äééêÑàçÄñàéççÄü ïàåàü, 2009, ÚÓÏ 35, ‹ 2, Ò. 83–97
group of synthetic antibacterial compounds, having a fluorine at-
om at position 6 and a piperazine ring at position 7 of quinolone-3-carboxylic acid. It was proved that the ac-
tivity of quinolones was decreased in the environment of certain metal ions by the formation of sparingly sol-
uble metal complexes. The proposed reason for such maintenance might be the chelate bonding of the quinolo-
ne to the metal. Again, it was proposed that metal ions, especially magnesium ions, were engaged in the mode
of action of quinolones. In this review article, selected structures of fluoroquinolones metal complexes were
performed and discussed in terms of their therapeutic application. The nuclease activity and antibacterial activ-
ity tests were presented and the effects of metal complexes were compared to free fluoroquinolones. Finally,
the results were introduced.
äééêÑàçÄñàéççÄü ïàåàüÚÓÏ 35‹ 22009
SERAFIN, STA CZAK
The third generation of quinolones are fluoroquinolo-
ne antibiotics, such as ciprofloxacin (1-cyclopropyl-6-flu-
(Cf, IV)), norfloxacin (1-ethyl-6-fluoro-4-oxo-7-piper-
azin-1-yl-1H-quinoline-3-carboxylic acid (Nf, V)), pe-
oxo-1,4-dihydro-3-quinolone carboxylic acid (Pf, VI)),
and ofloxacin (+/–)-9-fluoro-2,3-dihydro
1,4-benzoxazine-6-carboxylic acid (Oflo, VII)):
They were chemically modified to become more effi-
cient antibacterial agents, which exhibit a broad spec-
trum of high activity against gram-negative bacteria
(Pseudomonas aeruginosa, Neisseria gonorhoea, Hae-
mophilus influenzae) and lower activity against gram-
positive bacteria (Enterbacteriaceae, Staphylococcus
aureus) and also show significant activity against anaer-
obic bacteria .
Fluoroquinolones were discovered
and presented as
broad-spectrum antibacterial agents, which were deriva-
tives of quinolone carboxylic acid . Most of fluoroqui-
nolones have a carboxylic group at position 3 and a carbo-
nyl group at position 4: therefore they are usually referred
to 4-quinolones. Then, it was discovered that the addition
of the fluorine atom at position 6 and the
or methyl piperazinyl group at position 7 greatly enhanced
the spectrum of their activity. Differences at the moiety
present at N(1) and at C(7) position have a strong impact
on the microbiological activity and the pharmacokinetic
properties of drugs .
Fluoroquinolones are specific inhibitors of the bac-
terial DNA gyrase (topoisomerase II) and
DNA relegation activity and distort DNA in the complex
(topoisomerase IV) , and inactivation of these en-
zymes is lethal to the bacteria. Due to their specific mode
of action, they are considered to be the broad-spectrum
antibiotics active against gram-positive and gram-nega-
tive pathogens. Additionally, they combat infections
by microorganism that are resistant or multi-re-
sistant to other antimicrobials, such as amino glycosides
and tetracycline’s of β-lactams .
Fluoroquinolones are extremely useful for the treat-
ment of a variety of infections, especially urinary track
infections, but also soft tissue infections, respiratory
infections, bone-joint infections, typhoid fewer, sexu-
transmitted diseases, prostatitis, community-ac-
quired pneumonia, conjunctivitis, acute bronchitis,
and sinusitis .
Mechanism of fluoroquinolone action. The fluoro-
quinolones’ mode of action consists of interactions with
both enzymes topoisomerase IV and topoisomerase II.
These interactions are recognized as drug targets. The two
enzymes frequently vary in their sensitivities to many qui-
predominantly topoisomerase II is more sen-
sitive to gram-negative bacteria and topoisomerase IV is
more sensitive to gram-positive bacteria .
The development of the ternary complex of fluoroqui-
nolone, DNA, and also topoisomerase II or topoisomerase
IV supervene through the interactions in which quinolone
binding appears to infer transitions in DNA and
somerase respectively, that occur separately from the
DNA cleavage, which is the general mark of quinolones
action . Inhibition of DNA synthesis by fluoroquino-
lones requires the targeted topoisomerase to possess DNA
cleavage capability, and failures of the replication fork
with reversible fluoroquinolones–DNA–topoisomerase
complexes transform them into an irreversible molecule
reports appeared in the literature that were
connected with the molecular details of drug-DNA and
drug–enzyme interactions. The first drug–DNA models
were proposed by Shen and co workers and included hy-
drogen bond type interactions models between the DNA
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THE COMPLEXES OF METAL IONS WITH FLUOROQUINOLONES 85
unpaired bases and the quinolone, as well as stacked
dimerization of the drug . These models were modi-
fied and implied a possible interaction between the C(7)
substituent quinolone and the B subunit of DNA gyrase.
There was also many theories about the mode of action
of fluoroquinolones focused on the involvement of
nesium ions . One of the more recent model suggested
that ions Mg
played an important role in the drug bind-
ing to a DNA-gyrase complex. Certainly it is not yet
known whether the magnesium ions influence is due to its
stabilizing effect on the DNA topology or its ability to
chelate with the keto and carboxylate groups of quinolo-
nes [22, 23].
It was also reported
that a restrained strong interaction
between quinolones and plasmid or single-stranded DNA
appear only in the presence of a physiological concentra-
tion of Mg
. The satisfactory relationship between the
binding constants for the ternary DNA–drug–Mg
) and gyrase poisoning activity was indicated.
Nevertheless, the authors did not propose a structural
model for the ternary complex, with the exception of re-
porting that the data did not enforce a mechanism of action
based upon quinolone intercalation into B-DNA .
Norden et al. using similar experimental methods (CD
measurements) discovered a near perpendicular
orientation of the norfloxacin chromophore plane relative
to the DNA axis that precluded classical surface binding.
However, the possibility of classical intercalation was pre-
cluded based on DNA unwinding experiments .
Correlation fluoroquinolones with metal ions. In
1985, there was first information about concurrent admin-
istration of magnesium and
aluminium containing antacid
with ciprofloxacin resulted in a nearly complete loss of ac-
tivity of the drug . Antacids not only contain alumini-
um and magnesium, but also enclose other ions such as
calcium and bismuth. Thereby, several authors began to
observe the reasons for the decreased activity of fluoroqui-
nolones in the presence of
different ions (iron, zinc, calci-
um, aluminum, or magnesium), which were components
of other antacids or the multivitamin mixtures [27–30].
Due to these studies, it was reported that patients who oral-
ly administrated fluoroquinolones should avoid mixtures
containing multivalent cations, because quinolones were
chelate bonded to these metals, in consequence formed
metal complex in
the gastric system .
These studies were mainly addressed to identify the
groups directly attached to the metal site and establish
the structure of the coordination compounds thus formed
It seems that the role of metal ions is imperative for the
way of function of fluoroquinolones. The synthesis and
characterization of new metal complexes with fluoroqui-
nolones are a great importance for better understanding
the drug–metal ion interactions. It was suggested that the
reactions of metal ions with fluoroquinolones were essen-
tial for the activity of these antimicrobial agents, and the
metal ions (magnesium, copper, and iron) may bridge the
binding of the quinolone to DNA
gyrase or of bacterial
DNA directly [35, 36].
The uptake of norfloxacin by Escherichia coli was an-
alyzed under different pH conditions and by the monova-
lent/divalent metal ion concentrations. The simple diffu-
sion mechanism for fluoroquinolones incorporation into
cells was contributed by the result to the study. The uptake
process declined under acidic conditions
. The inherence
ions did not impact on the outcome to a
prominent field, while divalent ions caused a dramatic in-
clination in drug incorporation. The antibacterial activity
estimated under identical experimental conditions per-
formed a straight relationship with the uptake data. It was
suggested that the ability of the drug penetration into cells
an action of its net charge. The zwitterionic
form of a molecule represented the maximum permeation
properties, while the uptake was intensely diminished
when the drug bear a net charge as an effect of ionization
or complex formation with divalent ions .
Metal ions play a pivotal role in the actions of some
and natural antibiotics and are engaged in spe-
cific interactions of these molecules with proteins, nu-
cleic acids, and other bio-molecules .
Magnesium as a very popular ion in biological fluids,
being not only important for the activity of quinolones but
also for other antibacterial agents, such as aureolic acid
and its derivatives
, various tetracyclines, and some others
. Due to the facts some of metal–quinolone complexes
interact with DNA and impair its function, quinolones are
also classified as “metalloantibiotics” .
The increasing incidences of bacterial drug resistance
indicated an improvement of the existing antimicrobial
drugs and development of new ones. The most important
and characteristic target
in pathogenic microorganisms is
gyrase. As it was mentioned, quinolones are known as in-
hibitors of topoisomerase II. The molecular details of the
inhibition of gyrase activity still remain unclear, but most
models include divalent ions, either as a cofactor for the
gyrase activity, or as a neutralizing agent of the negative
groups of DNA . The concern about the ra-
tional design of new transition metal complexes, which
bind and cleave duplex DNA with high sequence or struc-
ture selectivity, is developing. According to these facts,
the further aim of referred works was to determinate bio-
logical activity of the new complexes .
Several authors reported
that the antibacterial activities
of fluoroquinolones were altered in the presence of diva-
lent cations . The in vivo behavior of fluoroquinolones
as antibacterial agents was strongly affected by their phys-
icochemical properties, in particular, their acid-base prop-
erties, as well as their capability to form complexes with
metal ions .
Recent data reported
a significant role of the Cu
in the mode of action of fluoroquinolones. It was suggest-
ed that the intercalation of the drug as a complex with met-
al ions would be an important step in this mechanism .
Additionally, quinolones impact on trace metal metabo-
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SERAFIN, STA CZAK
lism supposing to be potent inhibitors of copper- and zinc-
dependent enzymes .
The suggested way of the interaction between quinolo-
ne and metal ions was chelation between the metal and the
4-oxo and contiguous carboxyl groups. Quinolones can
bind several divalent metal ions, including Mg
, and Al
which may result in changes in their activity [47–49]. For
were found to decrease the activ-
ity of the drugs, whereas the Fe(III) and Zn(II) complexes
were thought to exhibit higher activity .
There are some data that present biological activity of
some quinolone–metal complexes against various micro-
organisms and some other positive effects on the treat-
ment of certain diseases
. Certain bacterial infections now
defy all know antibiotics, and antibiotic resistance is a
growing problem. It is obvious that there is a great need
for new antibacterial agents and metal complexes could be
active against multi resistant microorganisms .
Chemical information. The majority number of ana-
lytical methods were reported in the literature
for the de-
termination of quinolones in pure forms, dosage forms,
and biological fluids . The reported papers presented
several free fluoroquinolone structures, such as pefloxacin
methanesulfonate [53, 54], ciprofloxacin hexahydrate
, and ciprofloxacin lactate .
The crystal structure of fluoroquinolone complexes
evidence that the chemotherapeutic agents can take part in
the formation of complexes in a great
number of ways.
Low solubility of quinolones and their complexes in
the pH range 5–10 presents a great difficulty in preparing
single crystals of quinolone metal complexes. Only sever-
al crystal structures of coordinated quinolone to the metal
ion have been already known. The optimum pH range for
the formation of the metal complexes
is 3.5–4.5 for all
fluoroquinolones. At this pH quinolones mainly exist in
their protonated form and complexation with a metal ion
is accompanied by the liberation of a proton from the py-
ridine carboxylic group .
On the other hand, numerous crystal structures of
mixed complexes with coordinated quinolones and N-, S-,
or other O-
donors were reported. In the like manner,
metal–quinolone compounds in their ionic state can be
easily achieved. In several analytical investigations it was
presented that fluoroquinolone was coordinated to the
metal in the pH range higher than 7.
The complexes isolated from acidic media usually
contained single and/or doubly protonated quinolones that
were unable to bind to the metal ion and, in these cases,
only the electrostatic interaction was observed between
the drug and metal ions .
In other studies, it was found that neutral fluoroquino-
lones in the zwitterionic state were able to form simple
complexes. In these complexes, the quinolone is coordi-
the ring carbonyl group at position 4 and
through one of the oxygen atoms of the carboxylate group
at position 3. Moreover, fluoroquinolones can act bridging
ligands and then be capable of forming polynuclear com-
It is important to mention that, in the most cases, the
carboxylic group is not deprotonated and the hydrogen
atom of this group is hydrogen-bonded to the adjacent
4-oxo atom. Sometimes the carboxylic group is ionized
and the molecule presents in its zwitterionic form with
protonated terminal nitrogen of the piperazine ring in the
solid state .
Most of fluoroquinolones are sparingly soluble in a
wide range of pH . Mixing of an
aqueous solution of
metal salts and a quinolone solution mostly results in
precipitation, making it difficult in growing crystals of
A large number of chromatographic methods have
been reported for the determination of fluoroquinolones.
Ofloxacin , pefloxacin , norfloxacin , and
ciprofloxacin  were determined by high-performance
liquid chromatography (HPLC). Until presently, various
have been described for the
determination of quinolone [66, 67] by charge-transfer
complex formation with 2,3-dichloro-5,6-dicyano-p-ben-
zo-quinone, chloranilic acid, and 7,7,8,8-tetracyanoquin-
odimethane . Furthermore, there were a number of
other methods presented for their determination, such as
fluorimetry [69, 70], polarography , voltammetric
, and capillary electrophoresis .
CHARACTERISTIC OF METAL COMPLEXES
is one of two fluoroquinolones with
the widest clinical application. In 1986, it received Food
and Drug Administration approval .
The ability of ciprofloxacin to form metal complexes
and transport of ciprofloxacin through bacterial mem-
branes is extremely pH-dependent with peaking at neutral
pH [75, 76].
It was suggested that the zwitterionic and uncharged
structure of quinolone
was responsible for passive trans-
port through cytoplasmic membranes. In stomach pH is
low, whilst in the intestine is rather higher, so transport of
ciprofloxacin here would be best. Additionally, the intes-
tine is the place where the metal-quinolone complexation
occurs, decreasing absorption of the drug .
Bismuth complex. Ciprofloxacin was described
most active quinolone against Helicobacter pylori, but it
was inefficient in eradicating the bacteria from the
stomach of patients with gastritis . Additionally, it is
worth mentioning that the use of bismuth for the treatment
of gastric diseases is very popular [79, 80].
Turel et al.  explored the bismuth (III) complex of
] · 2H
O to find new and bet-
ter activities against Helicobacter pylori. In this work, the
crystal structure of this complex was presented, where Cf
was a doubly protonated and Cf was once protonated mol-
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THE COMPLEXES OF METAL IONS WITH FLUOROQUINOLONES 87
ecule of ciprofloxacin. One of the ciprofloxacin molecule
was protonated at the carbonyl oxygen and nitrogen of the
piperazine ring, and an other at nitrogen only. Two water
molecules participated in the hydrogen bond network.
Cerium complex. The crystal structure of the
cerium (III) complex with ciprofloxacin
lished. The quinolone was bonded to the metal through
3-carboxyl and 4-keto oxygen and the coordination num-
ber of the ligand was eight .
Cobalt complexes. The synthesis of the complex
] · 3H
O as single crystals was possible only
when it was isolated from a saturated solution of fluoro-
quinolone under the basic conditions (pH ~ 8). It was
proved that at higher pH, where the solubility of ciproflox-
acin was considerably higher, the coprecipitation of metal
hydroxide baffled the synthesis of the pure metal complex.
achieved that the complex was insoluble in water
and organic solvents. It decomposed in dilute solutions of
all strong acids. It was described by elemental analysis,
FAB-MS, TG analysis, IR spectroscopy, and magnetic
measurements. Mass spectrometry of the compound
marked bonding of the Co
ion to quinolone, forming a
] molecule. The IR spectrum of the compound
was similar to that of [Cu(Cf)
O. The cobalt ion
was coordinated to the two pyridine and two carboxylic
oxygen atoms of two quinolone molecules. Thermal anal-
ysis indicated that water molecules were included as lat-
tice water in the crystal structure of [Co(Cf)
] · 3H
Copper complexes. Jimenez-Garrido et al.  pre-
pared three mixed complexes of ciprofloxacin with Cu
(II), namely [Cu(Cf)
] · 6H
O and [Cu(Cf)
] · 2H
O. The single-crystal
structure of [Cu(Cf)
] · 6H
O was determined 
and characterized. The complex composed of the
] unit with two semicoordinated Cl
anions, and one uncoordinated water molecule. The metal
ion was in a tetragonally distorted octahedral environment
It was suggested that the binding of copper(II) de-
pended on the nature of other ligands (phenantroline)
presented in the solution . For the copper(II) com-
plex with nalidixic acid,
in the absence of the extra
ligand, chelation occurred through the 3-carboxylate
group, while in the presence of the ligand, chelation was
through the 3-carboxylate and also 4-keto groups. The
ciprofloxacin complexes in the absence of the ligand,
] · 6H
O, and in the presence of added
) · 2H
where Bipy – 2,2'-bipyridine), were explored. In both
complexes, copper (II) was coordinated to the carbonyl
group at position 4 and the oxygen of the carboxylate
group at position 3 of ciprofloxacin to form a six-mem-
bered ring . The second complex included the
cation, nitrate anion, and
two uncoordinated water molecules. It was a five-coor-
dinate complex with the central metal ion coordinated
with two nitrogen groups from Bipy, the keto and 3-car-
boxylate oxygen groups, and the disordered Cl
ions occupying the fifth site .
] · 6H
O complex of ciprofloxacin
with copper(II) was prepared by mixing an aqueous solu-
tions of ciprofloxacin and copper salts (chloride, sulfate).
The copper ion was surrounded by four oxygen atoms of
the ciprofloxacin carbonyl groups and positioned at the
center of inversion .
Another complex of copper with ciprofloxacin,
O, was described, where only
one molecule of quinolone was coordinated to the metal.
ion was a slightly distorted square pyramid with
the coordination environment around the central atom in
the structure. Ciprofloxacin was coordinated to copper
through the carbonyl atom and carboxylic atom. Two wa-
ter molecules were coordinated at a longer distance .
The first known mixed-valance Cu(II)–Cu(I) complex
with Cf [Cu
] was achieved by Drevensek
et al. . The complex was isolated due to the reaction
from a mixture of ciprofloxacin, copper(II) chloride dehy-
drate, and L-histidine in a molar ratio of 1 : 1 : 1. The unit
included two zwitterionic molecules of the ligand, Cu
ion, and two dichlorocuprate(I) anions. In this complex,
the copper(II) atom was distorted and surrounded by four
oxygen atoms in the equatorial positions and two chloride
ions of the dichlorocuprate(I) groups occupying the vacant
apical positions. The chloride ion of the CuCl
served as the first bridging ligand between the Cu(II) and
Cu(I) centers. The second bonding between two copper at-
oms, Cu(I) and Cu(II), indicated the quinolone oxygen
O(1) that is engaged in a weak interaction with the
It is necessary to mention that the absence of
dine resulted in the isolation of [Cu(Cf)
] · 2H
tainly, the added ligand played a role of a reducing factor
in the reaction and was not able to coordinate. The interac-
tion of copper and histidine is extremely important in bio-
logical fluids. Metal-catalyzed oxidation of proteins is a
strongly selective reaction that appears principally at pro-
tein sites with
transition metal binding capacity. Several
sites including histidine have affinity for Cu(II). It was re-
alized that copper binding to prior protein at a histidine-
rich region resulted in a facile oxidation of the protein
molecule, the reaction that was characterized by the vast
aggregation and precipitation of prion protein .
valance copper complexes were of great interest,
because they display interesting properties, provide infor-
mation on electron-transfer, and could serve as models for
copper-containing enzymes [94, 95]. Structure of the
mixed-valence complex Cu(II)/Cu(I) of ciprofloxacin is
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SERAFIN, STA CZAK
Iron complex. Wallis et al.  prepared from an
aqueous solutions the iron (III) complex with ciprofloxa-
cin and nitriloacetate (Nta) as an additional ligand,
[Fe(Cf)(Nta)] · 3.5H
O. It was important to use a dilute
ammonia solution to adjust the pH to 7. The compound
folded of a neutral [Fe(Cf)(Nta)] complex and 3.5 water
molecules. The iron was bonded to the keto and carboxy-
lic oxygen of Cf, and the coordination number of ligand
was six. The piperazinyl ring had
a positive charge on the
Vanadium complex. The vanadium complex was
isolated from an aqueous solution of VOSO
and Cf. The
crystals were very unstable and contained a large amount
of disordered water molecules, so the exact solution of the
structure was not possible to be achieved. The complex
O was characterized by chelate
bonding of vanadium to 4-oxo and carboxylic oxygen of
Zinc complexes. The pH dependence of the mak-
ing complexes between Zn(II) and Cf was studied in
. Two compounds of ciprofloxacin with Zn(II),
] · 2H
O and [Zn(Cf)
] · 3H
O, were gained.
X-ray diffraction indicated that the structure of the first
compound was ionic, consisting of the tetrachlorozin-
cate(II) dianion and two protonated monocationic ciprof-
loxacin molecules. The second compounds was achieved
as crystals from an aqueous solution of ciprofloxacin hy-
drochloride and the salt of zinc in a range
of pH 8 by the
addition of sodium hydroxide. On the basis of the analysis
of these two compounds, it was suggested that the second
compound was coordinated with Zn(II). This complex of
Cf with Zn(II) was insoluble in water, methanol, ethanol,
chloroform, acetone, ether, ethylene glycol, 2-propanol,
carbon tetrachloride, cyclohexanone, DMF
, and DMSO.
It decomposed in dilute solutions of all strong acids. Com-
plex ciprofloxacin with Zn(II) is shown below.
The molecule of norfloxacin (Nf) in its zwitterionic
form possesses a favorable solubility in acidic or basis sol-
vents, whereas its solubility in water, methanol, ethanol,
and chloroform is very poor
. On the other hand, the
metal complexes of norfloxacin can be better solved in
water, methanol, and ethanol. This increase in solubility
can improve the ability of drug in transport through the
membrane of a cell and then enhance the biological utili-
zation ratio and activity of the drug . It is worth to
cent that the hydrothermal reaction of norfloxacin (with
non methylated piperazine) with different metal ions at pH
between 7 and 8 resulted in a 2D squared grid of com-
plexes, where also N-piperazine is coordinated to the
metal . Zwitterionic structure of norfloxacin is
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THE COMPLEXES OF METAL IONS WITH FLUOROQUINOLONES 89
Transitional metal complexes
In vivo there are slightly low concentrations of transi-
tional metals, and their ligand environment can be consid-
erably altered when a therapeutically effective dose of
drug is administrated. This change in the balance between
the metal ion and ligand may have a intensive impact on
the antimicrobial activity of the
complex against potential-
ly susceptible bacteria .
The coordination compounds with transition metal
ions have not been completely examined. Especially, the
studies on the crystal structures of norfloxacin directly
chelated to transition metal ions are very rare.
Magnesium, calcium, and barium metal com-
plexes. Chen was the first one who described the syn-
of two dimeric complexes of norfloxacin with
. The crystallographic study of
these complexes proved that the carbonyl oxygen and
one of the oxygen atoms of the carboxylate group of
norfloxacin were directly coordinated to magnesium or
In 2001, Al-Mustafa isolated and introduced the char-
acterization of the complexes formed from the interaction
of norfloxacin and ciprofloxacin with magnesium,
um, and barium perchlorate in methanol . All of the
isolated complexes were synthesized by the reaction of the
metal salt with drug in a 1 : 2 molar ratio. The complexes
were white air-stable solids at room temperature. The ther-
mogravimetric analysis (TGA)  and differential
scanning calorimetry (DSC) data indicated that all of the
were unstable and decomposed in two steps at
temperatures above 270°C, which is characteristic of the
quinolone complexes. These achieved complexes were in-
soluble in benzene, chloroform, and dichloromethane, and
other nonpolar solvents are slightly soluble in water,
methanol, and ethanol and are soluble in DMF and DMSO
. Proposed structures of the Nf
Ca(II), Mg(II), and Ba(II) are shown below:
Copper complexes. In 2001, Chen et al. prepared the
mixed-ligand copper(I) complex [Cu(PPh
(Nf)] · ClO
. The crystal structure of this compound consisted of
cation and Cl anion. There was
no appreciable cation-anion interaction in the structure but
the static interaction one. The cooper ion in this complex
displayed a rather distorted tetrahedron, and was linked to
two phosphorus atoms of the triphenylophosphine (PPh
ligands, and two oxygen atoms of the ligand. Structure of
the mixed-ligand complex of Nf with Cu(II)/Cu(I) is
The most part of Nf complexes were known to behave
in a similar way, where the norfloxacin ligand was chelat-
ed to the copper ion through the O
displaying a stable six-membered chelating ring .
Consequently, the coordinate mode around Cu(I) in this
complex was quite different from those found in the
Fe(III), Co(II), and Zn(II) complexes with Nf proposed by
Gao et al. . The quinolone ring system was almost
planar, and the ethyl group sticked
out of the plane. The
piperazine ring was in the chair conformation, where the
terminal nitrogen atom was protonated, which probably
explained why it failed to coordinate to the Cu
charge of the quinolone molecule was neutralized by the
positive charge of the piperazinyl ring on the external ni-
trogen; and because of this norfloxacin behaved as a neu-
tral ligand in this complex.
Cobalt, iron, and manganese metal complexes.
Norfloxacin reacted with Mn(II), Fe(III), and Co(II
acetone or methanol solutions at room temperature to
form solid complexes with a characteristic color of the ap-
propriate metal ions. The metal (Mn(II), Co(II), and
Fe(III)) to ligand (norfloxacin) molar ratio for all com-
plexes was established on the basis of the elemental
analysis: 1 : 2 for Mn(II) and
Co(II) and 1 : 3 for Fe(III)
[108, 109]. All achieved complexes possessed different
numbers of water molecules in particular compounds
. The complexes [Mn(Nf)
O, and [Co(Nf)
O were de-
scribed by infrared spectra analysis. The Nf complexes in-
dicated all the features of a neutral molecule in the zwitte-
rionic form .
The novel complexes of norfloxacin with Co(II),
Fe(III), and also with Zn(II) achieved by Gao et al. 
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SERAFIN, STA CZAK
presented better solubility in water and ethanol than free
norfloxacin. Complexes of norfloxacin with Mn(II),
Co(II), and Fe (III) are shown below:
Al-Mustafa investigated the reaction of norfloxacin
(also ciprofloxacin) with iron(II) and iron(III) perchlorate.
The different colors of the solid complexes indicated that
the composition of the product depended on the metal to
ligand ratio (1 : 1, 1 : 2, 1 : 3). The complexes were soluble
in DMF and DMSO, slightly soluble in methanol, ethanol,
and practically insoluble in dichloromethane
and chloroform .
Silver complex. The silver complex of norfloxacin
was investigated to prevent bacterial infections for hu-
mans during burn treatment and to utilize its antibacterial
properties in topical applications, superior to those of sil-
ver and zinc sulfadiazine. In both examples, the charac-
teristic structures of these
complexes were highly connect-
ed with the slow release of the metal ions Ag
well as to their biological activity . Surprisingly, the
reaction of Nf with Ag
) in which norfloxacin only acted as a mon-
odentate ligand to bind to the Ag
ion by the N atom of the
piperidyl ring. To our knowledge, this complex was the
first example of the Nf complex with the metal ion involv-
ing only the coordination of the N atom of the piperidyl
ring, whereas the 4-oxo and 3-carboxylate oxygen atoms
did not take part in coordination . Due
these facts, the
new coordinate bonding of Nf in this complex yielded a
new light on understanding of norfloxacin drug action
M = Mn(II), Co(II).
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THE COMPLEXES OF METAL IONS WITH FLUOROQUINOLONES 91
The molecular structure of this complex consisted of
cationic molecules of [Ag(Nf)
and a slightly coordinat-
ed anion of N This mode of coordination was unex-
pected and unexampled in quinolone drug interactions to-
ward metal ions. The silver atom might be considered to
be 4-coordinated. Two neutral Nf ligands were in the
trans-position around the axis of N(1)–Ag–N(4), and the
atom was in a symmetric center. The strong intermo-
lecular hydrogen bonds were observed between O(1) and
O(2) as well as between O(4) and O(5). The hydrogen
bonds may prevent the carboxylate groups from coordi-
nating to the Ag
Zinc complexes. These norfloxacin complexes with
] · 4H
O and [Zn(H
were achieved by the hydrothermal reaction. In both cas-
es, the crystal structure of these complexes presented that
two ligands displayed coordination binding to the metal
through the ring carbonyl and one of the carboxylate oxy-
gen. Surprisingly, the apical positions were occupied by
two nitrogen atoms of piperazine rings, whereas the apical
positions in the second complex were occupied by two
water molecules. The authors suggested that in a neutral or
weakly basic solution the nitrogen atom of the piperazine
ring could take part in the coordination, while in a weakly
acidic solution this nitrogen was protonated and loose its
coordination capacity. Authors also reported
complexes expressed strong blue fluorescent emission
and could be used in the future as materials for blue-light
emitting diode devices .
Ofloxacin (Oflo) is characterized by a tricyclic struc-
ture. The presence of a methyl group at position 3 at the
oxazine ring provides an asymmetric center at this posi-
tion . The
methyl group is attached to the ring and be-
cause of this can exist in two optically active forms,
whereas the S-isomer is up to two orders of magnitude
more potent than the R-isomer . Ofloxacin has two
ionizable functional groups in position 4' and the carbox-
ylic acid group in position 6 . The
cule of ofloxacin is in the anionic form. The ofloxacin an-
ion probably binds through: ring carbonyl oxygen and one
oxygen of the carboxylate group; two oxygen atoms of
carboxylate group; one oxygen atom of the carboxylate
The N atom in the piperazinyl group of ofloxacin may
also participate in
complexion with divalent cations. Steric
hindrance from the methyl substituent of N in the piperazi-
nyl group of Oflo resulted in a weak interaction between
the nitrogen atom and the metal ion . It was found
that there was a better agreement of the compound vibra-
tion on frequencies when metal was chelated to
bonyl oxygen and one oxygen of the carboxylate group of
Oflo as compared to its bonding to other form. Metal–ox-
ygen stretching bands for the fluoroquinolones’ complex-
es are metal-sensitive and are shifted to higher frequencies
as the metal changes in the order Co < Ni < Cu > Zn and
Ca < Mg < Ba (Irving–Williams series) .
Transitional Metal Complexes
Magnesium complexes. The magnesium complexes
of a racemic form of Oflo and its only S-form levofloxacin
(S-Oflo) were achieved by Drevensek et al. . Two
] · 2H
O were gained by hydrother-
mal reactions, respectively and their crystal structures
were determined. In both examples, the ligands were
bonded through the keto and carboxylate oxygens achiev-
ing a mole ratio of 1 : 2 for Mg : Oflo complexes. The two
structures were almost the same with the exception of the
orientation of one of the
oxazine methyl groups at the
chiral center of the second combination, which was found
in the equatorial position, the other oxazine methyl groups
in both complexes being axial. This dissimilarity influ-
enced on the stacking pattern of quinolone molecules in
the cell. The insignificantly distorted octahedral coordina-
tion of magnesium was completed by
two water mole-
cules that were located in axial positions. The piperazine
nitrogen did not interact with magnesium, likely on ac-
count of steric crowding of the methyl group .
Copper, cobalt, and zinc complexes. The ofloxacin
complexes with Cu(II), Co(II), and Zn(II) salts were also
achieved with the presented formulas
] · 2H
] · 4H
O (M = Co or Zn). It was proved that
from an acidic solution of quinolones and various metals
ionic type compounds could be isolated as a complexes
. It was proved that the metal ion was coordinated to
ofloxacin in the complexes through the ring carbonyl and
one of the carboxylic oxygen atoms .
complexes of Co(II) and Zn(II) with Oflo were in-
soluble in water but soluble in different organic sol-
vents, such as dimethylformamide, methanol, or dime-
thyl sulfoxide. In addition, it was also possible to isolate
from methanol the Co(II) complex in a crystalline form,
] · 4MeOH. The structural data
showed that the Co(II) ions were in an octahedral local ge-
ometry surrounded by six oxygen atoms. Equatorial posi-
tions belonged to the two coordinating ofloxacin mole-
cules, and the axial (trans) positions were occupied by
methanol molecules .
The copper complex with ofloxacin, [Cu(Oflo)
O, was also isolated. The Cu
ion was chelate bond-
ed to quinolone through ring carbonyl and one of the car-
boxylic oxygen atom. Furthermore, one water molecule
was bonded to the copper and the next two water mole-
cules provided additional crystalline stability through a
network of hydrogen bond interaction .
Calcium and magnesium complexes. It was
that magnesium and calcium ions  perform an af-
finity to pefloxacin mesylate at pH 7.4. At the beginning
the carbonyl and carboxyl groups were the binding sites,
äééêÑàçÄñàéççÄü ïàåàüÚÓÏ 35‹ 22009
SERAFIN, STA CZAK
then the N-4'-piperazinyl atom was investigated as an-
other site to interact with magnesium and pefloxacin
ethyl ester .
Silver complex. The complex of pefloxacin with sil-
ver metal, [Ag
] · 6H
O, was isolated by dis-
solving the silver complex in an aqueous ammonia solu-
tion. The nature of bonding in this compound was much
different. Two silver atoms were coordinated by two car-
boxyl groups from two ligand molecules. The nitrogen at-
om of the piperazinyl moiety from the second pefloxacin
molecule was also
bonded to each silver atom. The silver
coordination was completed by an oxygen atom from a
water molecule [130, 131].
Short Analysis of the Metal–fluoroquinolone Structures
According to Turel’s  interpretation of the struc-
tural analysis presented that “in free fluoroquinolones the
ring carbonyl carbon–oxygen distances were between
1.246 and 1.276 Å and the distances
between carbon and
oxygen in carboxylic groups were in the range from 1.205
to 1.327 Å”. According to the facts, “the carboxylic group
was not dissociated one of the later bonds was much short-
er (double bond) whereas the other bearing the hydrogen
was longer (single bond)” [132, p. 230; 133]. The distanc-
es and angles within the
ligand moiety (quinolone) were
nearly similar to their zwitterionic forms .
The bonding of the metal to the quinolone oxygen at-
oms had impact on a slight lengthening of both ring carbo-
nyl and carboxylic carbon–oxygen bonds. Additionally, it
was discovered that the bond distances in the chelate
bonding of the metal to
ring carbonyl and one of the car-
boxylic oxygen atoms had similar lengths [131, 135, 136].
Near the carboxylic group, the metal–bonded oxygen pre-
sented longer carbon–oxygen distance than the non bond-
ed oxygen [132, 137, 138]. The coordination numbers of
the metal is in the range from 4 to 8 and the most common-
ly appeared coordination polyhedron
is octahedron. The
metal : ligand (quinolones) mole ratios were between 1 : 1
and 1 : 3 .
We summed that the most popular bonding noted for
metal–quinolone complexes was the chelate bonding of
the metal to ring carbonyl and one of the carboxylic oxy-
gen atoms. There were also some exceptions. In the com-
] · 6H
] · 4H
), the piperazine terminal nitrogen atom
might also take part in the bonding to the metal. It was also
discovered that several complexes with other ions (mag-
nesium and calcium) were dimeric . It is very proba-
ble that the different conditions of the synthesis had strong
impact on the differences in bonding of the
Only a few crystal structures of fluoroquinolones coor-
dinated to the metal ions are known. On the other hand, in
great number of crystal structures of mixed metal com-
plexes with coordinated quinolones were reported.
Antibacterial Activity of Metal Complexes
It was proved that millimolar concentration of magne-
sium ion was required for tight binding of quinolones to
DNA  and also the interaction between gyrase A and
quinolones was improved in the presence of magnesium
. These facts suggested that the interactions between
magnesium and quinolone were significant for the drug
mode of action. It was estimated that the intracellular con-
of magnesium ions was much higher than that
of quinolone . According to the stability constants, it
can be indicated that also in biological fluids a mixture of
1 : 1 and 1 : 2 magnesium–quinolone complexes, free qui-
nolones, and hydrated magnesium ions were present. It
was supposed that the magnesium–quinolone complexes
interact with their target to
create DNA–gyrase complex
. However, it was also established that a high con-
centration of extracellular magnesium could decrease the
transport of fluoroquinolones into bacterial cells .
There were discovered some analogies between the mag-
nesium complex with ofloxacin and the magnesium com-
plex of aureolic family drug (chromomycin, anticancer
antibiotics) and it was
tempting to propose that the binding
of the Oflo complex to DNA could be similar to the bind-
ing of the magnesium chromomycin complex .
The bismuth complex with ciprofloxacin showed the
same antimicrobial activity against gram-positive and
gram-negative bacteria as ciprofloxacin itself. No antifun-
gal effect was observed. The antibacterial effects
similar to those reported for the copper(II) and iron(III)
quinolone compounds. There were no microbiological
test against Helicobacter pylori .
It has been already known that free fluoroquinolones
(levofloxacin) exerts higher antibacterial activity than of-
loxacin [148–150]. The same situation was noticed with
the magnesium complexes with both chemotherapeutic
agents. The minimum
inhibitory concentration (MIC)
values of both complexes did not significantly differ from
free fluoroquinolones, presenting a general slight decrease
in their antibacterial activity. Congenial antibacterial ac-
tivities of metal complexes and free quinolones was re-
ported in the majority of studies of metal-quinolone com-
plexes. It was not a surprise because it
was probably a re-
sult of the intracellular biological conversion of the
From all results that were described by authors it can
be assumed that the antimicrobial activity of metal–cipro-
floxacin compounds was similar to the free ligand with
one exception: the magnesium complexes have often been
significantly less active than the
parent quinolone drugs,
suggesting that the role of this ion could be different from
the other metal ions studied. It was also found that the ac-
tivity of fluoroquinolones were reduced when the solu-
tions of fluoroquinolones were titrated with magnesium
ions . In addition, the bactericidal studies against
Staphylococcus aureus ATCC 25923 revealed that
quinolone ligand parent exhibited the “paradoxical effect”
(diminution in the number of bacteria killed at a high
äééêÑàçÄñàéççÄü ïàåàüÚÓÏ 35‹ 22009
THE COMPLEXES OF METAL IONS WITH FLUOROQUINOLONES 93
drug concentration), which was described and related to
the mechanism of action of quinolones, but the complex-
es did not suggest different mechanisms of bactericidal
Most antimicrobial activities of the copper complexes
with fluoroquinolones were comparable of those of free
ciprofloxacin. No essential differences in the antimicro-
bial activity among the tested
plexes was presented. It could be due to intercellular bio-
logical inversion complexes to free quinolones .
It should be mentioned that the zinc complex with nor-
floxacin possesses considerably better activity against
gram-negative bacteria than free norfloxacin. As an essen-
tial element for life zinc has multiple biological functions
many physiological processes, and its abundance is rel-
atively high. So, the zinc complexes achieved from coor-
dination with drug molecules may be important in the de-
velopment of new chemotherapy agents .
The complexes of iron Fe(III), [Fe(Nf)
O, and zinc(II), [Zn(Nf)
O, were tested in
vitro against gram-negative microorganisms E. coli and
Bacillus dysenteria bacteria. The complexes showed
stronger activity than norfloxacin itself .
The silver salt of norfloxacin having better antibacteri-
al action in topical burn treatments may be the result of
unique bonding between the ligand and Ag
and its mono-
nuclear structure. Such bonding may result in a larger con-
centration and the fast release of Ag
The compound Cu(Cf)
O was the first
complex of ciprofloxacin able to behave as an efficient
chemical nuclease. Previously, Mendoza et al. determined
the nuclease activity of the ternary copper(II) compound
of nalidixate acid and phenanthroline . They found
that it acted as a powerful nuclease in the presence of
MPA (mercaptopropionic acid) through a mechanism in-
volving hydroxyl radicals. Several authors investigated
the interaction of ciprofloxacin with DNA .
Ulrich et al.  studied the influence of Cu(II) and
Mg(II) on the binding of ciprofloxacin to DNA. Their re-
sults revealed different modes of action of ciprofloxacin in
the presence of Cu(II) and Mg(II). The authors found
ions were directly involved in ciprofloxacin
binding to DNA via phosphate oxygen was observed, and
the Cu(II) interaction with the N(7) position of purine
bases was proposed.
Tabassum et al.  investigated the binding of the
bisciprofloxacin borate copper(II) complex with calf thy-
mus DNA. From these studies they proposed intercalative
of this compound with DNA.
Jimenez-Garrido  proposed that in compound
] · 6H
O the positively charged piperazine
group of the ligand bonded with the negative charge of the
phosphate backbone in DNA via electrostatic interactions
and/or hydrogen bonds and that Cu(II) could interact with
the N(7) positions of the purine bases, strengthening the
binding with DNA. Nevertheless, intercalation of the
complex with DNA, as
has been proposed for the bis-
ciprofloxacin borate copper(II) compound could not be
ruled out. It was noted that the positive charge of ciprof-
loxacin in this complex can be considered a key factor re-
sponsible for its high nucleolytic activity, since the previ-
ously reported Cu(Cf)
O compound, where ciprof-
loxacin was in the anionic form, did not show nuclease
The first analyzing compound that possessed some nu-
clease activity in the absence of peroxide was the
Cu(II)/Cu(I) complex of ciprofloxacin [159, 160]. This
DNA cleavage activity was so important, because the
main compound did not contain phen
or other similar
ligand, which has previously been defined to cause DNA
cleavage [161, 162]. These facts suggested that the main
action of the complex may be different from that of the
copper–phenantroline complexes [163, 164]. Several al-
ternative ways of action were possible, for example, cop-
per could directly coordinate to purine bases and its
activated by peroxide as proposed Kawanishi and Yama-
moto . Another solution was that the piperazine ni-
trogen of the quinolone might be involved in the activity.
This atom either coordinate the copper ion under basic pH
conditions or it might also bind to DNA through positive
charges in a like aminoglycosides, which
were also well-
known class of chemical nucleases .
Lecomte  proved that, in the absence of magne-
sium, pefloxacin binds poorly to DNA and preferentially
to single-stranded rather than to double-stranded DNA.
It is obvious that more test are required to determine
more details of this activity and additionally the possible
selectivity of this reaction.
The most of bacterial infections now defy all known
antibiotics and the antibiotic resistance is a growing
problem in our environment. There is a great need for
new antibacterial agents and metal complexes as novel
derivatives of fluoroquinolones can play an important
role in this field.
article presents physicochemical and
pharmacokinetic information and also antibacterial
properties of fluoroquinolone complexes with different
The most of the described metal complexes with fluo-
roquinolones and metal–quinolone compounds were test-
ed for the activity against diversity of microorganisms. In
most cases, it was evidenced that the antimicrobial activity
of the complexes
was comparable to free fluoroquinolo-
nes. In certain examples the activities were also increased,
for example, the norfloxacin complexes with zinc, iron,
and silver. On the other hand, it was proved that the mag-
nesium complex with ciprofloxacin is characterized by a
slight decrease in its antibacterial activity. It was also dis-
that the vanadium-ciprofloxacin complex is
promising with the respect to its insulin-mimetic behavior
äééêÑàçÄñàéççÄü ïàåàüÚÓÏ 35‹ 22009
SERAFIN, STA CZAK
and to its concomitant low toxicity in the physiological
concentration range .
The mode of action of quinolones involves interactions
with topoisomerase IV and topoisomerase II (DNA gy-
rase). Due to this fact, it is interesting to investigate the
mode of action of fluoroquinolones as complexes with
other metal ions (palladium, platinum, ruthenium, titani-
) against cancer cell lines (cytotoxity).
Additionally, fluoroquinolones as metal complexes
ought to be examined in the respect of their potential drug
resistance. There is a chance that bacterial grams that are
insensitive to pure fluoroquinolones are sensitive to metal
complexes of fluoroquinolones.
Certainly, there is a need to continue research in this
and more results are expected to be published in the
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