J. Chil. Chem. Soc., 58, Nº 1 (2013)
CEFOPERAZONE METAL COMPLEXES: SYNTHESIS AND CHARACTERIZATION
J.R. ANACONA*1, ALINA BRAVO2 AND MARIA E. LOPEZ1
1Departamento de Química. Universidad de Oriente. Apartado Postal 208. Cumaná. Venezuela
2Departamento de Bioanálisis. Universidad de Oriente. Apartado Postal 208. Cumaná. Venezuela
(Received: January 4, 2012 - Accepted: September 3, 2012)
ABSTRACT
Cefoperazone (Hcefopz) interacts with transition metal(II) ions to give [M(cefopz)Cl] complexes (M = Fe, Co, Ni, Cu and Cd) and [Fe(cefopz)Cl]Cl which
were characterized by physicochemical and spectroscopic methods. The spectra indicated that the antibiotics act as monoanionic multidentate NO3 chelating agent
towards metal ions, via the amides, and carboxylate and N-azomoiety. The complexes are non-toxic, insoluble in water and common organic solvents and probably
have polymeric structures.
Keywords cefoperazone sodium; antibiotic; metal complexes; antibacterial activity
NiCl2.6H2O, CuCl2.2H2O or CdCl (1 mmol) in methanol (40 cm3). The
INTRODUCTION
reaction mixture was then stirred 2at room temperature for ca. 5h, and a
coloured precipitate formed. The precipitated complexes were filtered off,
washed with water, methanol and ether and dried under reduced pressure at
room temperature. All syntheses were carried out under a nitrogen atmosphere.
The cephalosporin antibiotics are comprised of several different classes
of compounds with dissimilar spectrums of activity and pharmacokinetic
profiles. All “true” cephalosporins are derived from cephalosporin C which
is produced from Cephalosporium acremonium. Cephalosporins are usually
bactericidal against susceptible bacteria and act by inhibiting mucopeptide
synthesis in the cell wall resulting in a defective barrier and an osmotically
unstable spheroplast. The exact mechanism for this effect has not been
definitively determined, but beta-lactam antibiotics have been shown to bind to
several enzymes (carboxypeptidases, transpeptidases, endopeptidases) within
the bacterial cytoplasmic membrane that are involved with cell wall synthesis
[1-4]. The different affinities that various beta-lactam antibiotics have for
these enzymes (also known as penicillin-binding proteins; PBPs) help explain
the differences in spectrums of activity of these drugs that are not explained
by the influence of beta-lactamases. Like other beta-lactam antibiotics,
cephalosporins are generally considered to be more effective against actively
growing bacteria. The cephalosporin class of antibiotics is usually divided
into three classifications or generations. The third generation cephalosporins
retain the gram positive activity of the first and second generation agents, but in
comparison, have much expanded gram negative activity [5,6]. Cefoperazone
belongs to the third generation cephalosporins and in continuation of our work
about metal based drugs [7-12] we report here the synthesis and characterization
of cefoperazone metal complexes. The chemical structure of cefoperazone
monosodium is shown in Figure 1.
RESULTS AND DISCUSSION
Cefoperazone has two ionisable groups (pKa = 2.55 and 9.55); it thus
exists predominantly as a monoanionic at a physiological pH. The elemental
analyses (Table 1) agree well with a 1:1 metal to ligand stoichiometry for
all the complexes. They are air-stable solids. The mononuclear complexes
are coloured, insoluble in water and other common organic solvents such
as ethanol, benzene, acetone, acetonitrile and ether but soluble in DMF and
DMSO. The general formulae [M(cefopz)Cl] and [Fe(cefopz)Cl]Cl have been
assigned to the complexes. Thermograms of the hydrated metal complexes,
provided as supplementary information, indicate endothermic decompositions
in the 80–90 °C range due to the loss of molecules of water of hydration, and
also reveal that the complexes are stable with no coordinated water and solvent
molecules. Attempts to form complexes of a well-defined stoichiometry, under
the above-mentioned conditions, with chromium(III), copper(I), zinc(II),
mercury(II) and manganese(II) ions were unsuccessful. The conductivity
values measured in DMSO at room temperature fall in the range of non-
electrolytes [13] suggesting that the chloride ion is coordinated to the metal(II)
ions. The exception was the iron(III) complex, [Fe(cefopz)Cl]Cl, which show
to be 1:1 electrolyte.
EXPERIMENTAL
IR spectra
The IR spectra of cefoperazone and its complexes are similar and have been
assigned mainly to those specific wavenumbers directly involved in complex
formation. The main IR wavenumbers are recorded in Table 2. Generally the
ring carbonyl absorption frequency will be shifted to higher wave numbers as
the ring becomes more and more strained. Thus, the lactam n(C=O) and the 2,3
piperazinedione n(C=O) bands appear at 1750 and 1690 cm-1 respectively in
the spectra of cefoperazone and in all the metal complexes [14], the exception
was the [Fe(cefopz)Cl] complex which presents the lactam n(C=O) band at
1710 cm-1. The (amide I) n(C=O) band of the ligand appears at 1660 cm-1
while the complexes showed a negative shift, at around the 1645–1640 cm-1
range indicating coordination through oxygen [15]. A shift of the amide(II)
band towards higher frequencies, indicates nonparticipation of the nitrogen
atom in the coordination [16]. All this suggests that coordination of the ligand
occurs through the oxygen atom from the amide carbonyl groups rather than
the lactam and piperazinedione carbonyl moieties where the shifting was not
significant, although the binding through b-lactamic carbonyl group cannot be
ruled out in the [Fe(cefopz)Cl] complex. The band at 1610 cm-1, corresponding
to the carboxylate asymmetrical stretching, is shifted to higher wavenumbers
(1620–1630 cm-1) after complexation with the metal(II) ions, thus indicating
coordination through that group. The remaining carboxylate bands, namely
Physical methods
The spectra of the ligand and its metal complexes were recorded as
KBr pellets in the 4000–400 cm-1 range with a Perkin-Elmer Series 2000
spectrophotometer. FTIR spectra as polyethylene pellets were registered
between 450–120 cm-1 using a Bruker IFS 66V spectrophotometer. UV–Vis
spectra were recorded using a Perkin-Elmer recording spectrometer. C, H, N
and S were analyzed on a LECO CHNS 932 model microanalytical instrument.
Metal contents were estimated spectrophotometrically on an atomic absorption
spectrometer. The halogen content was determined by combustion of the solid
complex (30 mg) in an oxygen flask in the presence of a KOH-H2O2 mixture.
The halide content was then determined by titration with a standard Hg(NO3)2
solution using diphenyl carbazone as an indicator. Thermograms were recorded
on a simultaneous thermal analyzer, STA-6000 (Perkin Elmer) instrument
at a heating rate of 4ºC min-1 up to 200°C. Magnetic susceptibilities were
measured on a Johnson Matthey Susceptibility Balance at room temperature
using Pascal’s constants for the diamagnetic corrections and mercury(II)
tetrathiocyanato-cobaltate(II) as calibrant. EPR spectra were recorded on a
Bruker ECS 106 spectrometer by the X–band.
Materials and methods
n
sym(COO), γ(COO), ω(COO) and ρ(COO), formerly at 1400, 785, 610 and
All chemicals were commercially obtained in their purest form and
were used without further purification. Solvents were redistilled by standard
techniques before use. The complexes were prepared by mixing cefoperazone
sodium salt (1 mmol) and metal salts: FeCl2.4H2O, FeCl3.6H2O, CoCl2.6H2O,
530 cm-1, respectively, also change as a result of coordination. Furthermore,
a carboxylate ligand can bind to the metal atom either as a monodentate or a
bidentate ligand, giving changes in the relative positions of the antisymmetric
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