidal properties [1]. In addition, since triazolopyrimidines are structurally analogs to purinic
nucleobases, several families and more especially 1,2,4-triazolo[1,5-a]
pyrimidines have been used as model systems to mimic the interaction
between purines and several metal ions [2,3]. Studies on the interaction
of 1,2,4-triazolo[1,5-a]pyrimidines with metal ions have also displayed
a great capability of these derivatives to act as versatile building units
for the synthesis of metal-organic multidimensional systems with
promising magnetic, luminescent, and biological properties [47].
Furthermore, previous studies have shown that their antitumoral and

Electronic Supplementary Information (ESI) available: CCDC reference numbers

980804980807.
Corresponding author at: Departamento de Qumica Inorgnica, Universidad de
Barcelona, 08028 Barcelona, Spain. Tel.: +34 93 402 12 68; fax: +34 93 490 77 25.
E-mail address: ana.caballero@qi.ub.es (A.B. Caballero).

http://dx.doi.org/10.1016/j.jinorgbio.2014.04.016
0162-0134/ 2014 Elsevier Inc. All rights reserved.

antiparasitic activities are often signicantly enhanced by the presence

of a metal ion [8,9].
Lanthanide ions are likewise subjects of increasing interest in
bioinorganic chemistry and medicine. A number of coordination compounds and nanoconjugates have been studied so far as luminescent
probes in biological systems with views in diagnostic applications
[10]. Lanthanide(III) ions have also shown biological properties, primarily based on their capability to replace Ca(II), Zn(II) and other biologically relevant metal ions [10]. These properties have led research into their
therapeutic applications, such as hyperphosphatemia and cancer treatment [1114]. However, to the best of our knowledge, no studies have
been reported on their antiparasitic potential.
In the last years, our group has made great effort in developing
new triazolopyrimidine-based metal complexes which show in vitro
and in vivo leishmanicidal and trypanocidal activity [8,9,1517].
Given the lack of research with lanthanides in this eld, we have decided to synthesize a series of lanthanide complexes which contain a
triazolopyrimidine derivative with the aim to explore their potential
as antiparasitic agents. In this case two Leishmania species the
European strand Leishmania infantum and the South-american
strand Leishmania braziliensis and Trypanosoma cruzi have been

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