In vitro and in vivo antiparasital activity against Trypanosoma cruzi of three novel 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one-based complexes Ana B. Caballero a,1 , Clotilde Marín b,2 , Antonio Rodríguez-Diéguez a, ⁎ ,1 , Inmaculada Ramírez-Macías b,2 , Elisa Barea a,1 , Manuel Sánchez-Moreno b, ⁎ ,2 , Juan M. Salas a,1 a Departamento de Química Inorgánica, Universidad de Granada, Severo Ochoa s/n, E-18071, Granada, Spain b Departamento de Parasitología, Universidad de Granada, Severo Ochoa s/n, E-18071, Granada, Spain abstract article info Article history: Received 10 December 2010 Received in revised form 21 March 2011 Accepted 21 March 2011 Available online 30 March 2011 Keywords: Trypanosoma cruzi Coordination chemistry Biological properties Conventional reactions of the versatile multidentate ligand 5-methyl-1,2,4-triazolo[1,5-a] pyrimidin-7(4H)- one (HmtpO) with metallic(II) perchlorate salts lead to three novel multidimensional complexes [Cu (HmtpO) 2 (H 2 O) 3 ](ClO 4 ) 2 ·H 2 O(1), {[Cu(HmtpO) 2 (H 2 O) 2 ](ClO 4 ) 2 ·2HmtpO} n (2) and {[Co(HmtpO)(H 2 O) 3 ] (ClO 4 ) 2 ·2H 2 O} n (3). We have tested the antiparasital activity in vitro and in vivo of the three new complexes against Trypanosoma cruzi showing very promising results and overcoming clearly the reference drug commonly used for the Chagas disease treatment, benznidazole. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Substituted-pyrimidinic ligands have been demonstrated to be excellent and versatile building blocks with charge and multi- connectivity ability to produce, under conventional and hydrothermal conditions, multidimensional coordination polymers with interesting properties [1–5]. Recently, we have shown that it is possible to synthesise new coordination compounds, with fascinating structures and interesting physical properties, by combining transition metal ions with the 1,2,4-triazolo[1,5-a] pyrimidine ligand (tp) and several pseudohalide auxiliary spacers [6]. Triazolopyrimidines are versatile ligands as they have several nitrogen atoms with accessible lone pairs to bind Lewis acids like metal ions [7]. It should also be highlighted that triazolopyrimidine derivatives have been the subject of chemical and biological studies due to their interesting pharmacology including antipyretic, analgesic, antiinflammatory, potential herbicidal, fungi- cidal, antitumoral and leishmanicidal properties [8–16]. With regard to their antiparasital properties, these bicyclic molecules and some of their metal complexes have shown to be especially active against diverse species like Leishmania spp. and Trypanosoma cruzi [17–22]. Chagas disease, caused by the protozoan T. cruzi, is a neglected disease that affects millions of people in areas of endemicity in Latin America, where approximately 100 million people are at risk [23]. This fact renders this kind of compounds as potential chemotherapeutic agents to combat this disease. HmtpO molecule (5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)- one) (Scheme 1) is an interesting triazolopyrimidine derivative considered as an analogue of the natural occurring nucleobase hypoxanthine. The synthesis of cis-[PtCl 2 (HmtpO) 2 ] has been reported by our group [24], and its anticancer activity has been tested against the human cancer cell lines MCF-7 breast carcinoma and A121 ovarian carcinoma. A preliminary communication on new antitumor Pt(IV) HmtpO complexes has just been reported [25]. Recently, the first organometallic Pd(II) and Pt(II) complexes with the HmtpO ligand and its anion mtpO - have been prepared, showing different coordination modes of this ligand [26]. Moreover, it has been demonstrated that such species interact with DNA. In view of these publications regarding to HmtpO ligand, it is clear that this ligand possesses a great interest due to its structural and biological properties. For this reason, we decided to synthesise novel coordination compounds containing HmtpO to study their biological properties. In this paper, we report the antiparasital properties of the following three new metal complexes: (a) the mononuclear unit [Cu(HmtpO) 2 (H 2 O) 3 ](ClO 4 ) 2 ·H 2 O(1), (b) the bidimensional framework {[Cu (HmtpO) 2 (H 2 O) 2 ](ClO 4 ) 2 ·2HmtpO} n (2) and (c) the monodimensional polymer {[Co(HmtpO)(H 2 O) 3 ](ClO 4 ) 2 ·2H 2 O} n (3). We have studied the antiproliferative in vitro and in vivo activity of these complexes against T. cruzi (epimastigote, amastigote and trypomastigote forms). More- over, unspecific mammal cytotoxicity was evaluated in vitro, and then submitted for in vivo experiments to perform a more profound study. Furthermore, we have also included a 1 H NMR study to obtain information about the nature and the percentage of the excretion of Journal of Inorganic Biochemistry 105 (2011) 770–776 ⁎ Corresponding authors. E-mail addresses: antonio5@ugr.es (A. Rodríguez-Diéguez), msanchem@ugr.es (M. Sánchez-Moreno). 1 Tel.: + 34 958240442. 2 Tel.: + 34 958242369. 0162-0134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2011.03.015 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio