Polyhedron 168 (2019) 113–126

Contents lists available at ScienceDirect

Polyhedron
journal homepage: www.elsevier.com/locate/poly

Energetically favorable anti-electrostatic hydrogen bonded cationic

clusters in Ni(II) 3,5-dimethylpyrazole complexes: Anticancer evaluation
and theoretical studies
Anshuman Gogoi a, Debajit Dutta a, Akalesh K. Verma b, Hiren Nath a, Antonio Frontera c,
Ankur K. Guha a, Manjit K. Bhattacharyya a,⇑
a
Department of Chemistry, Cotton University, Guwahati 781001, Assam, India
b
Department of Zoology, Cell & Biochemical Technology Laboratory, Cotton University, Guwahati 781001, Assam, India
c
Departament de Química, Universitat de les Illes Balears, Crta de valldemossa km 7.7, 07122 Palma de Mallorca (Baleares), Spain

a r t i c l e i n f o a b s t r a c t

Article history: Two new Ni(II) coordination complexes of pyrazole and acetato ligands, involving nitrate and chloride
Received 20 March 2019 counter anions, viz. [Ni(Hdmpz)2(CH3COO)(H2O)3]NO3
2H2O (1) and [Ni(Hdmpz)2(CH3COO)(H2O)3]Cl
Accepted 14 April 2019 (2) (where Hdmpz = 3,5-dimethylpyrazole), have been synthesized in purely aqueous medium at room
Available online 7 May 2019
temperature. The complexes have been characterized by elemental analysis, FT-IR, electronic
spectroscopy, PXRD, TGA and single crystal X-ray diffraction. The H-bonds established between the
Keywords: isostructural cationic [Ni(Hdmpz)2(CH3COO)(H2O)3]+ moieties of both complexes can be classified as
Synthesis
anti-electrostatic H-bonds (AEHBs) and these have been studied using DFT calculations. Remarkably, in
Anti-electrostatic hydrogen bond
Anticancer
one case these AEHBs exhibit favorable interaction energies, thus indicating that the attractive nature
Apoptosis of the H-bonds is able to compensate the pure electrostatic repulsion. The analyses of the cell viability
Docking results for the DL cell line show a significant concentration dependent decrease by compounds 1 and 2
with a negligible cytotoxic effect observed against normal cells (PBMC) in comparison to the cancer cells
(DL). The cytotoxic activity of these compounds in DL cells occurs via apoptosis. Molecular docking and
SAR analysis reveal that the compounds possess high binding affinities against most common cancer tar-
get proteins.
Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction chemistry, optics, magnetism and luminescence etc. [13,14]. Nickel

Utilization of supramolecular architectures via non-covalent
interactions is a vigorous field in crystal engineering, involving
the synthesis of new functional materials, and it is a powerful tool
for interesting structure formations [1–4]. The construction of
desired architectures with potential applications depends on vari-
ous synthetic factors, such as the nature of the metal centers [5,6],
counter ions [7,8] and the reaction conditions [9,10]. In this
respect, the suitable selection of organic moieties as ligands plays
a decisive role for the construction of architectures of desired
dimensionalities [11,12].
Complexes involving pyrazole ligands, due to their diverse
structural topologies, are efficient and versatile in various fields
that includes medicine, catalysis, separations, bio-mimetic
⇑ Corresponding author.
E-mail address: manjit.bhattacharyya@cottonuniversity.ac.in
Bhattacharyya).
pyrazole complexes with varied pharmacological actions, including
antifungal [15,16], antibacterial [17] and antiproliferative/anti-
cancer properties, have also been reported due to their role in
the development of newer drugs [18,19]. Nickel(II) thiosemicar-
bazone complexes have been reported to have cytotoxicity against
the K562 leukemic cell line [20]. A wide range of cytotoxic drugs
with different mechanisms of action have been used as anticancer
agents, singly or in combination with other drugs [21]. The main
drawback of these drugs is their life threatening side effects that
are caused mainly by their indiscriminate action against both
cancerous and normal cells in the host body. Therefore, there is
an urgent need to find new alternative drugs with enhanced anti-
cancer activity to fight against this disease [22].
Among the non-covalent interactions, hydrogen bonds are the
most common type of supramolecular interaction used by organic
ligands to control the secondary coordination sphere of metal ions
[23–25]. Hydrogen bonding between closed-shell ions of like
(M.K.
charge where the dominant electrostatic force is strongly opposed

https://doi.org/10.1016/j.poly.2019.04.043
0277-5387/Ó 2019 Elsevier Ltd. All rights reserved.
114 A. Gogoi et al. / Polyhedron 168 (2019) 113–126

is referred to as anti-electrostatic hydrogen bonding (AEHB) [26].
The term AEHB was introduced by Weinhold and Klein in 2014,
when they provided new quantum chemical evidence of hydrogen
bonding overcoming electrostatic repulsion [27]. The possibility of
‘‘anti-electrostatic” hydrogen bond (AEHB) formation between
like-charged ions has recently been theoretically predicted and
experimentally confirmed [28,29]. In addition, cation-cation and
anion-anion hydrogen bonded clusters can also overcome the elec-
trostatic repulsion which can be influenced by counter ions or sol-
vents [30,31].
It has also been established that when cationic complexes are
used as building blocks, the counter anions play a crucial role in
the determination of the supramolecular architectures [32,33].
For such metal complexes with functionalized hydrogen bonded
ligands, the contribution of the selected counter ions should be
expected to support the self-assembly processes. From studies on
the molecular assembly of several ionic metal complexes based
on substituted pyrazole ligands, the hydrogen-bonding interaction
between the counter anion and the NAH-pyrazole groups are the
main tool for the molecular self-assembly, although some other
factors, such as variation of the counter anion, can also drive the
supramolecular arrangements [34–36].
In the present work, we have synthesised (Scheme 1) two new
coordination complexes, viz. [Ni(Hdmpz)2(CH3COO)(H2O)3]
Scheme 1. Synthesis of 1 and 2.
NO3
2H2O (1) and [Ni(Hdmpz)2(CH3COO)(H2O)3]
Cl (2), involving
pyrazole and acetate ligands having different counter anions
(nitrate and chloride, respectively). The complexes were character-
ized by single crystal X-ray diffraction, electronic, vibrational spec-
troscopy, PXRD and TGA. The counter anions and Hdmpz ligands
are involved in variety of non-covalent interactions resulting in
the self-assembly of the cationic units of 1 and 2 into supramolec-
ular double chain structures. The crystal structures show
supramolecular association involving anti-electrostatic hydrogen
bonds that have been analyzed using DFT and NCI plot calculations.
It is interesting to observe that the behaviour of the anti-electro-
static hydrogen bonds in the complexes is influenced by the coun-
ter anions. The analyses of cell viability results for the DL cell line
show a significant concentration dependent decrease for com-
pound 2 compared to compound 1 and interestingly, a negligible
cytotoxic effect was observed against normal cells (PBMC) com-
pared to the cancer cells (DL).
2. Experimental
2.1. Materials and physical measurements
All reagents, viz. nickel(II) nitrate hexahydrate, nickel(II) chlo-
ride hexahydrate, 3,5-dimethylpyrazole and sodium acetate trihy-
drate, used in this work were obtained from Sigma Aldrich and
Merk (India) Ltd. and were used without further purification.
Deionized water was used as the reaction medium. Elemental anal-
yses (C, H and N) were carried out on a Perkin Elmer 2400 Series II
CHNS/O Analyzer. KBr phase FT-IR spectra were recorded on a Bru-
ker Alpha FT-IR spectrophotometer in the mid-IR region (4000–
400 cm1). The electronic spectra were recorded using a Shimadzu
UV-2600 spectrophotometer. For UV–Vis-NIR spectra, BaSO4 pow-
der was used as a reference (100% reflectance). Thermogravimetric
studies were carried out under a flow of N2 gas using a Mettler
Toledo TGA/DSC1 STARe system at a heating rate of 10 °C min1.
The powder X-ray diffraction (PXRD) data were recorded using

Table 1
Crystal data and structure refinement details for 1 and 2.

Parameters 1 2
Formula C12H29N5NiO10 C12H25ClN4NiO5
Formula weight 462.11 399.52
T (K) 293(2) 293(2)
k (Å) 0.71073 0.71073
Crystal system monoclinic triclinic

Space group P21/c P1
Unit cell dimensions
a (Å) 17.9772 (4) 7.3800 (6)
b (Å) 7.2977 (2) 8.6686 (7)
c (Å) 18.6249 (4) 14.5212 (13)
a (°) 90 101.359 (5)
b (°) 116.4380 (10) 92.449 (5)
c (°) 90 98.857 (5)
V (Å3) 2187.90(9) 897.36 (13)
Z 4 2
Calculated density (Mg m3) 1.403 1.479
F (0 0 0) 976 420
Crystal size (mm) 0.40  0.28  0.16 0.43  0.12  0.11
h range for data collection (°) 2.19 to 25.00 1.43 to 25.00
Limiting indices, h, k, l 21  h  21, 8  k  8, 22  l  22 8  h  8, 10  k  10, 17  l  17
Reflections collected 30 226 8748
Unique data (Rint) 3835 [Rint = 0.0315] 3057 [Rint = 0.0385]
Refinement method full-matrix least-squares on F2 Full-matrix least-squares on F2
Data/restraints/parameters 3853/0/292 3057/11/232
Goodness-of-fit on F2 1.036 1.193
Final R indices [I > 2r(I)] R1 = 0.0287, wR2 = 0.0770 R1 = 0.1146, wR2 = 0.3318
R indices (all data) R1 = 0.0354, wR2 = 0.0813 R1 = 0.1174, wR2 = 0.3327
Largest difference peak and hole (e Å3) 0.377 and 0.306 2.522 and 1.237
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
an XPERT-PRO X-ray powder diffractometer with Cu Ka radiation.
Room temperature magnetic susceptibility was measured at 300 K
on a Sherwood Mark 1 magnetic susceptibility balance by the
Evans Method.
2.2. Crystallographic data collection and refinement
Intensity data of 1 and 2 were collected on a Bruker SMART CCD
diffractometer with graphite monochromatised Mo Ka radiation
(k = 0.71073 Å). The crystal structures were solved by the direct
method and refined by full matrix least squares techniques with
SHELXL-97[37] via the WINGX [38] platform available for personal com-
puters. The hydrogen atoms in both the complexes were located in
difference Fourier maps and refined with isotropic atomic displace-
ment parameters, except for the lattice water molecules of 1. The
structural diagrams were drawn with DIAMOND 3.0 [39]. Data collec-
tion refinement parameters for complexes 1 and 2 are summarized
in Table 1.
2.3. Computational methods
The calculations of the non-covalent interactions were carried
out using GAUSSIAN-09 [40] and the M06-2X/def2-TZVP level of
theory. The Grimme’s dispersion correction has been used in the
calculations [41]. To evaluate the interactions in the solid state,
the crystallographic coordinates were used and only the position
of the H-bonds has been optimized. This procedure and level of
theory has been successfully used to evaluate similar interactions
[42]. The interaction energies were computed by calculating the
difference between the energies of the isolated monomers and
their assembled structures. The NCI plot is a visualization index
that efficiently allows the identification and visualization of
non-covalent interactions [43]. It is based on the electron density
and its derivatives and the isosurfaces correspond to both
favorable and unfavorable interactions. They are easily differenti-
ated by the sign of the second density Hessian eigenvalue and
are defined by the isosurface color. NCI analysis is a very
convenient tool to rationalize host–guest complementarity and to
know which interactions stabilize a complex. The color scheme
is a red-yellow-green-blue scale with red for q+cut (repulsive)
and blue for q cut (attractive). Yellow and green surfaces corre-
spond to weak repulsive and weak attractive interactions,
respectively [44].
2.4. MTT based cell viability assay and IC50 measurement
MTT is a largely used colorimetric assay for measuring cell pro-
liferations, cellular metabolic activity and cell viability [45,46].
The MTT assay is based on the ability of cellular oxidoreductase
enzymes (MDH and SDH) to reduce the tetrazolium salt into insol-
uble formazan crystals in the presence of nicotinamide adenine
dinucleotide phosphate (NADPH), which later produces a purple
color with DMSO. In the present study, compound 1 and 2 medi-
ated cell viability was measured by the MTT assay in DL (cancer
cells) and peripheral blood mononuclear cells (PBMC) (normal
cells) as per standard methods [46]. After incubation with differ-
ent doses (0, 0.01, 0.1, 0.5, 1, 5 and 10 mM) of the compounds
for 24 h, 10 mL of the MTT labelling reagent (5 mg/mL in phos-
phate-buffered saline) was added into each well, except the
empty wells. The microtiter plate was then incubated for four
hours in a CO2 incubator (5% CO2 and 95% air) at 37 °C. Following
that, 100 mL of DMSO was added into each well, with gentle shak-
ing. The plate was checked for complete solubilization of the pur-
ple formazan crystals, followed by measurement of the
absorbance (optical density, OD) of the samples at a wavelength
115
of 550 nm. The percentage cell viability was calculated from the
formula given below:
OD of Sample  OD of Blank
Cell viability ð%Þ ¼  100
OD of Control
A dose–response curve (% cell viability versus sample concen-
tration) was plotted and the sample concentration that inhibits
50% of the cell viability (IC50) was determined.
2.5. Apoptosis study using fluorescence microscopy
To understand the mechanism of cell death (cytotoxicity), com-
pounds 1 and 2 mediated apoptotic cell death was assessed using
the acridine orange/ethidium bromide (AO/EB) double staining
method [47]. Acridine orange is taken up by both viable and apop-
totic cells and emits green fluorescence when exposed to UV light.
Ethidium bromide is taken up only by apoptotic cells and emits red
fluorescence. In the present study, control and treated DL cells
were collected after 24 h treatment, washed with PBS and to the
cell suspension, 20 mL of AO/EB dye mixture (100 lg/mL of each
dye in distilled water) was added, mixed gently and incubated
for 5 min in the dark. The cells were thoroughly examined under
a fluorescence microscope and photographed. About 1000 cells
were analyzed, and the percentage of apoptotic nuclei was deter-
mined for three independent determinations. Viable cells were
identified by bright uniform green nuclei with organized struc-
tures; apoptotic cells contain condensed or fragmented chromatin
with red or orange nuclei [48].
2.6. Molecular docking
In the present study, the molecular interactions between the
compounds and cancer target proteins were studied using Molegro
Virtual Docker (MVD) software (www.molegro.com) along with
the Graphical User Interface (GUI). The 3-dimensional (3D) coordi-
nates of multiple cancer target proteins were downloaded from the
web for the Research Collaborator for Structural Bioinformatics
(RCSB) protein data bank (PDB). The PDB ids 4XV2 (melanoma, col-
orectal, thyroid and non-small cell lung cancer), 5LWE (ovarian
cancer, prostate cancer, pancreatic cancer, large B cell lymphoma,
melanoma), 4FLH (colon, brain, gastric, breast and lung cancer),
1XKK (non-small cell lung cancer, bladder cancer, breast cancer
and glioblastoma) were selected based on the potential roles in
multiple cancer types. The molecular arrangement and geometry
of the complexes were fully optimized using a semi-empirical
quantum chemistry method (PM3). All of the water and cofactor
compounds were deleted from the protein structures and the pro-
tein and complex structures were further prepared using the
parameter settings in the same software package [49]. The active
binding site region was defined as a spherical region which encom-
passes all protein within 15.0 Å of the bound crystallographic
ligand atom with selected coordinates of the X, Y and Z axes,
respectively. Default settings were used for all the calculations.
Docking was performed using a grid resolution of 0.30 Å and for
each of the 10 independent runs, a maximum number of 1500 iter-
ations were executed on a single population of 50 individuals. The
active binding site was considered as a rigid molecule, whereas the
complexes were treated as being flexible, i.e. all non-ring torsions
were allowed [50]. The protein-complex interaction was further
analyzed and visualized by Chimera software (https://www.cgl.
ucsf.edu/chimera/). Furthermore, Structure Activity Relationships
(SARs) of compounds 1 and 2 were examined based on the docking
results as well as bioassay results available in the NCBI database
(https://www.ncbi.nlm.nih.gov/) for the parental template (pyra-
zole complex) of both compounds.
116 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
2.7. Statistical analysis
The experimental results are expressed as mean values ± S.D.
All measurements were replicated three times. The data were ana-
lyzed by an analysis of variance (ANOVA) (P  0.05). The IC50 val-
ues were calculated from dose response curve analysis.
2.8. Syntheses
2.8.1. Synthesis of [Ni(Hdmpz)2(CH3COO)(H2O)3]NO3
2H2O (1)
Complex 1 was prepared by adding an aqueous solution of Ni
(NO3)2
6H2O (0.498 g, 2 mmol) dropwise to a mixed aqueous solu-
tion of Hdmpz (0.384 g, 4 mmol) and sodium acetate trihydrate
(0.272 g, 2 mmol) in a molar ratio of 1:2:1. The resulting green
solution was mechanically stirred for 2 hours at room temperature.
The clear solution was kept at 2–4 °C, from which block-shaped
green crystals suitable for single crystal X-ray diffraction were
obtained after several days. Yield: 89% (0.82 g). Anal. Calc. for C12-
H29NiN5O10: C, 31.16; H, 6.27; N, 15.14; Found: C, 31.28; H, 6.31; N,
15.17%. FT-IR spectral data (KBr disc, cm1): 3278(s), 3146(w,sh),
3042(w,sh), 2931(m,sh), 2874(sh), 1624(w,sh) 1580(s), 1470(w,
sh), 1381(m,sh), 1330(m,sh), 1278(m,sh), 1146(s), 1050(s), 1020
(s), 815(s), 697(m), 653(m,sh), 602(m) [s, strong; m, medium; w,
weak; br, broad; sh, shoulder].
2.8.2. Synthesis of [Ni(Hdmpz)2(CH3COO)(H2O)3]Cl (2)
Complex 2 was synthesized by a method similar to that of com-
plex 1, by adding an aqueous solution of NiCl2
6H2O (0.474 g,
2 mmol) dropwise to an aqueous solution of Hdmpz (0.384 g,
4 mmol) and sodium acetate trihydrate (0.272 g, 1 mmol) in a
molar ratio of 1:2:1. The resulting green solution was stirred
mechanically for 2 h at room temperature. Irregular shaped crys-
tals suitable for single crystal X-ray analysis were obtained after
a few weeks. Yield: 87.2% (0.65 g). Anal. Calc. for C12H25NiN4O5Cl:
C, 36.04; H, 6.25; N, 14.03. Found: C, 36.08; H, 6.28; N, 14.10%.
FT-IR spectral data (KBr disc, cm1): 3241(s, br), 3146(w,sh),
3109(w,sh), 3042(w,sh), 2984(w,sh), 2925(m,sh), 2874(sh), 2777
(w,sh), 1624(w,sh), 1580(s), 1551(w,sh), 1418(s), 1338(m,sh),
1285(s), 1258(m,sh), 1153(s), 1042(s), 1014(s), 874(m), 778(s),
705(m), 661(m,sh), 616(m), 529(m).
Fig. 1. Molecular structure of (a) 1 and (b) 2.
3. Results and discussion
3.1. Synthesis and general aspects
Complexes 1 and 2 have been isolated in high yield by reacting
one equivalent of NiX2
6H2O (X = NO 
3 and Cl ) with two equiva-
lents of Hdmpz and one equivalent of the acetato ligand in water.
Complexes 1 and 2 are soluble in water and also in common
organic solvents, viz. methanol, DMSO etc. Complexes 1 and 2
show room temperature meff values of 3.03 and 3.08 BM,
respectively.
3.2. Crystal structures of complexes 1 and 2
The structures of the mononuclear cations for 1 and 2 are sim-
ilar, as shown in Fig. 1(a) and (b). In both cases the Ni(II) ions are
coordinated to two pyrazolyl nitrogen atoms of two Hdmpz ligands
in a cis-fashion, three water molecules and an acetate ligand. Com-
plex 1 crystallizes in the triclinic centrosymmetric space group
P21/c, with Z = 4, while complex 2 crystallizes in the monoclinic

crystal system in space group P1, with Z = 2. There are two water
molecules and a nitrate anion in the crystal lattice of 1, while the
crystal lattice of 2 contains a chloride anion. The axial positions
of 1 and 2 are occupied by two coordinated water molecules and
the equatorial plane is formed by two Hdmpz ligands, one water
molecule and an acetate anion. The acetate anion is coordinated
in a monodentate fashion in both complexes with a NiAOacetate dis-
tance of 2.065(2) Å in 1 and 2.093(9) Å in 2. The NiAOH2O bond dis-
tances in 1 range from 2.069(1) to 2.090(2) Å, while the NiAOH2O
distances are found to be in the range 2.057(11)–2.116(8) Å for 2.
However, only small differences between the molecular cations
are observed, i.e. the dihedral angle between the pyrazole planes,
which is 66.04(2)° for 1 and 59.95(4)° for 2. This feature could be
related to the different interactions of the pyrazole NAH groups
with the corresponding to counter anions, viz. nitrate in 1 and chlo-
ride in 2 [51]. Table 2 lists the selected bond lengths and bond
angles for 1 and 2. As can be seen from Table 2, the coordination
geometry of the Ni(II) ions in the complexes can be best described
as slightly distorted octahedral.
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126 117

Table 2 [Ni(Hdmpz)2(H2O)3(CH3COO)]+ units via a variety of hydrogen

Selected bond lengths (Å) and angles (°) of the coordination metal core in 1 and 2. bonding interactions (Table 3), thereby forming a 1D supramolec-
Bond d (Å) Angle Degree (°) ular double chain. A detailed crystal packing analysis of 1 further
1 reveals two symmetrically equivalent CAH


C contacts [52], [C
Ni1AO1 2.065(2) O1ANi1AN3 172.6 (sp3)AH


C(sp2), [CAC = 3.999(4) Å] between carbon atom C(9)
Ni1AO3 2.090(2) O5ANi1AN1 175.8 of a Hdmpz ligand of one complex cation and carbon atom C(11)
Ni1AO4 2.087(2) O3ANi1AO4 172.6 of a Hdmpz ligand of another complex cation. The CAH


C con-
Ni1AO5 2.069(1) N3ANi1AN1 93.5
Ni1AN1 2.077(1) O1ANi1AO4 81.5
tacts extend the double chain into an infinite 2D network structure
Ni1AN3 2.078(2) O3ANi1AN3 94.5 along the ac plane [Fig. 3(c)]. Remarkably, the acetato ligands in the
O3ANi1AN1 88.7 cationic [Ni(Hdmpz)2(CH3COO)(H2O)3]+ units of 1 are involved in
O3ANi1AO5 87.1 strong anti-electrostatic OAH


O hydrogen bonding interactions
O1ANi1AO5 89.5
[Fig. 3(d)]. The hydrogen bonds are formed between the uncoordi-
O1ANi1AO4 81.5
O1ANi1AO3 91.1 nated oxygen atom (O2) of the acetate ligand and the coordinated
water molecules (O4), with a donor acceptor distance of 2.794
2
Ni1AO1 2.093(9) O3ANi1AN1 176.4 (2) Å, which is further analyzed below in the theoretical study.
Ni1AO3 2.116(8) O1ANi1AN3 172.3 As shown in Fig. 3(e) this anti-electrostatic hydrogen bonding
Ni1AO4 2.057(11) O4ANi1AO5 173.1 interaction forms a 1D chain along the crystallographic b-axis,
Ni1AO5 2.058(11) O4ANi1AO3 89.7 assisted by nitrate anions. The nitrate anions in the crystal lattice
Ni1AN1 2.072(10) N3ANi1AO4 90.4
with anti-electrostatic OAH


O hydrogen bonding adds a new
Ni1AN3 2.070(12) N3ANi1AO3 89.7
N3ANi1AN1 92.7 dimension to the crystal structure of 1, which can be described
N1ANi1AO1 90.2 as a 3D supramolecular architecture, thus highlighting the crucial
N1ANi1AO5 89.2 role of the nitrate anion in the crystal packing of 1.
N1ANi1AO4 92.7
As shown in Fig. 4(a), the cationic [Ni(Hdmpz)2(CH3COO)
N3ANi1AO5 96.0
(H2O)3]+ dimeric units in 2 are stablized by the formation of two
symmetrically equivalent OAH


O anti-electrostatic hydrogen
3.3. Crystal packing bonding interactions involving the oxygen atom (O1) of the acetate
ligand and coordinated water molecule (O3). The OAH


O bond
The crystal structure analysis reveals that the nitrate anion in 1 distance was found to be 1.772 Å, which clearly indicates strong
and chloride anion in 2 interact with three proximate complex OAH


O hydrogen bonding interactions between the cationic
units via intermolecular hydrogen bonding interactions (see Fig. 2). units. The presence of the chloride anion in the crystal lattice of
On examining the role of the lattice water molecules in the 2 strengthens the formation of anti-electrostatic OAH


O hydro-
crystal packing of 1, we observed that they interacts with the gen bonding interactions, which are further analyzed below in
nitrate anion to form nitrate water clusters with a discrete [(H2- the theoretical study. The above dimeric units extend into a 1D
O)4(NO3)2]2 core which has a chair-like conformation [Fig. 3(a)]. supramolecular double chain via OAH


Cl and NAH


Cl hydrogen
As shown in Fig. 3(b), these nitrate water clusters interact with bonding interactions (Table 3) involving the chloride anion in the

Fig. 2. Supramolecular synthons formed by [Ni(Hdmpz)2(H2O)3(CH3COO)]+ with (a) nitrate and (b) chloride anions.
118 A. Gogoi et al. / Polyhedron 168 (2019) 113–126

Fig. 3. (a) Perspective representation of a chair-like anion-water cluster with a discrete [(H2O)4(NO3)2]2 core; (b) supramolecular 1D double chain sustained by
nitratewater clusters; (c) 2D layered structure generated by CAH


C contacts in 1; (d) anti-electrostatic OAH


O hydrogen bonding interactions between [Ni(Hdmpz)2(-
CH3COO)(H2O)3]+ dimeric units in 1; (e) role of the nitrate anion in the 3D packing of 1, involving anti-electrostatic OAH


O hydrogen bonding interactions between the [Ni
(Hdmpz)2(CH3COO)(H2O)3]+ cationic moieties.

Table 3
Selected hydrogen bond distances (Å) and angles (°) for 1 and 2.

DAH


A d(DAH) d(D


A) d(H


A) —(DHA) Symmetry code

1
O3AH3OA


O8 0.954(1) 2.857(2) 1.914(2) 168.7 x, y + 1/2, +z + 1/2
O5AH5OB


O9 0.820(2) 2.665(3) 1.923(3) 149.9 x + 1, +y  1/2, z + 1/2
O4AH4OA


O2 0.789(3) 2.794(2) 2.007(3) 175.5 x, +y + 1, +z
O9AH9C


O10 0.890(4) 2.776(4) 1.902(4) 166.8 x + 1, y + 1, z
O9AH9D


O7 0.803(5) 2.803(4) 2.013(6) 167.2 x, y, z
O10AH10C


O8 0.986(5) 2.852(2) 1.882(5) 166.4 x, y, z
O10AH10D


O2 0.883(4) 2.778(2) 1.937(4) 158.6 x + 1, +y + 1/2, z + 1/2
N2AH2N


O6 0.796(3) 2.834(3) 2.090(3) 155.5 x, y, z
N4AH4N


O8 0.796(2) 3.137(3) 2.352(2) 168.3 x, y + 1/2, +z + 1/2
2
O3AH3OA


O1 0.932(16) 2.701(14) 1.771(16) 174.4 x, y, z
O4AH4D


O2 0.962(10) 2.681(13) 1.982(10) 127.7 x  1, +y, +z
O4AH4C


Cl 0.965(38) 3.634(10) 2.899(64) 133.5 x, y, z
O5AH5OB


Cl 0.931(8) 3.090(10) 2.294(4) 97.8 x, +y  1, +z
O3AH3OB


Cl 0.956(10) 3.275(12) 2.355(11) 161.2 x, +y  1, +z
N2AH2N


Cl 0.971(13) 3.205(14) 2.250(12) 167.3 x, y, z
N4AH4N


Cl 0.972(13) 3.183(13) 2.255(14) 159.2 x, +y  1, +z

crystal lattice of 2, thus again highlighting the crucial role of the held together by weak CAH


C contacts [52], resulting in an infi-
counter anion in the self-assembly process [Fig. 4(b)]. A detailed nite layered structure parallel to the crystallographic bc plane
structural analysis further reveals that the 1D double chains are [Fig. 4(c)]. CAH


C contacts [C(sp3)AH


C(sp2), [CAC = 3.867(2)
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126 119

Fig. 4. (a) Anti-electrostatic OAH


O hydrogen bonding interactions between cationic [Ni(Hdmpz)2(CH3COO)(H2O)3]+ units; (b) supramolecular double chain generated by
anti-electrostatic OAH


O hydrogen bonding and chloride induced OAH


Cl and NAH


Cl hydrogen bonding interactions (blue dotted lines represent AEHB and green
dotted lines represent OAH


Cl and NAH


Cl hydrogen bonding interactions); (c) 2D layered structure generated by CAH


C contacts in 2; (d) 3D supramolecular
architecture generated by OAH


O hydrogen bonding interactions in 2. (Color online.)

Table 4
Comparison of the CAH


C contacts (Å, °) observed in 1 and 2.

DAH


A d(D–H) d(D


A) d(H


A) <(DHA) Symmetry code

1
C11AH11A


C9 0.959(3) 3.999(4) 3.045(3) 172.9 x, y + 1, z
2
C1AH1A


C8 0.959(15) 3.867(20) 2.942(14) 162.3 x, y, z + 1

Å] were observed between carbon atom C(1) of the Hdmpz ligand
of one complex cation and carbon atom C(8) of the Hdmpz ligand
of another complex cation from an adjacent double chain. As
clearly shown in Fig. 4(c), the CAH


C bridges are symmetrically
equivalent, similar to that in 1. A comparison of the CAH


C con-
tacts in 1 and 2 is given in Table 4. The uncoordinated oxygen atom
O(2) of the acetate ligand of one complex unit is involved in a
strong intermolecular hydrogen bonding interaction with hydro-
gen atom H4A of the coordinated water molecule (O4) of a nearby
complex unit [1.982 Å and 127.7°]. This OAH


O hydrogen bond-
ing interaction involving the oxygen atom O(2) of the acetate
ligand propagates along the crystallographic a-axis, which further
extends the 2D layer into a 3D supramolecular architecture, similar
to that of 1 [Fig. 4(d)].
3.4. Powder X-ray diffraction (PXRD)
The powder X-ray diffraction (PXRD) patterns of complexes 1
and 2 were measured at room temperature. The peak positions of
the simulated (Mercury Software) and as-synthesized PXRD for 2
(see Fig. 5) are in agreement with each other, demonstrating the
good phase purity of the complex. Small differences in the reflec-
tion intensities and peak positions are observed between the sim-
ulated and experimental patterns, which can be attributed to the
variation in crystal orientation or particle size of the powder sam-
ple [53,54]. However, in the PXRD of 1, an appreciable difference in
2h has been observed (see supplementary Fig. S1). The evacuation
of the weakly bounded outer sphere water molecules in the crystal
lattice of complex 1 may contribute to the difference in the 2h val-
ues of the PXRD lines [55].
3.5. Theoretical studies
The theoretical study is devoted to the analysis of the inter-
molecular H-bonding interactions that are formed in compounds
1 and 2 between the cationic [Ni(Hdmpz)2(CH3COO)(H2O)3]+ units,
together with the influence of the counter ions. The H-bonds are
formed between the acetate ligands and the coordinated water
120 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
Fig. 5. Powder X-ray diffraction patterns of 2: as-synthesized (red) and simulated
from MERCURY software (black). (Color online.)
molecules, as detailed below. Previous theoretical studies have
suggested the possibility of finding cation–cation hydrogen
bonded cluster minima in the absence of solvent [56]. The presence
of a dissociation barrier makes these minima observable, even
though their overall binding energy is usually repulsive. Evidently,
the Coulombic energy governs an interaction that is repulsive in
the case of systems with the same charge. The analysis of previ-
ously reported minima structures in anti-electrostatic hydrogen
bonded systems indicates that attractive forces between the
groups involved in the HB interaction are responsible for the pres-
ence of such minima [42,57].
Fig. 6(a) shows a partial view of the X-ray structure of
compound 1 (anions omitted), where an infinite 1D chain of is
represented that is governed by the formation of OAH


O anti-
electrostatic H-bonding interactions. The interaction energy of a
dimer extracted from this infinite 1D chain [see Fig. 6(b)] is posi-
Fig. 6. (a) Partial view of the X-ray structure of compound 1. H atoms and anion omitted for clarity; (b and c) theoretical models used to evaluate the AEHB interactions
(distances in Å); (d) NCI plot of the fragment of the complex. The gradient cut-off is s = 0.35 au, and the color scale is 0.04 < q < 0.04 au. (Color online.)
tive (DE1 = +13.4 kcal/mol) due to the Columbic repulsion between
the two moieties of the same charge. In the case where the counter
ions are included in the theoretical model [see Fig. 6(c)], the inter-
action becomes favorable (DE2 = 14.7 kcal/mol), thus highlight-
ing the crucial role of the anion. In order to further characterize
the AEHB interactions, we have used the NCI plot index computa-
tional tools. The NCI plot enables the visualization and identifica-
tion of non-covalent interactions efficiently, because it allows an
assessment of host–guest complementarity and the extent to
which weak interactions stabilize a complex. A representation of
the NCI plot is shown in Fig. 6(d). It can be observed a small and
bluish isosurface is located between the H atom of the coordinated
water molecule and the O atom of the acetate ligand, thus charac-
terizing the short H-bond, which indicates that it is energetically
favorable in spite of the overall positive interaction energy. In addi-
tion, a more extended green isosurface is located between the H
atoms of the methyl groups, thus revealing the existence of weak
van der Waals interactions that further stabilize the assembly.
Fig. 7(a) shows a partial view of the X-ray of compound 2
(anions omitted) where an infinite 1D chain is represented. It is
formed by the infinite propagation of self-assembled dimers that
are stabilized by the formation of two symmetrically equivalent
OAH


O AEHBs [see blue dashed lines in Fig. 7(b)]. The interaction
energy of the self-assembled dimer is attractive, even though the
assembly is dicationic (DE3 = 5.9 kcal/mol). This clearly indicates
that the H-bonds are very strong since their stabilization energy is
able to compensate the electrostatic repulsion. This agrees with the
short H-bonding distance (1.76 Å). In the case where the counter
ions are included in the calculations [see Fig. 7(c)], the interaction
strengthens significantly (DE4 = 88.1 kcal/mol), thus highlighting
again the crucial role of the anion. A representation of the NCI plot
is shown in Fig. 7(d). Two dark blue isosurfaces between the H
atom of the coordinated water molecule and the O atom of the
acetate ligand can be observed, thus characterizing the strong H-
bonds. The NCI plot agrees well with the energetic and geometric
analysis and confirms the strong nature of the AEHBs in this partic-
ular assembly. In addition, two green isosurfaces characterize two
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
Fig. 7. (a) Partial view of the X-ray structure of compound 2. H-atoms and anion omitted for clarity; (b and c) theoretical models used to evaluate the AEHB interactions (blue
dashed lines). Distances in Å; (d) NCI plot of the fragment of the complex. The gradient cut-off is s = 0.35 au, and the color scale is 0.04 < q < 0.04 au. (Color online.)
additional and weaker H-bonds involving the other coordinated
water molecule that further stabilize the assembly.
3.6. Spectral studies
3.6.1. FT-IR spectroscopy
The FT-IR spectra of the prepared Ni(II) distorted octahedral
complexes are given in Fig. 8. The spectra of 1 and 2 are fully con-
sistent with their formulations. The IR spectra of the complexes
show peaks around 3146 cm1 for both complexes which are
assigned to m(NAH) absorptions coming from the monodentate
coordination mode of the Hdmpz ligands [58]. A strong and well-
Fig. 8. FT-IR spectra of 1 and 2.
121
defined band at 3278 cm1 for complex 1 and 3241 cm1 for com-
plex 2 was also observed, which corresponds to m(OAH) vibrations
and is generally associated with coordinated water molecules.
Weak absorptions observed at 2900–2770 cm1 can be attributed
to the m(CAH) vibration of the Hdmpz groups. The peaks at 1476,
1292 and 1146 cm1 in the complexes are attributable to pyrazole
ring stretching vibrations (CAN, NAN and C@N respectively) [59].
On the other hand, the peaks observed in the range 1020–1014 and
778–697 cm1 for the complexes can be attributed to in plane
deformation vibrations of the pyrazole ring [59]. Sharp peaks at
1580 cm1 for 1 and 1572 cm1 for 2 are attributed to in plane
stretching vibrations of the pyrazole ring that has been shifted to
lower frequencies on coordination of the Hdmpz ligands to the
metal centres [59(c)]. The asymmetric mas(COO) stretching for
the carboxyl vibrations of the acetato ligand appear at 1624 cm1
as weak shoulder for both the complexes, while the symmetric ms(-
COO) stretching appears at 1330 and 1338 cm1 for 1 and 2
respectively. The Dm values in the complexes are larger than
200 cm1, indicating monodentate coordination of the acetato
ligand [60]. Furthermore, the presence of the nitrate ion in com-
plex 1 was confirmed by a peak at 1385 cm1, attributed to the
asymmetric mas(NAO) stretching vibrations [61].
3.6.2. Electronic spectroscopy
The UV–Vis–NIR spectra of powdered samples obtained from
crystals of 1 and 2 are presented in Fig. 9. Complex 1 show three
ligand field bands at 1112, 654 and 390 nm, while these bands
for 2 are observed at 1068, 636 and 381 nm, respectively. These
are associated with the spin allowed transitions from the 3A2g
ground term to the three excited triplet terms, viz. 3T2g(F), 3T1g(F)
and 3T1g(P) [62]. The first spin-allowed transition, to the 3T2g(F)
122 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
Fig. 9. UV–Vis–NIR spectra of 1 and 2.
state, occurs at 1112 and 1068 nm for 1 and 2 respectively. The
electronic transition, 3A2g ? 3T1g(F) gives rise to the 654 nm
absorption for 1 and 636 nm for 2. It is observed that former
absorption band, corresponding to the 3A2g(F) ? 3T1g(F) transition,
shows a shoulder which may be a consequence of the transition
from the 3A2g(F) to 1Eg level, gaining intensity through a configura-
tion interaction with the 3T1g(F) level, although some investigators
prefer to interpret the doublet as arising from spin-orbit coupling
[63]. The peaks observed at 390 and 381 nm for 1 and 2 respec-
tively are due to the 3A2g ? 3T1g(P) transition. The UV band origi-
nating from the p ? p* transition of the Hdmpz ligand was found
at the expected position (285 nm) in both complexes [64].
The UV–Vis spectrum of 1 in water exhibits absorption bands at
231 and 269 nm, while for 2 a peak at 231 nm was observed. These
absorption peaks are assigned as the p–p* transition [64] of the
pyrazole group (Fig. 10). The absorption bands in the range 396–
400 nm for both complexes can be assigned as 3A2g(F) ? 3T2g(F)
transitions for octahedral Ni(II) ions and the bands at around
700 nm for 1 and 693 nm for 2 can be assigned to 3A2g ? 3T1g(P)
transitions.
3.7. Thermogravimetric analyses of the complexes
In order to examine the thermal stability of the two complexes,
TGA experiments were performed between 25 and 700 °C under an
Fig. 10. UV–Vis spectra of 1 and 2 in water (103 M).
Fig. 11. TGA curves of 1 and 2.
N2 atmosphere at a heating rate of 10 °C min1 (Fig. 11). The TG
analysis of complex 1 showed a weight loss in the temperature
range 70–138 °C corresponding to the release of two lattice water
molecules (observed weight loss 10.7%, calculated 11.2%) [65]. A
second weight loss in the temperature range 150–250 °C corre-
sponds to the loss of three coordinated water molecules, two
Hdmpz ligands [66] and CO2 from the acetate ligand [67] (observed
weight loss 65%, calculated 65.7%). A similar continuous weight
loss is also observed in the temperature range 80–400 °C for com-
plex 2. The loss of three coordinated water molecules takes place
between 75 and 125 °C. The experimental mass loss of 13.5% fits
well with the calculated mass loss of 12.9%. The remaining mass
undergoes decomposition in the temperature range 136–390 °C,
which corresponds to the loss of two Hdmpz ligands and a CO2
molecule from the acetate ligand (observed weight loss 55.2%, cal-
culated 56.1%) [68].
3.8. MTT based cytotoxicity and IC50 measurements
Transition metal complexes have been largely studied by
researchers for developing new chemotherapeutic agents because
of their multiple biological activities, such as antioxidant, antibac-
terial, antifungal and anticancer [69–72]. Fig. 12 shows the cell via-
bility results of both complexes; the IC50 values were calculated
from the percentage of cytotoxicity by dose–response curve fitting
Fig. 12. Cell viability results after compound 1, 2 and cisplatin (reference drug)
treatment for 24 h. A peripheral blood mononuclear cell (PBMC) was used as a
normal blood cell. Both compounds significantly decrease the cell viability in DL
cells as compared to the control group.
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126 123

Table 5 and are presented in Table 5. The analyses of cell viability results
IC50 values of cisplatin, compounds 1 and 2 on DL and PBMC cells. obtained for both compounds in the DL cell line showed a signifi-
Sl. No. Reference drug/Compounds IC50 (lM) cant concentration dependent decrease (P  0.05) in cell viability.
DL cells PBMC Interestingly, a negligible cytotoxic effect (10–15%) was observed
(Cancer cells) (Normal cells) against normal cells (PBMC) as compared to the cancer cell (DL) for
1 Cisplatin 0.45 06.31
both complexes. Pyrazole rings, which exhibited the highest ability
2 Compound 1 8.31 41.11 to form bifunctional adducts with DNA in vitro, may be a possible
3 Compound 2 5.22 43.21 reason for inducing cytotoxicity [73]. Furthermore, the DNA repair

Fig. 13. The upper panel shows the morphological features of apoptotic and viable cells with acridine orange and ethidium bromide (AO/EB) staining. Control DL cells showed
mostly viable cells, represented by green nuclei. Cisplatin treatment (24 h) showing apoptotic features with membrane damage and nuclear fragmentation. Treatment with
compounds 1 and 2 showing appearance of cells blebbing, chromatin condensation and fragmented nuclei (under 400) within the cytoplasm of the DL cells. The lower panel
presents the percentage of apoptotic cells after treatment with the reference drug (cisplatin), 1 and 2. Data are mean ± S.D., n = 3, ANOVA, P  0.05.

Fig. 14. Docking structure of compound 1 with EGFR kinase domain (a) PI3K- gamma receptors (b) B-RAF kinase (c) and CC chemokine receptor (d) hydrogen bonds between
the ligand and the receptors are shown in blue lines.
124 A. Gogoi et al. / Polyhedron 168 (2019) 113–126

mechanism is very poor in cancer cells [74] as compared to normal domain and PI3K- gamma receptors) that are involved in initiation,
cells, which may additionally contribute to compounds 1 and 2 progression and metastasis of several cancer types (melanoma, col-
mediating selective cytotoxicity in DL cells. Moreover, cancer cells orectal, thyroid, non-small cell lung cancer, ovarian cancer, pros-
have a higher oxidative status than normal cells and therefore suf- tate cancer, pancreatic cancer, large B cell lymphoma, brain,
fer more oxidative DNA damage [75]. gastric and glioblastoma) [81–84]. The docking scores of 1 and 2
with all the receptors under study showed comparable results with
3.9. Apoptosis study using fluorescence microscope their respective reference inhibitors (Figs. 14 and 15). Compound 1
interacts with B-RAF kinase, CC chemokine receptor, EGFR kinase
Treatment of DL cells with both complexes led to cell apoptosis domain and PI3K- gamma receptors by 4, 7, 6 and 2 hydrogen
bonds with various amino acid residues in the active site as, B-
as the mechanism of cell death, which was investigated morpho-
logically by the acridine orange/ethidium bromide dual staining RAF kinase: Phe595(1), Asp594(1), Lys483(2), CC chemokine:
Arg323(2), Asp327(1), Asp84(3), Glu322(1); EGFR kinase: Asn842
method (Fig. 13). Viable cells exhibited a uniform green fluores-
cence (acridine orange staining) whereas apoptotic cells show an (1), Lys745(1), Arg841(1), Asp855(3) and PI3K- gamma: Tyr867
(1), ASP964(1), whereas, compound 2 interacts with B-RAF kinase,
orange-red nuclear fluorescence (ethidium bromide staining) by
intercalation of ethidium bromide into damaged DNA in the apop- CC chemokine receptor, EGFR kinase domain and PI3K- gamma
totic cells. Cells treated with the compounds for 24 h demonstrated receptors by 6, 8, 5 and 4 hydrogen bonds with various amino acid
the morphological characteristics of apoptosis, such as cell bleb- residues, such as, B-RAF kinase: Asp594(1), Lys483(2), Phe595(1),
bing, irregular chromatin structure, followed by condensation
and the appearance of several apoptotic bodies near the cell mem-
brane. Moreover, results from several studies suggest that the
majority of metal-pyrazole complexes possess anticancer activities
due to formation of stable DNA adducts [76–78]. Pyrazoloacridine
was identified as a DNA topoisomerase inhibitor, induced apopto-
sis in myeloma and leukemia cells, and displayed pre-clinical activ-
ity in myeloma and leukemia cells [79]. We hypothesized that the
Ni(II) complexes of the present study may exert apoptosis in DL
cells through a similar pathway.

3.10. Molecular docking study

To gain more insight into the biological mode of action of 1 and

2, molecular docking studies were carried out with the common
isostructural cationic complex moiety of the compounds. Compu-
tational tools, such as molecular docking simulation and mod-
elling, have been widely used for drug development and the
discovery of multi-targeted inhibitors against many overexpressed
cancer target proteins [80]. The studies reveal that complexes 1
and 2 possess high binding affinities against most common cancer
target proteins (B-RAF kinase, CC chemokine receptor, EGFR kinase
Fig. 16. Docking scores of compounds 1 and 2 with B-RAF kinase, CC chemokine
receptor, EGFR kinase domain and PI3K- gamma receptors. The reference inhibitors
for B-RAF kinase, CC chemokine receptor, EGFR kinase domain and PI3K- gamma
receptors are Dabrafenib, vercirnon, quinazoline and AMG-511 respectively. As per
the MVD docking score algorithm, the lower the score, the better is the interaction.
Data are mean ± S.D., n = 3, ANOVA, P  0.05.

Fig. 15. Docking structure of compound 2 with EGFR kinase domain (a) PI3K- gamma receptors (b) B-RAF kinase (c) and CC chemokine receptor (d) hydrogen bonds between
the ligand and the receptors are shown in blue lines.
 A. Gogoi et al. / Polyhedron 168 (2019) 113–126 125

Table 6
Docking results of 1 and 2 with B-RAF kinase, CC chemokine receptor, EGFR kinase domain and PI3K- gamma receptors. Amino acids in bold show the common amino acids
involved in the molecular interactions between the reference inhibitors and the compounds under study; the number in brackets indicates the number of H-bonds.

Sl Nos. Receptors Reference ligands/Complexes No. of H-bond H-bond scores Interacting receptors amino acids in active site
1 B-RAF kinase Dabrafenib 4 2.55 Cys 532(2), Phe 595(1), Lys 483(1)
(4xv2) (Reference ligand)
Compound 1 4 2.51 Phe595(1), Asp594(1), Lys483(2)
Compound 2 6 2.72 Asp594(1), Lys483(2), Phe595(1), Asp594(2)
2 CC chemokine Vercirnon 6 1.91 Phe 324(1), Arg 323(1), Thr 81(1), Asp 84(1), Arg 78(1), Thr 81(1)
(5lwe) (Reference ligand)
Compound 1 7 1.99 Arg323(2), Asp327(1),
Asp84(3), Glu322(1)
Compound 2 8 2.91 Arg323(2), Arg78(1), Asp84(3), Asp327(1), Glu322(1)
3 PI3K- gamma AMG-511 5 2.50 Lys 833(1), Lys 802(1), Ala 805(1), Val 882(2)
(4flh) (Reference ligand)
Compound 1 2 1.81 Tyr867(1), ASP964(1)
Compound 2 4 2.41 ASP964(1), Lys833(2), Ser806(1)
4 EGFR kinase domain Quinazoline 3 2.50 Met 793(1), Thr 854(1), Asp 855(1)
(1xkk) (Reference ligand)
Compound 1 6 2.80 Asn842(1), Lys745(1), Arg841(1), Asp855(3)
Compound 2 5 2.73 Lys745(1), Asp855(3), Arg841(1)

The complexes were characterized by single crystal X-ray diffrac-

Fig. 17. SAR analysis of the isostructural cationic complex moiety of 1 and 2
involving key atoms during biological activities.
Asp594(2); CC chemokine: Arg323(2), Arg78(1), Asp84(3), Asp327
(1), Glu322(1); EGFR kinase: Lys745(1), Asp855(3), Arg841(1) and
PI3K- gamma: ASP964(1), Lys833(2), Ser806(1). The number in the
brackets indicates the number of H-bonds with the respective
amino acid (Fig. 16). The different interaction behaviors of 1 and
2 with B-RAF (Table 6) are due to differences in the structural dis-
tortion and orientation of the cationic moieties of the complexes
[85]. The SAR analysis (Fig. 17) for common structural parts of both
compounds enables understanding about the specific active atomic
sites in the molecular structures that result in the biological activ-
ities [86]. From the docking based SAR analyses of the isostructural
cationic units of 1 and 2, it has been observed that the oxygen and
nitrogen atoms with atom labels O1, O2, O3, O4, O5, N1, N2, N3 and
N4 take part in the interactions with B-RAF kinase, CC chemokine
receptor, EGFR kinase domain and PI3K- gamma receptors. These
results provide a specific molecular level understanding of the pos-
sible biological activities of the reported complexes.
4. Conclusion
Two new Ni(II) coordination complexes involving pyrazole and
acetato ligands with different counter anions have been reported.
tion, electronic, vibrational spectroscopy, PXRD and TGA. The acet-
ato ligands in the isostructural cationic moiety of both the
complexes are involved in strong anti-electrostatic hydrogen
bonding interactions that have been studied using DFT calculations
and NCI plot index analysis. The interaction energy of the cationic
moieties, extracted from the infinite 1D chain of 1, is positive and,
interestingly, the interaction becomes favorable in the presence of
the nitrate ion, thus highlighting the crucial role of the anion.
Remarkably, in the case of compound 2, these AEHBs are able to
compensate the electrostatic repulsion between the cationic units.
The anticancer activity of both complexes against DL cells showed
significant cytotoxicity, mostly contributed by apoptotic cell death.
Analyses of cell viability results for the DL cell line show a signifi-
cant concentration dependent decrease by the compounds with a
negligible cytotoxic effect against normal cells (PBMC) in compar-
ison to the cancer cells (DL). Docking based SAR analysis reveals
that the oxygen and nitrogen atoms in the isostructural cationic
complex unit of both complexes are involved in the interactions
with the cancer target proteins. Cytotoxic and apoptotic effects of
these compounds in DL malignant cancer cells indicated that both
compounds could be good candidates for further pharmacological
studies to develop effective anticancer agents in the future.
Acknowledgements
The authors acknowledge the financial support from University
Grants Commission (UGC), New Delhi [Grant number: F. No. 42-
377/2013]. Financial support from the MINECO of Spain (project
CTQ2017-85821-R FEDER funds) is gratefully acknowledged. The
authors thank the Department of Chemistry, IIT, Guwahati for pro-
viding the single crystal X-ray diffraction data. The authors are also
thankful to the CSIR-NEIST, Jorhat for providing the PXRD data and
the Department of Chemistry, Gauhati University for TGA data.
Appendix A. Supplementary data
CCDC 1838104 and 1868598 contains the supplementary crys-
tallographic data for 1 and 2 respectively. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/re-
trieving.html, or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033;
or e-mail: deposit@ccdc.cam.ac.uk.
126 A. Gogoi et al. / Polyhedron 168 (2019) 113–126
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.poly.2019.04.043.
References
[1] G.R. Desiraju, Nature 412 (2001) 397.
[2] C.B. Aakeroy, N.R. Champness, C. Janiak, CrystEngComm. 12 (2010) 22.
[3] H.J. Schneider, Angew. Chem. Int. Ed. 48 (2009) 3924.
[4] H. Eshtiagh-Hosseini, M. Mirzaei, M. Biabani, V. Lippolis, M. Chahkandi, C.
Bazzicalupi, CrystEngComm. 15 (2013) 6752.
[5] J.F. Ma, J.F. Liu, X. Yan, H.Q. Jia, Y.H. Lin, J. Chem. Soc., Dalton Trans. (2000)
2403.
[6] C.B. Aakeröy, N.R. Champness, C. Janiak, CrystEngComm. 12 (2010) 22.
[7] M. Mirzaei, H. Eshtiagh-Hosseini, Z. Bolouri, Z. Rahmati, A. Esmaeilzadeh, A.
Hassanpoor, A. Bauza, P. Ballester, M. Barceló-Oliver, J.T. Mague, B. Notash, A.
Frontera, Cryst. Growth Des. 15 (2015) 1351.
[8] L. Carlucci, G. Ciani, D.M. Proserpio, S. Rizzato, Chem. Eur. J. 5 (1999) 237.
[9] H.R. Khavasi, B.M.M. Sadegh, Inorg. Chem. 49 (2010) 5356.
[10] O.S. Jung, S.H. Park, K.M. Kim, H.G. Jang, Inorg. Chem. 37 (1998) 5781.
[11] P. Ovejero, M.J. Mayoral, M. Cano, J.A. Campo, J.V. Heras, E. Pinilla, M.R. Torres,
J. Organomet. Chem. 692 (2007) 4093.
[12] (a) B.H. Ye, M.L. Tong, X.M. Chen, Coord. Chem. Rev. 249 (2005) 545;
(b) D. Dutta, H. Nath, A. Frontera, M.K. Bhattacharyya, Inorg. Chim. Acta 487
(2019) 354.
[13] M.V. Lunagariya, K.P. Thakor, R.R. Varma, B.N. Waghela, C. Pathak, M.N. Patel,
MedChemComm 9 (2018) 282.
[14] K. Karrouchi, E.B. Yousfi, N.K. Sebbar, Y. Ramli, J. Taoufik, Y. Ouzidan, M. Ansar,
Y.N. Mabkhot, H.A. Ghabbour, S. Radi, Int. J. Mol. Sci. 18 (2017) 2215.
[15] J.R. Eedijk, Heterocyclic nitrogen-donor ligands, Pergamon, Oxford, 1987, p. 73.
[16] S. Abdolmaleki, M. Ghadermazi, A. Fattahi, S. Shokraii, M. Alimoradi, B.
Shahbazi, A.R.J. Azar, J. Coord. Chem. 70 (2017) 1406.
[17] D. Ajo, A. Bencini, F. Mani, Inorg. Chem. 27 (1988) 2437.
[18] T. Harit, F. Malek, B. El Bali, A. Khan, K. Dalvandi, B.P. Marasini, S. Noreen, R.
Malik, S. Khan, M.I. Choudhary, Med. Chem. Res. 21 (2012) 2772.
[19] A. Chauhan, P.K. Sharma, N. Kaushik, Int. J. Chem. Technol. Res. 3 (2011) 11.
[20] H. Yu, W. Zhang, Q. Yu, F.P. Huang, H.D. Bian, H. Liang, Molecules 22 (2017)
1772.
[21] P. Kumar, B. Narasimhan, K. Ramasamy, V. Mani, R.K. Mishra, A.B.A. Majeed,
Curr. Top. Med. Chem. 15 (2015) 1050.
[22] H. Bahron, S.S. Khaidir, A.M. Tajuddin, K. Ramasamy, B.M. Yamin, Polyhedron
161 (2019) 84.
[23] S.A. Cook, A.S. Borovik, Acc. Chem. Res. 48 (2015) 2407.
[24] H.W. Roesky, M. Andruh, Coord. Chem. Rev. 236 (2003) 91.
[25] J. Reedijk, Chem. Soc. Rev. 42 (2013) 1776.
[26] F. Weinhold, R.A. Klein, Angew. Chem. Int. Ed. 53 (2014) 1.
[27] F. Weinhold, R.A. Klein, Angew. Chem. 126 (2014) 11396.
[28] (a) E.M. Fatila, E.B. Twum, A. Sengupta, M. Pink, J.A. Karty, K. Raghavachari, A.
H. Flood, Angew. Chem., Int. Ed. 55 (2016) 14057;
(b) W. Zhao, B. Qiao, C.H. Chen, A.H. Flood, Angew. Chem., Int. Ed. 56 (2017)
13083;
(c) E.M. Fatila, E.B. Twum, J.A. Karty, A.H. Flood, Chem. Eur. J. 23 (2017) 10652.
[29] D. Mungalpara, A. Valkonen, K. Rissanen, S. Kubik, Chem. Sci. 8 (2017) 6005.
[30] (a) I. Mata, I. Alkorta, E. Molins, E. Espinosa, Chem. Phys. Lett. 555 (2013) 106;
(b) I. Mata, E. Molins, I. Alkorta, E. Espinosa, J. Phys. Chem. A 119 (2015) 183.
[31] A. Shokri, M. Ramezani, A. Fattahi, S.R. Kass, J. Phys. Chem. A 117 (2013) 9252.
[32] M. Munakata, M. Wen, Y. Suenaga, T. Kuroda-Sowa, M. Maekawa, M. Anahata,
Polyhedron 20 (2001) 2037.
[33] M. El-Massaoudi, S. Radi, Y.N. Mabkhot, S.S. Al-Showiman, H.A. Ghabbour, M.
Ferbinteanu, N.N. Adarsh, Y. Garcia, Inorg. Chim. Acta 482 (2018) 411.
[34] S. Bhattacharya, A. Goswami, B. Gole, S. Ganguly, S. Bala, S. Sengupta, S. Khanra,
R. Mondal, Cryst. Growth Des. 14 (2014) 2853.
[35] S.W. Jin, X.H. Ye, L. Jin, L. Zheng, J.W. Li, B.P. Jin, D.Q. Wang, Polyhedron 81
(2014) 382.
[36] (a) M. Guerrero, J. Pons, M. Font-Bardia, T. Calvet, J. Ros, Polyhedron 29 (2010)
1083;
(b) R. Mondal, T. Basu, D. Sadhukhan, T. Chattopadhyay, M.K. Bhunia, Cryst.
Growth Des. 9 (2009) 1095.
[37] G.M. Sheldrick, Acta Crystallogr., Sect: A 64 (2008) 11.
[38] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837.
[39] K. Brandenburg, Diamond 3.1f, Crystal Impact GbR, Bonn, Germany, 2008.
[40] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
G. Scalmani, V. Barone, G.A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A.
Marenich, J. Bloino, B.G. Janesko, R. Gomperts, B. Mennucci, H.P. Hratchian, J.V.
Ortiz, A.F. Izmaylov, J.L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F.
Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V.G.
Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, K. Throssell, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M.
Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith, R.
Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J.
Tomasi, M. Cossi, J.M. Millam, M. Klene, C. Adamo, R. Cammi, J.W. Ochterski, R.
L. Martin, K. Morokuma, O. Farkas, J.B. Foresman, D.J. Fox, Gaussian 09,
Revision C.02, Gaussian, Inc., Wallingford CT, 2016.
[41] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 132 (2010) 154104.
[42] I. Alkorta, I. Mata, E. Molins, E. Espinosa, Chem. Eur. J. 22 (2016) 9226.
[43] J. Contreras-García, E.R. Johnson, S. Keinan, R. Chaudret, J.P. Piquemal, D.N.
Beratan, W. Yang, J. Chem. Theory Comput. 7 (2011) 625.
[44] E.R. Johnson, S. Keinan, P. Mori-Sanchez, J. Contreras-Garcia, A.J. Cohen, W.
Yang, J. Am. Chem. Soc. 132 (2010) 6498.
[45] T. Mosmann, J. Immunol. Methods 65 (1983) 55.
[46] (a) A.K. Verma, S.B. Prasad, J. Ethnopharmacol. 148 (2013) 869;
(b) T. Mosmann, Immunol. Methods 65 (1983) 55.
[47] M.K. Squier, J.J. Cohen, Mol. Biotechnol. 19 (2001) 305.
[48] A.K. Verma, S.B. Prasad, Anti-Cancer Agents Med. Chem. 13 (2013) 1096.
[49] A. Swargiary, A.K. Verma, K. Sarma, Med. Chem. Res. 22 (2013) 2870.
[50] R. Thomsen, M.H. Christensen, J. Med. Chem. 49 (2006) 3315.
[51] M. Cano, J.V. Herasa, M. Luz Gallego, J. Perles, C. Ruiz-Valero, E. Pinillaa, M.
Rosario Torres, Helv. Chim. Acta 86 (2003) 3194.
[52] (a) S. Chakravorty, J.A. Platts, B.K. Das, Dalton Trans. 40 (2011) 11605;
(b) S.M.N. Islam, D. Dutta, A.K. Guha, M.K. Bhattacharyya, J. Mol. Struct. 1175
(2019) 130.
[53] P. Ghosh, A. Roychowdhury, M. Corbella, A. Bhaumik, P. Mitra, S.M. Mobin, A.
Mukherjee, S. Basu, P. Banerjee, Dalton Trans. 43 (2014) 13500.
[54] (a) L. Croitor, D. Chisca, E.B. Coropceanu, G.F. Volodina, O. Petuhov, M.S. Fonari,
J. Mol. Struct. 1137 (2017) 136;
(b) D. Dutta, S.M.N. Islam, U. Saha, S. Chetry, A.K. Guha, M.K. Bhattacharyy, J.
Chem. Crystallogr. 48 (2019) 156.
[55] (a) D. Dutta, S. Chetry, A. Gogoi, B. Choudhury, A.K. Guha, M.K. Bhattacharyya,
Polyhedron 151 (2018) 381;
(b) R. Bala, A. Kaur, M. Kashyap, D. Janzen, J. Mol. Struct. 1063 (2014) 203.
[56] F. Weinhold, Angew. Chem. Int. Ed. 56 (2017) 14577.
[57] G. Frenking, G.F. Caramori, Angew. Chem. Int. Ed. 54 (2015) 2596.
[58] J. Li, Y.H. Xing, H.Y. Zhao, Z.P. Li, C.G. Wang, X.Q. Zeng, M.F. Ge, S.Y. Niu, Inorg.
Chim. Acta 362 (2009) 2788.
[59] (a) A. Direm, M. Tursun, C. Parlak, N. Benali-Cherif, J. Mol. Struct. 1093 (2015)
208;
(b) N. Sundaraganesan, E. Kavitha, S. Sebastian, J.P. Cornard, M. Martel,
Spectrochim. Acta, Part A: Mol. Biomol. Spectrosc. 74 (2009) 788;
(c) M.K. Ehlert, S.J. Rettig, A. Storr, R.C. Thompson, J. Trotter, Can. J. Chem. 68
(1990) 1494.
[60] G.B. Deacon, R.J. Phillips, Coord. Chem. Rev. 33 (1980) 227.
[61] P.F. Barron, J.C. Dyason, P.C. Healy, J. Chem. Soc., Dalton Trans. (1986) 1965.
[62] A.B.P. Lever, Inorganic Electronic Spectroscopy, 557, Elsevier, New York, 1984.
[63] B.N. Figgis, M.A. Hitchman, Ligand Field Theory and Its Applications, 209,
Wiley-VCH, New York, 2000.
[64] P. Ovejero, M.J. Mayoral, M. Cano, M.C. Lagunas, J. Organomet. Chem. 692
(2007) 1690.
[65] Y. Ma, B. Mu, R.D. Huang, Transit. Met. Chem. 43 (2018) 103.
[66] A. Gogoi, S.M.N. Islam, A. Frontera, M.K. Bhattacharyya, Inorg. Chim. Acta 484
(2019) 133.
[67] S.J. Bora, B.K. Das, J. Solid State Chem. 192 (2012) 93.
[68] S. Demir, G.K. Kantar, Y. Topcu, Q. Li, Transit. Met. Chem. 37 (2012) 257.
[69] A.K. Yudin, Chem. Sci. 6 (2015) 30.
[70] P. Rathi, D.P. Singh, Spectrochim. Acta, Part A: Mol. Biomol. Spectrosc. 136
(2015) 381.
[71] R.A. Shiekh, I.A. Rahman, M.A. Malik, N. Luddin, S.A.M. Masudi, S.A. Al-Thabaiti,
Int. J. Electrochem. Sci. 8 (2013) 6972.
[72] P. Arthi, A. Haleel, P. Srinivasan, D. Prabhu, C. Arulvasu, A.K. Rahiman,
Spectrochim. Acta, Part A: Mol. Biomol. Spectrosc. 129 (2014) 400.
[73] E. Ciesielska, A. Szulawska, K. Studzian, J. Ochocki, K. Malinowska, K. Kik, L.
Szmigiero, J. Inorg. Biochem. 100 (2006) 1579.
[74] R.S. Day, C.H. Ziolkowski, D.A. Scudiero, S.A. Meyer, A.S. Lubiniecki, A.J. Girardi,
S.M. Galloway, G.D. Bynum, Nature 288 (1980) 724.
[75] T. Helleday, N. Engl, J. Med. 373 (2015) 1570.
[76] N. Ribeiro, S. Roy, N. Butenko, I. Cavaco, T. Pinheiro, I. Alho, F. Marques, F.
Avecilla, J.C. Pessoa, I. Correia, J. Inorg. Biochem. 174 (2017) 63.
[77] S. Thota, S. Vallala, R. Yerra, D.A. Rodrigues, N.M. Raghavendra, E.J. Barreiro, Int.
J. Biol. Macromol. 82 (2016) 663.
[78] J. Quirante, D. Ruiz, A. Gonzalez, C. López, M. Cascante, R. Cortés, R. Messeguer,
C. Calvis, L. Baldomà, A. Pascual, J. Inorg. Biochem. 105 (2011) 1720.
[79] D. Atamanyuk, B. Zimenkovsky, R. Lesyk, J. Sulfur Chem. 29 (2008) 151.
[80] H. El Hamdani, M. Amane, B.B. Mohammed, K. Yamni, J. Mol. Struct. 1181
(2019) 627.
[81] N. Li, D. Batt, M. Warmuth, Curr. Opin. Invest. Drugs (London, England) 8
(2007) (2000) 452.
[82] Z. Tu, R. Xiao, J. Xiong, K.M. Tembo, X. Deng, M. Xiong, P. Liu, M. Wang, Q.
Zhang, J. Hematol. Oncol. 9 (2016) 10.
[83] J.N. Gallant, J.H. Sheehan, T.M. Shaver, M. Bailey, D. Lipson, R. Chandramohan,
M.R. Brewer, S.J. York, M.G. Kris, J.A. Pietenpol, M. Ladanyi, V.A. Miller, S.M. Ali,
J. Meiler, C.M. Lovly, Cancer Discov. (2015) CD-15-0654.
[84] J.V. Fresno, E. Casado, P. Cejas, C. Belda-Iniesta, M. González-Barón, Cancer
Treat. Rev. 30 (2004) 193.
[85] P. Krishnamoorthy, P. Sathyadevi, R.R. Butorac, A.H. Cowley, N.S.P. Bhuvanesh,
N. Dharmaraj, Dalton Trans. 41 (2012) 4423.
[86] M.A. Peterson, M. Oliveira, M.A. Christiansen, C.E. Cutler, Bioorg. Med. Chem.
Lett. 19 (2009) 6775.