Synthesis, characterization and biological studies of mononuclear copper(II) complexes with ciprofloxacin and N, O donor ligands

Article abstract of DOI:10.1016/j.inoche.2012.10.018

The mixed ligand Cu(II) complexes of ciprofloxacin and N, O donor Schiff bases have been prepared and characterized by physicochemical techniques. In these complexes, ciprofloxacin acts as bidentate deprotonated ligand bound to the metal through the pyrid

Full text of DOI:10.1016/j.inoche.2012.10.018

Inorganic Chemistry Communications 27 (2013) 51–55
Contents lists available at SciVerse ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Synthesis, characterization and biological studies of mononuclear copper(II)
complexes with ciprofloxacin and N, O donor ligands
Mohan N. Patel ⁎, Chintan R. Patel, Hardik N. Joshi
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388 120, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The mixed ligand Cu(II) complexes of ciprofloxacin and N, O donor Schiff bases have been prepared and char-
acterized by physicochemical techniques. In these complexes, ciprofloxacin acts as bidentate deprotonated
ligand bound to the metal through the pyridone oxygen and one carboxylate oxygen. The antimicrobial activ-
ity of the complexes has been tested on three Gram(−ve) and two Gram(+ve) microorganisms in terms of
minimum inhibitory concentration (MIC) and colony forming unit (CFU). The interaction study of the com-
plexes with Herring Sperm DNA (HS-DNA) has been performed by absorption titration and viscosity mea-
surement. The DNA cleavage activity has been carried out by gel electrophoresis experiment using
supercoiled form of pUC19 DNA. Potential cytotoxic effect of complexes has been investigated by brine
shrimp lethality assay method. The complexes have been also screened for their enzymatic behaviour in
terms of IC50 value.
Received 4 September 2012
Accepted 11 October 2012
Available online 17 October 2012
Keywords:
Copper(II) complexes
MIC
DNA interaction
DNA cleavage activity
Cytotoxicity
Enzymatic behaviour
©
2012 Elsevier B.V. All rights reserved.
Copper(II) complexes with diverse drugs have been the subject of
a large number of research studies [1,2], most probably due to the bi-
ological role of copper(II) and its synergetic activity with the drug [3].
It was already reported that some quinolone-metal complexes exert
biological activity against various microorganisms or have some
other positive effects in the treatment of certain diseases [4,5]. The
antifungal and antibacterial properties of a range of copper(II) com-
plexes have been evaluated against several pathogenic fungi and
bacteria [6,7].
activities, because of its biological relevance [11–18]. A large number
of mixed ligand copper(II) complexes have been shown to exhibit su-
peroxide dismutase activity [19] and pharmacological activity [1]. This
activity depends on the Cu(II)/Cu(I) redox process, which is related to
the flexibility of the geometric transformation around the metal centres
[20].
In continuation of our previous work [21], herein we report mono-
nuclear mixed ligand copper(II) complexes of ciprofloxacin and N, O
donor Schiff bases. The synthesized complexes were characterized
by physicochemical and spectroscopic techniques and explored for
their biological activity such as; antimicrobial activity, DNA interac-
tion study, SOD mimics activity and cytotoxicity.
Quinolones, a commonly used term for the quinolonecarboxylic
acids or 4-quinolones, are a group of synthetic antibacterial agents
containing a 4-oxo-1,4-dihydroquinoline skeleton [8]. Ciprofloxacin
1
(
1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-
Schiff base N′-(4-fluorobenzylidene)benzohydrazide (L ) was pre-
quinoline carboxylic acid) is a member of this large family and is used
for the treatment of certain diseases caused by various Gram(−ve)
and Gram(+ve) microorganisms [9]. They are extremely useful for
the treatment of a variety of infections, including urinary tract infec-
tions, soft tissue infections, respiratory infections, bone-joint infections,
typhoid fever, sexually transmitted diseases, prostatitis, community-
acquired pneumonia, acute bronchitis and sinusitis [10]. In general,
quinolones can act as antibacterial drugs that effectively inhibit DNA
replication and are commonly used as treatment for many infec-
tions [10]. In literature, complexes of ciprofloxacin with diverse metal
ions such as copper(II), vanadium(IV), magnesium(II), uranium(VI),
manganese(II), iron(III), cobalt(II), nickel(II), molybdenum(II) and
europium(III) have been reported and explored for their biological
pared by condensation of 4-fluoro benzaldehyde and benzohydrazide.
A solution of 4-fluoro benzaldehyde (10 mmol) was added to a solu-
tion of benzohydrazide (10 mmol). The resulting solution was refluxed
for 4–5 h on water bath after addition of 1–2 drops of acetic acid. On
cooling the solution at room temperature product was separated,
which was filtered and washed with methanol. The product was
recrystallized from hot methanol.
Similarly Schiff bases N′-(4-chlorobenzylidene)benzohydrazide
2
3
(L ), N′-(4-bromorobenzylidene)benzohydrazide (L ), N′-(2-chloro
4
benzylidene)benzohydrazide (L ), N′-(4-methylbenzylidene)ben-
5
6
zohydrazide (L ), N′-(4-methoxybenzylidene)benzohydrazide (L )
7
and N′-(4-(benzyloxy)benzylidene)benzohydrazide (L ) were pre-
pared by condensation of different substituted aldehydes and ben-
1
7
zohydrazides. Schiff bases (L –L ) were characterized by elemental
analysis, 1H and C NMR spectroscopy. The reaction scheme used
for the preparation of Schiff bases and proposed structures are
13
⁎
Corresponding author. Tel.: +91 2692 226856x218.
E-mail address: jeenen@gmail.com (M.N. Patel).
1387-7003/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.inoche.2012.10.018

52
M.N. Patel et al. / Inorganic Chemistry Communications 27 (2013) 51–55
Scheme 1. Proposed structure and reaction scheme for the preparation of Schiff bases.
Scheme 2. General synthesis and proposed structures of complexes.
shown in Scheme 1. Physicochemical parameter data of ligands L –L7
are shown in the supplementary material.
1
desiccator. The proposed structure of complexes is shown in
Scheme 2. Physico-chemical parameters and microanalysis data of
the synthesized complexes are in good agreement with proposed
structure and are shown in the supplementary material.
2 2
Methanolic solution of CuCl ·2H O (1 mmol) was added to a
methanolic solution of neutral bidentate ligand (L –L ) (1 mmol),
followed by addition of previously prepared methanolic solution of
1
7
9
Visible emission spectra of the copper(II) complexes i.e. d system
ciprofloxacin in the presence of CH
mixture was adjusted at ~6.8 using dilute solution of CH
3
ONa (1 mmol). The pH of reaction
ONa. The
were recorded in DMSO. Complexes exhibited the only broad peak at
λmax =~660 nm, which was attributed to d–d transition, in which
3
resulting solution was refluxed for 3 h on a water bath, followed by
concentrating it to half of its volume. A fine amorphous product
obtained was washed with chloroform and dried in vacuum
Cu(II) atom was in distorted square pyramidal environment [22].
The λmax value observed for the synthesized complexes 1 to 7 are
667 [23], 655 [24], 665 [23], 673 [25], 650 [24], 662 [26] and 672
1
Fig. 1. LC–MS spectrum of complex [Cu(CPF)(L )Cl].

M.N. Patel et al. / Inorganic Chemistry Communications 27 (2013) 51–55
53
Table 1
Table 2
Antimicrobial activities of CPFH, copper(II) salt and complexes in terms of minimum
b
Binding constant (K ), IC50 and LC50 values of the synthesized complexes.
inhibitory concentration (MIC) (μM).
Complex
K
b
(M−1)
IC50 (μM)
LC50 (μM)
Compound
Gram positive
S. aureus B. subtilis S. marcescens P. aeruginosa E. coli
2698.0 2815.0 2756.0 2404.0 3402.0
Gram negative
1
5
[
Cu(CPF)L Cl] (1)
2.68×10
2.55×10
2.35×10
2.20×10
0.70×10
0.44×10
0.32×10
0.64
0.82
0.87
1.02
2.19
2.50
2.68
7.76
10.00
12.59
14.45
39.81
47.86
58.88
2
5
5
5
5
5
5
[Cu(CPF)L Cl] (2)
3
[
[
[
[
[
Cu(CPF)L Cl] (3)
CuCl
CPFH
2
·2H
2
O
4
Cu(CPF)L Cl] (4)
1.52 1.04 1.52 1.32 1.36
5
Cu(CPF)L Cl] (5)
1
[
[
[
[
[
[
[
Cu(CPF)L Cl] (1)
0.58
0.63
0.69
0.76
1.50
1.53
1.55
0.29
0.34
0.41
0.47
1.01
1.04
1.05
0.39
0.43
0.51
0.53
1.50
1.54
1.55
0.45
0.51
0.58
0.63
1.30
1.34
1.36
0.51
0.58
0.67
0.73
1.29
1.35
1.36
6
Cu(CPF)L Cl] (6)
2
Cu(CPF)L Cl] (2)
7
Cu(CPF)L Cl] (7)
3
Cu(CPF)L Cl] (3)
4
Cu(CPF)L Cl] (4)
5
Cu(CPF)L Cl] (5)
6
and these data are further supported by observation of ν(M\O) at
~540–575 cm
Cu(CPF)L Cl] (6)
7
−1
−1
Cu(CPF)L Cl] (7)
[32] and ν(M\N) at ~490–535 cm
[33]. Signifi-
cant wave numbers are given in the supplementary material.
The structure of complexes was further confirmed by molecular
+
[26] nm respectively, which are similar to the complexes reported in
ion peak [M] at 670.11 m/z and [M+2] at 672.11 m/z in the LC–
the literature. The possibility of trigonal bipyramidal geometry at the
metal centre was ruled out because the peak of λmax greater than
MS spectrum of complex 1 (Fig. 1). Some other fragments are ob-
served at m/z=672.11, 428.02, 393.06, 340.02, 342.22, 331.13,
305.02, 247.06, 203.07, 163.05 and 242.09, respectively. The proposed
mass fragmentation pattern for complex 1 is shown in the supple-
mentary material.
The antibacterial activity of the Cu(II) salt, ciprofloxacin and its
complexes were tested against two Gram(+ve) Staphylococcus aure-
us, Bacillus subtilis and three Gram(−ve) Serratia marcescens,
Escherichia coli and Pseudomonas aeruginosa organisms using double
dilution method and represented in Table 1. Data reveals that, com-
plexes 1, 2, 3 and 4 are more potent against all microorganisms
than other complexes i.e. 5, 6 and 7, ciprofloxacin and copper(II)
salt. An acceptable reason for this increase in bactericidal activity
may be considered in the light of Overtone's concept [34] and chela-
tion theory [35] or may be due to the effect of the metal ion on the
normal cell process.
8
00 nm along with the shoulder at ~660 nm was not observed in
the case of the synthesized complexes [27].
The magnetic moment measurement for any geometry in
copper(II) complexes results in the range of 1.76–1.86 BM, which is
very close to spin-only value i.e. 1.73 BM. The observed values in
our case were very close to the spin-only values for single unpaired
9
electron, and confirm the copper in +2 state with d configuration
6
3
2g g
(t e ) [28]. The copper content in the complex is determined by
spectrophotometric titration technique [29]. The calculated result
from the equivalent endpoint reveals the metallic content of the com-
plex. Spectrophotometric titration curves and table for equivalent
endpoint determination of the complexes are shown in the supple-
mentary material.
Ring mode vibrations of the ligands are affected by coordination to
Cu(II), corresponding to
a
shift in energy for bands in the
In addition to our study regarding bactericidal activity in terms of
CFU/mL of the metal complexes against same microorganisms, a de-
crease in number of colonies with increasing the concentration of
complexes is revealed. The CFU/mL for different microorganisms
against complexes is shown in the supplementary material.
Fig. 2 shows the absorption spectra of complex 1 in the presence of
increasing amounts of HS-DNA at room temperature. Complex binding
with DNA through intercalation usually results in hypochromism and
bathochromism, due to intercalative mode involving a strong stacking
interaction between an aromatic chromophore and the base pairs of
DNA [36]. To compare the binding strength of complexes quantitatively,
−
1
1
700–400 cm
region of the IR spectra. In the IR spectra, bands at
−
1
1
708 and 1624 cm in case of ciprofloxacin correspond to ν (C_O)carb
−
1
and ν(C_O)
p
respectively. The peak at 1708 cm
corresponding to
ν(C_O)carb of ciprofloxacin is disappeared on complexation with
−
1
metal ion and replaced by ν(COO)as=~1580 cm
and ν(COO)
1350 cm respectively [30]. Unidentate nature for the carboxylato
group of ciprofloxacin is proved by frequency separation of
s
=
−
1
~
−
1
~
220 cm
s
(Δν=νCOOas\νCOO ) [31]. Deprotonation of the hy-
droxyl group of ciprofloxacin is indicated by disappearance of band
−
1
at 3519 cm
band at 1624 cm
served between 1620 and 1635 cm
from spectra due to hydrogen bonding [30]. The
−
1
responsible for ν(C_O)
p
in ciprofloxacin is ob-
in case of complexes [18],
−
1
1
Fig. 2. Electronic absorption spectra of [Cu(CPF)(L )Cl] in phosphate buffer (Na
NaH PO , pH 7.2) in the absence and presence of increasing amount of DNA. The [Cu]
complex=10 μM; [DNA]=0–150 μM. The incubation period is 10 min at room tem-
perature, Inset: Plot of [DNA]/(ε –ε ) versus [DNA]. Arrow shows the absorbance
change upon increasing DNA concentrations.
2 4
HPO /
2
4
a
f
Fig. 3. Effect of increasing amount of EtBr, CPFH and complexes on the relative viscosity
of herring sperm DNA at 37± 0.1 °C.

54
M.N. Patel et al. / Inorganic Chemistry Communications 27 (2013) 51–55
intercalation mode [41] and the increase in relative viscosity is of
same magnitude reported by different research groups [42]. Out of
all the synthesized complexes complex 1 binds more strongly than
the other.
The cleavage of plasmid pUC19 DNA was monitored by gel electro-
phoresis to investigate the ability of the copper(II) complexes to serve
as metallonucleases [43]. When pUC19 DNA is subjected to gel elec-
trophoresis, Form I shows the fastest migration compared to Forms
II and III as shown in Fig. 4. Form II migrates very slowly prior to its
relaxed structure, whereas Form III migrates somewhere between
the positions of Form I and Form II. These clearly show that the rela-
tive binding efficacy of complexes to DNA is much higher than the
Fig. 4. Photogenic view of cleavage of pUC19 DNA (300 μg/mL) with a series of copper(II)
complexes (200 μM) using 1% agarose gel containing 0.5 μg/mL ethidium bromide. All re-
actions were incubated in TE buffer (pH 8) in a final volume of 15 μL, for 24 h at 37 °C.
1
Lane 1, DNA control; lane 2, CuCl
2
·2H
2
O; lane 3, ciprofloxacin; lane 4, [Cu(CPF)(L )Cl];
2
3
4
binding efficacy of metal salt or ciprofloxacin (Table 3).
lane 5, [Cu(CPF)(L )Cl]; lane 6, [Cu(CPF)(L )Cl]; lane 7, [Cu(CPF)(L )Cl]; lane 8,
5
6
7
•−
[
Cu(CPF)(L )Cl]; lane 9, [Cu(CPF)(L )Cl], lane 10, [Cu(CPF)(L )Cl].
2
The superoxide radicals (O ) were generated in vitro using a
non-enzymatic (NBT/NADH/PMS) system and determined spectro-
photometrically by measuring absorbance at 560 nm and plotted to
have a straight line (Fig. 5). Percent inhibition of the reduction of
NBT plotted against the concentration of the complex (Fig. 5). The su-
peroxide scavenging data shown in Table 2 are in the range of 0.64–
2.68 μM. Results show that complexes exhibit greater scavenging ac-
tivity toward superoxide radicals, which may be accredited to the
redox potential of the Cu(II) complex which depends on the geome-
try at the metal centre.
The in vitro lethality test has been carried out using brine shrimp
eggs i.e. Artemia cysts. The shrimp lethality assay is considered as a
useful tool for preliminary assessment of toxicity. Brine shrimp le-
thality bioassay is a development in the assay procedure of bioactive
compound. All the synthesized compounds were screened for their
cytotoxicity (brine shrimp bioassay) using the protocol of Meyer et
al. [44]. The mortality rate of brine shrimp nauplii was found to in-
crease with increasing the concentration of the complexes. Results
for the lethality were noted in terms of deaths of larvae. A plot of
Log of sample's concentration versus percentage of mortality showed
a linear correlation. From the graph, the LC50 values of the samples
were calculated and found in the range of 7.76–58.88 μM (Table 2).
Copper(II) complexes of ciprofloxacin bind to DNA ingeniously
but distinctly different. The antibacterial activity of ciprofloxacin is
changed upon coordination with copper(II) ion. Hypochromism and
bathochromism of band in absorption titration, and increase in rela-
tive viscosity of DNA suggest that all complexes bind with DNA via
classical intercalative mode. Complexation of drug with metal ion en-
hances their DNA cleavage ability. As the electro negativity of the
substituted group on neutral bidentate N, O donor ligands increases,
Table 3
Complex mediated DNA cleavage data by gel electrophoresis.
Lane no.
Compound
Form I
SC
Form II
OC
Form III
L
% Cleavage
1
2
3
4
5
6
7
8
9
Control
82
76
61
11
14
17
19
36
40
48
18
24
39
62
61
60
57
44
37
27
–
–
CuCl
2
·2H
2
O
–
7.31
25.6
86.6
82.9
79.3
76.8
56.1
51.2
41.5
Ciprofloxacin
–
1
[Cu(CPF)L Cl] (1)
27
25
23
24
20
22
25
2
[Cu(CPF)L Cl] (2)
3
[Cu(CPF)L Cl] (3)
4
[Cu(CPF)L Cl] (4)
5
[Cu(CPF)L Cl] (5)
6
[Cu(CPF)L Cl] (6)
7
10
[Cu(CPF)L Cl] (7)
the intrinsic binding constants K
monitoring the changes of absorbance with increasing concentration of
HS-DNA. From the plot of [DNA]/(ε –ε ) vs. [DNA] (inset in Fig. 2), the K
value of complexes was determined and was found in the range of
b
of the complexes were determined by
b
f
b
5
0
.32–2.68×10 (Table 2). This K
b
value is much lower than that of clas-
sical intercalator (ethidium bromide), but higher than reported
II
1
[
Cu (phen)(bnp)H
and [Ni(sf) (bipyam)] [40] complexes.
The effects of complexes, ethidium bromide (EB) and ciprofloxa-
2 4 2 2 2 2
O] [37], [CuL (ClO ) ] [38], [Zn(erx) (H O) ] [39],
2
cin (CPFH) on the viscosity of rod-like DNA are shown in Fig. 3. In
our case increasing the amounts of complexes, the relative viscosity
of DNA increases steadily, hence complexes bind to DNA via
Fig. 5. Plot of absorbance (Abs560) as a function of time (t) to determine % inhibition of formazan formation at various concentrations of complex 1 (0.25 μm to 3 μm) as a function of
time and the plot of percentage of inhibiting NBT reduction with an increase in the concentration of complex 1.

M.N. Patel et al. / Inorganic Chemistry Communications 27 (2013) 51–55
55
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Appendix A. Supplementary material
Materials, instrumental details, physicochemical parameters of li-
gands and complexes, characteristic absorption bands of IR spectra, de-
termination of copper by spectrophotometric titration, proposed mass
fragmentation pattern of complex 1, CFU/mL for complexes against dif-
ferent microorganisms, method for determination of MIC, absorption ti-
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