Synthesis, Characterization, Single-Crystal XRD, and Biological Evaluation of Nickel(II) Salen Sulfadiazine Complex

Article abstract of DOI:10.1080/15533174.2015.1137038

Nickel(II) salen sulfadiazine complex was prepared and characterised by the spectral studies such as FT-IR, UV-Vis and NMR, and single-crystal XRD. The nickel(II) complex was screened for in vitro antimicrobial activities against various test organisms Aeromonas hydrophila, Serratia marcescens, Bacillus licheniform, Pseudomonas aeruginosa, Acinetobacter baumanii, Aspergillus niger, and Candida albicans by the well diffusion method and in vitro anticancer activity against the human breast cancer cell line HeLa. The NiO obtained by the thermal decomposition of Ni (salen) sulfadiazine complex was characterised using TEM images and their SAED pattern.

Full text of DOI:10.1080/15533174.2015.1137038

Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry
ISSN: 1553-3174 (Print) 1553-3182 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt20
Synthesis, Characterization, Single Crystal XRD
and biological evaluation of Nickel(II)salen
sulphadiazine complex
S. Jone Kirubavathy, R. Velmurugan, B. Tamilarasan, R. Karvembu, N. S. P.
Bhuvanesh & S. Chitra
To cite this article: S. Jone Kirubavathy, R. Velmurugan, B. Tamilarasan, R. Karvembu, N. S. P.
Bhuvanesh & S. Chitra (2016): Synthesis, Characterization, Single Crystal XRD and biological
evaluation of Nickel(II)salen sulphadiazine complex, Synthesis and Reactivity in Inorganic,
Metal-Organic, and Nano-Metal Chemistry, DOI: 10.1080/15533174.2015.1137038
To link to this article: http://dx.doi.org/10.1080/15533174.2015.1137038
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Date: 18 March 2016, At: 23:35

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Synthesis, Characterization, Single Crystal XRD and biological evaluation of
Nickel(II)salen sulphadiazine complex
S. Jone Kirubavathya, R. Velmurugana, B. Tamilarasana, R. Karvembub, N. S. P. Bhuvaneshc, S.
Chitrad,*
aDepartment of Chemistry, Kongunadu Arts and Science College, Coimbatore 641029, India
bDepartment of Chemistry, National Institute of Technology, Tiruchirappalli 620015, India
cDepartment of Chemistry, Texas A&M University, College Station, TX 77842, USA
dDepartment of Chemistry, P.S.G. R. Krishnammal College for Women, Coimbatore 641 004,
India
*Corresponding author. E-mail: chitrapsgrkc@gmail.com
Abstract
Nickel(II)salen sulphadiazine complex was prepared and characterised by the spectral
studies such as FT-IR, UV-Vis, NMR and single crystal XRD. The Nickel(II) complex was
screened for in-vitro antimicrobial activities against various test organisms Aeromonas
hydrophila, Serratia marcescens, Bacillus licheniform, Pseudomonas aeruginosa, Acinetobacter
baumanii, Aspergillus niger and Candida albicans by the well diffusion method cultured on
Sabrouds dextrose agar as medium and in-vitro anticancer activity against the human breast
cancer cell line HeLa. The NiO obtained by the thermal decomposition of Ni (salen)
sulphadiazine complex was characterised using TEM images and their SAED pattern.
Keywords
Nickel (II), sulphadiazine, antimicrobial, anticancer, thermal decomposition.
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INTRODUCTION
Schiff bases are condensation products of primary amines with carbonyl compounds,
namely aldehyde or ketone and they were first reported by Schiff in 1864[1]. The common
structure of these compounds is the azomethine group with a general formula R-C=N- in which
alkyl, aryl, cyclo alkyl or heterocyclic groups may be variously substituted, and are also known
as imines or azomethines. Several studies [2 - 4] showed that the presence of a lone pair of
electrons in the sp2 hybridized orbital of nitrogen atom of the azomethine group is of
considerable chemical and biological importance. Because of the relative easiness of preparation,
synthetic flexibility, and the special property of C=N group. The C-N linkage is essential for
biological activity, antibacterial, antifungal, anticancer and anti-malarial activities [5, 6]. Schiff
bases are generally excellent chelating agents especially when a functional group like –OH or –
SH is present close to the azomethine group so as to form a five or six membered ring with the
metal ion. Schiff base compounds are very popular ligands because of their easy formation and
rich coordination chemistry with a large variety of metal ions those have allowed their use as
catalysts in different asymmetric reactions [7, 8]. Several compounds incorporating piperazinyl
guanidine, when condensed with salicylaldehyde were found to exhibit cardiovascular and
vasodepressive activity [9]. Versatility of Schiff base ligands and biological, analytical and
industrial applications of their complexes make further investigations in this area highly
desirable.
Sulfadiazine is a sulfonamide with well known antibacterial activities and used clinically
as a topical agent either alone or in combination with other compounds in the treatment of wound
and burn infections. Interest in the metal complexes of sulfadiazine is due to its use as
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pharmaceuticals. At present, the possibility of using metal complexes of sulfadiazine as
antimicrobial agents has received some attention. However, the literature on the chemistry of
Schiff base complexes derived from sulpha drugs especially their structural characteristics, is
rather incomplete.
In continuation of our efforts in the search of antimicrobial agents and to check with its
cytotoxicity, we have synthesized nickel salen complex with sulphadiazine and screened them
for antimicrobial and cytotoxic activities.
EXPERIMENTAL
Materials and Methods
All chemicals used were of analar grade. All the reagents, starting materials and solvents
were purchased commercially from sigma aldrich and used without any further purification.
Apparatus and materials involved in synthesis were clean and dry. The melting points were
recorded on a Raaga 840 melting point apparatus. Microanalytical data of the compounds were
recorded in the Elementar Vario EL III CHN Analyser. The FT-IR spectrum was recorded on a
Shimadzu spectrophotometer in the range 4000-500 cm-1. The electronic spectrum was recorded
by using a Shimadzu UV Vis. spectrophotometer (double beam) in the range of 200– 800 nm.
Conductivity measurements were carried out by using Elico Conductivity Bridge, (Conductivity
1
meter). H and 13C NMR spectra were recorded on a Jeol 400 MHz Spectrometer TMS as an
internal standard. X-ray diffraction for the [Ni(salen)]sulphadiazine complex was made on a
Bruker APEX-2 X-Ray diffractometer with graphite monochromated Mo-Kα radiation (λ =
0.71073 Ǻ). The crystal structure was solved by direct methods. Structure refinements were
performed by full matrix least squares procedures using SHELXTL (XS) on F2.
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Synthesis of [Ni(salen)]sulphadiazine complex
Synthesis of Ni complex is done by refluxing ethanolic solution of the following reaction
mixtures, sulphadiazine (0.005mol), salicylaldehyde (0.005mol), ethylenediamine (0.001 mol)
and nickel nitrate (0.001mol) for 5 hrs. After completion of the reaction the complex obtained
was filtered, washed with ether and dried. Yield: 72%. Red crystalline Solid, For C26 H24 N6 Ni
O4 S, anal. calcd., % : C, 49.22; H, 4.20;
N, 14.60, Found, % : C, 49.20; H, 4.15; N, 14.69.
Determination of X-ray crystal structure
A Bruker APEX-2 X-ray (three-circle) diffractometer was employed for crystal screening,
unit cell determination, and data collection. The X-ray radiation employed was generated from a
Mo sealed X-ray tube (Kα= 0.71073Ǻ with a potential of 40 kV and a current of 40 mA) fitted
with a graphite monochromator in the parallel mode (175 mm collimator with 0.5 mm pinholes).
A solution was obtained readily using SHELXTL (XS) [10]. Hydrogen atoms were placed in
idealized positions and were set riding on the respective parent atoms. All non-hydrogen atoms
were refined with anisotropic thermal parameters. The structure was refined (weighted least
squares refinement on F2) to convergence [11]. Olex2 was employed for the final data
presentation and structure plots.Supplementary material for the crystal structure has been
deposited with the Cambridge Crystallographic Data (no: 1041536; deposit@ccdc.cam.ac.uk or
http://ccdc.cam.ac.uk)
Antibacterial Activity
The sulphadiazine has potency to cure the wound infection also acts as antimicrobial
agent, so that the complex of the sulphadiazine also expected to possess increased biological
activity [12, 13]. The antimicrobial activity of sulphadiazine and the title complex was studied
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using the procedure as reported in the literature [14]. On chelation the polarity of the metal ion is
reduced to a greater extent, thereafter it enhances the activity of the complex. [15].
Anticancer study - Cell treatment procedure and MTT assay
Cytotoxicity of the compounds were carried out on human breast cancer cell line (MCF-
7) was obtained from National Centre for Cell Science (NCCS), Pune India. For the screening
experiment, the cells were seeded onto 96-well plates at plating density of 10,000 cells/well and
incubated to allow for cell attachment at 37°C, 5% CO2, 95% air and 100% relative humidity for
24hrs prior to the addition of the compounds. The compounds were dissolved in DMSO and
diluted in the respective medium containing 1% fetal bovine serum (FBS). After 24hrs the
medium was replaced with the respective medium with 1% FBS containing the compounds at
various concentrations and incubated at 37°C under conditions of 37°C, 5% CO2, 95% air and
100% relative humidity for 48rs. Triplication was maintained and the medium not containing the
compounds served as control. After 48hrs, 15 μL of MTT (5 mg mL-1) in phosphate buffered
saline (PBS) was added to each well and incubated at 37°C for 4hrs. The medium with MTT was
then removed and the formed formazon crystals were dissolved in 100 μL of DMSO. The
absorbance was then measured at 570nm using microplate reader. The % cell inhibition was
determined using the following formula
% Cell Inhibition  100 Abs sample / Abs control x100.




Nonlinear regression graph was plotted between % Cell inhibition and Log concentration
and IC50 was determined using Graph Pad Prism software [16, 17].
RESULTS AND DISCUSSION
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The title complex is red crystalline solid stable in air allowing physical measurements, dissolves
in DMF to give stable solutions at room temperature. Its melting point is 240 – 245C and is
uncorrected. The molar conductance of the metal complexes (10-3 M) was found to be 0.12 Scm-
1mol-1 proving its non-electrolytic behavior [18, 19]. The analytical data of the ligand and the
complex is in good agreement with the experimental values and the molecular formula for the
complex is found as [Ni (C16H14N2O2)(C10H10N4O2S)] and it is shown in experimental section.
FT-IR Spectra
The FT-IR spectral data give valuable information regarding the nature of the functional
group attached to the metal atom. A characteristic azomethine linkage of (-HC=N-) is observed
at 1573 cm-1 and (>C=N-) in pyrimidine ring is assigned for the band that appears at 1488 cm-1.
A band appears at 3333 cm-1 in Ni complex confirming the presence of –NH2 in the complex.
The band at 1154 cm-1 is due to symmetric vibration of SO2 [20, 21].
The FT-IR-spectra of complex gives the band for the occurrence of non-ligand band
which is seen at 646 cm-1 of M-N bond. No change in the band appearing at 1488 cm-1 shows
that >C=N- linkage for the pyrimidine ring is not involved in co-ordination. The SO2 bands in
both sulphadiazine and complex remain unchanged, so that we can come to know that there is no
participation of SO2 group in coordination. No band coordination around 3700 cm-1 indicates
there is no water molecule present in the complex.
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Electronic spectral data
The electronic spectral data is in relevance with the proposed geometry of complex. The
electronic spectrum of Ni(II) complex (Fig. 1) shows absorption at respective regions. The zero
magnetic moment indicates diamagnetic Ni(II) complex with square planar geometry. Square
planar complex of Ni(II) have no affinity for axial ligand coordination in solution [22]. The
electronic absorption spectral bands of the complex Ni(II) is recorded over the range 200-800 nm
in DMF and its λmax value also assigned and it exhibits two absorption band at 450 nm and 420
3
3
3
nm. These may be assigned to the transition A1g→ B2g and A1g →3Eg [23]. The characteristic
d-d transition band of square planar Ni(II) complex over the range 440 nm is seen. The observed
bathochromic shift in the position of visible band is analogous to weaker ligand field energy
which is responsible for red shift for the complex[24].
NMR spectral data
1
1
The H NMR spectrum of the Ni complex exhibits signals at following ranges. The H NMR
spectra of the complex shows triplet at δ 3.43 ppm for the hydrogens attached to C-8 and C-9.
Two multiplets around δ 6.50 to 7.63 ppm correspond to the aromatic protons in the complex. In
the pyrimidine ring a doublet appears for the hydrogen of C-18 and C-20 at δ 7.9 ppm which
differs from azomethine hydrogen analog to (-CH=N-) group. For the hydrogen of C-19 a triplet
appears at δ 7.17 ppm. The singlet at δ 8.48 ppm is due to (-NH-) attached to the SO2 group. Free
NH2 of the sulphadiazine shows a signal at δ 5.97 ppm .
13C NMR spectra provide further support for the structural probability of the complex.
The signals for C-18 and C-20, C-19, C-4 and C-13, C-2 and C-15, C-8 and C-9 appears at δ
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157.2 ppm, δ 112 ppm, δ 120.3, δ 133.5 and δ 163.9 ppm respectively. Aromatic carbons give
signals at δ 115.4 ppm for C-23 & C-25 and δ 124.9 ppm for the C-22 & C-26. The azomethine
1
carbons (C-1 & C-16) attached to nitrogens gives signal at 163.94 ppm [25]. The H-NMR and
13C NMR spectra of the Ni(II) complex is shown in Fig. 2 and 3 respectively.
Thermal analysis (TGA/DTA) of [Ni(salen)]sulphadiazine complex
The thermogravimetric analysis gives information about the thermal stability of the
complex and suggests a general scheme for thermal decomposition. In the present investigation,
heating rates were suitably controlled at 10C/min under nitrogen atmosphere and the weight
loss was measured from the ambient temperature upto 800C. Ni (II) complex of the template
synthesis shows the mass loss in accordance with elimination of certain group. At 100º C there is
no depression in group which reveals that there is no water molecule in the complex both outer
and inner co-ordination sphere. There is a gradual depression up to 280º C with loss of 5% of
mass which may be due to the elimination of sulphurdioxide gas. Then above 280º C a heavy
mass loss of 61% is seen till 390º C corresponds to the loss of co-ordinated and non co-ordinated
part of the sulphadiazine leaving the metal oxide as residue. The thermogram of the Ni(II)
complex is depicted in Fig. 4.
Single crystal X-ray diffraction of [Ni(salen)]sulphadiazine complex
The complex crystallizes in the triclinic system with space group P-1, Z=2 with the unit cell
dimensions a=9.031(2)Ǻ , b=10.927(3) Ǻ, c=14. 580(4) Ǻ, α=69.853(2), β=73.048(3), γ= 67.
912(2). The structure of the Ni complex consists of [Ni(salen)] and one unco-ordinated
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sulphadiazine moiety. Ni(II) is co-ordinated by two nitrogen and two oxygen from the salen
ligand forming a square planar geometry and the sulphadiazine moiety remains unco-ordinated.
The bond lengths for imino nitrogen atom are Ni(1)-N(1) and Ni(1)-N(2) are 1.843(2) and
1.845(2) respectively and the bond lengths for Ni-O i.e. Ni(1)-O(1) and Ni(1)-O(2) are
1.8479(17) and 1.8429(17) respectively. The different bite angles around the square plane i.e.
O(1)-Ni(1)-N(1), N(1)-Ni(1)-N(2), N(2)-Ni(1)-O(2), O(2)-Ni(1)-O(1), N(1)-Ni(1)-O(2) and
N(2)-Ni(1)-O(1) are 94.87(8), 86.08(10), 94.65(9), 84.38(7), 179.05(8) and 178.49(8)
respectively show that there are slight distortions. No molecule of water is found in the hydrated
form. One molecule of sulphadiazine is found unco-ordinated. Table 1 and 2 shows Crystal data
and structural refinement parameters and selected bond length (Ǻ) and bond angle ()
respectively. The ORTEP representation and the packing diagram of the title complex is shown
in Fig. 5 and Fig. 6 respectively.
TEM and SAED pattern
The NiO nanoparticle was synthesized at 600ºC using Ni complex as precursors and their
properties studied with the help of transmission electron microscope and SAED pattern. Fig. 7
show the TEM images of the synthesized NiO nanoparticle, with an image magnification. Fig. 8
demonstrates the SAED pattern of the synthesized NiO nanoparticle.
Antimicrobial activity
The antibacterial activity of the Ni(II) complex was tested against the bacteria Aeromonas
hydrophila, Serratia marcescens, Bacillus licheniform, Pseudomonas aeruginosa and
Acinetobacter baumanii respectively by the well diffusion method using Mueller Hinton agar
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nutrient as the medium. The antifungal activities were screened for the organisms Aspergillus
niger and Candida albicans by the well diffusion method cultured on Sabrouds dextrose agar as
medium. The inhibition zones were developed, at which the concentration was inferred as very
good activity for Pseudomonas aeruginosa and Acinetobacter baumanii bacterial strains at all
concentration levels, 22-26 mm and moderate activity for other strains, can be seen in Figure 9.
The results of antibacterial and antifungal screening has been compared with the standard
Ciprofloxacin and Clotrimazole in each case. The minimum inhibitory concentration of the title
complex against Pseudomonas aeroginosa and Acinetobacter baumanii are 250 and 125μg/ml
respectively. In the case of fungal strains Aspergillus niger and Candida albicans the complex
shows moderate activity. The inhibition zones are shown in Figure 10. The increased activity of
the Ni(II) complex than sulphadiazine can be explained based on chelation theory[26, 27].
Anticancer activity
In cancer study, complex is screened for human breast cancer cell at different concentration. The
inhibitory concentration (IC50) was noted in the series of dilutions, which gives appropriate cell
inhibition % and rise in the graph (Fig. 11). For the Nickel Salen complex the % inhibition
property increases to the increase in concentration as 2.2380 to 47.9145. IC50 is employed to
stand for the cytotoxicities of the compounds against the cancer cell lines; the smaller the IC50
value in the same condition is, the higher the cell growth inhibitory potency. The average IC50
value was calculated by Graph Pad Prism software is 116 µM which is moderate level of
inhibition [28, 29]. The IC50 value of the nickel nitrate and sulphadiazine was checked and found
to be >100 µM. DMSO when used as control without test sample, it does not exhibit any
cytotoxic activity against cancer cell line .The data suggest that the compounds are less cytotoxic
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on HeLa cells at moderate concentrations(200-50µg/ml). It may be noted that the typical IC50
values for the commercial drug cisplatin falls in the range 1.34-2.20 µM on HeLa cells.
The importance of metal based anticancer drugs increased abundantly after the success of
cisplatin and its successors which are presently promising candidates in clinical evaluation. The
mode of action in the anticancer drug is through the formation of metal-DNA adducts and
through cellular redox homeostasis. In this case, the Ni(II) complex is more stable with
ethylenediamine ligands and kinetically inert having a lower reactivity with biomolecules[30].
The importance of such work lies in the possibility that the next generation of metal complexes
might be more efficacious as anticancer agents. A detailed investigations with tailoring new
complexes and analyzing their stability under biological conditions could be helpful in designing
more potent anticancer agents for the therapeutic use in the future.
Conclusion
In this study, Ni(II) salen sulphadiazine complex has been synthesized and characterized by
various spectral techniques and the structure was confirmed using single crystal X-ray diffraction
studies. Ni(II) is coordinated with two nitrogen atoms and two oxygen atoms forming square
planar geometry and the sulphadiazine moiety remains unchanged. The synthesised complex has
been screened for their in-vitro antimicrobial activity against various test organisms and found to
be good. The in-vitro anti-cancer study shows the IC50 value of 116µM against the human breast
cancer cell lines.
Acknowledgement
All authors thank the management of Kongunadu Arts and Science College and PSGR
Krishnammal College for Women, Coimbatore for providing research facilities, KMCH College
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of Pharmacy, Coimbatore to carry out the biological activities. One of the authors S.J. thank
UGC-Hyderabad (MRP No. 4995/14 (SERO-UGC) for financial support.
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[30]. Jungwirth, U.; Kowol, C. R.; Keppler, B. K.; Hartinger, C. G.; Berger, W.; Heffeter, P.;
Anticancer activity of metal complexes: Involvemnet of redox processes, Antioxid Redox
Signal, 2011, 15(4), 1085-1127.
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Table 1: Crystal data and structural refinement parameters
Empirical formula
Formula weight
Temperature
C26 H24 N6 Ni O4 S
575.28
110.15 K
Wavelength
0.71073 Å
Crystal system
Space group
Triclinic
P -1
Unit cell dimensions
a = 9.031(2) Å
b = 10.927(3) Å
c = 14.580(4) Å
= 69.853(2)°
= 73.048(3)°.
= 67.912(2)°.
1229.7(5) Å3
Volume
Z
2
Density (calculated)
Absorption coefficient
F (000)
1.554 Mg/m3
0.921 mm-1
596
Crystal size
0.523 x 0.417 x 0.325 mm3
1.514 to 27.455°
-11<=h<=11, -14<=k<=14, -18<=l<=18
5553 [R(int) = 0.0175]
25.242° 99.8 %
0.7456 and 0.6255
Full-matrix least-squares on F2
5553 / 33 / 343
1.061
Theta range for data collection
Index ranges
Independent reflections
Completeness to theta
Max. and Min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
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Final R indices [I>2 sigma (I)]
R indices (all data)
R1 = 0.0398, wR2 = 0.0950
R1 = 0.0433, wR2 = 0.0972
0.873 and -0.858 e.Å-3
Largest diff. peak and hole
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Table: 2. Selected bond lengths and bond angles
Ni(1)-O(1)
Ni(1)-O(2)
1.8479(17)
1.8429(17)
1.843(2)
Ni(1)-N(1)
Ni(1)-N(2)
1.845(2)
O(2)-Ni(1)-O(1)
O(2)-Ni(1)-N(2)
N(1)-Ni(1)-O(1)
N(1)-Ni(1)-O(2)
N(1)-Ni(1)-N(2)
N(2)-Ni(1)-O(1)
C(1)-O(1)-Ni(1)
C(16)-O(2)-Ni(1)
C(7)-N(1)-Ni(1)
C(7)-N(1)-C(9)
C(9)-N(1)-Ni(1)
C(8)-N(2)-Ni(1)
C(10)-N(2)-Ni(1)
84.38(7)
94.65(9)
94.87(8)
179.05(8)
86.08(10)
178.49(8)
126.71(15)
127.31(17)
126.94(17)
118.4(2)
114.57(19)
114.7(2)
127.08(18)
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NH2
NH2
HO
O
N
N
S
O
O
NH
Reflux
5hrs
H2N
+
+
O
Ni(NO3)2
.6H2O
+
NH2
N
N
S
O
O
NH
O
N
i
N
N
Scheme 1. Synthesis of Nickel (II) complex
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Fig. 1. Electronic Spectrum of Ni(II) complex
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Fig. 2. H1 NMR Spectra [Ni(salen)]sulphadiazine complex
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Fig. 3. C13 NMR spectra of [Ni(salen)]sulphadiazine complex
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Fig. 4. Thermogram of Ni(II) complex
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Fig. 5. ORTEP diagram of [Ni(salen)]sulphadiazine complex.
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Fig. 6. Packing diagram of [Ni(salen)]sulphadiazine complex
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Fig. 7. TEM images of NiO nanoparticle
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Fig. 8. SAED pattern of NiO particle
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Figure 9: Anti bacterial activity of complex
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