In vitro leishmanicidal and trypanocidal evaluation and magnetic properties of 7-amino-1,2,4-triazolo[1,5-a]pyrimidine Cu(II) complexes

https://doi.org/10.1016/j.jinorgbio.2017.11.027Get rights and content

Highlights

  • Two dinuclear Cu (II) triazolopyrimidine complexes have been synthesized and characterized.

  • Magnetic properties of both compounds have been studied.

  • Antiparasitic activity has been assayed against three leishmania strains and T. cruzi.

  • Clearly superior antiparasitic efficacy in comparison with reference drugs was demonstrate.

Abstract

Two triazolopyrimidine complexes have been obtained from reaction between 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and Cu (II) salts. Crystal structures of [Cu2(μ-7atp)4Cl2]Cl2·4H2O (1) and [Cu2(μ-7atp)4(H2O)2](NO3)4·H2O (2) have been studied by X-ray diffraction methods and characterized by spectroscopic and thermal analysis. Magnetic studies of these dinuclear complexes have revealed the existence of moderate antiferromagnetic interactions between the copper ions, with J values of − 91.2 and − 96.1 cm 1 respectively. It must be highlighted that the antiparasitic activity of these new complexes has been studied in vitro against three different strains of leishmania spp. and Trypanosoma cruzi, showing a higher efficacy than the 7atp ligand and the reference commercial drugs.

Graphical abstract

Two dinuclear copper (II) complexes using triazolopyrimidine derivative 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) as ligand have been synthesized. Both compounds have been characterized by spectroscopic and thermal analysis and X-ray diffraction. Magnetic properties have been studied and antiparasitic activity against Trypanosomatidae family strains has been assayed, showing higher efficacy than the reference drugs.

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Introduction

Leishmaniasis is the name that has been assigned to a group of neglected diseases, considered by World Health Organisation (WHO) as one of the seven primary illnesses that affect to all continents, usually located in tropical and subtropical poor regions [1]. It is now endemic in almost 100 countries, mainly in the New World, but present in Europe and Asia by migration. More than 350 million people around the world are at risk, and two million new cases arise every year, with an annual mortality rate higher than 60,000, a number that is only surpassed by malaria among parasitic diseases [2]. The main transmission vectors are dipteral insects that belong to the genera Phlebotomus in the Old World and Lutzomyia in the New World. Chagas disease, also known as American Trypanosomiasis, is a lethal chronic illness caused by Trypanosoma cruzi, which currently affects 8–10 million people worldwide, primarily in South and Central America [3], being transmitted mostly by contact with faeces/urine of infected blood-sucking triatomine bugs.

Pentavalent antimonials like sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime) have been used in the treatment of Leishmaniasis for over 50 years. However, the molecular structure of antimonials, their metabolism and mechanism of action are still being explored [4], [5]. Existing non-antimonial antiparasitic prodrugs as Anfotericine B are also being used as Leishmaniasis treatment [6], but its high price hinders the access and implementation in poor regions, which are the most affected areas, and present adverse side effects too, especially kidney failure. On the other hand, Nifurtimox and Benznidazol are two nitro heterocyclic derivatives commonly used as drugs with trypanozidal effect [7], [8]. Biochemical studies over the past two decades have pointed out a number of potential targets, e.g. glycolysis, particularly inhibition of ADP phosphorylation and beta-oxidation of fatty acids [9], [10]. Even though antimonials are still the first-line antiparasitic drugs, they exhibit several limitations like severe side effects including anorexia, vomiting, peripheral polyneuropathy or allergic dermopathy [11], [12], the need of daily parenteral administration and drug resistance [13], [14], [15]. Thus, there is an urgent need for new and more efficient therapies to fight Leishmaniasis and Chagas disease, minimizing its impact in society. In this regard, triazolopyrimidine derivatives have proved their notable pharmacology including antipyretic, analgesic, anti-inflammatory, herbicidal, fungicidal, antimicrobial, antitumor and antiparasitic properties [16], [17], [18], [19], [20]. In fact, since their synthesis was first time reported by Bülow and Haas in 1909 [21], several technological applications have been described for these ligands [22]. Triazolopyrimidine derivatives and their metal complexes also exhibit their effect in the fields of medicine, pharmacy or agriculture. In addition, our group has also studied the magnetic and luminescent properties of the coordination compounds based on different metal ions with these ligands [23], [24].

Still, the increasing interest around triazolopyrimidines does not only lie in this regard, but also in their biomimetic character, since they bear a resemblance to the natural occurring purine nucleobases adenine and guanine. These bicyclic molecules and some of their metal complexes have shown moreover to be especially active against diverse species of Leishmania spp. and T. cruzi [25], [26], [27], [28], [29]. This fact renders this kind of compounds as potential chemotherapeutic agents to combat diseases which are related with parasites. Several other authors have also pointed to metal complexes as a promising alternative to fight tropical parasitic diseases caused by members of Trypanosomatidae family such as Leishmaniasis and Chagas disease [30], [31], [32], [33], [34], [35], as well as other tropical illnesses such as malaria [36], being observed a synergetic effect in the antiparasitic efficacy if we combine triazolopyrimidine derivatives with different metal ions in coordination complexes [37], [38], [39], [40], [41], [42]. Based on the above findings, and looking for the design of new drug candidates for potent, selective and less toxic trypanozidal therapeutic agents, we have selected 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) to form new antiparasitic metal complexes. 7atp derivative is a biomimetic compound analogous to canonical nucleobase adenine, with four N donor atoms able to interact with metal ions instead of the five of the purine nucleobase (see Scheme 1). Coordination compounds containing triazolopyrimidine ligands bonded to metallic centres have previously shown antiproliferative in vitro activity against T. cruzi [43] and against some of the Leishmania spp. strains that we have used in the assays reported in this work [44], [45].

Two synthesized Cu(II) complexes based on 7atp derivative are reported herein. Their molecular formulas are [Cu2(μ-7atp)4Cl2]Cl2·4H2O (1) and [Cu2(μ-7atp)4(H2O)2](NO3)4·H2O (2), in which triazolopyrimidine derivative acts as bridge between both Cu(II) centres. In this regard, we have designed the syntheses, characterized thermal and spectroscopically these compounds, and studied its magnetic behaviour. Moreover, the in vitro anti-proliferative activities against extracellular forms of three species of Leishmania spp. (L. infantum, L. braziliensis and L. donovani) and Trypanosoma cruzi have been assayed. Toxicities against macrophage J774.2 and Vero cells have been determined and compared with values found for the reference Glucantime and Benznidazol drugs and pure 7atp ligand.

Section snippets

General

All metallic salts and 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) ligand used as reagents were purchased from commercial sources and used as received without further purification.

Preparation of [Cu2(μ-7atp)4Cl2]Cl2·4H2O (1)

A solution containing 7atp (0,1 mmol, 0,148 g) was mixed with other of CuCl2·2H2O (0,1 mmol, 0,170 g) using the minimum volume of H2O as solvent, stirring and heating at 80 °C during 30 min. After evaporation at room temperature for two days, green crystals suitable for XRD characterization were obtained by vacuum

Crystal structure of [Cu2(μ-7atp)4Cl2]Cl2·4H2O (1)

Compound 1 crystallizes in the orthorhombic Cmca space group. X-ray crystal structure of 1 is displayed in Fig. 1. Selected bond lengths and angles are given in Table S1. The structure consists of dinuclear cationic [Cu2(μ-7atp)4Cl2]2 + coordination entities, crystallization water molecules and chloride anions stabilizing the crystal structure. The copper metal centres of the paddlewheel adopts a slightly distorted square pyramidal coordination geometry with the bond angles only deviating a bit

Conclusions

Two novel triazolopyrimidine dinuclear Cu(II) complexes have been synthesized and completely characterized by X-ray diffraction and spectroscopic, thermal and magnetic analysis. Magnetic studies of these dinuclear complexes have revealed the existence of moderate antiferromagnetic interactions between the copper ions, with J values of − 91.2 and − 96.1 cm 1. Both compounds 1 and 2 improve the effect of commercial drugs and 7atp ligand, showing much less toxicity against hosting cells despite they

Acknowledgements

This work was carried out in the frame of the “Red de iones metálicos en sistemas biológicos. Red de Excelencia CTQ2015-71211-REDT” network and the Junta de Andalucía (FQM-1484 and FQM-195).

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