Ana B. Caballero

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.

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.

Biological activity of three novel complexes with the ligand 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one against Leishmania spp.

OBJECTIVES We report on new 1,2,4-triazolo[1,5-a]pyrimidine complexes that have been developed and examined for both antiproliferative in vitro activity against Leishmania infantum and Leishmania braziliensis, and report their possible mechanism of action on L. infantum and L. braziliensis. RESULTS Antileishmanial effects are described for newly synthesized Cu(II) and Co(II) complexes containing 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO) as a ligand. These complexes display a wide structural diversity: (i) mononuclear unit, [Cu(HmtpO)2(H2O)3](ClO4)2·H2O (1); (ii) two-dimensional framework, {[Cu(HmtpO)2(H2O)2](ClO4)(2)·2HmtpO}n (2); and (iii) chains, {[Co(HmtpO)(H2O)3](ClO4)(2)·2H2O}n (3). Compounds 1 and 2 appeared to be the most active against L. infantum (IC50 20.0 and 24.4 μM, respectively), and compounds 1 and 3 the most active against L. braziliensis (IC50 22.1 and 23.5 μM, respectively), with IC50s similar to those of the reference drug, glucantime (18.0 μM for L. infantum and 25.6 μM for L. braziliensis). These compounds were not toxic towards J774.2 macrophages. IC25 decreased infection capacity and severely reduced the multiplication of intracellular amastigotes, following the trend 1>3>2 for L. infantum and 3>1>2 for L. braziliensis. These complexes had an effect on the energy metabolism of the parasites at the level of the NAD+/NADH balance and the organelle membranes, causing their degradation and cell death. CONCLUSIONS Cellular proliferation, metabolic and ultrastructural studies showed that the compounds 2>1>3 were highly active against L. infantum and L. braziliensis.

Influence of pseudohalide ligands on the structural versatility and properties of novel ternary metal complexes with 1,2,4-triazolo(1,5-a)pyrimidine†

Eight new multidimensional metal(II) complexes [Zn(tp)2(NCS)2] (1), [Ni(tp)2(H2O)2(µ-tp)2Ni(NCS)4]n (2), [Co(tp)2(H2O)2(µ-tp)2Co(NCS)4]n (3), [Cd(tp)2(NCS)2]n (4), [Mn(tp)2(NCS)2(H2O)2] (5), [Zn(tp)2(NCO)2] (6), [Cd(tp)(NCO)2]n (7) and [Cd(tp)(N3)2]n (8) have been synthesized by conventional reactions of the 1,2,4-triazolo[1,5-a]pyrimidine with metallic(II) salts in the presence of thiocyanate, cyanate and azide as auxiliary ligands. X-Ray diffraction studies on these compounds show that species 1, 5 and 6 are mononuclear units in which zinc and manganese have tetrahedral and octahedral coordination geometry, respectively. Complexes 2 and 3 are isostructural and consist of neutral chains with triazolopyrimidine bridging ligands through N1, N3 nitrogen atoms. Compound 4 exhibits a 2D rectangular-grid-like structure and complexes 7 and 8 are cyanate-bridged chains formed by defective cubanes. Magnetic and luminescent properties of these materials have also been studied.

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

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 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 first steps, and there is a distinct lack of research in the parasitology field. 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 fight the so considered neglected diseases leishmaniasis and Chagas disease.

Metal-Based Therapeutics for Leishmaniasis

When we speak of metals in medicine, many of us still associate them almost unconsciously with toxic rather than curative effects. However, despite the known toxic effect of some metal ions in humans, many metal ions (in adequate dosages) are required for many critical functions in our organism. Scarcity of some of them even can lead to a disease. Well-known examples include anemia resulting from iron deficiency, growth retardation arising from insufficient zinc, and heart disease in children owing to copper deficiency.

Leishmanicidal and Trypanocidal Activity of Metal Complexes with 1,2,4-Triazolo[1,5-a]pyrimidines: Insights on their Therapeutic Potential against Leishmaniasis and Chagas Disease

Since their first synthesis back in the early 20th century, 1,2,4-triazolo[1,5- a]pyrimidines have aroused increasing interest in very diverse areas ranging from chemotherapy to agriculture or even photography. Their similarity to purines confers a potential bioactivity and this feature has been wisely exploited for therapeutic use, including antifungal, antipyretic, analgesic, antiinflammatory, antitumoral and antiparasitic properties. In this review, we focus on the compounds that these nitrogen heterocycles form with metal ions and their antiparasitic activity and therapeutic potential against two neglected diseases of tropical prevalence, leishmaniasis and Chagas disease.

Bis(cyanato-κN)bis­(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-κN3)zinc

In the title complex, [Zn(NCO)2(C7H8N4)2], the ZnII ion exhibits a distorted tetrahedral coordination geometry. The coordination environment is formed by two 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) ligands, coordinated through the N atom in position 3, and two cyanate anions interacting by their N atoms. Supramolecular dimers are generated by stacking interactions between the pyrimidine rings of two ligands related by an inversion center [centroid–centroid distance = 3.5444 (18) Å].

DPDS–DPS in situ transformation at room temperature via a 1,2-nucleophilic addition mechanism

A cleavage–reorganization reaction at room temperature has been detected in three metal organic coordination compounds synthesized from a DPDS [di(4-pyridyl)disulphide] ligand: Mn(NCS)2(DPS)4 (1), [Fe(NCS)2(DPS)2]·2H2O (2) and Zn(NCO)2(DPS) (3), [DPS = di(4-pyridyl)sulphide]. The in situ reorganization process is explained by a 1,2-nucleophilic addition mechanism.

Bis(7-amino-1,2,4-triazolo[1,5-a]pyrimidin-4-ium) bis(oxalato-κ2O1,O2)cuprate(II) dihydrate

The structure of the title ionic compound, (C5H6N5)2[Cu(C2O4)2]·2H2O, consists of a centrosymmetric copper(II) oxalate dianion, two monoprotonated molecules of the adenine analog 7-amino-1,2,4-triazolo[1,5-a]pyrimidine (7atp) and two water molecules of crystallization. The CuII ion, located on an inversion center, exhibits a sligthly distorted square-planar coordination geometry, in which two oxalate anions bind in a bidentate fashion. The triazolopyrimidine ligand is protonated at the N atom in position 4, instead of its most basic N atom in position 3. This fact may be explained by the network stability, which is provided through the formation of a two-dimensional wave-like network parallel to (50) by N—H⋯O, O—H⋯N and O—H⋯O hydrogen bonds. These nets are further connected via C—H⋯O interactions.

4,7-Phenanthrolinium perchlorate-5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one-water (1/1/2).

The asymmetric unit of the title compound, C12H9N2 +·ClO4 −·C6H6N4O·2H2O, contains a monoprotonated 4,7-phenanthrolinium (47phen) cation, a perchlorate anion balancing its charge, a neutral molecule of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO) and two interstitial water molecules. In the crystal structure, the acidic H atoms of 47phenH+ and HmtpO form strong hydrogen bonds with the water molecules, which in turn act as hydrogen-bond donors, forming links between them and towards the carbonyl O atom of HmtpO, the non-protonated N atom of 47phen+ and one of the O atoms of the anion.