Elsevier

Polyhedron

Volume 27, Issue 1, 20 January 2008, Pages 349-356
Polyhedron

Mononuclear dioxomolybdenum(VI) complexes with the quinolones enrofloxacin and sparfloxacin: Synthesis, structure, antibacterial activity and interaction with DNA

https://doi.org/10.1016/j.poly.2007.09.013Get rights and content

Abstract

The neutral mononuclear dioxomolybdenum(VI) complexes of the quinolone antibacterial agents enrofloxacin and sparfloxacin have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, enrofloxacin and sparfloxacin act as bidentate deprotonated ligands bound to the metal through the pyridone oxygen and one carboxylate oxygen. The central molybdenum atoms are six-coordinate with slightly distorted octahedral geometry. The lowest energy model structure of each complex has been proposed with molecular modeling calculations. The antimicrobial activity of the complexes has been tested on three different microorganisms. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques.

Graphical abstract

The synthesis, the characterization, the antibacterial activity and the interaction with calf-thymus DNA of the neutral mononuclear dioxomolybdenum(VI) complexes with the quinolone antibacterial agents enrofloxacin and sparfloxacin are presented.

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Introduction

Quinolones is a term commonly used for the quinolonecarboxylic acids or 4-quinolones, a group of synthetic antibacterial agents containing a 4-oxo-1,4-dihydroquinoline skeleton [1], [2], [3]. Quinolones are extremely useful for the treatment of diverse infections [4], [5], [6]. The activity of quinolones as antibacterial drugs is due to the effective inhibition of DNA replication. The proposed mechanism of the interaction between quinolone and metal cations was chelation between the metal and the 4-oxo and adjacent carboxyl groups [7].

Enrofloxacin, Herx (Fig. 1a), is a typical second-generation quinolone antimicrobial drug with a broad spectrum of activity against a wide range of Gram-negative and Gram-positive bacteria, including those resistant to β-lactam antibiotics and sulfonamides [8], [9]. Enrofloxacin is the first fluoroquinolone developed for veterinary application and is potentially available for the treatment of some urinary tract, respiratory tract and skin infectious diseases in pets and livestock [10], [11], [12], [13]. It is also used for the treatment of uncomplicated and complicated urinary tract infections, pyelonephritis, sexually transmitted diseases, prostatitis, skin and tissue infections, urethral and cervical gonococcal infections [14], [15], [16]. Sparfloxacin, Hsf (Fig. 1b), is a third-generation quinolone antimicrobial drug mainly used for the treatment of acute exacerbations of chronic bronchitis and community-acquired pneumonia [17].

The role of molybdenum as an element of biological interest is well known [18], [19], [20], [21]. Molybdenum can be found in the Mo nitrogenases [22] and in the molybdenum oxidases [23], enzymes that catalyze a number of biologically important oxotransfer reactions, such as the conversion of sulfite to sulfate, aldehyde to the corresponding carboxylic acid, or nitrate to nitrite [21]. For Mo, only two ciprofloxacin complexes as polyoxometalates have been characterized [24], while dioxomolybdenum(VI) binary complexes have been reported only with the first-generation quinolones pipemidic acid [25] and oxolinic acid [26] as well as with the second-generation quinolone N-propyl-norfloxacin [27].

We have initiated the study of the structure, spectroscopic and biological properties of diverse transition metal complexes with various quinolone antibacterial drugs [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. Here, we present the interaction of MoO22+ with the second-generation quinolone enrofloxacin and third-generation quinolone sparfloxacin in an attempt to examine the mode of coordination and the biological properties of the resultant complexes. More specifically, the complexes have been synthesized and characterized with elemental analysis and diverse spectroscopic techniques (IR, UV–Vis and NMR spectroscopies). Molecular modeling techniques have been employed to assess the lowest energy model structure of the complexes. The biological activity of the complexes has been evaluated by determining the minimum inhibitory concentration (MIC) against three microorganisms. The interaction of the complexes with calf-thymus (CT) DNA has been investigated with UV and circular dichroism (CD) spectroscopy.

Section snippets

Materials

Enrofloxacin, sparfloxacin and CT DNA were purchased from Sigma, NaCl was purchased from Merck, trisodium citrate was purchased from Riedel-de Haen, MoO2(acac)2, KOH and all the solvents were purchased from Aldrich Co. Agarose was purchased from BRL. Tryptone and yeast extract were purchased from Oxoid (Unipath, Hampshire, UK). All the chemicals for the synthesis of the compounds were reagent grade and were used as purchased.

DNA stock solutions (5 mM) were prepared by dilution of CT DNA to

Synthesis and spectroscopic study of the complexes

The complexes have been prepared in high yield (75%) via the addition of methanolic solutions of the deprotonated quinolone to MoO22+ at a 2/1 ratio. Both complexes are soluble in DMSO and DMF and are non-electrolytes.

In Table 1, the characteristic absorptions of the IR spectra of complexes 1 and 2 are listed. In the IR spectra of complexes 1 and 2, the absorptions at 1733 cm−1 in the spectrum of Herx and at 1716 cm−1 for Hsf, respectively, attributed to the absorption of the ν(Cdouble bondO)c (c = 

Conclusions

The synthesis and characterization of two neutral mononuclear MoO22+ complexes with the second and third-generation quinolone antibacterial drugs enrofloxacin and sparfloxacin, respectively, has been realized with physicochemical and spectroscopic methods. In both complexes, the quinolone ligands are bound to the metal via the pyridone and one carboxylate oxygen atoms. Each molybdenum(VI) atom is six-coordinate and the environment around could be described as distorted octahedron. With the use

Acknowledgements

The work was partially supported by E.L.K.E (70/4/6495) and the “Excellence in the Research Institutes” Program, Action 3.3.1 co-funded by the Greek Ministry of Development and E.U. We thank Dr. I. Eskioglou, Department of Medical Laboratories, Technological and Educational Institution of Larissa, Larissa, Greece for the supply of the microorganisms and Dr. A. Papakyriakou, Institute of Physical Chemistry, NCSR “Demokritos”, Greece, for the supply of the molecular modeling routine.

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