Hindawi Publishing Corporation
Bioinorganic Chemistry and Applications
Volume 2014, Article ID 718175, 11 pages
http://dx.doi.org/10.1155/2014/718175
Research Article
Synthesis, Characterization, and Biological Activity of
N -[(Z)-(3-Methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4ylidene)(phenyl)methyl]benzohydrazide and Its Co(II), Ni(II),
and Cu(II) Complexes
Jonnie N. Asegbeloyin,1 Oguejiofo T. Ujam,1 Emmanuel C. Okafor,1 Ilknur Babahan,2
Esin Poyrazoglu Coban,3 Ali Özmen,3 and Halil Biyik3
1
Department of Pure and Industrial Chemistry, University of Nigeria, Enugu State, Nsukka 410001, Enugu State, Nigeria
Department of Chemistry, Adnan Menderes University, 09010 Aydin, Turkey
3
Department of Biology, Adnan Menderes University, 09010 Aydin, Turkey
2
Correspondence should be addressed to Jonnie N. Asegbeloyin; joniyi2001@yahoo.com
Received 3 April 2014; Accepted 10 June 2014; Published 15 September 2014
Academic Editor: Nick Katsaros
Copyright © 2014 Jonnie N. Asegbeloyin et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Reaction of 1-phenyl-3-methyl-4-benzoyl-pyrazol-5-one and benzoyl hydrazide in refluxing ethanol gave N -[(Z)-(3-methyl5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)(phenyl)methyl]benzohydrazide (HL1 ), which was characterized by NMR
spectroscopy and single-crystal X-ray structure study. X-ray diffraction analyses of the crystals revealed a nonplanar molecule,
existing in the keto-amine form, with intermolecular hydrogen bonding forming a seven-membered ring system. The reaction of
HL1 with Co(II), Ni(II), and Cu(II) halides gave the corresponding complexes, which were characterized by elemental analysis,
molar conductance, magnetic measurements, and infrared and electronic spectral studies. The compounds were screened for their
in vitro cytotoxic activity against HL-60 human promyelocytic leukemia cells and antimicrobial activity against some bacteria and
yeasts. Results showed that the compounds are potent against HL-60 cells with the IC50 value ≤5 𝜇M, while some of the compounds
were active against few studied Gram-positive bacteria.
1. Introduction
Compounds derived from 4-acylpyrazol-5-one have continued to receive considerable attention due to their pharmaceutical importance and high biological activity [1–3].
They also enjoy a range of applications as a substructure
in dye chemistry and synthesis [4]. The facile incorporation of conjugated systems with special features into the
pyrazolone core leads to the formation of compounds with
intense colour. Hydrazones and other Schiff bases are among
the most studied 4-acylpyrazol-5-one derivatives, more so
considering the fact that molecules with hydrazine moiety
have been noted for their biological activity [5], especially
as potential inhibitors for many enzymes [6]. The interest
in the chemistry of 4-acylpyrazol-5-one Schiff bases stems
from their interesting ligating ability due to the presence of
multielectron rich donor atoms [7–9]. This is augmented by
their tendency to exist in various tautomeric forms [10–12].
The ability of this class of compounds to form coordination
compounds with a wide range of transition metals has been
utilized in analytical chemistry, where they have been used
as effective chelating and extracting reagents for many metal
ions [13–15]. The literature is replete with studies of 4acylpyrazol-5-one Schiff bases and their metal complexes.
However, the study of biological activities of this class of
compounds and their metal complexes is largely restricted
to studies on microorganisms. Few reports are available in
the literature on the study of their anticancer properties
[16, 17]. With the increasing search for nonplatinum based
2
anticancer drugs with less side effects, and similar, or better cytotoxicity, it is imperative to investigate the possibility of the use of 4-acylpyrazolone derivatives for cancer
chemotherapy. In this paper, we report synthesis and characterization of N -[(Z)-(3-methyl-5-oxo-1-phenyl-1,5-dihydro4H-pyrazol-4-ylidene)(phenyl)methyl]benzohydrazide and
its Co(II), Ni(II) and Cu(II) complexes, the in vitro antimicrobial activity against some bacteria and yeasts, and their
antiproliferative effect on human promyelocytic leukemia
cells.
Bioinorganic Chemistry and Applications
dimethyl formamide (DMF), followed by slow evaporation of
the solution at room temperature for 1 week.
2. Experimental
2.3. Synthesis of Ni(II), Cu(II) and Co(II) Metal Complexes of
HL1 . To an ethanolic solution (20 mL) of N -[(Z)-(3-methyl5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)(phenyl)
methyl]benzohydrazide (0.43 g, 0.001 mol), ethanolic solution (10 mL) of the metal chloride (0.001 mol) was added with
constant stirring. The coloured mixture was then refluxed
for 4 h. The resulting metal complex was filtered hot, washed
with boiling mixture of 1 : 1 water/ethanol, dried under
suction, and kept in vacuum over CaCl2 .
2.1. Chemicals and Instrumentation. All the solvents are of
analytical grade and were used without further purification. 1-phenyl-3-methylpyrazol-5-one, methyl benzoate and
hydrazine mono-hydrate were used as supplied by Fluka.
1-phenyl-3-methyl-4-benzoyl-pyrazol-5-one and benzoylhydrazide were synthesized in accordance with reported procedures [18, 19]. Elemental analyses of C, H and N were performed using Carlo Erba Elemental analyzer EA 1108. Melting
points were obtained with a Fisher John melting point
apparatus. Magnetic moments were done on a magnetic susceptibility balance—Sherwood Scientific Cambridge, Model
No.MK-I. The molar conductance measurements of the
metal complexes were done in DMF/DMSO using Innolab
conductivity meter Level 1. The percentage of metal in the
complexes was determined using an Agilent ICP-MS7500Ce.
IR spectra were recorded on a Perkin Elmer Spectrum 100 at
the University of Waikato, Hamilton, New Zealand. 1 H and
13
C NMR spectra were obtained from a Bruker AV 500 MHz
for 1 H and 125 MHz for 13 C using a 5 mm quadra nuclei
probe (QNP). The X-ray crystallographic data were obtained
at the University of Auckland on a Bruker SMART APEX II
diffraction equipped with a CCD area detector, using MoK𝛼
radiation (𝜆 = 0.71073 Å). The software SMART was used
for the collection of data frames, for indexing reflections,
and to determine lattice parameters; SAINT was used for
the integration of the intensity of the reflections and for
scaling [20]. SADABS was used for empirical absorption
correction [21]. The structures were solved using SHELXS97, and SHELXL-97 was also used for structure refinements
and reporting [22]. The structures were refined by fullmatrix least-squares based on Fo 2 with anisotropic thermal
parameters for non-hydrogen atoms.
2.4. Microorganisms and Condition for Cultivation. Fifteen
bacteria and five yeast cultures were used in the study. Ten
bacterial strains and two yeast strains were obtained from
the American Type Culture Collection (ATCC, Rockville,
MD, USA). Other microorganism strains were obtained
from Adnan Menderes University Faculty of Medicine. The
Gram-negative (G−) were Escherichia coli ATCC 25922,
Salmonella typhimurium ATCC 14028, Proteus sp., Serratia
marcescens, and Enterobacter sp. and the Gram-positive
(G+) were Micrococcus luteus ATCC 9341, Staphylococcus
aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228,
Bacillus cereus ATCC 11778, Bacillus subtilis ATCC 6633,
Bacillus thuringiensis, Enterococcus faecalis ATCC 29212,
Enterococcus faecalis ATCC 51299, Streptococcus pneumoniae
ATCC 49617, and Listeria monocytogenes. Also, yeast strains
such as Candida utilis, Candida albicans ATCC 90028, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae ATCC 9763 were used. Escherichia coli ATCC 25922,
Staphylococcus aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, Salmonella typhimurium ATCC 14028,
Listeria monocytogenes, Proteus sp., Serratia marcescens, and
Enterobacter sp. were cultured in nutrient broth (NB) (Merck)
at 37∘ C; Streptococcus pneumoniae ATCC 49617, Enterococcus
faecalis ATCC 29212, and Enterococcus faecalis ATCC 51299
were cultured in brain heart infusion broth (BHIB) (Merck)
at 37∘ C for 24 h.; Micrococcus luteus ATCC 9341, Bacillus
cereus ATCC 11778, Bacillus subtilis ATCC 6633, and Bacillus
thuringiensis were cultured in nutrient broth (NB) (Merck) at
30∘ C; Candida utilis, Candida albicans ATCC 90028, Candida
glabrata, Candida tropicalis, and Saccharomyces cerevisiae
ATCC 9763 were cultured in malt extract broth (MEB)
(Merck, USA) at 30∘ C for 24 h.
2.2. Synthesis of 𝑁 -[(Z)-(3-Methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)(phenyl)methyl] benzohydrazide
(HL1 ). Synthesis and crystallization of HL1 was done by a
modification of literature procedure [23] as follows.
A solution of 4-benzoyl-3-methyl-1-phenylpyrazol-5-one
(2.78 g; 0.01 mol) in 30 mL ethanol was mixed with a solution
of benzoyl hydrazide (1.36 g; 0.01 mol) in ethanol (20 mL).
The mixture refluxed for 2 h and cooled (Figure 1). The
yellow precipitate formed was isolated by gravity filtration
and recrystallized from ethanol. Crystals suitable for X-ray
crystallographic analysis were obtained by slow dissolution
of HL1 in ethanol by warming and addition of few drops of
2.5. Antimicrobial Assay. The antimicrobial activities of all
the synthesized compounds were determined by the disc
diffusion method [24, 25], and the minimum inhibitory
concentration (MIC) was obtained by broth dilution method
[25].
2.6. Disc Diffusion Method. The standard method of Antimicrobial Disc Susceptibility Tests reported by the National
Committee for Clinical Laboratory Standards [25] was used.
Fresh stock solutions (1000 𝜇g⋅mL−1 ) of all the synthesized
compounds were prepared in DMSO. The inoculum suspensions of the tested bacteria and yeasts were prepared from the
Bioinorganic Chemistry and Applications
3
O
H2 N
O
H3 C
NH
NH
O
H3 C
CH3 CH2 OH
+
N
O
N
N
N
Reflux
O
N
2
3
1
3
2
1
4
O
O
NH
NH
N
H3 C
N
H3 C
15
H3 C
5
16
N
N
N
OH
H
N
N
O
6
NH
6
17
19
NH
7
N 18
20
21
O
8
9
14
10
O
13
11
12
24
23
22
4
5
Figure 1: Synthesis of HL1 .
broth cultures (18–24 h) and the turbidity equivalent adjusted
to 0.5 McFarland standard tube to give a concentration of
1 × 108 bacterial cells and 1 × 106 yeast cells/mL. To test
the antimicrobial activity of all the synthesized compounds,
a Mueller Hinton Agar (MHA) plate was inoculated with
0.1 mL broth culture of bacteria or yeast. Then a hole of
6 mm in diameter and depth was made on top with a sterile
stick and filled with 50 𝜇L of synthesized compounds. Plates
inoculated with E. coli ATCC 25922, S. typhimurium ATCC
14028, S. aureus ATCC 25923, S. epidermidis ATCC 12228,
E. faecalis ATCC 29212, Enterococcus faecalis ATCC 51299,
S. pneumoniae ATCC 49617, Listeria monocytogenes, Proteus
sp., S. marcescens, and Enterobacter sp. were incubated at
37∘ C for 24 h, while those with M. luteus ATCC 9341, Bacillus
subtilis ATCC 6633, B. cereus ATCC 11778, B. thuringiensis, S.
cerevisiae ATCC 9763, C. albicans ATCC 90028, C. glabrata,
C. utilis, and C. tropicalis were incubated at 30∘ C for 24 h. At
the end of incubation time, the diameters of the inhibition
zones formed on the MHA were evaluated in millimeters.
Disc of chloramphenicol (C30), gentamicin (CN10), tetracycline (TE30), erythromycin (E15), ampicillin (AMP10),
and nystatin (NS100) were used as positive controls. The
measured inhibition zones of the study compounds were
compared with those of the reference discs.
2.7. Minimum Inhibitory Concentration (MIC). Minimum
inhibitory concentration (MIC) was determined by reported
method [25]. The study bacteria were inoculated in nutrient
broth and incubated at 30–37∘ C for 24 hr while the yeasts
were inoculated in Malt Extract Broth and incubated at
30∘ C for 48 h. The inoculums were adjusted according to
0.5 McFarland standard tube. Initially, 100 𝜇L of Mueller
Hinton Broth (MHB) was placed in each well. After, the
compounds were dissolved in DMSO (2 mg mL−1 ) and transferred into the first well. Two fold serial dilution of the
compounds were carried out to determine the MIC, within
the concentration range 256 to 0.125 𝜇g mL−1 . Cultures were
grown at 30–37∘ C (18–20 h) and the final inoculum was
approximately 106 cfu mL−1 . The lowest concentration of the
study compounds that resulted in complete inhibition of the
microorganisms was represented as MIC (𝜇g mL−1 ). Similar
procedures were done on positive controls, streptomycin (I.
E. Ulagay). In each case, the test was performed in triplicate
and the results were expressed as means.
2.8. Cell Antiproliferation Test. HL-60 promyelocytic leukaemia cells were purchased from ATCC. Cells were grown in
RPMI-1640 medium supplemented with 10% heat inactivated
fetal calf serum, 1% L-glutamine, and 1% penicillin/CO2 .
4
Bioinorganic Chemistry and Applications
Table 1: Selected bond lengths (Å) and bond angles (∘ ) for HL1 (estimated standard deviations are in brackets).
O(1)-C(8)
O(2)-C(18)
N(1)-C(7)
N(1)-N(2)
N(2)-C(8)
C(7)-N(1)-N(2)
C(8)-N(2)-N(1)
C(16)-N(3)-N(4)
C(18)-N(4)-N(3)
C(18)-N(4)-C(19)
N(3)-N(4)-C(19)
Bond lengths and atomic distances (Å)
1.2396(9)
N(3)-C(16)
1.2655(9)
N(3)-N(4)
1.3299(10)
N(4)-C(18)
1.3820(9)
N(4)-C(19)
1.3487(10)
C(1)-C(2)
Bond angles (∘ )
123.33(7)
N(1)-C(7)-C(17)
119.20(7)
N(1)-C(7)-C(6)
106.36(6)
O(1)-C(8)-N(2)
112.14(6)
O(1)-C(8)-C(14)
129.16(7)
N(2)-C(8)-C(14)
118.67(6)
O(2)-C(18)-N(4)
All media and supplements were obtained from Life Technologies. HL 60 cells were seeded in T-25 tissue culture
flasks at a concentration of 1 × 105 /mL and incubated with
increasing concentrations (5, 10, 20, and 40 𝜇M) of the study
compounds. Cell counts and IC50 values were determined at
24 and 72 h using a Thoma slide. Experiments were done in
triplicate. The percentage of cell divisions compared to the
untreated control was calculated as follows:
[
(C72 h + drug − C24 h + drug)
] × 100
(C72 h − drug − C24 h − drug)
(1)
= % cell division,
where C72 h + study compound is the cell number after 72 h
of treatment with study compound, C24 h + compound is the
cell number after 23 h of treatment with study compound,
C72 h − compound is the cell number after 72 h without
treatment with compound, and C24 h − compound is the cell
number after 24 h without treatment with compound.
3. Results and Discussion
3.1. X-Ray Crystal Structure of HL1 . The crystal structure of
HL1 has been reported in literature [23] but was redetermined
to investigate if the new method of crystal isolation could
affect the R-factor which was earlier reported as 0.0542
[23], and control the intramolecular rearrangement of the
molecule from structure (4) to any of the other tautomers,
see Figure 1. The data and structure refinement parameter
details are given in Table 2. The crystal structure of HL1 was
solved by direct method. The nitrogen and oxygen atoms were
located followed by other atoms in subsequent refinements.
All nonhydrogen atoms were refined as anisotropic. The Xray crystal structures and atom numbering schemes of HL1
are as shown in Figure 2. The selected bond lengths and
angles are shown in Table 1. The crystal data and structure
refinement details are presented in Table 2. The compound
is a nonplanar molecule. The measured angle between the
pyrazolone ring plane C(18) C(17) C(16) N(3) and C(6) C(1)
C(5) plane is 71.4∘ . In addition the angle between C(8) N(2)
1.3097(11)
1.4003(10)
1.3766(10)
1.4140(10)
1.3899(13)
125.71(7)
112.99(7)
122.97(7)
122.98(7)
114.05(7)
124.30(7)
C(3)
C(4)
C(5)
C(2)
C(1)
C(6)
C(15)
C(7)
C(16)
C(17)
N(3)
C(18)
N(2)
N(4)
C(8)
C(24)
C(19)
O(2)
C(14)
N(1)
O(1)
C(9)
C(10)
C(11)
C(13)
C(12)
C(20)
C(21)
C(23)
C(22)
Figure 2: Molecular structure of HL1 showing the atom numbering
scheme with thermal ellipsoids at the 50% probability level.
N(1) and C(6) C(7) N(1) planes is 33.6∘ . The phenacyl group
adopts a gauche conformation about the N–N vector. The
angle between the phenacyl C(13) C(14) C(9) and N(2) C(14)
C(8) planes is 29.9∘ . The hydrazino nitrogen atoms adopted
the trans-conformation which is more preferred when not in
a ring system [26, 27]. The bond length of hydrazino (>N–
N<) nitrogen atoms 1.3820(9) Å the carbonyl (>C=O) group
1.2396(9) Å is in agreement with literature reports [23, 28].
The ring carbon–oxygen O(2)–C(18)bond length 1.2655(9) Å
is longer but in good agreement with earlier reports on
the pyrazolone ring carbonyl group [23, 29]. The molecular
structure of the compound indicated intermolecular hydrogen bonding between the hydrogen atom on N(2) and the
O(2) forming a non planar seven membered ring system.
Intramolecular hydrogen bonding is also observed in the
molecule as shown in the crystal packing motif in Figure 3.
3.2. Analytical and Physical Data. All the metal complexes
are colored and soluble in polar solvents (dimethyl sulfoxide,
dimethyl formamide, and anhydrous ethanol) but insoluble
in solvents such as hexane, pentane, tetrahydrofuran and
Bioinorganic Chemistry and Applications
5
Table 2: Crystal data and structure refinement details for HL1 .
Identification code
Formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a/Å
b/Å
c/Å
𝛼/∘
𝛽/∘
𝛾/∘
Volume (Å3 )
𝑍
Calculated density (Mg/m3 )
Absorption coefficient
(mm−1 )
𝐹(000)
Crystal size (mm3 )
Theta range for data
collection
Limiting indices
Reflections
collected/unique
Completeness to theta
Absorption correction
Max. and min.
transmission
Refinement method
Data/restraints/parameters
Goodness of fit on 𝐹2
Final 𝑅 indices [𝐼 > 2𝜎(𝐼)]
𝑅 indices (all data)
Largest diff. peak and hole
HL
1
C24 H20 N4 O2
396.44
109(2)
0.71073
Triclinic
P-1
9.0895(2)
10.9699(3)
11.0637(3)
89.5410(10)
78.6940(10)
66.0660(10)
985.59(4)
2
1.336
0.088
416
0.70 × 0.49 × 0.28 mm
2.50 to 34.28∘
−14 ≤ ℎ ≤ 13, −17 ≤ 𝑘 ≤ 16,
−16 ≤ 𝑙 ≤ 17
29726/7289 [𝑅(int) = 0.0274]
27.50∘ 100.0%
Multiscan
0.9759 and 0.9412
Full-matrix least-squares on
𝐹2
7289/0/278
1.028
𝑅1 = 0.0439, 𝑤𝑅2 = 0.1199
𝑅1 = 0.0535, 𝑤𝑅2 = 0.1282
0.440 and −0.289 e A−3
carbon tetrachloride. Analytical and physical data of all the
study compounds are shown in Table 3. The complexes are
nonelectrolytes in DMSO, as evident from the molar conductivity values which range from ∼9 to 13 Ohm−1 cm2 mol−1
[30–32].
3.3. FT-Infrared Spectra. The relevant stretching frequencies
are tabulated in Table 4. The absorption bands in the region
∼3000–3280 cm−1 in the spectral of HL1 and the metal complexes were assigned to NH stretching vibrations. Two strong
v(C=O) bands are observable in the keto-amine form of HL1 ,
one assignable to v(C=O) of the lateral chain comprising the
hydrazide moiety and the other to the v(C=O) of pyrazolone
a
o
b
O(1)
O(2)
c
Figure 3: A view of the crystal packing of HL1 showing the
intramolecular and intermolecular hydrogen bonding.
ring [33–35]. These strong vibrational bands (cm−1 ) were
observed at 1645 and 1596, respectively. The v(C=O) band
assigned to the hydrazide moiety shifted to lower frequencies
in the metal complexes, suggesting that the carbonyl oxygen
was involved in coordination to the metal ions [36–38]. Bands
in the region of 1566–1570 cm−1 have been assigned to imino
v(C=N) in all the metal complexes. The bands in the region of
1437–1440 cm−1 in the metal complexes have been assigned to
v(C–O) [33, 39] resulting from enolization and deprotonation
before coordination [14, 40].
The bands in the region ∼1025–1120 cm−1 in the ligand
and the metal complexes have been assigned to v(N–N).
Bands in the range ∼510–520 cm−1 in the metal complexes
were assigned to v(M–O) while bands in the range ∼420–
480 cm−1 were assigned to v(M–N) [41–43]. vO–H of water of
crystallization was observed in the region ∼3370–3470 cm−1
in the metal complexes. HL1 reacted as the enol-imino form
(Figure 1 (5)), when coordinated to metal ions in solution,
coordinating via pyrazolone ring enolic (C–O), azomethine
(C=N), and hydrazide side chain (C=O).
3.4. 1 H and 13 C NMR Spectra. The possible keto forms of
HL1 are as shown in Figure 1. The X-ray structure confirmed
that it crystallized in the keto-amine form (4). The conjugated
system that extended from the pyrazolone ring confers extra
stability on form (4). In the 1 H NMR spectrum the 3-methyl
protons signal was observed as singlet upfield at 2.17 ppm.
The phenyl protons appeared as multiplets in the range 7.26–
8.07 ppm while the signal due to –NH was observed at
8.83 ppm. The 13 C-NMR spectrum of the ligand exhibited
17 carbon signals comprising 16 sp2 and one sp3 (–CH3 )
carbons; the signal at 𝛿16.06 has been assigned to carbon
of the pyrazolone core side 3-methyl. Carbons of benzene
rings are present at 𝛿 118.47–165.18. The most deshielded
carbons have been assigned relevant signals downfield. The
assignments are as follows: C-1 = 127.55, C-2 = 127.42, C-3 =
129.70, C-4 = 127.42, C-5 = 127.55, C-6 = 131.43, C-7 = 138.75,
C-8 = 163.64, C-9 = 130.69, C-10 = 148.27, C-11 = 132.78, C12 = 130.04, C-13 = 128.83, C-14 = 130.04, C-15 = 15.44, C-16
= 149.28, C-17 = 120.34, C-18 = 154.55, C-19 = 138.22, C-20
= 119.85, C-21 = 129.70, C-22 = 125.26, C-23 = 129.70 and C24 = 119.85 ppm (see (4) in Figure 1). All assignments were
consistent with literature on related studies [44–48].
6
Bioinorganic Chemistry and Applications
Table 3: Elemental analysis and physical data of the ligand and complexes.
Compound Colour
HL1
MF
Yellow
Elemental analysis % found
(calculated)
C
H
N
72.68
5.21
14.28
(72.73)
(5.05)
(14.14)
66.34
4.98
12.99
(66.43)
(4.65) (12.92)
66.78
4.81
13.02
(66.45)
(4.65) (12.92)
65.61
5.15
13.41
(66.08)
(4.62) (12.85)
Yield %
C24 H20 N4 O2
85
CoL1 2 ⋅H2 O Yellow
C48 H40 N8 O5 Co
70
NiL1 2 ⋅H2 O
Green
C48 H40 N8 O5 Ni
67
CuL1 2 ⋅H2 O
Green
C46 H40 N8 O5 Cu
60
𝜇eff B.M
M
𝜆𝑀
ohm−1 cm2 mol−1
Melting
Point ∘ C
—
—
—
196
6.35
(6.79)
6.60
(6.76)
7.63
(7.33)
4.93
11.56
286
2.94
12.50
272
1.90
10.34
260
Table 4: Relevant IR absorption bands for the ligand and metal complexes.
Compound
L1
Cu(L1 )2 ⋅H2 O
Ni(L1 )2 ⋅H2 O
Co(L1 )2 ⋅H2 O
a
VO–H
—
3448
3376
3468
VN–H
3132
3311
3059
3275
VC=Oa
1645
1597
1621
1623
VC=Ob
1596
—
—
—
VC=N
—
1567
1570
1566
VN–N
1117
1026
1027
1025
VC–O
—
1440
1437
1438
VM–O
—
519
509
510
VM–N
—
418
460
472
Hydrazide moiety, b pyrazolone ring.
Table 5: Electronic spectra data of ligand and metal complexes.
Compounds
HL
1
Bands (cm−1 ) (𝜀,
Lmol−1 cm−1 )
Assigned transition
42,533 (10600)
32,786 (7500)
29,411 (9100)
𝑛 → 𝜋∗
𝑛 → 𝜋∗
𝜋 → 𝜋∗
CoL1 2 ⋅H2 O
21,276 (228)
20,408 (224)
10,204 (165)
CuL1 2 ⋅H2 O
13,424(255)
16,354(135)
22,722 (245)
NiL1 2 ⋅H2 O
23,809 (225)
14,174 (172)
12,545 (142)
T1g (F) → 4 T1g (P)
T1g (F) → 4 A2g (F)
4
T1g (F) → 4 T2g (F)
4
4
B1g → 2 A1g ,
B1g → 2 B2g
2
B1g → 2 Eg
2
2
A2g → 3 T1g (P)
A2g → 3 T1g (F)
3
A2g → 3 T2g (F)
3
3
3.5. Electronic Spectra and Magnetic Studies. The significant
electronic absorption bands in the spectra of the ligand
and the metal complexes recorded in DMSO solution are
presented in Table 5. The ligand shows high frequency bands
at 42,533, 32,786, and 29,411 cm−1 which were assigned to
n → 𝜋∗ and 𝜋 → 𝜋∗ transitions [49, 50]. For a typical
d9 octahedral Cu2+ complex the 2 D free-ion term is split into
two levels by the Oh symmetry and further split on distortion
to D4h or C4v symmetry [51]. Three spin allowed transitions
can be observed in the visible and near IR regions. In the
present study the Cu(II) complex show bands at 16,354, 13,424
and 22,722 cm−1 which have been assigned to 2 B1g → 2 B2g ,
2
B1g → 2 A1g and 2 B1g → 2 Eg transitions respectively [52–
54]. The observed magnetic moment of 1.90 B.M is suggestive
of an octahedral geometry for Cu(II) complex [54]. Ni(II)
with d8 configuration in an octahedral field has a ground
state of 3 F, which is split into 3 A2g , 3 T2g , and 3 T1g (F) states
and the excited state designated as 3 T1g (P). Three bands
can be observed in the spectra. The Ni(II) complex displays
three bands at 12,545, 14,174, and 23,809, cm−1 assignable
to 3 A2g → 3 T2g (F), 3 A2g → 3 T1g (F), and 3 A2g →
3
T1g (P) transitions, respectively [55]. The magnetic moment
of 2.93 B.M for Ni(II) complex is an indication of its octahedral geometry. The three bands observed at 21,276, 20,408,
and 10,204 cm−1 for Co(II) complexes have been assigned to
4
T1g (F) → 4 T1g (P), 4 T1g (F) → 4 A2g (F) and 4 T1g (F) →
4
T2g (F) transitions, respectively [52]. The magnetic moment
of 4.94 B.M and the observed electronic transitions indicate
high spin octahedral geometry of the complex [56].
On the basis of microanalytical data, magnetic moments,
conductivity measurements, and spectral analysis, Figure 4
has been proposed for the metal complexes.
3.6. Antimicrobial Test Results. The results of antimicrobial
activities of the study compounds reported as inhibition
zone diameter (mm) are showed in Table 6. The inhibition
zone diameter of the reference antibiotics used on the test
microorganisims are presented in Table A which can be
found in Supplementary Material available online at http://
dx.doi.org/10.1155/2014/718175. The MIC values which suggested that some of the studied compounds exhibited appreciable antimicrobial activity are showed in Table 7. The
ligand, Co(II) and Cu(II) complexes showed appreciable
activities against some pathogen bacteria, while the Ni(II)
complex did not show any antimicrobial activity. The ligand
(HL1 ) showed significant antimicrobial activity against four
Gram- positive bacteria Micrococcus luteus ATCC 9341,
Bioinorganic Chemistry and Applications
7
NH
H3 C
N
N
O
O
N
M
N
O
O
N
N
CH3
NH
Figure 4: Proposed structures of the metal complexes {M = Co(II), Cu(II), Ni(II)}.
40 𝜇M
(b)
150
100
100
CuL1 2 ·H2 O, DMSO
(c)
−50
5 𝜇M
0
Co + DMSO
40 𝜇M
20 𝜇M
10 𝜇M
5 𝜇M
0
50
Co
50
Proliferation (%)
150
Co + DMSO
40 𝜇M
(a)
Co
20 𝜇M
NiL1 2 ·H2 O, DMSO
HL1 , DMSO
Proliferation (%)
20 𝜇M
−50
10 𝜇M
0
10 𝜇M
40 𝜇M
20 𝜇M
10 𝜇M
5 𝜇M
−50
Co + DMSO
0
50
5 𝜇M
50
100
Co + DMSO
100
Co
Proliferation (%)
150
Co
Proliferation (%)
150
CoL1 2 ·H2 O, DMSO
(d)
Figure 5: Inhibitory percentage (%) of compounds at 5–40 𝜇M on HL-60 cancer cell line.
Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC
11778, and Bacillus subtilis ATCC 6633; the Co complex
showed antimicrobial activity against two Gram-positive
bacteria Bacillus cereus ATCC 11778 and Bacillus subtilis
ATCC 6633. Cu(II) complex exhibited antimicrobial activity against three Gram-positive bacteria Micrococcus luteus
ATCC 9341, Staphylococcus aureus ATCC 25923, and Bacillus
cereus ATCC 11778. However, none of the study compounds
exhibited antimicrobial activity against tested Gram-negative
bacteria and yeasts. Gram-negative bacteria are noted for the
protective lipopolysaccharide (LPS) in the outer membrane of
their cell walls, which protects the sensitive inner membrane
and the cell wall from drugs and dyes [57]. This protective
lipopolysaccharide is absent in Gram-positive bacteria. In
order for these compounds to exert bacteriostatic or bactericidal actions, they must access intracellular targets [58, 59].
8
Bioinorganic Chemistry and Applications
Table 6: Antimicrobial activities of HL1 and the metal complexes (inhibition zone diameter (mm).
Test microorganism
Escherichia coli
ATCC 25922
Salmonella typhimurium
ATCC 14028
Micrococcus
luteus, ATCC 9341
Staphylococcus aureus
ATCC 25923
Staphylococcus epidermidis
ATCC 12228
Bacillus cereus
ATCC 11778
Bacillus subtilis
ATCC 6633
Bacillus thuringiensis∗
Enterococcus faecalis
ATCC 29212
Enterococcus faecalis
ATCC 51299
Streptococcus pneumoniae
ATCC 49617
Proteus sp.∗
Serratia marcescens∗
Enterobacter sp.∗
Listeria monocytogenes∗∗
Candida albicans
ATCC 90028
Candida utilis∗
Candida tropicalis∗
Candida glabrata∗
Saccharomyces cerevisiae
ATCC 9763
HL1
CoL1 2 ⋅H2 O
NiL1 2 ⋅H2 O
CuL1 2 ⋅H2 O
—
—
—
—
—
—
—
—
15
—
—
12
15
—
—
14
—
—
—
—
15
13
—
10
13
8
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(—): zone of inhibition not included in the diameter of the well.
∗
Special gift from Faculty of Medicine, Adnan Menderes University. ∗∗ Food isolated.
Table 7: Minimum inhibitory concentration of compounds (MIC,
𝜇g⋅mL−1 ).
Test microorganisms
Micrococcus luteus,
ATCC 9341
Staphylococcus aureus
ATCC 25923
Bacillus cereus
ATCC 11778
Bacillus subtilis
ATCC 6633
HL1 CoL1 2 ⋅H2 O CuL1 2 ⋅H2 O Str
4
NT
16
32
4
NT
4
32
4
4
64
64
8
128
NT
64
Note: Str: streptomycin.
(NT): Not tested.
Therefore in Gram-negative bacteria, these compounds must
cross the outer membrane, a substantial permeability barrier
and thus a major determinant of antimicrobial resistance in
these bacteria [59]. The observed results of the antimicrobial
tests suggest that the compounds were not able to permeate
the protective outer membrane of the Gram negative bacteria
to the extent of having antimicrobial effects. The observed
better antimicrobial action exhibited by the ligand may be
ascribed to the formation of hydrogen bonds with the active
centre of cell constituents, resulting in interference with the
normal function of the cell [60]. On coordination, the site
for hydrogen bonding is minimized in the resultant metal
complexes.
MICs were measured for the compounds that showed
appreciable growth inhibition zones; the study was restricted
to microorganisms that were affected by the compounds.
From the results of MIC tests shown in Table 7, it can be seen
that MIC of selected compounds against bacterial pathogens
varied from 4 to 128 𝜇g mL−1 . The lowest MICs were observed
Bioinorganic Chemistry and Applications
9
Table 8: Antiproliferative activities of investigated compounds against human cancer (HL-60) cell line.
Compounds
IC50 (𝜇M)
HL1
3.36 ± 1.12
CoL1 2 ⋅H2 O
2.52 ± 0.22
for HL1 (4–8 𝜇g mL−1 ) against the four tested microorganisms. Low MICs were also recorded for Cu complex (Staphylococcus aureus ATCC 25923) and Co complex (Bacillus
cereus ATCC 11778). The results suggest that the compounds
showed good antimicrobial activity against these organisms.
3.7. Results of Cell Proliferation Test. HL-60 (human promyelocytic leukemia cells) cell line is a leukemic cell line that
has been used for laboratory research. The HL-60 cultured
cell line provides a continuous source of human cells for
studying the molecular events of myeloid differentiation and
the effects of physiologic, pharmacologic, and virologic processes. The results of antiproliferative activities of investigated
compounds against human cancer (HL-60) cell line are
presented in Table 8. The results indicated that HL1 and its
Cu(II) complex exhibit cytotoxic effects at the lowest tested
concentration with IC50 value between ∼3 and 5 𝜇M while the
Co(II) and Ni(II) complexes exhibit better cytotoxic effects
with IC50 value ∼2-3 𝜇M. Figure 5 shows effects of different
concentrations of tested compounds on HL-60 cell line. It is
evident from Figure 5 that all the compounds (at <5–40 𝜇M)
were able to inhibit the proliferation of more than 50% of
the HL-60 cell. The tested compounds can be described
as potent anticancer agents due to their considerably high
antiproliferative effects. This is consistent with documented
facts by the US NCI screening program, that if the IC50
value (following the incubation of a compound and cell lines
between 48 and 72 h) is less than 10 𝜇M, the compound is
considered to have in vitro cytotoxic activity [61].
4. Conclusions
A 4-acylpyrazolone hydrazone and some of its metal complexes have been synthesized and characterized. The crystal
and spectra data showed that the ligand crystallized in
the keto-amine form and coordinated as a monoanionic
tridentate ONO donor ligand. Physicochemical and spectral
data show that the metal to ligand ratio is 1 : 2 in the
Ni(II), Cu(II), and Co(II) complexes. The electronic data
and magnetic moments are in favour of octahedral geometry
for Ni(II), Cu(II), and Co(II) complexes. The compounds
exhibited better antimicrobial activity against Gram-positive
bacterial strains studied. The cytotoxicity test results showed
that the compounds are potential anticancer agents.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
NiL1 2 ⋅H2 O
2.66 ± 0.54
CuL1 2 ⋅H2 O
4.20 ± 1.44
Acknowledgments
The authors are thankful to the Nigerian Education Trust
Fund (ETF) and the University of Nigeria, Nsukka, for
research grant offered to Jonnie N. Asegbeloyin for a research
visit to Adnan Menderes University, Turkey, Zeynep Tasci of
Department of Inorganic Chemistry, Ege University, Izmir,
for magnetic moment measurements, and Dr. Tania Groutso
(University of Auckland) for collection of the X-ray data sets.
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