Synthesis, structure and antimicrobial activity of manganese(II) and cobalt(II) complexes of the polyether ionophore antibiotic Sodium Monensin A

doi:10.1016/j.jinorgbio.2007.06.033

Journal of Inorganic Biochemistry

Volume 102, Issue 1, January 2008, Pages 26-32

https://doi.org/10.1016/j.jinorgbio.2007.06.033 Get rights and content

Abstract

Mononuclear neutral manganese(II) and cobalt(II) complexes with the antibiotic Sodium Monensin A (Mon-Na, 1b) were synthesized and characterized. The crystal structures of M(Mon-Na)₂Cl₂ · H₂O (M = Mn, 2; M = Co, 3) were determined by X-ray crystallography. The complexes crystallize in monoclinic space group C2 with a tetrahedrally coordinated transition metal attached to oxygen atoms of deprotonated carboxyl groups of two Sodium Monensin molecules and two chloride ions. The sodium ion remains in the cavity of the ligand and cannot be replaced by Mn(II) or Co(II). The complexes were additionally characterized by different spectroscopic techniques (UV–Visible, EPR, FAB-MS). A preferable octahedral environment around the transition metal centers is observed in polar solvents while the complexes retain their tetrahedral structure in non-polar media. The antimicrobial activity of 1b, 2 and 3 was tested against Gram(+) and Gram(−) bacteria.

Introduction

The polyether ionophores represent a large group of biologically active compounds produced by Streptomyces. Their unique structure consists of an alkyl-rich backbone providing a lipophilic exterior, while oxygens of different type are located internally, thus forming a cavity capable of binding metal ions [1]. A distinguishing feature of each polyether ionophore is the selectivity of cation binding which relates to compound’s characteristics and properties.

Monensin is a widely used monovalent polyether ionophore antibiotic produced by Streptomyces cinnamonensis. A broad study on the properties of Monensin has been started since its isolation by Agtarap et al. in 1967 [2]. The main chemical form of the ionophore is Monensin A (MonH), 1a (Scheme 1), accompanied by two minor factors (Monensin B and Monensin C) formed by the microorganism. It is a powerful veterinary drug but is also applied as a growth promoter in live stock production and specifically as a coccidiostat in poultry [3], [4], [5], [6]. Monensins readily complex alkali ions with an affinity which decreases in the order Na⁺ > K⁺ > Rb⁺ > Li⁺ > Cs⁺. Their mononuclear complexes together with those ones of the Ag⁺ and Tl⁺ ions are characterized both in solution and in solid state [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. In all reported cases the monovalent metal ion is coordinated by six oxygens to create shell-like complexes as it was proved by X-ray crystallography. The carboxyl group is deprotonated although the O atom does not participate in the metal ion coordination sphere but is engaged in head-to-tail H-bond formation with one or two hydroxyl groups. The only example where the carboxyl group is not deprotonated, is the complex MonH · Na⁺Br⁻, where the bromide ion serves as a counter ion to form the corresponding neutral complex [18].

The antimicrobial mode of action of Monensin could be explained by a disturbance of pH and Na⁺/K⁺ equilibrium in bacteria cells, activating a variety of processes which lead to cell death [19], [20], [21]. Consistent with its mode of action, the effectiveness of Monensin appears to be sensitive to the local cation environment [22], [23], [24], [25], [26]. Very recently it was shown that polyether antibiotics are highly effective as ionophores for Pb²⁺ and could react with a broad range of cations not just monovalent ones as often assumed [27], [28], [29], [30].

Nowadays the main form of Monensin, commercially available and applicable in live stock production is the sodium salt of Monensin A, 1b (Sodiated Monensin A, Sodium Monensin A, MonNa) (Scheme 1). To the best of our knowledge, in most studies performed up to now, acid Monensin A, its derivatives or acid Monensin B as initial reagents have been used [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], although the complex Ag⁺(Mon⁻) was prepared from a Sodium Monensin in basic water–ethanol solutions [12].

We have initiated a study on the coordination ability of Sodium Monensin A toward heavy metal ions in order to establish: (i) if complexation occurs, and (ii) if sodium ions, already bound into the cavity, could be replaced by the corresponding metal ions introduced. In the present paper we report the preparation, X-ray structure determination and antimicrobial activity of two new complexes of Sodium Monensin A with manganese(II) and cobalt(II).

Section snippets

Materials

All chemicals and solvents were used as purchased and were of reagent grade. Sodium Monensin A was supplied by BIOVET Ltd, Bulgaria, CoCl₂ · 6H₂O and MnCl₂ · 4H₂O – by Riedel de Häen AG. The solvents (acetonitrile, methanol) were received from Fluka and Merck, respectively and were used without further purification.

Synthesis of Monensin A, 1a and complexes 2, 3

1a: Free acid MonH was obtained from MonNa as previously reported [41]. Yield 589 mg, 88%. Analysis of 1a for Na (AAS) showed the presence of ∼0.2% Na, which could not be removed

Description of the crystal structures of 2 and 3

ORTEP diagrams and crystal packing of 2 and 3 are displayed in Fig. 1, Fig. 2. Selected bond distances and angles are listed in Table 2. In both complexes two molecules of Sodium Monensin A complex with one transition metal center. Each MonNa acts as a monodentate neutral ligand via coordination of one carboxylate oxygen atom to the transition ion, forming metal-oxygen bond. The two other sites in the inner coordination sphere of the metal ion are occupied by the chloride anions from the

Conclusion

The newly obtained manganese(II) and cobalt(II) complexes of the polyether ionophore antibiotic Sodium Monensin A were characterized using spectroscopic methods and X-ray crystallography. Two molecules of Sodium Monensin A are monodentately bound to the transition metal(II) ions via a carboxylate oxygen atom, and two chloride ions occupy the third and fourth places in the inner sphere of the metal ion, forming neutral tetrahedral complexes. The sodium ions of the starting compound MonNa could

Acknowledgements

M.M. gratefully acknowledges the financial support of this work by AvHumboldt Foundation. The authors thank MSci Vasil Atanasov and BSci Rumyana Zhorova, Sofia University, for their assistance.

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Synthesis, structure and antimicrobial activity of manganese(II) and cobalt(II) complexes of the polyether ionophore antibiotic Sodium Monensin A

Abstract

Introduction

Section snippets

Materials

Synthesis of Monensin A, 1a and complexes 2, 3

Description of the crystal structures of 2 and 3

Conclusion

Acknowledgements

Int. J. Parasitol.

Vet. Parasitol.

J. Mol. Biol.

Biochim. Biophys. Acta – Biomembrane

Biochim. Biophys. Acta – Biomembrane

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Struct.

Biochem. Biophys. Res. Commun.

Adv. Inorg. Chem. Radiochem.

Helv. Chim. Acta

J. Am. Chem. Soc.

Antimicrob. Agents Chemother.

Acta Cryst. B

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Acta Cryst. E

J. Org. Chem.

J. Chem. Soc., Perkin Trans.

J. Phys. Chem.

J. Am. Chem. Soc.

J. Solid Chem.

Monat. für Chem.

Acta Cryst.

J. Anim. Sci.

Appl. Env. Microb.

J. Anim. Sci.

J. Anim. Sci.