Anti-diabetic and anti-parasitic properties of a family of luminescent zinc coordination compounds based on the 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand

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Highlights

  • The novel 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand has been designed.

  • A new family of zinc coordination compounds based on this ligand is reported.

  • Luminescence studies have been performed.

  • Compounds show interesting anti-diabetic properties.

  • Anti-parasitic activities has been analysed.

Abstract

We report on the formation of a triazolopyrimidine derivative ligand, 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (7-amtp), and a new family of coordination compounds based on this ligand and zinc as metal ion, synthesized by conventional routes. These materials possess different mononuclear structures, namely [ZnCl2(7-amtp)2] (1), [Zn(7-amtp)2(H2O)4](NO3)2·2(7-amtp)·6H2O (2) and [Zn(7-amtp)2(H2O)4](SO4)·1.5H2O (3) derived from the use of different zinc (II) salts, in such a way that the counterions govern the crystallization to a large extent. These compounds present and show variable luminescent properties based on ligand-centred charge transfers which have been deeply studied by Time Dependent Density Functional Theory (TD-DFT) calculations. When these compounds are transferred to solution, preserving complex entities as corroborated by NMR studies, they present interesting anti-diabetic and anti-parasitic capabilities, with a comparatively higher selectivity index than other previously reported triazolopyrimidine-based materials. The results derived from in vivo experiments conducted in mice also confirm their promising activity as anti-diabetic drug being capable of dropping glucose levels after oral administration. Therefore, these new materials may be considered as excellent candidates to be further investigated in the field of luminescent coordination compounds with biomedical applications.

Graphical abstract

We report on the formation of a family of luminescence zinc coordination compounds based on the novel 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand. These materials show interesting luminescence, anti-diabetic and anti-parasitic properties.

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Introduction

Diabetes mellitus (DM) is a group of metabolic disorders which raises blood sugar levels over a prolonged period. This disease generates a huge social and economic problem to the world society since DM has become one of the most relevant health issues in the first world countries, with 422 million adults affected all over the world, and more than a half of them living in these countries [1]. For this reason, a great quantity of drugs are used for the treatment of diabetes to control plasma glucose levels and achieve insulin-mimetic effects, in which each class of drug has different mechanisms of action. Unfortunately, common anti-diabetic drugs are associated with several adverse effects, so that the search for new drugs that can fight this disease effectively with minimal side effects is still an ongoing research field [2]. Recent studies aim to develop new drugs that can be administered orally for the treatment of diabetes, most of them based on organic compounds [[3], [4], [5]]. As an alternative to this type of materials, coordination compounds have shown promising activity as hypoglycaemic agents for the pharmacotherapy of diabetes [[6], [7]]. Among them, compounds containing Zn (Zn2+) have been investigated on recent studies using animal models. In particular, some clinical reports strongly support the thought that Zn2+ deficiency occurs in diabetic conditions, suggesting that Zn2+ supplementation will benefit or correct the diabetes-induced Zn2+ status [[8], [9]]. This cation plays essential structural roles in many proteins and enzymes but also has shown insulin enhancing activity in vivo [10]. Considering the different families of Zn2+ compounds synthesized and found in literature, it may be envisaged that mononuclear Zn2+ coordination compounds could present interesting anti-diabetic properties [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]].

As expected, a delicate rational design of the organic ligand to be coordinated to the central cation plays a key role. In this line, several ligands containing N atoms have demonstrated to be excellent and versatile building blocks that, with the appropriate charge and multi-connectivity patterns, produce, under conventional routes, multidimensional coordination compounds with fascinating physical properties. In this respect, we previously reported the synthesis, structural characterization and anti-diabetic evaluation of multidimensional coordination compounds composed of this kind of ligands [26] and zinc and vanadium ions. Of particular interest is the fact that the metal–organic hybrid nature of these materials offers potentially limitless arrangement types and topological architectures [[27], [28]], reinforcing their versatility of use.

In the last ten years, we and others have reported the use of different triazolopyrimidine derivative ligands with specific antiparasitic activities, with a particular focus on the behaviour of the adenine-derivative 7-amino-1,2,4-triazolo[1,5-a]pyrimidine ligand (7-atp) [[29], [30], [31], [32], [33], [34], [35], [36], [37]]. Based on these previous results, a new amine derivative triazolopyrimidine ligand (7-amino-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine; 7-amtp hereafter) is designed and synthesized in this work (Scheme I). Additionally, three coordination compounds based on 7-amtp ligand and Zn2+ are synthesized and characterized, and their anti-diabetic activity evaluated. In this line, it is worth it to mention that the antidiabetic properties of trizolopyrimidine-derivative ligands have been previously reported [[38], [39], [40], [41], [42]] but, to the best of our knowledge, this is the first time where a potential anti-diabetic compound merges the biological activity of this type of ligands with the insulin enhancing activity of the Zn2+ cation. (See Scheme II.)

Equally important is the fact that, due to its extended aromaticity and to the presence of several heteroatoms in the ring, this ligand should be a good candidate to show luminescent properties, which might be enhanced when coordinated to Zn2+ ions [[43], [44], [45]]. In this sense, coordination compounds containing metal ions with closed shell configuration, such as d10 metals (Zn2+ and Cd2+) have attracted extensive interest in recent decades, given their ability to render fascinating structures [[46], [47], [48], [49], [50], [51]]. This fact is a consequence of the absence of ligand field constraints, associated with the d10 configuration of these ions, which provides flexible coordination environments that can be adapted to a wide variety of geometries. Hence, they allow fine tuning of the structures and/or topologies. Moreover, the closed-shell configuration also possesses some additional advantages regarding the photoluminescence (PL) properties [[52], [53]], since the absence of potential quenching processes derived from dd transitions permits efficient luminescent emission. This fact should allow us to develop multifunctional materials with interesting luminescent and biological properties.

Therefore, we report herein the synthesis and characterization of a new family of Zn2+ coordination complexes based on the novel triazolopyrimidine derivative 7-amtp ligand, [ZnCl2(7-amtp)2] (1), [Zn(7-amtp)2(H2O)4](NO3)2·2(7-amtp)·6H2O (2) and [Zn(7-amtp)2(H2O)4](SO4)·1.5H2O (3). 13 compounds are mononuclear entities in which 7-amtp coordinates via N3 atom (see Scheme I for atom numbering) to zinc ions. Luminescent measurements of compounds have been performed along in vitro anti-parasitic activities and in vivo anti-diabetic properties have been studied in the diabetic murine model STZ-CD1, constituting, to the best of our knowledge, the first report on Zn-based compounds as glucose lowering agents.

Section snippets

(7-amtp)·(H2O)

The free 7-amtp ligand crystallizes in the orthorhombic Pbca space group with two crystallographically independent molecules in the asymmetric unit, which also contains two crystallization water molecules, one of them disordered between two positions. The crystal architecture is mainly built by hydrogen bonds with water molecules interacting between them (O…O distance, 2.648(3)/2.756(3) Å) and acting as donor towards N3 and N4 atoms of the organic moiety (O…N distances, 2.827(3)/2.850(3),

Conclusion

In summary, the novel 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand and new family of zinc coordination compounds have been synthesized and characterized by single crystal X-ray diffraction: [ZnCl2(7-amtp)2] (1), [Zn(7-amtp)2(H2O)4]·(NO3)2·(7-amtp)2·6H2O (2) and [Zn(7-amtp)2(H2O)4]SO42·1,54H2O (3). They are mononuclear compounds in which 7-amine-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine coordinates by N3 atom to zinc ions. Solid state photoluminescence spectra of compounds 1–3 showed

Materials and physical measurements

All reagents were obtained from commercial sources and used as received. Elemental analyses were carried out at the “Centro de Instrumentación Científica” of the University of Granada on a THERMO SCIENTIFIC analyser model Flash 2000. The IR spectra on powdered samples were recorded with a BRUKER TENSOR 27 FT-IR and OPUS data collection program. The UV spectra in solution were collected on an Agilent Technologies Cary 100 Spectrophotometer. Powder DRX data were collected on a Bruker D2 Phaser

Declaration of competing interest

There is not any conflict of interest.

Acknowledgements

Financial support was given by Junta de Andalucía (Spain) (project number FQM-195, FQM-394 and FQM-1484) and the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI/FEDER, UE) (PGC2018-102052-A-C22 and PGC2018-102052-B-C21) (University Faculty Training Plan – FPU Grants). The authors thank for technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF).

Abbreviations

7-atp 7-amino[1,2,4]triazolo[1,5-a]pyrimidine

7-amtp 7-amino-5-methyl [1,2,4]triazolo[1,5-a]pyrimidine

tn 1,3-propanediamine

bpym 2,2′-bipyrimidine

mal malonate

HmtpO 7-hydroxy-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine

AMPKα AMP-activated protein kinase

ERK2/MAPK1 mitogen-activated protein kinase-1

FBS fetal bovine serum

GLUT4 glucose transporter type 4

GSK-3β glycogen synthase kinase-3

HBSS Hank's Balanced Salt Solution

HOMO highest occupied molecular orbital

IC inhibitory concentration

IC50 half maximal inhibitory

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