Unexpected influence of metallamacrocyclic architecture of heterometallic pyrazinehydroximate Cu(II)-Bi(III) and Cu(II)-La(III) complexes on their antibacterial activity against Mycolicibacterium smegmatis (original) (raw)

Highlights

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Pyrazinehydroximate metallacrowns are the first examples of new promising class of metal-based antimicrobial compounds.
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The parent free ligand H2pyzha is inactive against Mycolicibacterium smegmatis strain.
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Abstract

Tuberculosis (TB) continues to be a significant global health threat. Hundreds of pure organic molecules are reported annually as promising anti-TB agents. Currently, the metal compounds have gained increasing attention. Nevertheless, the question remains whether or not metal complexes have any significant advantages over purely organic compounds. Herein we reported the first attempt to examine the antimycobacterial activity of pyrazinehydroximate Bi[15-MCCu(II)Pyzha-5] and La[15-MCCu(II)Pyzha-5] metallacrown complexes. These complexes present a typical 15-MC-5 metallacrown structure with a neutral ring consisting of five [Cu(II)-N single bond O] repeating units and the Bi(III) or La(III) metal ion in the central cavity. Both complexes exhibited enhanced antimycobacterial activity towards Mycolicibacterium smegmatis as a model for Mycobacterium tuberculosis, whereas the parent free pyrazinehydroxamic acid H2pyzha was inactive. The effect of the central metal ions on the antimycobacterial activity was discussed on the basis of DFT calculations.

Introduction

According to the World Health Organization, tuberculosis (TB) remains one of the leading world’s deadliest infectious diseases [1], and the research and development of antitubercular drugs to overcome drug resistance in Mycobacterium tuberculosis (M. tuberculosis) that reduce the length or toxicity of existing treatment regimens are urgently needed and remain an important goal for anti-TB therapy [2]. Nowadays, treatment of M. tuberculosis infections is primarily based on the first-line drugs, such as isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin [3]. In the search for new antitubercular agents with improved efficacy, pyrazinamide (PZA), along with isoniazid (INH) and rifampicin (RIF), forms the cornerstone of modern TB therapy [4]. It is interesting to note, that the basis of the remarkable sterilizing activity of PZA in patients remains puzzling since this fragment-size drug exhibits a poor in vitro potency (MIC = 30–100 mg/ml) [5]. Therefore, the discovery of novel next-generation pyrazine derivatives possessing a high anti-TB activity is very important. Recently numerous pyrazine-based compounds have been developed as new antitubercular chemotypes [6].

Although purely organic derivatives have traditionally dominated in the search for new therapeutic drugs, nowadays there is increasing interest in the potential use of metal-based antimicrobial compounds owing to the rise of antimicrobial resistance [7]. The choice of metal ions is not restricted to the set of essential metals, but it could also be applied to nonessential transition metals, bismuth and lanthanides [8]. It should be noted that coordination of an organic fragment to a metal ion often enhances its antimicrobial ability as compared to the free ligand and initial metal salt [9]. The key parameters required to maximize such properties are the nature of metal ions, the composition of an organic ligand, and the suitable molecular structure [10]. To further improve the antimicrobial activity of metal complexes, bimetallic compounds could be used [11]. Remarkably, manganese metallamacrocyclic compounds have recently been found to possess increased antimicrobial properties [12].

In this context, due to our interest in heteronuclear metallamacrocyclic 15-metallacrown-5 (15-MC-5) complexes, we introduce herein metallacrowns based on the pyrazinehydroxamic acid ligand (Pyzha). The choice of this ligand was inspired by our first examples of Cu(II)-Bi(III) metallacrowns [13], [14], which not only enrich the structural diversity of metallacrowns, but also offer a promising unique class of metal-based antimycobacterial compounds. It is generally considered that bismuth is a nontoxic green heavy metal, and its compounds have been used as active pharmaceutical drugs for over a century [15]. Recently, bismuth complexes based on pyridine-based organic ligands showed excellent antimycobacterial activity against M. tuberculosis [16]. As a result, it will be reasonable to investigate novel heterometallic complexes with the metallacrown structures.

It should be noted that 15-MC-5 metallacrowns as the inorganic analogues of organic crown ethers are one of the most interesting types of heterometallic metallamacrocyclic complexes due to their fascinating architectures and potentially unique properties [17], [18], [19], [20], [21], [22]. In these complexes, the planar metallamacrocycle consists of five [Cu(II)–N single bond O] repeat units with five hydroximate oxygen atoms surrounding a central metal. In the presence of the bismuth(III) ion, the hydroximate ligands self-assemble into such a planar metallamacrocycle with Bi(III) ion in the center [13]. A relevant aspect of this structure is that the ligand scaffold can also incorporate lanthanide ions characterized by the same charge and similar ionic radii as Bi3+[14]. Note, that the pyrazinehydroximate ligands as members of hydroximate family have been used successfully in the synthesis of Cu(II)-Ln(III) metallacrowns [23], [24], [25], [26]. Thus, these metallacrowns offer an essential advantage of the pyrazine heterocycles and can be nominated as a potential antimycobacterial agents.

According to literature data, there have been no reports so far on the antitubercular activity of the 15-MC-5 metallacrown complexes. To the best of our knowledge, this article reports the first attempt to examine the biological activity of pyrazinehydroximate Bi[15-MCCu(II)Pyzha-5] and La[15-MCCu(II)Pyzha-5] metallacrowns against Mycolicibacterium smegmatis (M. smegmatis), as a model for M. tuberculosis is commonly used as non-pathogenic, faster growing mycobacterium with the same cell wall structure, which shares over 2000 genetic homologs with M. tuberculosis [27]. Both Cu(II)-Bi(III) and Cu(II)-Ln(III) pyrazinehydroximate metallacrowns appear to demonstrate antimycobacterial activity on M. smegmatis, in contrast to the parent free pyrazinehydroxamic acid H2pyzha.

Section snippets

General details

All reagents were purchased from commercial sources and used without further purification. The elemental analysis was performed using the elemental analyzer Elementar Vario EL cube. X-ray fluorescence spectrometry was used to determine the stoichiometry of lanthanum, copper, and chlorine in 3. A SPEKTROSKAN MAX-GVM (Spectron Ltd., St. Petersburg, Russia) wavelength dispersive X-ray fluorescence spectrometer with fundamental parameters method software was used to perform all the measurements.

Synthesis and characterization

Following a previously described synthetic procedure for Cu(II)-Bi(III) 15-MC-5 metallacrowns [13] Cu(II)-La(III) pyrazinehydroximate metallacrown (3) has been prepared using the common one-pot methodology with some modification (Scheme 1).

Complexes 2 and 3 are air-stable, well soluble in DMSO, and slightly soluble in water. The absorption spectra of Cu(II)-Bi(III) MC (2) and Cu(II)-La(III) MC (3) in aqueous solution (Fig. 1) exhibit very similar absorption bands in the range of 200–460 nm with

Conclusions

In summary, 15-MC-5 metallacrowns represent a family of unique heteronuclear metallamacrocyclic complexes with great potential for biomedical applications. Using appropriate ligands and selecting suitable metal ions, one can design complexes possessing desiable properties. With an idea to explore the unique structure of 15-MC-5 metallacrown complexes, we investigated the Cu(II)-Bi(III) (2) and Cu(II)-La(III) (3) metallacrowns based on the pyrazinehydroximate ligand (Pyzha). The single-crystal

CRediT authorship contribution statement

Marina A. Katkova: Writing – original draft, Methodology, Conceptualization. Galina S. Zabrodina: Formal analysis. Grigory Yu. Zhigulin: Writing – original draft, Investigation. Roman V. Rumyantsev: Writing – original draft, Investigation, Formal analysis. Mikhail A. Kiskin: Formal analysis. Irina G. Fomina: Formal analysis. Olga B. Bekker: Investigation, Formal analysis. Sergey Yu. Ketkov: Writing – review & editing, Supervision. Igor L. Eremenko: Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by the Ministry of Science and Higher Education of the Russian Federation within the scientific tasks of the Razuvaev Institute of Organometallic Chemistry RAS. This work was supported by the Ministry of Science and Higher Education of the Russian Federation as part of the State Assignment of the Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences. IRS and IFS was performed using the equipment of the JRC PMR IGIC RAS.

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