Ivayla Pantcheva

In this study, we present the preparation and characterization of a novel thallium(I) coordination compound of the polyether ionophorous antibiotic salinomycin (SalH). The complex [TlSal(H₂O)] exists as two subunits, SalTl1 and SalTl2, which differ slightly in their structural parameters. Salinomycin acts in a pentadentate coordination mode through oxygen donor atoms, and the six-fold arrangement around the metal centers is completed by interaction with a water molecule. In the overall complex structure, the two mononuclear species SalTl1 and SalTl2 are connected via a hydrogen bond network by a third water molecule. The inclusion of the heavy metal ion into the structure of the polyether ionophore reduces its biological activity against Gram-positive microorganisms and cervical cancer cells at in vitro conditions.

In this study we present the preparation and characterization of novel thallium(I) coordination compound of the polyether ionophorous antibiotic salinomycin (SalH). The complex [TlSal(H2O)] exists as two subunits SalTl1 and SalTl2 which differ slightly in their structural parameters. Sali-nomycin acts in a pentadentate coordination mode through oxygen donor atoms and the six-fold arrangement around the metal centers is completed by interaction with water molecule. In the overall complex structure, the two mononuclear species SalTl1 and SalTl2 are connected via hy-drogen bond network by third water molecule. The inclusion of the heavy metal ion into the structure of the polyether ionophore reduces its biological activity against Gram-positive microor-ganisms and cervical cancer cells at in vitro conditions.

The polyether ionophore monensin A (MonH), applied as silver monensinate, reacts with caesium cations to form a dinuclear complex [Mon₂Cs₂] the structure of which has been solved by single‐crystal X‐ray diffraction. Two Cs⁺ ions are located in the hydrophilic cage of two ligand anions, achieving coordination number eight. In addition, the metal cations are bridged by two functional groups of monensinate A, completing the inner tenfold coordination sphere. NMR studies show that the dinuclear complex dissociates to its mononuclear counterparts in methanol solutions. Further molecular dynamics theoretical modelling of the interaction of monensinate A with alkali metal ions reveals the effect of solvent polarity on the zipping ability of the ligand. Thus, in methanol, used as an explicit solvent, potassium and rubidium cations fully occupy the cavity of the ligand, whereas the sodium monensinate exists in an “open” form, with Na⁺ ions still interacting with the monodentate carboxylate group. The replacement of methanol by the less polar chloroform induces the folding of monensinate A and the formation of “closed” structures with all group 1 metal cations. The obtained data explain the specifics in the behaviour of monensinate A caused by the environment, e. g., physical state or solvent.

Monensic acid is a natural polyether ionophore and is a therapeutic of first choice in veterinary medicine for the control of coccidiosis. Although known as a sodium-binding ligand, it can also form a variety of coordination species depending on experimental conditions applied. In this study, we present the crystal structures and properties of Co(II) and Mn(II) complexes of sodium monensinate (MonNa) derived from the reaction of MonNa with cobalt or manganese dinitrates. The newly obtained coordination compounds have the same composition [M(MonNa)₂(NO₃)₂] but the transition metal ions are placed in a different environment. The two nitrate ligands behave mono- or bidentately bound in the Co(II)- and Mn(II)-containing species, respectively, while the monensinate ligands act in a similar manner through their monodentate carboxylate functions. The formed CoO₄ and MnO₆ units determine the geometry of the corresponding inner coordination cores of the complexes as a tetrahedron in the case of Co(II), and as a strongly distorted octahedral structure in Mn(II) species. The effect of inorganic anions on the antibacterial performance of sodium monensinate appears to be negligible, while the presence of Co(II) or Mn(II) cations preserves or enhances the activity of unmodified MonNa, which differentially affects the growth of Bacillus subtilis, Bacillus cereus, Kocuria rhizophila, Staphilococcus aureus, and Staphilococcus saprophyticus strains.

The commercial veterinary antibiotic sodium monensinate (MonNa) binds mercury(II) or zinc(II) cations as thiocyanate [Hg(MonNa)₂(SCN)₂] (1) or isothiocyanate [Zn(MonNa)₂(NCS)₂] (2) neutral coordination compounds. The structure and physicochemical properties of 1 and 2 were evaluated by the methods of single crystal and/or powder X-ray diffraction, infrared, nuclear magnetic resonance, X-ray photoelectron spectroscopies, and electrospray-mass spectrometry. The primary cores of the two complexes comprise HgS₂O₂ (1) and ZnN₂O₂ (2) coordination motifs, respectively, due to the ambidentate binding modes of the SCN–ligands. The directly bound oxygen atoms originate from the carboxylate function of the parent antibiotic. Sodium cations remain in the hydrophilic cavity of monensin and cannot be replaced by the competing divalent metal ions. Zinc(II) binding does not influence the monensin efficacy in the case of Bacillus cereus and Staphylococcus aureus whereas the antimicrobial assay reveals the potential of complex 2 as a therapeutic candidate for the treatment of infections caused by Bacillus subtilis, Kocuria rhizophila, and Staphylococcus saprophyticus.

In the present study, we report the solid-state isolation and structural characterization of novel iron(III) complexes of the veterinary antibiotic monensin. Monensic acid (MonH × H₂O) forms a dinuclear complex of composition with FeCl₃ [FeCl(Mon)₂]₂ (1), while its interaction with FeSO₄ leads to the isolation of a triangular oxo-ferric coordination species [Fe₃O(Mon × H₂O)₆(H₂O)₂(OH)] (2). During the procedure resulting in 2, oxidation of the Fe(II) ions by atmospheric oxygen was observed. In the presence of organic bases, both complexation reactions proceeded to successfully deprotonate the carboxylic function of the ligand. Iron(III) complexes 1 and 2 were characterized by IR, EPR, NMR, and Mössbauer spectroscopies as well as with thermal (TG-DTA/MS) and elemental analyses. In addition, the structures of the two coordination compounds were modelled and selected calculated parameters were compared with the experimental results. The biological assay revealed the enhanced antibacterial potential of the newly obtained complexes against the Gram-positive aerobic microorganisms Bacillus cereus and Bacillus subtilis.

Two trinuclear oxo-centred iron(III) coordination compounds of monensic and salinomycinic acids (HL) were synthesized and their spectral properties were studied using physicochemical/thermal methods (FT–IR, TG–DTA, TG–MS, EPR, Mössbauer spectroscopy, powder XRD) and elemental analysis. The data suggested the formation of [Fe₃(µ₃–O)L₃(OH)₄] and the probable complex structures were modelled using the DFT method. The computed spectral parameters of the optimized constructs were compared to the experimentally measured ones. In each complex, three metal centres were joined together at the axial position by a μ₃–O unit to form a {Fe₃O}⁷⁺ core. The antibiotics monoanions served as bidentate ligands through the carboxylate and hydroxyl groups located at the termini. The carboxylate moieties played a dual role bridging each two metal centres. Hydroxide anions secured the overall neutral character of the coordination species. Mössbauer spectra displayed asymmetric quadrupole doublets that were consistent with the existence of two types of high-spin iron(III) sites with different environments—two Fe[O₅] and one Fe[O₆] centres. The solid-state EPR studies confirmed the +3 oxidation state of iron with a total spin S_t = 5/2 per trinuclear cluster. The studied complexes are the first iron(III) coordination compounds of monensin and salinomycin reported so far.

The chirality of the polyether ionophore monensic acid A can be successfully used to study its coordination ability in solution. A complementary approach to gain new insights into the complexation chemistry of the antibiotic (studied previously by circular dichroism (CD) spectroscopy in the ultraviolet range (UV-CD)) is presented. (1) Methods: The CD spectroscopy in the visible (VIS-CD) and near-infrared (NIR-CD) range is applied to evaluate the affinity of deprotonated monensic acid A (monensinate A) towards Ni(II) or Co(II) cations in methanolic solution. Competition experiments between a variety of colorless divalent metal ions for binding the ligand anion were also performed. (2) Results: The stability constants of the species observed in binary Ni(II)/Co(II)-monensinate systems and their distribution were reevaluated with the VIS- and NIR-CD techniques. The data confirmed the formation of mono and bis complexes depending on the metal-to-ligand molar ratio. The studies on the systems containing two competing divalent metal cations exclude the formation of ternary complex species but provide an opportunity to also calculate the stability constants of Zn(II), Mg(II), and Ca(II) monensinates. (3) Conclusions: The advantages of CD spectroscopy in the VIS-NIR range (“invisible” ligand and metal salts, “visible” chiral complex species) simplify the experimental dataset evaluation and increase the reliability of computed results.

The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M⁴⁺ and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce⁴⁺. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL₂(OH)₂] and [CeL(NO₃)₂(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO₃)₂(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin.