The Interactions of Metal Ions With Quinolone Antibacterial Agents

Coordination Chemistry Reviews 232 (2002) 27 /47
www.elsevier.com/locate/ccr
The interactions of metal ions with quinolone antibacterial agents

Iztok Turel *
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
Received 9 October 2001; accepted 18 January 2002
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1
General aspects and characteristics of quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2
The influence of metal ions on the activity of quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Crystal structures of quinolones and their metal compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1
Free drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2
Metal and boron complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1
Magnesium complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2
Calcium complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3
Boron complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.4
Vanadium complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.5
Iron complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.6
Cobalt complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.7
Nickel complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.8
Copper complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.9
Silver complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.10
Zinc complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.11
Cadmium complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.12
Cerium complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.13
Short analysis of the metal /quinolone structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3
Ionic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1
Magnesium compound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2
Bismuth compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3
Iron compound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.4
Platinum compound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.5
Copper compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.6
Zinc compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Thermal analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Infrared spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Protolytic equilibria of quinolones and their metal compounds. Determination of stability constants and the stoichiometry of complexes
6. UV /vis spectroscopy studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. NMR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. The mode of action of quinolones. Interactions of quinolones with DNA and the role of metal ions in these processes . . . . . . . . . .
9. Bioactivity of quinolone /metal compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: bipy, 2,2?-bipyridine; CD, cyclodextrin; cfH, ciprofloxacin; cxH, cinoxacin; DNA, deoxyribonucleic acid; DMSO,
dimethylsulfoxide; DTA, differential thermal analysis; DTG, derivative thermogravimetry; DSC, dynamic scanning calorimetry; ESR, electron
spin resonance; EGA, evolved gas analysis; erxH, enrofloxacin; FClH, quinolone without a trivial name (see Scheme 2); GMP, guanosine-5?monophosphate; kinoH, quinolone without a trivial name (see Scheme 2); M, metal; MIC, minimal inhibitory concentration; nalH, nalidixic acid;
nfH, norfloxacin; nta, nitrilotriacetate; ofloH, ofloxacin; oxoH, oxolinic acid; pfH, pefloxacin; phen, 1,10-phenantroline; PPh3, triphenylphosphine;
QH, neutral quinolone molecule; QH2 , protonated quinolone molecule; QH32 , doubly protonated quinolone molecule; QH 9 , zwitterionic form;
Q , deprotonated quinolone molecule; SAR, structure /activity relationship; TG, thermogravimetry.
* Tel.: 386-1-2419-124; fax: 386-1-2419-220.
E-mail address: [email protected] (I. Turel).
0010-8545/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
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I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47
Abstract
The quinolones are a group of synthetic antibacterial agents structurally related to nalidixic acid. The absorption of quinolone
drugs is lowered when they are consumed simultaneously with magnesium or aluminium antacids. Many other ions found in
pharmaceuticals cause similar effect. The proposed reason for such behaviour is the chelate bonding of the quinolone to the metal.
In the review article, selected crystal structures of quinolone /metal compounds are presented and discussed. The results of different
physico-chemical methods (thermal analysis, potentiometric measurements, IR, UV /vis, NMR spectroscopy) as well as some results
of bioactivity tests are also included. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Quinolones; Metal ions; Crystal structures; Spectroscopy; DNA; Bioactivity
1. Introduction
1.2. The influence of metal ions on the activity of

quinolones
1.1. General aspects and characteristics of quinolones
Hoffken et al. [6] first reported that concurrent

administration of magnesium /aluminium containing
antacid with ciprofloxacin (cfH) resulted in a nearly
complete loss of activity of the drug in serum.
Antacids not only contain magnesium or aluminium,
but can also contain calcium or bismuth ions. In the
treatment of anaemia, iron is orally administered while
zinc is present in multivitamin mixtures. Several authors
have begun to study the reasons for the reduced activity
of quinolones in the presence of the ions mentioned
above [7 /23]. According to these results, it was suggested that multivalent cations should be avoided in
patients receiving quinolone antibacterials.
The uptake of norfloxacin (nfH) by Escherichia coli
was investigated at different pH and monovalent /
divalent metal ion concentrations [24]. The results of
the study supported a simple diffusion mechanism for
quinolone incorporation into cells. The uptake process
decreases under acidic conditions. The presence of Na
and K ions does not affect the results to an appreciable extent, whereas divalent ions cause a dramatic
decrease in drug incorporation. The antibacterial activity evaluated under identical experimental conditions
shows a direct relationship with the uptake data. It was
suggested that the ability of the drug to penetrate into
cells is a function of its net charge. The molecule in
zwitterionic form exhibits maximum permeation properties, whereas the uptake is strongly reduced when the
drug bears a net charge as a result of ionization or
complex formation with divalent ions.
The proposed mechanism of the interaction between
quinolone and metal cations was chelation between the
metal and the 4-oxo and adjacent carboxyl groups. Since
these functional groups are required for antibacterial
activity, it could be anticipated that all of the quinolones
will interact with metal ions. However, the authors
proposed that there may be differences between the
quinolones regarding the extent of interaction [7].
The term quinolones is commonly used for the

quinolonecarboxylic acids or 4-quinolones, which are a
group of synthetic antibacterial agents containing a 4oxo-1, 4-dihydroquinoline skeleton (Scheme 1). Since
the introduction of nalidixic acid (nalH) [1] (Scheme 1)
into clinical practice in the early 1960s, a number of
structurally related highly potent broad-spectrum antibacterial agents has been isolated [1,2].
Modifications of nalH were made based on structure /
activity-relationships (SARs). It was discovered that a
fluorine atom at position 6 and a piperazine ring at
position 7 greatly enhance the spectrum of activity. The
fluoroquinolones are very active against aerobic Gramnegative microorganisms but less active against Grampositive microorganisms [1,3]. They are extremely useful
for the treatment of a variety of infections, including
urinary tract infections, soft tissue infections, respiratory infections, bone-joint infections, typhoid fever,
sexually transmitted diseases, prostatitis, communityacquired pneumonia, acute bronchitis and sinusitis
[1,2,4]. Recently, a relatively new approach to the
rational design of antitumor agents has been introduced
based on some new quinolone molecules that display a
novel mode of action [5].
The formulas of the quinolones mentioned in this
review are presented in Scheme 2 but many other
quinolones are known and are also used in clinical
practice nowadays.
Scheme 1. The formulas of 4-oxo-1, 4-dihydroquinoline (left) and

nalidixic acid (right).
29
Scheme 2. The formulas of quinolone molecules that appear in the text.
2. Crystal structures of quinolones and their metal

compounds
2.1. Free drugs
The crystal structures of several free quinolone
molecules have been determined: nalidixic acid (nalH)
[25,26], pefloxacin (pfH) methanesulfonate [27,28], cinoxacin (cxH) [29], nfH [30,31], cfH hexahydrate [32],
cfH lactate [33], norfloxacin dihydrochloride [34,35], 5aminooxolinic acid [36], oxolinic acid [37], lomefloxacin
[38], rosoxacin [39], piromidic acid [40,41] and sparfloxacin [42]. It is interesting to note that in most cases the
carboxylic group is not deprotonated and the hydrogen
atom of this group is hydrogen bonded to an adjacent 4oxo atom. In a few examples [30 /32,42], the carboxylic
group is ionized and the molecule thus exists in a
zwitterionic form with protonated terminal nitrogen of
the piperazine ring in a solid state.
2.2. Metal and boron complexes
All quinolones are sparingly soluble in water in the
pH range between 4 and 9. Mixing of a water solution of
metal salt and a quinolone solution mostly results in a
precipitation, making it difficult to grow crystals of
complexes. Nevertheless, the complexes of silver, cobalt,
zinc, cadmium, boron and a few copper complexes have
30
been prepared and their crystal structures reported in

the literature. In addition some mixed ligand complexes
have been isolated. A real breakthrough in the isolation
of quinolone /metal complexes was achieved by using
hydrothermal reactions introduced by the group of
Xiao-Zeng You [43 /45]. They have prepared complexes
with quinolones coordinated to magnesium, calcium,
copper(I) and zinc. In some of these crystal structures
the bonding modes are significantly different from those
reported before. All of these structures are discussed
below. The numberings from original papers have been
used throughout the text.
2.2.1. Magnesium complex
A complex of magnesium(II) with the formula
[Mg2(H2O)6(nfH)2]Cl4 /4H2O was isolated by the hydrothermal reaction [43]. It can be described as a 2:2 dimer
in which the two magnesium ions are bridged by two
oxygen atoms from carboxylate groups of the two
norfloxacin molecules. Each magnesium ion is octahedrally coordinated with the oxygen atom of the quinolone
), one of the two
carbonyl (Mg(1) /O(1) /1.997(2) A
oxygen atoms of the carboxylate (Mg(1)/O(2)/
) and water mole2.084(2), Mg(1) /O(2A) /2.116(2) A
cules. The coordination mode of carboxylate can be
considered as a monodentate bridging type.
2.2.2. Calcium complex
A calcium complex, [Ca2(Cl)(nfH)6]Cl3 /10H2O was
also isolated by the hydrothermal reaction [43]. This
complex is also a dimer, but the bridging group is a
chloride ion. The coordination geometry around each
calcium ion can best be described as a distorted
pentagonal bipyramid. Three norfloxacin molecules act
in a bidentate coordination mode through the oxygen
atom of the quinolone carbonyl (Ca(1) /O /2.384(2) /
) and one of the two oxygen atoms in the

2.413(2) A
).
carboxylate moiety (Ca(1) /O /2.383(3) /2.395(3) A
The chloride ion completes the seven-coordination
).
around the calcium (Ca(1) /Cl(1) /2.862(9) A
2.2.3. Boron complexes
Boron complexes have been used in the synthesis of
some quinolone molecules. The crystal structures of two
boron complexes have been reported. In the
difluoroboric /quinolone complex [46], boron is coordi ) and
nated to ring carbonyl oxygen (B/O(4) /1.468 A
to the oxygen atom of a carboxylic group (B /O /1.467
).
A
In the bis(acetato)-quinolone complex [47] the boron
atom is coordinated by four oxygen atoms and adopts a
slightly distorted tetrahedral geometry. The boron atom
)
is bonded to the carboxylic (B(1) /O(1) /1.501(4) A
) atoms of a
and carbonyl (B(1) /O(3) /1.458(5) A
quinolone molecule. The coordination sphere is completed by two oxygen atoms of the acetate groups (Fig.
1).
2.2.4. Vanadium complex
A vanadium complex [48] was prepared from a water
solution of VOSO4 and cfH. The crystals were very
unstable and contained a high amount of disordered
water molecules, so the exact solution of the structure
has not yet been possible. The tentative formula of the
complex is [VO(cfH)2]SO4 /10H2O with a typical chelate
bonding of metal to 4-oxo and carboxylic oxygens of
quinolone.
2.2.5. Iron complex
The iron(III) complex with cfH and nitriloacetate
(nta) as ligands, [Fe(cfH)(nta)] /3.5H2O was isolated
from water solutions of cfH.HCl, Fe(NO3)3 and nitrilo-
Fig. 1. View of the boron /quinolone complex. Adapted from Ref. [47].
31
Fig. 2. View of [Fe(cfH)(nta)] complex. Adapted from Ref. [49].
triacetate (nta) (disodium salt) [49]. Dilute ammonia

solution was used to adjust the pH to 7. The structure
consists of a neutral [Fe(cfH)(nta)] complex and 3.5
water molecules (Fig. 2). The iron is coordinated to the
) and the carboxylic
keto (Fe(1) /O(1) /1.942(8) A
) of the cfH ligand to
oxygen (Fe(1) /O(2) /1.91(1) A
form a six-membered ring. The remaining four coordination sites are occupied by an nta ligand (Fe(1) /
, Fe(1) /O(6) /1.969(9) A
, Fe(1) /
O(4)/2.037(9) A
O(8)/1.983(9) A, Fe(1) /N(4) /2.21(1) A). The piperazinyl ring of the cfH ligand is protonated on the
external nitrogen.
2.2.6. Cobalt complex
A compound of cobalt(II) with the formula
Na[Co(cx)3]/6H2O was isolated from a methanolic
Fig. 3. Perspective view of [Co(cx)3] anion. Adapted from Ref. [50].
solution of cxH and CoSO4 [50] (Fig. 3). The structure

consists of anionic monomeric units of [Co(cx)3] and
uncoordinated water molecules that provide crystalline
stability through a network of hydrogen bond interactions. Three cinoxacinate ions are chelated through oxo
) and carboxylic (Co(1) /
(Co(1) /O(3)/2.166(9) A
O(1)/2.182(8) A) oxygens.
2.2.7. Nickel complexes
A mixed ligand complex [Ni(cx)2(DMSO)2] /4H2O
was prepared from a dimethylsulfoxide (DMSO) solution of cxH and NiSO4 [51].The structure of the complex
consists of monomeric [Ni(cx)2(DMSO)2] units and
uncoordinated water molecules that provide crystalline
stability through a network of hydrogen bond interactions. The metal ion is bonded to two bidentate
cinoxacinate ligands that bind through one carboxylate
) and the exocyclic
oxygen atom (Ni /O(1) /2.003(2) A
). The
carbonyl oxygen atom (Ni /O(3) /2.015(2) A
octahedral coordination environment is completed by
two DMSO molecules coordinated via the oxygen atom
).
(Ni /O(6) /2.140(2) A
Later on, the same authors reported the complex with
the same formula but a slightly different crystal structure [52].
2.2.8. Copper complexes
Two copper(II) complexes were prepared with cfH,
two with cxH and one with ofloxacin. Additionally, five
mixed ligand complexes were also isolated.
Both copper/cfH complexes were prepared from
water solutions of cfH and copper(II) salts (chloride,
sulphate). In the complex [Cu(cfH)2Cl2]/6H2O the
copper atom is positioned at the center of inversion
and surrounded by four oxygen atoms, Cu(1) /O(1) /
and Cu(1) /O(2)/1.931(2) A
[53] (Fig. 4).
1.928(2) A
The two chloride ions are axially coordinated to copper
) and appear to be
at longer distances (2.688(2) A
32
Fig. 4. Perspective view of [Cu(cfH)2Cl2]. Adapted from Ref. [53].
Fig. 5. View of [Cu(cfH)(H2O)3]SO4 2H2O. Reproduced with

permission */Ref. [54].
disordered over three positions. In the second complex

of copper and cfH [Cu(cfH)(H2O)3]SO4 /2H2O [54] (Fig.
5), only one molecule of quinolone is coordinated to the
metal. The coordination environment around the central
copper(II) ion in the structure is a slightly distorted
square pyramid. Ciprofloxacin is bonded to the metal
) and a
through a carbonyl atom (Cu /O(3)/1.939(1) A
carboxylic atom (Cu /O(1)/1.915(2) A). Two water

molecules are coordinated to copper in the basal plane
) and (Cu/O(9) /1.989(2) A
).
(Cu /O(8) /1.972(2) A
The apical water molecule is coordinated at a longer
). The formulas of the
distance (Cu/O(10) /2.174(2) A
copper complexes of cxH are [Cu(cx)2]/2H2O and
[Cu(cx)2(H2O)] /3H2O [55,52].
In the former, the copper(II) ion is coordinated to two
cinoxacinate anions through a carbonyl oxygen atom
) and carboxylate oxygen
(Cu(1) /O(3) /1.903(4) A
), thus forming a CuO4 chro(Cu(1) /O(1) /1.896(4) A
mophore in a crystallographically planar configuration
(Fig. 6). The complex was isolated from a DMSO
solution of cxH and Cu(NO3)2.
The latter compound was isolated from the first
compound, which was dissolved in aqueous ammonia.
The copper(II) ion is found in a distorted square
pyramidal environment in the second complex. It is

coordinated to four oxygen atoms of the two cinoxaci , Cu /O(1) /
nate ligands (Cu /O(3)/1.943(5) A
1.933(4) A) and a water molecule (Cu /O(1W) /

).
2.226(5) A
The
copper(II)
complex
with
ofloxacin,
[Cu(oflo)2(H2O)] /2H2O was isolated [56]. The geometry
around copper(II) ion is a slightly distorted square base
pyramid with ordinary chelate bonding of quinolone to
the metal through ring carbonyl (Cu(1) /O(33) /
) and one of the
1.956(3), Cu(1) /O(13) /1.943(3) A
carboxylic oxygen atoms (Cu(1) /O(11) /1.911(3),
). Additionally, a water moCu(1) /O(31) /1.922(3) A
lecule is coordinated to the metal (Cu(1) /O(1)/
).
2.198(7) A
In the complex [Cu(phen)(nal)(H2O)]NO3 /3H2O [57]
(Fig. 7) the copper ion displays a distorted squarepyramidal coordination, being linked to two nitrogen
atoms of the 1,10-phenantroline (phen) ligand (Cu /
, Cu /N(22)/2.014(2) A
), two oxyN(11)/1.999(2) A
,
gen atoms of the nal ligand (Cu/O(11) /1.914(2) A
Cu /O(2)/1.934(2) A) and a water molecule in the

).
apical site (Ow(1) /Cu /2.277(3) A
A distorted square-pyramidal coordination around
copper(II) was also found in the [Cu(phen)(cx)(H2O)]NO3 complex [58] with similar bonding to that described
above. The bond distances to the metal are: (Cu(1) /
, Cu(1) /N(24)/2.002(7) A
, Cu(1) /
N(15)/1.995(5) A
O(15) /1.913(6) A, Cu(1) /O(2)/1.914(4) A, Cu(1) /

). Preliminary crystal data for the
O(1W) /2.238(7) A
complex [Cu(oxo)(bipy)]NO3 /H2O suggest that the
bonding mode is also similar [58].
The structure of [Cu(cfH)(bipy)(Cl)0.7(NO3)0.3](NO3) /
2H2O [59] consists of the [Cu(cfH)(bipy)(Cl)0.7(NO3)0.3] cation, a nitrate anion and two water
molecules. The structure is disordered, with the occupancy of the coordinated Cl and NO3 being 0.7:0.3.
The copper ion displays a five-coordinate squarepyramidal coordination with two nitrogen donors
33
Fig. 6. Perspective view of [Cu(cx)2] 2H2O. Adapted from Ref. [55].
,
from 2,2?-bipyridine (bipy) (Cu(1) /N(4) /1.977(3) A
), the 4-keto (Cu(1) /O(1)/
Cu(1) /N(5) /1.994(4) A
) and 3 /carboxylate oxygen donors (Cu(1) /
1.924(3) A
, and the disordered Cl /NO3 anion
O(2)/1.920(3) A
, Cu(1) /O(7) /2.549(2) A
)
(Cu(1) /Cl(1) /2.549(2) A
occupying the fifth site.
All these mixed ligand complexes were prepared by
mixing a water solution of Cu(NO3)2 and an ethanolic
solution of N/N ligand (phen, bipy) with subsequent
addition of an aqueous quinolone (nalH, cfH, oxolinic
acid (oxoH)) solution.
The crystal structure and characterization of the
mixed ligand complex of copper(I), triphenyl phosphine and nfH, [Cu(PPh3)2(nfH)]ClO4, were published
[44]. The copper ion displays a rather distorted tetrahedral geometry, being linked to two nfH oxygens
)
(Cu(1) /O(2) /2.0763(18), Cu(1) /O(1)/2.074(2) A
and two phosphorus atoms of triphenylphosphine
ligand (Cu(1) /P(2) /2.2389(8), Cu(1) /P(4)/2.2472(8)
).
A
Fig. 8. Structure of the silver complex of pefloxacin. Adapted from

Ref. [60].
2.2.9. Silver complex

A silver complex of pfH, [Ag2(pf)2(H2O)2]/6H2O [60]
(Fig. 8) was isolated by dissolving a powdered silver
complex in an aqueous ammonia solution. The bonding
in this compound is substantially different from those
described above. Two silver atoms are bridged by a pair
of carboxyl groups from two pefloxacin molecules (Ag /
, Ag /O(13) /2.285(3) A
). The termO(12) /2.329(3) A
inal piperazinyl nitrogen atom from another pefloxacin
Fig. 7. Crystal structure of [Cu(phen)(nal)(H2O)]NO3 3H2O. Adapted from Ref. [57].
34
molecule also coordinates to each silver atom (Ag /

). The silver coordination is comN(4P) /2.431(3) A
pleted by an oxygen atom from a water molecule (Ag /
). The two silver atoms are at a
O(1W) /2.454(4) A
.
distance of 2.901(1) A
2.2.10. Zinc complexes

The complex [Zn(nalH)2(H2O)2](ClO4)2 /2H2O [61]
was prepared by mixing a solution of nalH in chloroform and an acetone solution of Zn(ClO4)2. The
structure contains zinc in an octahedral ZnO6 environment. The nalidixic acid bonds to metal in a bdiketonate-like chelation through carbonyl oxygen
) and carboxylic oxygen (Zn /
(Zn /O(3)/2.048(5) A
O(1)/2.083(5) A). The octahedral coordination sphere

of the dicationic complex is completed by two axial
).
water ligands (Zn /O(4)/2.116(5) A
Two zinc /norfloxacin complexes, [Zn(nf)2]/4H2O
and [Zn(H2O)2(nfH)2](NO3)2 were isolated by hydrothermal synthesis [45]. The X-ray crystal structure of the
first complex revealed that two nf anions are coordinated to the metal through ring carbonyl (Zn(1) /O(3)/
) and one of the carboxylate oxygens (Zn(1) /
2.095(3) A
). Interestingly, the apical positions
O(2)/2.070(3) A
are occupied by two nitrogen atoms of piperazine rings
), resulting in the formation
(Zn(1) /N(1A) /2.253(3) A
of a 2-D square grid with a nanosized hydrophobic tube
cavity, that could be very useful for host/guest chemistry. In the second complex, the chelate bonding of the
quinolone oxygen atoms to the metal is similar as in the
first complex (Zn(1) /O(6)/2.057(3), Zn(1) /O(5)/
), but the apical positions are occupied by
2.028(3) A
two water molecules (Zn(1) /O(3)/2.160(4)). The
authors suggest that in a neutral or weakly basic
solution, the nitrogen atom of the piperazine ring can
take part in the coordination, while in the weakly acidic

solution, this nitrogen is protonated and loses its
coordination capacity. Authors also reported that both
complexes show strong blue fluorescent emission and
could be used as advanced materials for blue-light
emitting diode devices.
The zinc complex [Zn(cx)2(DMSO)2]/4H2O [51] (Fig.
9) is structurally related to the nickel complex described
above. The bonding distances are: Zn(1) /O(1) /
, Zn(1) /O(3)/2.058(2) A
and Zn(1) /
2.019(2) A
O(6)/2.164(3) A.
2.2.11. Cadmium complexes

The complex [Cd2(cx)4(DMSO)2]/2H2O [62] was prepared from a DMSO solution of cxH and CdCl2. Each
dimer contains cadmium atoms bridged by two carboxylate oxygen atoms from two cx ligands generating a
Cd2O2 ring. The metal environment is formed by two
carboxylate and keto oxygen atoms from the cinoxacinate monoanions, one oxygen atom of the DMSO
molecule and a carboxylate oxygen atom which acts as
a bridging atom. One of the coordinated cinoxacinate
molecules acts as a bidentate chelate and bridging ligand
and the other as a bidentate chelate ligand. The
distortion of the octahedron is not severe, with all
.
Cd /O bond lengths in the range of 2.237(6) /2.350(7) A
The complex [Cd2(cx)4(H2O)2]/10H2O [63] (Fig. 10)
was prepared by dissolving [Cd2(cx)4(DMSO)2]/2H2O in
hot water. Each cadmium atom is heptacoordinated.
The metal environment consists of two keto oxygens
, Cd(1) /O(3?A) /2.341(5) A
)
(Cd(1) /O(3)/2.319(6) A
,
and two carboxylic oxygens (Cd(1) /O(1)/2.216(6) A
(Cd(1) /O(1?A) /2.333(6) A) from two different cinoxacinate monoanions. In addition, two carboxylate oxygen atoms from a third cinoxacinate ligand (Cd(1) /
Fig. 9. View of [Zn(cx)2(DMSO)2]. Adapted from Ref. [51].
35
Fig. 10. View of [Cd2(cx)4(H2O)2]. Adapted from Ref. [63].
, (Cd(1) /O(2?)/2.526(7) A
) and a
O(1?)/2.357(6) A
water molecule in the seventh position are coordinated
). Two of the
to cadmium (Cd(1) /O(6) /2.283(6) A
cinoxacinate ions act as tridentate chelate bridging
ligands and the other as a bidentate chelate ligand.
2.2.12. Cerium complex
The crystal structure of cerium(III) complex of cfH
[Ce(cf)2(H2O)4]Cl(H2O)3.25(C2H5OH)0.25 was published
[64]. The quinolone is again coordinated through 3carboxyl and 4-keto oxygens and the coordination
number of cerium is eight.
2.2.13. Short analysis of the metal /quinolone structures
The analysis of the structural data has revealed that in
free quinolones the ring carbonyl carbon /oxygen dis and the
tances are in the range from 1.246 to 1.276 A
distances between carbon and oxygen in carboxylic
. Typically,
groups are in the range from 1.205 to 1.327 A
if the carboxylic group is not dissociated one of the later
bonds is much shorter (double bond) whereas the other
bearing the hydrogen is longer (single bond). As
indicated in paragraph 2.1. some quinolone molecules
exist as the zwitter ions and the lengths of both
carboxylic carbon oxygen bonds are thus nearly equal
).
(ca. 1.25 A
The bonding of the metal to the quinolone oxygen
atoms (described in Section 2.2) results in a slight
lengthening of both ring carbonyl and carboxylic
carbon /oxygen bonds. But of course, we should always
be aware of other effects that could also influence the
bond lengths (hydrogen bonding, etc.). It was also found
that in the chelate bonding of the metal to ring carbonyl
and one of the carboxylic oxygens both metal /oxygen
bond distances are of similar lengths. Within the
carboxylic group, the metal-coordinated oxygen expresses somehow longer carbon /oxygen distance than
the noncoordinated oxygen. The most noticeable exception is [Zn(nalH)2(H2O)2](ClO4)2 /2H2O where the later
) is much longer as the former
bond distance (1.299(9) A
) [61].
(1.230(8) A
There are no other distinctive differences in bond
lengths between free quinolones and their metal complexes.
Some specific properties of metal /quinolone complexes are presented in Table 1. The most frequent are
the copper(II) complexes of the quinolones which is
probably not unusual in view of many copper(II)
complexes with other ligands. Up to now the complexes
of quinolones with 12 different elements were reported.
The coordination numbers of the central atoms range
from four to eight and the most frequently observed
coordination polyhedron is octahedron. The mole ratios
metal:quinolone are between 1:1 and 1:3.
We can conclude that the most common bonding
observed for metal /quinolone complexes is the chelate
bonding of the metal to ring carbonyl and one of the
carboxylic oxygens. There are few complexes that are
somehow different. In the complexes, [Ag2(pf)2(H2O)2]/
6H2O [60] and [Zn(nf)2] /4H2O [45], piperazine terminal
nitrogen atom is also involved in the bonding to the
metal. It was also found that few complexes (Ca, Mg,
Cd) are dimeric [43,62,63]. We could hardly use any
systematic approach (as Hard and Soft Acid and Base
concept) to classify the complexes. It seems that the
differences in bonding of the reported complexes are
mostly affected by different conditions used in synthesis.
2.3. Ionic compounds

All of these compounds were isolated from acidic
solutions of quinolone and appropriate metal salts.
These compounds generally consist of protonated qui-
36
Table 1
Selected data of the quinolone /metal complexes
Formula of the complex
(reference)
Atoms involved Coordination

in the bonding to number of the
the metal
central atom
[Mg2(H2O)6(nfH)2]Cl4 4H2O [43] O(P), O(C),

O(H2O)
[Ca2(Cl)(nfH)6]Cl3 10H2O [43]
O(P), O(C), Cl
[B(C12H8F2NO3)(F)2] [46]
O(P), O(C), F
O(P), O(C),
[B(C13H8Cl FNO3)(C4O4H6)2]
[47]
O(acetate)
[VO(cfH)2]SO4 10H2O [48]
O(P), O(C),
O(vanadyl)
[Fe(cfH)(nta)] 3.5H2O [49]
O(P), O(C), O
and N (nta)
Na[Co(cx)3] 6H2O [50]
O(P), O(C)
O(P), O(C),
[Ni(cx)2(DMSO)2] 4H2O [51]
O(DMSO)
[Cu(cfH)2Cl2] 6H2O [53]
O(P), O(C), Cl
[Cu(cfH)(H2O)3]SO4 2H2O [54] O(P), O(C),
O(H2O)
[Cu(cx)2] 2H2O [55]
O(P), O(C)
[Cu(cx)2(H2O)] 3H2O [52]
O(P), O(C)
[Cu(oflo)2(H2O)] 2H2O [56]
O(P), O(C)
O(P), O(C),
[Cu(PPh3)2(nfH)]ClO4 [44]
P(PPh3)
[Cu(phen)(nal)(H2O)]NO3 3H2O O(P), O(C),
[57]
O(H2O),
N(phen)
[Cu(phen)(cx)(H2O)]NO3 [58]
O(P), O(C),
O(H2O),
N(phen)
[Cu(cfH)(bipy)(Cl)0.7(NO3)0.3]O(P), O(C),
(NO3) 2H2O [59]
N(bipy, NO3), Cl
[Ag2(pf)2(H2O)2] 6H2O [60]
O(C), N(piperazine), O(H2O)
[Zn(nalH)2(H2O)2](ClO4)2
O(P), O(C),
2H2O [61]
O(H2O)
[Zn(nf)2] 4H2O [45]
O(P), O(C),
N(piperazine)
[Zn(H2O)2(nfH)2](NO3)2 [45]
O(P), O(C),
O(H2O)
O(P), O(C),
[Zn(cx)2(DMSO)2] 4H2O [51]
O(DMSO)
[Cd2(cx)4(DMSO)2] 2H2O [62]
O(P), O(C),
O(DMSO)
[Cd2(cx)4(H2O)2] 10H2O [63]
O(P), O(C),
O(H2O)
[Ce(cf)2(H2O)4]Cl(H2O)3.25O(P), O(C),
(C2H5OH)0.25 [64]
O(H2O)
6
7
4
4
5
6
6
6
6
5
4
5
5
4
5
5
5
6
6
6
protonated at the terminal nitrogen atom of piperazine

residue. The hydrogen atom of the carboxylic group is
hydrogen bonded to the carbonyl oxygen atom, thus
preventing the bonding of the metal to this part of the
molecule. The magnesium ion is coordinated by six
water molecules forming a [Mg(H2O)6]2 cation with a
nearly regular octahedral geometry. This is the only
example of a metal /quinolone ionic compound reported
with the water molecules coordinated to the metal.
2.3.2. Bismuth compounds
Two bismuth(III) compounds of cfH have been
prepared (cfH3)(cfH2)[BiCl6] /2H2O [66] (Fig. 12) and
(cfH3)2[Bi2Cl10]/4H2O [67]. In the former, one of the cfH
molecules is protonated at carbonyl oxygen and the
terminal nitrogen of the piperazine residue, whereas the
other is protonated only at the latter nitrogen atom. The
charge of the isolated hexachlorobismuthate(III) anions
is compensated by protonated cfH molecules. Due to
their high charge, [BiCl6]3 anions are not very common as the formation of polynuclear anions seems to be
preferred [68 /70].
In the latter compound Bi(III) ions are coordinated
by chloride ions forming dinuclear [Bi2Cl10]4 anions.
Both quinolone molecules are doubly protonated in this
compound.
2.3.3. Iron compound
Four chloride ions are coordinated to the iron(III)
ion, forming a slightly distorted tetrahedron in the
enrofloxacin compound (erxH3)[FeCl4]Cl [71] (Fig.
13). The carboxylic group is not deprotonated and a
carbonyl oxygen O(1) is protonated; the consequence is
that this part of the molecule is unable to bind to the
metal. The quinolone molecule is additionally protonated at the nitrogen atom N(24), thus its charge is /2.
6
6
7
8
O(P), ring carbonyl oxygen; O(C), carboxylic oxygen.
nolone cations and chlorometalate or simple inorganic

anions.
The solubility of all ionic quinolone compounds is
much greater than that of molecular complexes, which
are only sparingly soluble.
2.3.1. Magnesium compound
In the magnesium adduct of cfH (cfH2)2[Mg(H2O)6](SO4)2 /6H2O [65] (Fig. 11), magnesium is
not bonded to the quinolone molecule. The quinolone is
2.3.4. Platinum compound

The formula of the platinum(II) compound of pefloxacin is (pfH2)2 [PtCl4]/2H2O [72]. The coordination
geometry of platinum is square planar. The terminal
nitrogen atom of the pefloxacinum cation is protonated.
An intramolecular hydrogen bond between the carboxylic hydrogen and the keto ring oxygen forms a
pseudo six-membered ring.
2.3.5. Copper compounds
Four chloride ions are coordinated to the copper(II)
ion, forming a rather distorted tetrahedron in
(nfH3)(nfH2)[CuCl4]Cl /H2O [35] (Fig. 14). There are
two nonequivalent norfloxacin molecules in the asymmetric unit. In the first (indicated by A), the carbonyl
O(1) and piperazine nitrogen N(24) are both protonated. In the second (indicated by B), only N(24) is
protonated. There are distinctive layers of quinolone
molecules in the structure, and the distances between
37
Fig. 11. View of (cfH2)2[Mg(H2O)6](SO4)2 6H2O. Adapted from Ref. [65].
Fig. 12. View of (cfH3)(cfH2)[BiCl6] 2H2O. Adapted from Ref. [66].
aromatic rings in the neighboring layers are around 3.5

; thus, interactions between p-electronic systems are
A
possible (Fig. 15).
The second compound of quinolone and copper(II)
(kinoH3)[CuCl4] /H2O [71] is similar to the first. It
contains tetrachlorocuprate(II) ions and protonated
quinolone molecules. A distinctive pattern was observed
in this compound (Fig. 16) */two neighboring quinolone
molecules form a dimeric pair via carboxylic groups,
which is otherwise typical for free carboxylic acids.
2.3.6. Zinc compounds
The zinc compound (nfH3)(nfH2)[ZnCl4]Cl /H2O [35]
is isotypic to the copper /norfloxacin compound (see
above).
The zinc compound of cfH with the formula

(cfH3)[ZnCl4]/H2O [73] is also very similar to the zinc
compound of norfloxacin. There are distinctive layers of
quinolone molecules in the structure which are crosslinked through extensive hydrogen bonding.
The inspection of the bond lengths in the isolated
ionic type complexes have revealed the following facts:
/ the quinolone molecules could be mono- or doubly
protonated,
/ in monoprotonated species only the terminal nitrogen
atom of piperazine ring is protonated,
/ in doubly protonated species additionally the ring
carbonyl oxygen is protonated. If this is the case, this
carbon/oxygen bond is substantially lengthened
).
(1.30/1.33 A
3. Thermal analyses
Fig. 13. View of (erxH3)[FeCl4]Cl. Reproduced with permission from

Elsevier Science */Ref. [71].
Only a few references are available on the thermal

properties of free quinolones [74 /76]. It has been found
that polymorphism is very common for quinolones. The
polymorphs show different melting points, solubilities,
chemical reactivity and stability.
38
Fig. 16. Schematic view of two neighboring quinolone molecules in

(kinoH3)[CuCl4] H2O forming a dimeric pair via carboxylic groups
(intermolecular hydrogen bonds). Reproduced with permission from
Elsevier Science */Ref. [71].
Fig. 14. View of (nfH3)(nfH2)[CuCl4]Cl H2O. Reproduced with

permission from Elsevier Science */Ref. [35].
Fig. 15. Distinctive layers of quinolone molecules in (nfH3)(nfH2)[CuCl4]Cl H2O. Reproduced with permission from Elsevier Science */
Ref. [35].
The formation of cyclodextrin (CD) /norfloxacin

complexes has also been studied by thermal and other
methods [77]. It has been proposed that quinolone is
incorporated in the CD framework.
The thermal behaviour of three metal complexes,
Na[Co(cx)3]/10H2O, Ni2(cx)3(ClO4)/8H2O and Cu(cx)2 /
H2O, has been studied by thermogravimetry (TG) and

differential thermoanalysis (DTA) [78]. It was found
that the complexes decompose in two steps: dehydration
is followed by decomposition of the anhydrous complexes to metal or metal oxide. Similar behaviour was
also found for Zn(II), Cd(II) and new Co(II) complexes
[79].
The thermal properties of [Cd2(cx)4(DMSO)2] /2H2O
and [Cd(cx)2(H2O)] were compared [62]. The TG curves
of the complexes show three well-separated thermal
events. The first (100 /150 8C) corresponds to the
elimination of two water and two DMSO molecules
from the first compound, and to the elimination of only
the water molecule from the second compound.
It was found that it is possible to obtain anhydrous
complexes from the hydrated mixed ligand complexes
Cu /nal /bipy (phen) by heating the samples to 110 8C
[57]. It was proposed that the mixed ligand complexes
are more stable than the Cu(nal)2 complex.
A series of mixed ligand complexes of the types Cu /
oxo/bipy (phen) and Cu /cx/bipy (phen) were also
characterized by the TG method [58]. It was observed
that in these systems it is also possible to obtain
anhydrous complexes by heating the samples up to
120 8C. These anhydrous complexes are stable up to
temperatures near 260 8C.
The thermal study of the mixed ligand complexes of
the type Zn /nal /phen (bipy) has revealed that the
decomposition is dependent on the diammine present
in the structures [80]. The difference suggests that the
diammine strongly changes the acid /base behaviour of
the metal ion, becoming harder with bipy than with
phen. This means that the complexes with bipy have a
stronger affinity for oxygen than the complexes with
phen.
The thermal behaviour of copper/cfH compounds
[Cu(cf)2Cl2]/6H2O and (cfH3)(cfH2)[CuCl4]Cl /H2O was
studied by TG, dynamic scanning calorimetry (DSC)
and evolved gas analysis (EGA) methods [81,53]. In the
first compound the dehydration is followed by decarboxylation, whereas in the second the dehydration is
followed by pyrolysis with simultaneous evolution of
water, hydrochloric acid and carbon dioxide.
The thermal properties of bismuth compounds of cfH

[66], copper and zinc complexes of norfloxacin [35] were
also studied. In each of these compounds, dehydration is
followed by complex pyrolysis. It was possible to
determine the water content of the compounds, though
it was also found that not all water molecules are
equivalently bonded. The weaker-bonded water molecules could be lost in metal/quinolone complexes even
by drying in air at room temperature (r.t.) or by drying
in vacuo [53].
A study of the thermal properties of magnesium
compounds of quinolones (cfH2)2[Mg(H2O)6](SO4)2 /
6H2O, [Mg(cf)2]/4H2O and [Mg(nf)2]/4H2O was also
performed [82]. The derivative thermogravimetry
(DTG) curves for dehydration reactions are all split
into two peaks, suggesting the presence of two differently bonded water molecules in the structure. The final
decomposition product was MgO for the first compound and MgF2 for the other two compounds. Due to
these observations, the authors proposed that Mg(II) is
coordinated to the quinolone in [Mg(cf)2]/4H2O and
[Mg(nf)2] /4H2O. Recently the same authors have also
studied the thermal behaviour of Mg(II), Zn(II) and
Co(II) compounds with cfH. It was found that the
complexes decompose in two steps, dehydration and
pyrolytic decomposition of the anhydrous complexes to
form metal oxide or metal fluoride [83].
In conclusion, the thermal analyses of metal /quinolone complexes have shown that in general they decompose in two steps. The first step is dehydration at lower
temperatures, which is followed by pyrolytic decomposition at higher temperatures. The final product could
be the metal, metal oxide or metal fluoride.
4. Infrared spectroscopy
Infrared (IR) spectra of quinolones are quite complex
due to the presence of numerous functional groups in
the molecules. The IR spectrum of anhydrous norfloxacin was assigned [75]. The valence vibration of the
carboxylic stretch n(C /O)c was found at 1725 cm 1 and
the pyridone stretch n (C /O)p at 1628 cm 1. It was
found that the IR spectrum of norfloxacin dihydrate
does not exhibit a well-defined carboxylic stretch.
The IR spectra of cfH and cfH hexahydrate do not
have a n (C /O)c absorption [32]. According to the
crystal structure of cfH /6H2O, the authors have concluded that the carboxylic group is deprotonated and
the molecule exists in zwitterionic form. It is known that
ionic carboxylates [84] show no carbonyl stretching at
about 1700 cm 1, but have two characteristic bands in
the range of 1650 /1510 cm 1 and 1400 /1280 cm 1
that could be assigned as n(O /C /O) asymmetric and
symmetric stretching vibrations. It is very difficult to
unequivocally assign these vibrations in the spectra of
39
cfH due to the numerous other bands present in these

regions; however, the combination of IR and Raman
spectroscopies enabled the authors to propose some
possible assignments. The asymmetric stretching
vibrations */n(O /C /O)a were found in cfH /6H2O at
1578 and at 1589 cm 1 in an anhydrous cfH, whereas
the corresponding symmetric stretching vibrations */
n (O /C /O)s were found at 1380 cm 1 (cfH /6H2O)
and 1376 cm 1 (cfH). It was also found that after
heating of both samples to higher temperatures
(270 8C), a peak at 1727 cm 1 appeared in the spectra.
It seems that the role of a carboxylic group in the
structure is changed during heating, though the mechanism of this phenomenon was not explained.
Several authors have used IR data to characterize
metal compounds of quinolones, mainly focusing only
on the most typical vibrations. It was found that when
the metal is bonded to quinolone 4-oxo and carboxylic
oxygens there is no n(C /O)c absorption in the spectra,
whereas n (C/O)p is shifted upon bonding. Also, some
new absorptions often appeared in the spectra of
complexes [53,54,82,85 /88].
The range of nalH metal complexes was studied by IR
spectroscopy [89]. The authors have calculated the
differences between n (O /C /O)a and n(O /C /O)s and
have concluded that in some complexes nalH acts as a
bridging ligand (Ca, Mg, Mn, Ni, Zn, Cd), whereas in
other complexes (Co, Fe, Cu, Pd) it acts as a chelate
ligand.
Mendoza-Daz et al. have studied mixed ligand
complexes of the type Cu (Zn)/nal/phen (bipy)
[57,58,80]. The solid state IR spectra showed bands
corresponding to both ligands. In the region 1800/1300
cm 1, bands of 4-oxo and 3-carboxylate appeared. The
results suggest that the bonding mode of the nalidixate
ion should be the same in all complexes.
Ruiz et al. have studied mixed ligand complexes of the
type M/cx /DMSO (M2 /Cu2, Cd2, Ni2, Zn2)
[51,55,62,63]. They have assigned the most significant
bands: 3600 /3200 cm 1 (n (O /H)), 1650 /1600 cm 1
(n(O /C /O)a/n(C /O)p), which appeared in all complexes.
The infrared spectrum of [Fe(cfH)(nta)] /3.5H2O [49]
is very complex due to the additional absorptions of nta.
The authors were not able to assign the difference n(O /
C /O)a/n (O /C /O)s from which the bonding mode of
the carboxylic group could be predicted. They have
concluded that the bonding mode of more complex
ligands containing carboxylate groups bonded to the
metal could not be unambiguously established on the
basis of IR spectra alone.
Lecomte et al. [90,91] have studied the interactions of
magnesium and different quinolones (sparfloxacin, pefloxacin) by IR spectroscopy. They have recorded the
IR spectra in D2O solutions at different pH values. At
pH 4, n (C/O)p was found at 1632 cm 1 and n(C /O)c
40
at 1698 cm 1 for sparfloxacin. At pH 12, n(C /O)p was

at 1622 cm 1, n(O /C /O)a was at 1580 cm 1 and n(O /
C /O)s was at 1400 cm 1. In the presence of Mg(II) (pH
7.4) the bands were shifted, so they have suggested that
magnesium is located between the keto and carboxylate
oxygens of the quinolone. With regard to the different
shifts of pfH and sparfloxacin, they have suggested that
the structures of the magnesium complexes of these
drugs are different.
The combination of thermal methods and IR spectroscopy was used to study the properties of [Cu(cfH)2Cl2]/
6H2O and (cfH3)(cfH2)[CuCl4]Cl /H2O [81]. The heating
of the samples changed the positions and the appearance
of some bands, which is probably a consequence of
changes in the coordination sphere of the metal.
Additionally, water molecules or hydrochloric acid
molecules are removed from the structures by heating
and some hydrogen bonds are broken or rearranged; the
result is a shift of band frequencies towards higher
wavenumbers. The most notable fact is that in
[Cu(cfH)2Cl2]/6H2O, apart from shifts of bands that
could be explained by a different hydrogen bonding
scheme, a peak at 1723 cm1 appeared in the spectrum
after heating. Obviously, then, the role of the carboxylic
group is altered in the structure.
In all ionic type compounds with known X-ray
structures, similar types of IR spectra appeared
[35,66,71]. The carboxylic group is involved in hydrogen
bonding, and in all examples it was possible to assign the
intense band in the 1714 /1663 cm 1 region as n(C /O)c.
The position of n (C/O)p was not changed according to
the metal complexes described above, and appeared at
around 1630 cm 1.
5. Protolytic equilibria of quinolones and their metal

compounds. Determination of stability constants and the
stoichiometry of complexes
The protolytic equilibria of quinolones were extensively studied. Different methods (potentiometric measurements, UV /vis spectroscopy, polarography,
fluorescence spectroscopy and NMR spectroscopy (the
results of the latter technique are collected in Section 7))
were used to evaluate the macro- and microconstants of
the species present in solution [59,92/98]. The differences in the determined values are probably due to the
methodology and conditions used.
Nalidixic acid has a single protonation constant
(pKa :/6) in the pH range of 2 /9 [85,92,93,99,100]. It
is protonated in a strong acid solution to form a
naphthyridinium cation with a pKa of /0.86 [101].
The drug exists in its undissociated form over a pH
range of 1.6 /3.6.
Fluoroquinolone analogues with the piperazinyl
group in the 7-position contain two relevant ionizable
Scheme 3. Protolytic equilibria in fluoroquinolone drugs water solutions.
functional groups. The protolytic equilibria of fluoroquinolone analogues are expressed in Scheme 3. These
molecules can exist in four possible forms: an acidic
cation H2Q , a neutral nonionized species HQ, an
intermediate zwitterion HQ 9 and a basic anion Q,
depending on the pH. At low pH values, both the 7piperazinyl group and 3-carboxyl group are protonated,
whereas at high pH values, neither is protonated. The
carboxyl group is normally a stronger acid than the
ammonium group, the reason being that the neutral
nonionic form is spontaneously rearranged to the
zwitter ion. Two macroscopic dissociation constants
can be determined for fluoroquinolones. The first (Ka1)
applies to the 3-carboxyl proton and the second (Ka2) to
the 7-piperazinyl proton. The pKa1 of cfH and nfH was
found at around 6. The decrease in acidity of the
carboxylic group compared with benzoic acid (pKa
4.2) is explained by the intramolecular hydrogen bond
to the keto oxygen [102]. The pKa2, which is due to the
presence of an ionizable proton on the external piperazinyl nitrogen, was found at around 8.5. A further
protonation step at very acidic conditions was also
found (pKa :/0), which could be explained by the
deprotonation of the keto group [103]. It is interesting
to note that in non-aqueous solutions, the pK values of
nfH were found at 0.74 and 8.26, respectively [85].
Numerous authors have also determined the stability
constants of metal /quinolone complexes.
The stability constants for the binding of nalH by
several divalent metal ions were determined by UV /vis
and fluorescence spectroscopies [92]. The magnitudes of
the formation constants support the physiological significance of the 1:1 complexes and the lack of importance of the 2:1 (drug:metal) complexes.
The interaction of nalH with Al(III), Mg(II) and
Ca(II) was studied by UV /vis spectroscopy [99]. The
stoichiometry of the nalH /Al complex was estimated to
be 3:1 by the method of continuous variations. Efforts
directed at determining formation constants of nalH /M

complexes have been unsuccessful.
It was also found that ternary complexes are formed
between
guanosine-5?-monophosphate
(GMP) /
copper(II) /nal [100]. This supports the suggestion that
the metal ion-mediated binding of nalH to singlestranded deoxyribonucleic acid (DNA) in vitro also
shows a preference for guanine residues. These results
imply the initial formation of a mixed ligand complex
between the drug and DNA (with the metal ion acting as
a bridge).
The study of complexation equilibria of the nalidixate
and cinoxacinate with [Cu(phen)]2 and [Cu(bipy)]2
was also performed [104]. The study indicates that the
stability of these types of complexes is strongly related
to the metal environment. These results suggest that
inside the living cells a possible interaction of quinolone
with some metal ion will be strongly controlled by the
type of ligand bound to the cation.
The complexation of quinolones (nalH, cfH) and
iron(III) was studied by UV /vis spectroscopy
[105,106]. The author proposed the formation of
Fe(quinolone)2 complexes. The described procedure
could also be used for the determination of trace
amounts of iron.
The formation constants of iron(III) /fluoroquinolone analogues (cfH, nfH, enoxacin, ofloxacin) were
determined by UV /vis spectroscopy [85]. The authors
established the stoichiometric compositions of the complexes by Jobs method of continuous variations, which
indicate the formation of a 1:1 complex. The formation
constant of the nfH /Fe(III) complex was lower than
that found by Issopoulos [105,106].
The stability constants of metal complexes and
quinolones were determined by potentiometry and
spectrophotometry [107]. The values of the stability
constants for Al(III), Mg(II) and Ca(II) complexes were
Ca B/Mg B/ B/Al. The stability constants of lomefloxacin complexes with divalent transition metal ions
followed the Irving /Williams series [108] (Mn B/Fe B/
Co B/Ni B/Cu /Zn).
It was found that ofloxacin reacts with Cu(II) to form
complexes 1:1 (drug:metal) (pH 4.00), 2:1 (pH 7.02) and
3:1 (pH 8.30) [109]. The 1:1 and 3:1 complexes were
confirmed by a polarographic method.
The ability of Al(III) to form complexes with nfH was
investigated by potentiometry and fluorescence spectroscopy [110]. The stability constants of numerous complexes formed in the system were calculated.
The interaction of Co(II), Ni(II), Cu(II) and Zn(II)
with cxH has been studied by means of pH-metric,
spectrophotometric and ESR methods [52]. In all
systems, complexes with different stoichiometric ratios,
in which cxH acts both as a neutral and a deprotonated
ligand, are formed. The anomalous sequence of the
stepwise stability constants observed for Co(II) and
41
Ni(II) suggests changes in stereochemistry when Co(cx)2

and Ni(cx)2 are formed. For the Cu(II) system, the
sequence in the stepwise stability constants indicates the
preferential formation of the [Cu(cx)] monocomplex.
The formation constants of nfH and cfH /Cu(II)
complexes were determined by potentiometric titrations
[59]. The addition of cfH to metal ions resulted in the
formation of ML and ML2 complexes. The overall and
stepwise formation constants were calculated and the
speciation plots were constructed.
Some metal (Ca(II), Co(II), Ni(II), Cu(II), Zn(II),
Al(III), Fe(III)) complexes of cfH were studied by
potentiometric and spectroscopic methods in solution
[94]. It was found that different protonated complexes
are formed before precipitation in the systems studied.
In the more acidic region a 1:1 complex is favored,
whereas a 1:2 (metal:drug) complex prevailed at higher
pH values. As the coordination of the second ligand is
more favored than that of the first, it seems probable
that the 1:1 complex is more distorted. Jobs technique
confirmed that the 1:1 /Cu:cfH complex is the major
component of the system at pH 2.5. Iron and aluminium
form the complexes with a 1:3 metal to ligand ratio.
The interaction of nfH with di- and trivalent cations
was studied by potentiometric titrations [111]. The
formation constants were used to predict a rank order
of metals that may be expected to hinder the gastrointestinal absorption of the fluoroquinolones in vivo.
The effects of metal ions on the pharmacokinetics of
orally administered nfH in dogs were investigated. The
data indicated the likely formation of a 1:2 metal ion /
quinolone complex at the pH of the upper gastrointestinal tract from which the fluoroquinolones are absorbed.
The complex formations of different quinolones with
various metal cations were investigated by pH-titrations
and NMR spectroscopy [86]. The order of stability
constants among trivalent metal cations was Fe(III)/
Al(III), and that among divalent metal cations was
Cu(II) /Fe(II) /Zn(II) /Mg(II) /Ca(II). It was proposed that quinolones interact with Al(III) in the
stomach, but with Mg(II) in the intestines when
coadministered with antacid containing Al(III) and
Mg(II).
Alkaysi et al. have used Jobs technique and molar
ratio methods to determine the stoichiometry of metal /
nfH complexes [112]. The determined ratios were
nfH:Al(III) /2:1 and nfH:Mg(II)/3:1. It has been
reported that the formation of a complex with Al(III)
enhanced the water solubility of the drug.
The UV /vis experiments employing the continuous
variation method showed that the typical stoichiometry
for the Al(III)/cfH chelate is 1:1 [13]. Steric hindrance
by the first cfH molecule may significantly affect
chelation of subsequent molecules.
42
Jobs method was also used to determine the stoichiometry of the mixed ligand complexes Cu /bipy /nal and
Cu /phen /nal [57]. The study was possible owing to the
fact that in solution, [Cu(bipy)]2 or [Cu(phen)]2 exist
practically without any dissociation. It was found that
the [Cu(bipy)]2:nal and [Cu(phen)]2: nal ratios are
1:1. Similar results were also found in Cu-bipy (phen)
complexes with oxoH and cxH [58].
The complexation of nalH and nine fluoroquinolone
drugs with Mg(II) and Ca(II) was studied by spectrofluorometry [113]. Scatchard plots were used to determine the stoichiometry of ligation. Based on these
results, a 2:2 ratio was proposed involving coordination
at the carboxylic acid, the adjacent 4-keto group and the
terminal nitrogen of the piperazine ring.
The complexation of lomefloxacin with five metal
ions (Al(III), Ca(II), Mg(II), Bi(III) and Fe(III)) was
studied [114]. The stability constants and stoichiometries
were determined by measuring the change of aqueous
solubility of lomefloxacin as a function of metal ion
concentration. It was established that calcium forms a
1:1 complex, magnesium, bismuth and iron a 1:2
(metal:drug) complex and aluminium a 1:3 complex.
To sum up, the pKa values of most free quinolones
have been determined by various methods. Additionally
the stability constants of several quinolone /metal complexes have been reported. It is hard to make some
general conclusions but it seems that the values of
stability constants with divalent transition metal ions
follow the Irving /Williams series [108].
6. UV /vis spectroscopy studies

Apart from the data used for the calculation of
stability constants and determination of stoichiometry,
the changes in the UV part of the quinolone spectra
were also studied. The UV spectra of quinolones are pH
dependent. In the representative example cfH, three
main maxima at 274 /278, 324 and 340 nm are observed,
which are all shifted at different pH values. The changes
can be attributed to the extent of ionization of the
carboxylic group. Numerous authors have also studied
the changes in spectra upon the addition of metal ions
[15,52,82,85,92,99,100,105 /107,109,112]. Some authors
have also interpreted the d/d transitions of some
metal/quinolone complexes.
The d /d transitions were studied in the complexes
Cu /phen /oxo (nal, cx) and Cu /bipy /oxo (nal, cx) [58].
In the first type of complexes the lmax appears between
636.6 and 632.9 nm. In the second group the lmax
appears between 626.7 and 617.3 nm. From these results
it is clear that the main effect on the average ligand field
is caused by the diammine, and that all antibacterial
agents used have almost the same contribution to the
average ligand field.
The diffuse reflectance spectra of [Ni(cx)2(DMSO)2]/

4H2O and Ni(cx)2 /2H2O show d /d bands and a metal
ligand charge transfer band. The d /d bands were
assigned as electronic transitions of an Ni(II) ion in an
octahedral environment which was in agreement with
the crystal structure of [Ni(cx)2(DMSO)2] /4H2O [51].
The diffuse reflectance spectrum of Na[Co(cx)3] /10H2O
together with the magnetic moment (4.97 BM) is
consistent with the presence of a high-spin octahedral
cobalt(II) ion [63]. Ligand field parameters were calculated giving Dq /854 cm 1 and b /0.98. The spectrum
of Cu(cx)2 /2H2O is in agreement with a square planar
coordination around copper(II) confirmed by X-ray
crystallography [63].
7. NMR spectroscopy
The 1H and 13C-NMR spectra of nfH were recorded
in deuteroacetic acid and the resonances were assigned
[75]. Norfloxacin solutions were also titrated with DCl
and NaOH and the pKa values were determined [103].
Three pKa values were determined, which correspond to
deprotonation of the carboxylic group (pKa 0.6),
pyridone nitrogen (pKa 6.9) and external piperazine
nitrogen (pKa 9.25). These assignments were corrected
according to the 13C-NMR study of nfH in 3 M DCl
solution [34]. The authors have suggested that the pKa at
0.6 is that of the keto oxygen atom and the pKa at 6.9 is
that of the carboxylic group.
A series of isolated 6,7- and 7,8-disubstituted quinolones was also characterized by 1H spectroscopy [115].
The acid /base properties of seven fluoroquinolone
derivatives were studied by NMR spectroscopy [93]. The
basicities of the functional groups were quantified in
terms of macroconstants, and also at the submolecular
level in terms of microconstants. The microspeciation
was also presented.
1
H-NMR was used to probe the interactions experienced by cfH following uptake into large unilamellar
liposomes [116]. It was shown that cfH is located in the
aqueous interior of the liposomes and is self-associated
in the form of small stacks. cfH does not precipitate,
even though its intraliposomal concentration can exceed
its solubility in aqueous solutions by almost two orders
of magnitude.
Interaction between nfH and b-CD in solution was
characterized by 1H-NMR [77]. It was suggested that
the piperazine group of nfH is that part of the molecule
which is bound inside the b-CD cavity.
The complexation of lomefloxacin, nfH and the metal
ions (Al(III), Mg(II) and Fe(III)) was studied with 1H
and 13C-NMR in D2O solutions [38]. Studies using
Al(III) resulted in the appearance of three or four
additional peaks with the addition of a metal ion to
the drug solution due to slow exchange between the
complexed and the free drug. Two complexes were

proposed to have stoichiometries of 2:1 and 3:1 (drug:metal) based on peak widths and variable temperature
studies. The crystal structure of free lomefloxacin was
used together with NMR data on the aluminium
complexes in molecular modeling of the lomefloxacin /
Al (3:1) complex. The authors suggested that three
lomefloxacin molecules are coordinated to aluminium
through carboxylic oxygen and 4-keto oxygen.
Benigno Macas Sanchez et al. reported that only
minor shifts were found in the 1H-NMR spectra of
compounds isolated from systems containing quinolone
(cfH, ofloxacin) and metal (Al(III), Mg(II), Ca(II),
Fe(II)) [87]. Small shifts could be due to the change in
the counteranion or to a different association of the
quinolone molecules. No functional group seemed to be
lost or modified in the prepared compounds.
19
F-NMR was used to measure the affinity of
magnesium for six fluoroquinolones [90,91]. It was
proven that magnesium is located between the keto
and the carboxylate groups. The binding constants for
the 1:1 Mg2 /drug complexes were determined. Sparfloxacin and pfH, with affinity constants (Ka) of (10.19/
0.6) /102 and (219/1) /102 M1, respectively, were the
least and the most bound.
The extent of pfH stacking depends strongly on pH
and was studied by 1H, 13C and 19F-NMR [117]. The
authors concluded that pfH is monomeric at the
concentration 10 4 M. At such a concentration of
pfH and high cation /quinolone ratios, 1:1 and 1:2
(drug:cation) complexes with magnesium and calcium
form at pH 7.4 [118]. It was supposed that the binding
sites are first the carbonyl and carboxylic groups, then
the terminal nitrogen piperazinyl atom. When the pfH
concentration is increased, the affinity of this drug
increases. This is due to the formation of a 2:2 complex
which enhances the stacking of this fluoroquinolone.
19
F-NMR spectra show that in the absence of
magnesium, pfH binds poorly to DNA and preferentially to single-stranded rather than to double-stranded
DNA [119]. The data show that the quinolone ring of
pfH has little mobility in the ternary complex. In this
complex, pfH could be bound to two magnesium ions,
each cation acting as a bridge between this molecule and
a phosphate group of the DNA backbone.
The NMR titration experiments have revealed that
the binding ability of levofloxacin (this molecule is an S enatiomer of ofloxacin, see Scheme 2) toward Al(III) is
much stronger than that of cfH and lomefloxacin at pD
2.5 [120]. In contrast to the complexation with Al(III),
the binding of these drugs with other metal ions such as
Ca(II) and Mg(II) is much weaker. NMR signals have
shown no appreciable downfield shift by the addition of
Ca(II) and Mg(II). Based on these results, it was
concluded that the fluoroquinolone antimicrobials ex-
43
amined in the present study at pD 2.5 exist as stable

complexes in the presence of Al(III).
The coordination mode of quinolone DR-3862 in the
presence of Al(III) was studied by 13C-NMR [86]. The
chemical shift changes of the carbon atoms near the
carbonyl group of DR-3862 were very large, and the
bonding of Al(III) to the carbonyl and carboxylic
groups was proposed.
The participation of the carbonyl and carboxylic
groups in the chelating reaction of different quinolones
was also confirmed by 13C-NMR measurements of the
Al(III) and Mg(II) complexes [107].
The 13C solid state NMR spectrum of [Cd2(cx)4(DMSO)2]/2H2O revealed that each carbon atom (C4,
C16, C15, CDMSO) shows two signals as a consequence of
the two cxH ligands being coordinated in different ways
to cadmium in the asymmetric unit [62].
The 13C-NMR study was performed in Zn /nal/phen
(bipy) systems [80]. The authors proposed that the
nalidixate is coordinated through the carbonyl and
carboxylate groups in a trigonal bipyramidal geometry
(with the diammine in the equatorial position, the drug
bonded to one equatorial and one axial position and the
remaining position for the anion as chloride or nitrate).
The complexation of Cu(II) and nalH was studied by
13
C-NMR [121]. It was found that the site of binding
depends upon the nature of the other ligands present in
solution. In the absence of added ligands, chelation via
the 3-carboxylate group was observed, while interaction
with [Cu(phen)]2 is via chelation with both carboxylate
and 4-oxo groups.
From the 13C-NMR study in the Cu(II) /cfH system
[59] it appears that in an acidic solution, the primary
source of interaction with the metal ion is through the
oxygen donors, whereas in basic solutions, there is an
additional interaction of the copper(II) with the piperazinyl nitrogen donor.
A similar conclusion was drawn from the proton
relaxation times (T1) determined from the titration data
in acidic and basic media in the Cu(II) /cfH system
[122]. The authors claimed that it is plausible that more
than one species is present in the solution at high pH
values.
We can summarize that 1H, 13C and 19F-NMR
spectra have been used to study the behaviour of
quinolones and their metal complexes in solution. The
spectra of free quinolones were assigned and the
chemical shift changes have confirmed the chelate
bonding of metal ions to quinolone ring carbonyl and
carboxylic oxygens. The changes in spectra also indicated that for quinolones bearing the piperazine ring at
position 7, the terminal nitrogen of this ring system
could be involved in the bonding to the metal in solution
at higher pH values.
44
8. The mode of action of quinolones. Interactions of

quinolones with DNA and the role of metal ions in these
processes
Bacterial DNA topology is controlled by three
enzymes, DNA gyrase introduces negative supercoiling;
DNA topoisomerase I counters the action of gyrase to
prevent the accumulation of excess supercoiling; and
DNA topoisomerase IV plays a central role in the
resolution of interlinked, replicated daughter chromosomes. Numerous classes of compounds have been
demonstrated to interfere with both prokaryotic and
eukaryotic enzymes. Among these, very active and
widely prescribed drugs are currently being utilized for
the treatment of bacterial infections and human cancers
[123]. DNA gyrase and DNA topoisomerase IV are both
sensitive to the 4-quinolone class of antibacterial
compounds in vitro. The activity of quinolones is due
to the inhibition of the supercoiling of DNA catalyzed
by the enzyme DNA gyrase. Contradictory reports have
appeared in the literature on the molecular details of
drug /DNA and drug /enzyme interactions [124 /143].
Shen and coauthors have proposed drug/DNA models
which imply hydrogen-bond type interactions between
the DNA unpaired bases and the quinolone, as well as a
stacked dimerization of the drug [127 /129]. Their results
were also not quite consistent with the previously
reported fact that nalidixic acid binds to single-stranded
DNA only in the presence of an excess of copper ions
[144]. The model has been modified and includes a
possible interaction between the C-7 substituent and the
quinolone pocket on the B subunit of DNA gyrase [145].
Palumbo et al. have stressed the role of magnesium in
the quinolone /DNA interaction [146,147]. It was suggested that Mg(II) acts as a bridge between the
quinolone and the phosphate group of the DNA, and
that this complex is stabilized by stacking interactions
between the condensed rings of the drug and the DNA
bases in a single-stranded region or a distorted B-form
in plasmid. In the subsequent study it was confirmed
that DNA-affinity of the quinolone, modulated by
Mg(II), plays an important role in poisoning the
cleavable gyrase /DNA complex and, consequently, in
eliciting antibacterial activity by this family of drugs.
The results obtained with different 6-substituted compounds support the idea that position 6 of the drug,
besides playing a pharmacokinetic role, is involved in
recognition of the enzyme pocket. Llorente and coworkers [148] have proposed another model based on the
intercalation of quinolone into the double helix of
DNA. However, the results reported by Hurley et al.
in their parallel study of quinobenzoxazines and nfH
have shown that in the presence of Mg(II), only the
former are able to form a stable intercalated complex
with DNA [149]. It was later found that nfH, which can
only play an external binding role, was able to modulate
the photochemical reaction of the quinobenzoxazines on

DNA [150].
Recently new studies have also been performed where
an important role of metal ions in the mechanism of
action of these drugs was again proposed. From a
theoretical /experimental study on the structure and
activity of certain quinolones and the interaction of
their Cu(II) complexes on a DNA model, it was
suggested that the intercalation of the quinolone complexed to a metal is an important step in these processes
[151].
The conformational equilibria of DNA gyrase A
(subunit of the enzyme) in the presence of Mg(II) and
cfH were studied. It was proposed that the magnesium
mediated quinolone binding to the enzyme might be
involved in the mechanism of action of this family of
drugs [152].
We can conclude that the mode of action of these
drugs and related processes were extensively studied in
the past. The topic is extremely important due to the fact
that several quinolones are used in clinical practice. But
obviously there are still several questions to be answered.
9. Bioactivity of quinolone /metal compounds

The complexes of iron(III) */[Fe(nfH)2(H2O)2]Cl3 /
6H2O and zinc(II) /[Zn(nfH)2]Cl2 /7H2O were tested in
vitro against the Gram negative microorganisms E. coli
and Bacillus dysenteria bacteria [88]. The complexes
showed stronger activity than nfH.
The biological activity of the Cu /phen/nal complex
and its individual components was tested against
Entamoeba histolytica (HM 1 ), E. coli and Clostridium
symbiosum [153]. The complex showed the highest
inhibitory activity on axenic and monoxenic amobease.
E. coli showed high susceptibility to the Cu /phen/nal
complex, whereas C. symbiosum did not. The authors
concluded that Cu /phen/nal could have a potential use
as an alternative drug in chemotherapy of some
bacterial infections in disease caused by E. histolytica .
In contrast, the iron complex of nalH showed
amoebical activity only at concentrations higher than
those used with nalH [154].
The results of in vitro experiments demonstrated that
under reductive conditions [Cu(phen)(nal)] behaves as
a powerful nuclease capable of degrading plasmid DNA
[155]. These results support the hypothesis that the
mechanism of action of quinolones could be mediated
by a transition metal ion such as copper.
The complex [Cu(cx)2]/2H2O was screened for activity
against several bacteria (minimal inhibitory concentration (MIC) values) showing the same antimicrobial
activity as the corresponding ligand [55]. The number of
bacteria killed after 3 h of incubation with [Cu(cx)2]/
2H2O and Na[Co(cx)3]/10H2O complexes was

determined against E. coli (ATCC 25922) [63]. The
copper compound presents a paradoxical effect */the
diminution in the number of bacteria killed at high drug
concentrations [156 /159].
The compounds (cfH3)(cfH2)[BiCl6]/2H2O, (kinoH3)[CuCl4]/H2O and (erxH3)[FeCl4]Cl were tested against
different microorganisms [66,71]. In the employed
experimental procedure, the metal compounds showed
the same antimicrobial activity against bacteria as the
reference free quinolone drugs.
Two bismuth compounds, (cfH3)(cfH2)[BiCl6]/2H2O
and (cfH3)2[Bi2Cl10] /4H2O, were tested against Helicobacter pylori [67]. The results show that the activity of
both bismuth(III) compounds is comparable to that of
cfH hydrochloride.
Two magnesium(II) complexes, [Mg(FCl)2]/H2O and
[Mg(cf)2(H2O)2]/2H2O, were tested against various
Gram positive and Gram negative microorganisms
[160]. The results show that both magnesium complexes
are significantly less active than the parent quinolone
drugs. It was also found that the activity of quinolones is
reduced when the solutions are titrated with magnesium
ions.
It was also established that Cu(II) and Ni(II) are
effective in induction of the cytotoxicity of some
quinolones (nalH, oxoH) against leukemia cells in vitro,
whereas Mg(II) was not effective [161]. The different
effects of the metals on quinolone cytotoxicity can be
explained by their different modes of interaction with
quinolone. The authors claim that the transition metals
can form DNA intercalated agents with quinolone,
which can cause the cytotoxicity.
It was also found that the vanadium /cfH complex is
promising with respect to its insulin-mimetic behaviour
and concomitant low toxicity in the physiological
concentration range [48].
Some of the isolated metal /quinolone complexes
have been tested for activity against variety of microorganisms and some other biotests have also been
performed. In most tests it was found that the activity
of the complexes is comparable to free quinolones. In
certain examples the activity was also increased (or
lowered) but there is no evidence of any further clinical
tests. It is expected that more such results are to be
published in the future.
Acknowledgements
The author wishes to thank Dr A. Demsar, Dr B.
Modec and Dr N. Lah, for their assistance.
45
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The Interactions of Metal Ions With Quinolone Antibacterial Agents

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Coordination Chemistry Reviews 232 (2002) 27 /47

The interactions of metal ions with quinolone antibacterial agents

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

1.2. The influence of metal ions on the activity of

1.1. General aspects and characteristics of quinolones

Hoffken et al. [6] first reported that concurrent

The term quinolones is commonly used for the

Scheme 1. The formulas of 4-oxo-1, 4-dihydroquinoline (left) and

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Scheme 2. The formulas of quinolone molecules that appear in the text.

2. Crystal structures of quinolones and their metal

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

been prepared and their crystal structures reported in

) and one of the two oxygen atoms in the

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Fig. 2. View of [Fe(cfH)(nta)] complex. Adapted from Ref. [49].

triacetate (nta) (disodium salt) [49]. Dilute ammonia

Fig. 3. Perspective view of [Co(cx)3] anion. Adapted from Ref. [50].

solution of cxH and CoSO4 [50] (Fig. 3). The structure

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Fig. 4. Perspective view of [Cu(cfH)2Cl2]. Adapted from Ref. [53].

Fig. 5. View of [Cu(cfH)(H2O)3]SO4 2H2O. Reproduced with

disordered over three positions. In the second complex

carboxylic atom (Cu /O(1)/1.915(2) A). Two water

pyramidal environment in the second complex. It is

1.933(4) A) and a water molecule (Cu /O(1W) /

Cu /O(2)/1.934(2) A) and a water molecule in the

O(15) /1.913(6) A, Cu(1) /O(2)/1.914(4) A, Cu(1) /

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Fig. 6. Perspective view of [Cu(cx)2] 2H2O. Adapted from Ref. [55].

Fig. 8. Structure of the silver complex of pefloxacin. Adapted from

2.2.9. Silver complex

Fig. 7. Crystal structure of [Cu(phen)(nal)(H2O)]NO3 3H2O. Adapted from Ref. [57].

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

molecule also coordinates to each silver atom (Ag /

2.2.10. Zinc complexes

O(1)/2.083(5) A). The octahedral coordination sphere

take part in the coordination, while in the weakly acidic

2.2.11. Cadmium complexes

Fig. 9. View of [Zn(cx)2(DMSO)2]. Adapted from Ref. [51].

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Fig. 10. View of [Cd2(cx)4(H2O)2]. Adapted from Ref. [63].

2.3. Ionic compounds

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Atoms involved Coordination

[Mg2(H2O)6(nfH)2]Cl4 4H2O [43] O(P), O(C),

protonated at the terminal nitrogen atom of piperazine

O(P), ring carbonyl oxygen; O(C), carboxylic oxygen.

nolone cations and chlorometalate or simple inorganic

2.3.4. Platinum compound

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

Fig. 11. View of (cfH2)2[Mg(H2O)6](SO4)2 6H2O. Adapted from Ref. [65].

Fig. 12. View of (cfH3)(cfH2)[BiCl6] 2H2O. Adapted from Ref. [66].

aromatic rings in the neighboring layers are around 3.5

The zinc compound of cfH with the formula

Fig. 13. View of (erxH3)[FeCl4]Cl. Reproduced with permission from

Only a few references are available on the thermal

I. Turel / Coordination Chemistry Reviews 232 (2002) 27 /47

carboxylic atom (Cu /O(1)/1.915(2) A). Two water

1.933(4) A) and a water molecule (Cu /O(1W) /

Cu /O(2)/1.934(2) A) and a water molecule in the

O(15) /1.913(6) A, Cu(1) /O(2)/1.914(4) A, Cu(1) /

O(1)/2.083(5) A). The octahedral coordination sphere

at 1698 cm 1 for sparfloxacin. At pH 12, n(C /O)p was