Lanthanide complexes containing 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one and their therapeutic potential to fightleishmaniasis and Chagas disease☆

Ana B. Caballero a,⁎, Antonio Rodríguez-Diéguez a, Juan M. Salas a, Manuel Sánchez-Moreno b, Clotilde Marín b,Inmaculada Ramírez-Macías b, Noelia Santamaría-Díaz a, Ramón Gutiérrez-Sánchez c

a Departamento de Química Inorgánica, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spainb Departamento de Parasitología, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spainc Departamento de Estadística, Universidad de Granada, Severo Ochoa s/n, 18071 Granada, Spain

a b s t r a c ta r t i c l e i n f o

Article history:Received 15 January 2014Received in revised form 25 April 2014Accepted 28 April 2014Available online 6 May 2014

Keywords:TriazolopyrimidineAntiparasiticLeishmaniaTrypanosoma

In the last years, numerous and significant 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 rangeof coordination compounds with interesting structural, physical and also biological properties. Consequently,lanthanide complexes have found applications mainly in catalysis, gas adsorption, photochemistry and asdiagnostic tools. However, research on their therapeutic potential and the understanding of their mechanismof action is still taking its first steps, and there is a distinct lack of research in the parasitology field. In the presentwork, we describe the synthesis and physical properties of seven new lanthanide complexes with theanionic 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, resultson the in vitro antiproliferative activity against Leishmania spp. and Trypanosoma cruzi are described. The highactivity of the new compounds against parasite proliferation and their low cytotoxicity against reference hostcell lines show a great potential of this type of compounds to become a new generation of highly effective andnon-toxic antiparasitic agents to fight the so considered neglected diseases leishmaniasis and Chagas disease.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

In the last decades, triazolopyrimidine derivatives have beenthe subject of chemical and biological studies due to their interestingpharmacology including antipyretic, analgesic, antiinflammatory, herbi-cidal, fungicidal, antitumoral and leishmanicidal properties [1]. In addi-tion, since triazolopyrimidines are structurally analogs to purinicnucleobases, several families and more especially 1,2,4-triazolo[1,5-a]pyrimidines have been used as model systems to mimic the interactionbetween purines and severalmetal ions [2,3]. Studies on the interactionof 1,2,4-triazolo[1,5-a]pyrimidines with metal ions have also displayeda great capability of these derivatives to act as versatile building unitsfor the synthesis of metal-organic multidimensional systems withpromising magnetic, luminescent, and biological properties [4–7].Furthermore, previous studies have shown that their antitumoral and

antiparasitic activities are often significantly enhanced by the presenceof a metal ion [8,9].

Lanthanide ions are likewise subjects of increasing interest inbioinorganic chemistry and medicine. A number of coordination com-pounds and nanoconjugates have been studied so far as luminescentprobes in biological systems with views in diagnostic applications[10]. Lanthanide(III) ions have also shown biological properties, primar-ily based on their capability to replace Ca(II), Zn(II) and other biological-ly relevantmetal ions [10]. These properties have led research into theirtherapeutic applications, such as hyperphosphatemia and cancer treat-ment [11–14]. However, to the best of our knowledge, no studies havebeen reported on their antiparasitic potential.

In the last years, our group has made great effort in developingnew triazolopyrimidine-based metal complexes which show in vitroand in vivo leishmanicidal and trypanocidal activity [8,9,15–17].Given the lack of research with lanthanides in this field, we have de-cided to synthesize a series of lanthanide complexes which contain atriazolopyrimidine derivative with the aim to explore their potentialas antiparasitic agents. In this case two Leishmania species – theEuropean strand Leishmania infantum and the South-americanstrand Leishmania braziliensis – and Trypanosoma cruzi have been

Journal of Inorganic Biochemistry 138 (2014) 39–46

☆ Electronic Supplementary Information (ESI) available: CCDC reference numbers980804–980807.⁎ Corresponding author at: Departamento de Química Inorgánica, 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.2014.04.0160162-0134/© 2014 Elsevier Inc. All rights reserved.

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