Copper(II) complexes with ligands derived from 4-amino-2,3-dimethyl-1- phenyl-3-pyrazolin-5-one: Synthesis and biological activity

Article abstract of DOI:10.3390/11110904

The synthesis of Cu(II) complexes derived from Schiff base ligands obtained by the condensation of 2-hydroxybenzaldehyde or terephtalic aldehyde with 4-aminoantipyrine (4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) is presented. The newly prepared compounds were characterized by ¹H-NMR, UV-VIS, IR and ESR spectroscopy. The determination of the antimicrobial activity of the ligands and of the complexes was carried out on samples of Escherichia coli, Klebsiella pneumoniae, Acinetobacter boumanii, Pseudomonas aeruginosa, Staphylococcus aureus and Candida sp. The qualitative and quantitative antimicrobial activity test results proved that all the prepared complexes are very active, especially against samples of Ps. aeruginosa, A. Boumanii, E. coli and S. aureus.

Full text of DOI:10.3390/11110904

Molecules 2006, 11, 904-914
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Copper(II) Complexes with Ligands Derived from 4-Amino-2,3-
dimethyl-1-phenyl-3-pyrazolin-5-one: Synthesis and Biological
Activity
1
,
1
2
2
2
Tudor Rosu *, Simona Pasculescu , Veronica Lazar , Carmen Chifiriuc and Raluca Cernat
1
2
Faculty of Chemistry, Department of Inorganic Chemistry, University of Bucharest, 050107,
Romania. Fax: (040) 21 3159249. E-mail: Simona Pasculescu: simonapasc@yahoo.com
Faculty of Biology, Department of Microbiology, University of Bucharest, 050107, Romania.
Tel. (040) 21 3181576. E-mails: Veronica Lazar: lazar@botanic.unibuc.ro; Carmen Balotescu:
carmen_balotescu@yahoo.com; Ramona Cernat: cernat@botanic.unibuc.ro
*
Author to whom correspondence should be addressed; E-mail: rosu.tudor@unibuc.ro or
t_rosu0101@yahoo.com
Received: 9 August 2006; in revised form: 22 September 2006 / Accepted: 5 November 2006 /
Published: 17 November 2006
Abstract: The synthesis of Cu(II) complexes derived from Schiff base ligands obtained
by the condensation of 2-hydroxybenzaldehyde or terephtalic aldehyde with 4-amino-
antipyrine (4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) is presented. The newly
1
prepared compounds were characterized by H-NMR, UV-VIS, IR and ESR
spectroscopy. The determination of the antimicrobial activity of the ligands and of the
complexes was carried out on samples of Escherichia coli, Klebsiella pneumoniae,
Acinetobacter boumanii, Pseudomonas aeruginosa, Staphylococcus aureus and Candida
sp. The qualitative and quantitative antimicrobial activity test results proved that all the
prepared complexes are very active, especially against samples of Ps. aeruginosa, A.
Boumanii, E. coli and S. aureus.
Keywords: Schiff bases, antimicrobial activity, copper complexes, aminoantipyrine.

Molecules 2006, 11
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05
Introduction
The well-known Cu(II) ion forms a series of coordination compounds with well defined structures.
It plays an important role in the numerous biological processes that involve electron transfer reactions
or the activation of some anti-tumor substances [1]. Copper is an essential micronutrient for feeding
and a co-factor of several enzymes involved in oxidative metabolism: β-hydroxylases, quercetinase,
ceruloplasmine, cytochromoxidase, mono-aminoxidase, superoxydismutase, ascorbic acid oxidase and
tyrosinase. The catalytic role of these enzymes is the result of two processes: a) the reduction of the
2
+
+
Cu cation to Cu ; b) the fixation of the molecular oxygen [2]. As a cofactor of ceruloplasmin, copper
contributes to the oxidation of Fe(II) to the corresponding Fe(III) form. Being related to transferin, the
latter may cross the cell membranes [3]. Copper also has functions in erythropoiesis and hemoglobin-
genesis, favoring, together with molybdenum, intestinal absorption, sediment mobilization and
increases in plasmatic iron levels. Apart from its numerous functions in metabolic processes, copper is
also recognized as a part in the immune function [3]. Superoxydismutase, which transforms toxic
2
+
superoxide radicals in oxygen and peroxide, is dependent on copper and zinc. The Cu ion is involved
in the expression of genes for the metal-binding proteins [3] and it is also found in copper-protein
combinations displaying a pseudotetrahedral symmetry and having effects in bio-systems. Through
aminoxidase, copper interferes in the metabolism of the conjunctive tissue, contributing to the
trophicity of vascular sides [4-8]. Taking into account the daily necessary quantity of Cu(II) in the
organism (2-3 mg/day), its distribution and metabolism in the organism, toxicity, numerous simple or
complex combinations of copper are used in the treatment of a variety of diseases, including
inflammatory processes, cancer, ulcers, nervous system and heart diseases. This paper presents the
synthesis and characterization of Cu(II) complexes with Schiff bases obtained by the condensation of
4
-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with 2-hydroxybenzaldehyde and terephthalic
aldehyde, respectively (Figure 1).
Figure 1. Ligand structures.
ASAAP
ATAAP
Furthermore, and taking into consideration the use of copper complexes in the treatment of some
diseases, mentioned above, we have tested the antimicrobial activity of the prepared ligands and
complexes using strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter boumanii,
Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Candida tropicalis isolated
from different pathological products from patients with infections associated with the use of
cardiovascular prosthetic devices. The antimicrobial activity of the Schiff bases of antipyrine and their
complexes have been discussed previously [9-16].

Molecules 2006, 11
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06
Results and Discussion
Synthesis
The Schiff base ligands ASAAP and ATAAP were prepared by the condensation in methanol of
one or two molecules of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with 2-hydroxy-
benzaldehyde and terephthalic aldehyde, respectively. The Cu complexes Cu(C H N O )(H O) ]Cl
1
8
16
3
2
2
2
(
2 28 6 2 4 2
a) and [Cu (C30H N O )(SO ) ] (b) were then prepared by reaction of the appropriate ligands with
aqueous solutions of a suitable Cu(II) salt.
Properties
-1
2
-1
The molar conductivity value (32.7 Ω ·cm ·mol ) of the Cu(C H N O )(H O) ]Cl complex in
1
8
16
3
2
2
2
nitrobenzene indicates that this compound is a 1:1 electrolyte, while the molar conductibility value
-1.
2.
-1
2 28 6 2 4 2
below 10 Ω cm mol in nitrobenzene for the [Cu (C30H N O )(SO ) ] complex indicates that the
latter is a non-electrolyte.
The complexes were also investigated by thermo-gravimetry (TG). Experimental data for these
analyses are presented in Figure 2. The weight loss between 125–158°C for the
16 3 2 2 2
Cu(C18H N O )(H O) ]Cl complex is attributed to the loss of two water molecules per molecule of
complex.
Figure 2. TG, DTG and ATD curves for: Cu(C18
Cu )(SO ] (b).
16 3 2 2 2
H N O )(H O) ]Cl (a);
[
2
(C30
H
28
N
6
O
2
4 2
)
(
a)
The second step (410-670°C) corresponds to the elimination of one molecule of ligand per molecule of
complex. The thermal analysis curve of the [Cu )(SO ] complex presents two weight
(b)
2
(C30
H
28
N
6
O
2
4 2
)
loss steps (196-270°C and 380-694°C). The final residue was analyzed by IR spectroscopy and was
identified as CuO and the % Cu corresponded to the calculated one.
IR Spectra
Compared to the IR spectra of the ligands, it was observed that the frequency of the specific band
-1
-1
of the νC=N bond (1653, 1654 cm ) is moved towards lower wavenumbers by approx. 13 - 15 cm in
the spectra of the complexes, which confirms the coordination of the nitrogen atom to the metallic ion.
-1
In the IR spectrum of the ASAAP ligand, a wide medium intensity band occurs in the 3210-3370 cm

Molecules 2006, 11
9
07
-1
range, along with a narrow band of medium intensity (1140 cm ), assigned to the phenolic –OH
groups. In the IR spectrum of complex (a) the first band disappears and the second band moves
2
+
towards lower wavenumbers, indicating coordination of the ligand to the Cu ion through the
-1
-1
phenolic –OH group oxygen. In this spectrum two narrow intense bands at 897 cm and 572 cm
specific for coordinated water molecules [17] are also seen. For both complexes the specific ν>C=O band
-
1
(
cyclic keto group present in the pyrazolone ring: 1615, 1596 cm ) moves towards lower
-1
wavenumbers (1589, 1580 cm ), suggesting the coordination of the ligand to the metallic ion via the
C=O group.
>
Table 1: IR spectral data for the prepared ligands and complexes.
2
-
ν
SO
4
Compound
νC=N
νAr-OH ν>C=O ρr
ρw
ν1
ν2
ν3
ν4
C
18
H
17
N
3
O
2
1653 3210-
370
1615
-
-
-
-
-
-
3
1
140
[
Cu(C18
H
16
N
3
O
2
)(H
2
O)
2
]Cl (a)
1640
1654
1639
-
1594 897 572
-
-
-
-
-
-
-
1
120
-
C
30
H
28
N
6
O
2
1595
565
-
-
-
1
1050
1105
574
610
641
[Cu (C H N O )(SO ) ] (b)
-
995
462
2
30 28
6
2
4 2
1
170
Moreover, in the spectrum of complex (b) a characteristic band corresponding to the bidentate
2
-
coordination of the SO
4
ion appears. Thus, the ν
1
2 d
and ν frequencies specific to a T arrangement
appear as medium intensity bands, and the ν
3
and ν
4
frequencies each split into three bands, which
suggest a low symmetry, probably reduced towards C2v [17].
Electronic spectra.
As seen from the data presented in Table 2, the [Cu(C H N O )(H O) ]Cl complex presents a
1
8
16
3
2
2
2
-1
single absorption band at 14600 cm corresponding to the d–d transition, indicating the low C2V
2
+
2 28 6 2 4 2
symmetry of the Cu ion [18,19]. The brown colored [Cu (C30H N O )(SO ) ] complex presents two
types of d – d type transitions, whose values are characteristic of a deformed tetrahedral symmetry,
with the term of the fundamental state d [19].
xy
Table 2. Electronic spectra of the synthesized complex combinations.
-
1
Compound
Transitions d-d (cm )
Geometry
2
2
x -y → xz; yz; xy
4600
xy→xz; yz xy→z ; x -y Td
3570 14830 deformed
[Cu(C18
H
16
N
3
O
2
)(H
2
O)
2
]Cl
C
2v
1
2
2
2
-
[Cu
2
(C30
H
28
N
6
O
2
)(SO
4 2
) ]
1

Molecules 2006, 11
9
08
ESR spectra
2
+
The ESR spectral data concerning the Cu ion in tetrahedral symmetry are relatively poor. These
present a special interest due to the fact that, in the case of hyperfine interaction, the values of the A
constants are considerably lower than the observed ones for a complex of Cu(II) with a O or D
h
4h
geometry, and the values of the {g} tensor are higher [20-24]. The room temperature ESR spectrum of
the complex [Cu(C H N O )(H O)]Cl, as a powder, is presented in Figure 3.
1
8
16
3
2
2
16 3 2 2 2
Figure 3. ESR for [Cu(C18H N O )(H O) ]Cl, as a powder, at room temperature.
2
+
The values of the {g} tensor confirm the C symmetry of the Cu pentacoordinated ion [24]. For
2
v
the Cu(II) complex with low symmetry, the fundamental state for the paramagnetic electron is not
described by a single d function, but there is a mixture of them. The mixture degree of these functions
increases as the symmetry decreases [24]. The high values of the {g} tensor confirm a low symmetry.
2 28 6 2 4 2
The ESR spectrum for the complex [Cu (C30H N O )(SO ) ] as a powder, at room temperature, is
presented in Figure 4.
2 28 6 2
Figure 4. ESR for [Cu (C30H N S O10)], as a powder, at room temperature.
The {g} tensor values, g = 2.088 and g = 2.406, confirm the T symmetry [20-23]. As noted, the
1
2
d
spectrum does not present interactions that would indicate a hyperfine structure. The lack of hyperfine
2
+
structure or the presence of very small hyperfine splitting for the Cu ion in T
were explained by C.A. Bates et al., by mixing the 4p orbital of the metallic ion with the 3dxy orbital
which defines the fundamental state [20]. The values of the electronic transitions, of the {g} tensor,
d
or lower symmetry
z

Molecules 2006, 11
and IR spectral data lead to the conclusion that the Cu ion of the [Cu(C H N O )(H O) ]Cl
9
09
2
+
1
8
16
3
2
2
2
complex is pentacoordinated with a C2v symmetry (Figure 5a) [24], while in the
2
+
[
2 28 6 2 4 2
Cu (C30H N O )(SO ) ] complex the Cu ion has a deformed tetrahedral geometry (Figure 5b) [19].
Figure 5. Structures of the complexes [Cu(C H N O )(H O) ]Cl (a) and
1
8
16
3
2
2
2
2 28 6 2 4 2
[Cu (C30H N O )(SO ) ] (b).
HC
N
CH
N
O
O
CH
O
O
H C
CH3
O
3
N
CH3
CH3
Cu S
S Cu
H O
N
N
2
Cl
Cu
H C
N
O
O
O
O
N
CH3
3
O
N
O
O
N
H O
2
(
a)
(b)
Antimicrobial activity assays
The antimicrobial activity of the complexes and ligands was screened by adapted qualitative,
diffusimetric methods (i.e. distribution of the tested solutions on filter paper disks, in agar wells or in
spots on solid media that have been inoculated with test microbial strains) and quantitative methods
based on serial two-fold dilutions of the tested compounds in order to establish the corresponding
Minimal Inhibitory Concentrations (MIC). Five bacterial strains, i.e. Escherichia coli, Klebsiella
pneumoniae, Acinetobacter boumanii, Pseudomonas aeruginosa, Staphylococcus aureus and two
fungal strains, i.e. Candida albicans and Candida tropicalis, freshly isolated from different clinical
sources from patients with infections associated with the use of cardiovascular prosthetic devices and
o
identified by conventional methods were cultivated on solid media and incubated at 37 C for 24 hrs
prior to testing.
Figure 6. Appearance of the qualitative screening test showing the activity of
16 3 2 2 2
[Cu(C18H N O )(H O) ]Cl by the three adapted agar diffusion methods.

Molecules 2006, 11
9
10
The qualitative screening results demonstrated that the three examined diffusion methods all
exhibited different sensitivities in detecting the antimicrobial potential of the tested compunds. The
most efficient one for the different bacterial strains proved to be the spot method, as exemplified in
Figure 6. The quantitative assay results (Figure 7) showed that the tested compounds exhibited
variable MICs and selective antimicrobial activity, depending on the microbial strains. All tested
compounds proved to be active on Ps. aeruginosa, well known for its high constitutive and acquired
resistance rates. The Schiff base ASAAP and the complex [Cu(C H N O )(H O) ]Cl exhibited high
1
8
16
3
2
2
2
bactericidal activity towards E. coli and A. Boumanii, while the Schiff base ligands ASAAP and
ATAAP and the [Cu )(SO ] complex also showed good activity against S. aureus, Ps.
2
(C30
H
28
N
6
O
2
4 2
)
aeruginosa and E. coli, proving their potential usefulness as broad spectrum antimicrobial agents.
Figure 7. The graphic representation of the MIC values (mg/mL) of the tested
compounds towards different bacterial strains.
1
0
,9
,8
,7
,6
,5
,4
,3
,2
0
0
0
0
0
0
0
0,1
0
[Cu(C18H16N3O2)(H2O)2]Cl
ASAAP
ATAAP
Cu2(C30H28N3O2)(SO4)2]
[
microbial strain
Conclusions
2
+
The IR, electronic transition and {g} tensor value data lead to the conclusion that the Cu ion in
the complex[Cu(C18 )(H O) ]Cl is pentacoordinated with a C2v symmetry (Figure 5a), whereas
in the complex [Cu )(SO
b). The sensitivity spectrum of the microbial strains towards the ligands and the corresponding
H
16
N
3
O
2
2
2
2
+
2
(C30
H
28
N
6
O
2
4 2
) ] the Cu ion has a deformed tetrahedral geometry (Figure
5
complexes was determined by qualitative and quantitative methods and the following conclusions were
reached:
a) the qualitative anti-microbial activity screening results of the tested compounds proved that the
most efficient test method was the spot method.
b) the quantitative anti-microbial activity test results proved that both the ligands and the complex
combinations have specific anti-microbial activity, depending on the microbial species tested.

Molecules 2006, 11
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11
Experimental
General
The reagents used in this work were commercial products (Merck and Chimopar Bucuresti).
Electronic spectra were recorded using a Jasco V-550 spectrophotometer, in diffuse reflectance mode,
-1
using MgO dilution matrices. IR spectra (KBr pellets) were recorded in the 4000-400 cm region with
a BioRad FTS 135 spectrophotometer. ESR spectra were recorded on a ART-6 model IFA-Bucuresti
type spectrophotometer, equipped with a field modulation unit at 100kHz. The measurements were
done in the X band, on micro-crystalline powder at room temperature using DPPH as standard. The
1
H-NMR spectra were recorded using a Bruker DRX 400 spectrometer. Chemical elemental analyses
were done with a Carlo-Erba LA-118 microdosimeter (for C, N) and an AAS-1N Carl-Zeiss-Jena
spectrometer [Cu(II)], respectively. Chlorine was determined by gravimetric analysis. The complexes
were studied by thermo-gravimetry (TG) in a static nitrogen atmosphere, with a sample heating rate of
1
0°C/min., using a DuPont 2000 ATG thermobalance. Molar conductances of the complexes were
measured in nitrobenzene at room temperature using a Consort type C-533 conductivity instrument.
Synthesis of the Schiff base 1-phenyl-2,3-dimethyl-4-(N-salicylidene)-3-pyrazolin-5-one (ASAAP)
A solution of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (0.203 g, 1 mmol) in methanol
(
20 mL) was added to a solution of o-hydroxybenzaldehyde (0.15 mL, 1 mmol) in methanol (10 mL).
The mixture obtained was refluxed for an hour, then stirred for 3 hrs at room temperature and left at
the same temperature for a day. The resulting intense yellow colored precipitate was filtered, washed
with methanol and dried. Elemental analysis: Calc. C%, 70.35; N%, 13.66; Found. C%, 71.16; N%,
-1
1
1
3.21. IR: 1653 cm (azomethine group) [8,9]; H-NMR spectra [CDCl
3
, δ (ppm), J (Hz)]: δ = 2.41 (s,
3
H, -CH ); 3.16 (s, 3H,-CH ); 6.90 (m, 1H, H-Ar); 6.95 (d, 1H, H-Ar); 7.24-7.56 (m, 7H, H-Ar); 9.84
3
3
(
s, H, -N=CH-); δ>7 (H-OH).
Synthesis of the Schiff base bis(1-phenyl-2,3-dimethyl-3-pyrazolin-5-one-4-imino) terephthalic
aldehyde (ATAAP)
A solution of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (0.253 g, 1.25 mmol) in methanol
(
15 mL) was added to a solution of terephthalic aldehyde (0.067 g, 0.5 mmol) in methanol (15 mL).
The resulting yellow solution was refluxed for 30 minutes and then left at room temperature for
approx. 6 hrs. The intense yellow precipitate formed was filtered, washed with methanol and dried.
-
1
Elemental analysis: Calc. C%, 71.42; N%, 16.66; Found. C%, 72.11; N%, 16.21; IR: 1654 cm
1
(
(
azomethine group) [8,9]. H-NMR spectra [CDCl
3
, δ (ppm), J (Hz)]: δ= 9.61 (s, 2H, -N=CH-); 7.88
s, 4H, Ar-H 1,4- disubstituted); 7.57-7.37 (m,10H, Ar-H); 3.21 (s, 6H, N-CH
3
3
); ≈2.5 (s, 6H, -CH ).
Synthesis of the complex [Cu(C18
H
16
N
3
O
2
)(H O) ]Cl (a)
2
2
A methanol solution (15 mL) of ASAAP (0.307 g, 1 mmol) was added to CuCl
2 2
·2H O (0.170 g, 1
mmol) dissolved in distilled water (10 mL). This solution was refluxed for 2 hrs and left at room

Molecules 2006, 11
9
12
temperature for three days. A brown-red precipitate was formed, which was filtered, washed with
ethanol and dried. The elemental analysis results (calc.: C%, 48.81; N%, 9.49; Cu%, 14.46; Cl%, 8.04;
found: C%, 49.33; N%, 9.09; Cu%, 14.25; Cl%, 7.83) confirm the molecular formula
[
Cu(C H N O )(H O) ]Cl.
18 16 3 2 2 2
2 28 6 2 4 2
Synthesis of the complex [Cu (C30H N O )(SO ) ] (b)
A DMF solution (15 mL) of ATAAP (0.252g, 0.5 mmol) was added to CuSO ·5H O (0.250 g, 1
4
2
mmol) dissolved in distilled water (15 mL). The resulting green solution was refluxed for two hours,
during which time the green color turned brown. This solution was left at room temperature for four
days. A brown precipitate was formed, which was filtered, washed with ethanol and dried. The
elemental analysis data (calc.: C%, 43.69; N%, 10.19; Cu%, 15.53; found: C% 44.12; N%, 16.11;
Cu%, 15.24) confirms the molecular formula [Cu (C H N O )(SO ) ].
2
30 28
6
2
4 2
Biological assays
The fresh cultures obtained from clinical isolates were suspended in sterile saline and adjusted to a
standard density of 0.5 MacFarland. The microbial suspensions were plated on solid Mueller Hinton
medium and solutions of the test compounds (10 µL) prepared in DMF (1 mg/mL) were added on filter
paper disks, in agar wells or in spots. Concomitantly, the disks were impregnated with the same
concentration of gentamycin, which was used as reference standard for reporting the antibiotic
sensitivity. The plates were incubated at 37°C for 24 hrs. During incubation, the tested compounds
diffused around the test area creating a concentration gradient. The antimicrobial activity was recorded as
any area of microbial growth inhibition that occurred in the diffusion area. The quantitative
antimicrobial activity assays wer performed by the two-fold serial microdilution method in liquid
medium (nutrient broth for bacterial and liquid YPG for fungal strains). Serial two-fold dilutions of a
stock solution of test compound in DMF (from 1000 to 62.5 µg/mL) were performed in 60 multi-well
plates, in a total volume of 200 µL medium and standard microbial suspension (50 µL) was added in
each well. After 18-24 hours, the plates are examined visually for evidence of bacterial growth. Results
are recorded as minimum inhibitory concentrations (MIC) at the highest dilution (lowest
concentration) of the tested compound that completely inhibited microbial growth.
Acknowledgements
The authors thank Organic Chemistry Department - ICECHIM, Bucharest for microanalysis and
IFIN - Horia Hulubei, Bucharest, Romania, for help with EPR spectroscopy.
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Sample availability: Samples of the ligands ASAAP and ATAAP and the complexes (a) and (b) are
available from MDPI.
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2006 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.