Erbium(III) complexes with fluoroquinolones: Structure and biological properties

Lanthanides are a group of elements that have atomic numbers between 57 (lanthanum) to 71 (lutetium) [1]. Lanthanides are crucial constituents of several contemporary technologies, including magnets, electric car batteries, lasers, phosphors and image agents. Due to their particular chemical properties, such us high Lewis acidity and unique coordination chemistry, these metals could play a key role in selective absorption, transporting and embodiment into enzymes [2]. As for the biomedical applications of lanthanides, gadolinium–carrying complexes such as Magnevist, Dotarem [3] and Artirem [4] are used extensively as MRI contrast agents, while 177Lu holds an important place as radiotherapy factor in targeted radiotherapy of neuroendocrine tumors and prostate cancers [5]. Other lanthanides act as hypophosphatemic agents for patients with kidney dialysis, as luminescent probes in cell studies, or for alleviation of bone pain in osteosarcoma [6]. In the last few years, Ln3+–based nanoparticles have also gained considerable attention as potential agents in the field of photodynamic therapy [7].

Erbium is a member of the lanthanide family, and it is found in small amounts in human body, without possessing any essential biological role, apart from stimulating the metabolism [8]. In the recent years, erbium(III) complexes have been tested for potential biological activity. Erbium(III) complexes with Schiff bases have depicted in vitro antibacterial [[9], [10], [11]], antifungal [9,10], antimalarial [12], antioxidant [13,14] and anticancer [11,15] activity, while those with carbonyl compounds have shown anticancer potency [16] and antioxidant capacity [16,17]. Erbium(III) complexes with substituted salicylaldehydes have also shown antioxidant properties and noteworthy affinity for DNA and albumins [18]. Furthermore, erbium(III) complexes with diverse ligands have shown anticancer [19], antimicrobial [20], anti–inflammatory [21], and DNA–cleaving [22] activity.

Quinolones (HQ) are a class of extended–spectrum synthetic antibacterial drugs and are clinically used as therapeutics in the treatment of various bacterial infections, by inhibiting the bacterial enzymes DNA–gyrase and topoisomerase IV [23,24]. Their structure consists of a 4–oxo–1,4–dihydroquinoline skeleton and they have been approved for the treatment of patients with urinary tract infections, soft tissue infections, respiratory infections, bone–joint infections, typhoid fever, sexually transmitted diseases, prostatitis, community acquired pneumonia, acute bronchitis and sinusitis [25]. Due to non–activity of the first synthesized quinolone, nalidixic acid, against Gram–negative bacteria, a structural alteration of this first–generation quinolone was vital for the expansion of the antibacterial activity [24,26]. By the addition of a fluorine atom at the sixth position of the quinolone ring, novel quinolones, named fluoroquinolones, were developed with wider spectrum of activity [27].

The first developed fluoroquinolone flumequine (Hflmq, Fig. 1) is massively used in veterinary medicine for the management of digestive, pulmonary and urinary tract infections [28]. Enrofloxacin (Herx, Fig. 1), a second–generation fluoroquinolone antibiotic, is used as a drug to treat numerous Gram–negative veterinary bacterial infections of the respiratory and gastrointestinal system [29]. The third–generation fluoroquinolones levofloxacin (Hlevo, Fig. 1) [30] and sparfloxacin (Hsf, Fig. 1) [31] act efficiently against both gram–positive and gram–negative bacteria, by focusing on DNA–gyrase [32]. Because of their high bioavailability, they have been used for the therapy of patients with lower respiratory tract infections such as pneumonia, bronchitis and chronic obstructive pulmonary disease [25,32].

Based on the research work of our lab, it has been observed that quinolone complexes with transition metal ions Cu(II) [[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]], Co(II) [37,43,45,46], Mn(II) [[47], [48], [49]], Ni(II) [[50], [51], [52], [53]] and Zn(II) [[54], [55], [56], [57]] have portrayed similar or improved biological activity compared to the free quinolones. Quinolones have a noteworthy capacity of binding to common lanthanide(III) ions and forming complexes with improved bactericidal activity, which derives from particular chemical properties of these metals [58]. To the best of our knowledge, there are not any reports concerning Er(III)–quinolone complexes, although the research interest concerning the biological relevance of lanthanide(III) complexes is increasing nowadays [1,2,5,11].

For the purpose of the current research, four novel erbium(III) complexes of the quinolones Herx, Hlevo, Hflmq and Hsf were synthesized. The composed complexes, namely [Er(Hlevo)4](PF6)3 (complex 1), [Er(flmq)3(MeOH)2] (complex 2), [Er(erx)3(MeOH)2] (complex 3) and [Er(sf)3(MeOH)2] (complex 4) were characterized by physicochemical and spectroscopic techniques, and single–crystal X–ray crystallography (the crystal structure of complex 1 was determined). Complexes 1–4 were evaluated in vitro for their: (i) binding aptitude for calf–thymus (CT) DNA which was examined by UV–vis spectroscopy and viscosity measurements and via their capacity to displace ethidium bromide (EB) from the DNA–EB adduct, ii) affinity for serum albumins, i.e. bovine serum albumin (BSA) and human serum albumin (HSA), which was monitored by fluorescence emission spectroscopy, and (iii) potential antimicrobial activity by determining the minimum inhibitory concentration (MIC) against four bacteria, i.e. two Gram–positive (i.e. Escherichia coli XL1 (E. coli), Xanthomonas campestris ATCC 33013 (X. campestris)) and two Gram–negative ones (i.e. Staphylococcus aureus ATCC 29213 (S. aureus) and Bacillus subtilis ATCC 6633 (B. subtilis)).

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