Studies on nucleic acid/protein interaction, molecular docking and antimicrobial properties of mononuclear nickel(II) complexes of piperazine based Schiff base

Article abstract of DOI:10.1016/j.inoche.2014.08.029

The mononuclear nickel(II) complexes (1-3) of ligands bappz [1,4-bis(3-aminomethyl)piperazine] and its Schiff bases L¹ with 5-methyl salicylaldehyde; and L² with 5-bromosalicylaldehyde have been synthesized and characterized. The sin

Full text of DOI:10.1016/j.inoche.2014.08.029

Studies on nucleic acid/protein interaction, molecular docking and antimi-
crobial properties of mononuclear nickel(II) complexes of piperazine based
Schiff base
Arumugam Jayamani, Nallathambi Sengottuvelan, Sung Kwon Kang,
Young-Inn Kim
PII:
DOI:
Reference:
S1387-7003(14)00376-1
doi: 10.1016/j.inoche.2014.08.029
INOCHE 5716
To appear in:
Inorganic Chemistry Communications
Received date:
Accepted date:
5 August 2014
28 August 2014
Please cite this article as: Arumugam Jayamani, Nallathambi Sengottuvelan, Sung
Kwon Kang, Young-Inn Kim, Studies on nucleic acid/protein interaction, molec-
ular docking and antimicrobial properties of mononuclear nickel(II) complexes of
piperazine based Schiff base, Inorganic Chemistry Communications (2014),
0.1016/j.inoche.2014.08.029
doi:
1
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1
Studies on nucleic acid/protein interaction, molecular docking and
antimicrobial properties of mononuclear nickel(II) complexes of piperazine
based Schiff base
a
b
c
Arumugam Jayamani , Nallathambi Sengottuvelan *, Sung Kwon Kang ,
d
Young-Inn Kim
a
b
Department of Industrial Chemistry, DDE, Alagappa University, Karaikudi -3
c
Department of Chemistry, Chungnam National University, Daejeon 305-764, Korea
d
Department of Chemistry Education and Interdisciplinary Program of Advanced
Information and Display Materials, Pusan National University, Pusan 609-735, Korea
*
Corresponding author. Tel. /fax: +91 9488260744.
E-mail address: nsvelan1975@yahoo.com (N. SENGOTTUVELAN).
Abstract
The mononuclear nickel(II) complexes (1–3) of ligands bappz [1,4-bis(3-
1
2
aminomethyl)piperazine] and its Schiff bases L with 5-methyl salicylaldehyde; and L with
-bromosalicylaldehyde have been synthesized and characterized. The single crystal X-ray
5
study showed that the complex 1 crystallized in the orthorhombic Pbca space group with
distorted square planar geometry. The ligands and their nickel(II) complexes presented good
binding propensity to bovine serum albumin protein (BSA). The strong binding interaction of
the prepared complexes with calf thymus DNA (CT-DNA) was confirmed by absorption,
fluorescence, circular dichroism spectral analysis and molecular docking studies in the order
as follows: 3 > 2 > 1. The Schiff bases and their Ni(II) complexes were also screened for
antimicrobial activity. All the complexes exhibited higher antimicrobial activity than free
ligands.

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2
Keywords: Schiff base ligands; Antimicrobial activity; Nickel(II) complexes; DNA binding
studies; Electrochemical studies.
Continued interest on the development of DNA binding agents has been driven by the
goals for obtaining novel antitumor drugs, DNA sequencing agents and DNA conformation
probes [1]. The interaction of drugs and their compounds with blood plasma proteins
especially with serum albumin has involved in the transport of metal ions and metal
complexes of drugs through the blood stream, is of increasing interest. Nickel is an important
transition metal and its coordination compounds display interesting binding properties with
proteins and nucleic acids [2]. The N- and O- containing ligands and their nickel(II)
complexes have become important due to their wide biological activity anti-HIV activities
etc. Bappz ligand molecule provides two pendant aminopropyl arms and two tertiary amines
incorporated in the six-membered piperazine ring, which induces some sort of strain
especially in the middle chelate ring when the two N-donor atoms of piperazine bind with
2
+
Ni ion [3]. Schiff bases derived from the salicyaldehyde and its derivatives are well known
as polydentate ligands, coordinating in deprotonated or neutral forms. Schiff base complexes
possess suitable biometric properties that can mimic the active sites and hence they have
wide applications in as illness treatment, biochemical reactions and also as biological
regulators [4].
Recently our research group reported that the mononuclear copper(II) complexes
1
using Schiff base ligands L [N, Nʹ-bis(2-hydroxy-5-methylbenzyl)-1,4-bis(3-iminopropyl)
2
piperazine] and L [N, Nʹ-bis(2-hydroxy-5-bromobenzyl)-1,4-bis(3-iminopropyl)piperazine]
have molecular motion between N and N O compartments on varying pH and have good
4
2
2
DNA interaction properties [5]. In order to study the change in molecular motion and DNA
binding properties due to nickel(II) atoms, in this paper we have reported the synthesis
1
(
Scheme 1) of mononuclear nickel(II) complexes ([Ni(bappz)](ClO ) [6], [NiL ](ClO ) [7]
4
2
4 2

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3
2
1
2
and [NiL ](ClO ) [8]) of ligands bappz, Schiff bases L and L (Scheme 1), respectively
4
2
were synthesized and characterized by elemental analysis, IR, UV-visible, ESI-Mass
spectroscopy. The preparation of ligands and their crystal structure were reported in our
previous work [5].
The X ray crystallographic analysis [9] of complex 1 (ORTEP diagram with 30%
thermal probability ellipsoids shown in Figure 1, crystallographic data are listed in Table 1
and selected bond angle and bond distances are given in Table S1) shows that, the structure
II
2+
of the complex [Ni(bappz)](ClO ) (1) consists of monomeric isolated [Ni (bappz)] cations
4
2
and two perchlorate counter anions in which one of the carbon atoms (C13) is disordered
over two positions with an occupancy ratio of 0.62 (2) : 0.38 (2). The sum of the different
angles around the Ni atoms is 359.98° indicating slightly distorted square-planar geometry
around the metal atom. The distortion may conveniently be measured by the trans angles that
are ideally 180° for a square-planar complex and 109.5° in a tetrahedral complex. The
II
average N–M–N angles for the present Ni (173.9°) complex are larger than those for already
II
the reported Cu (165.6°) complex with the same ligand [10]. The Ni–N(2) and Ni–N(15)
distances (average 1.913 Å) are shorter than the Ni–N(6) and Ni–N(9) distances (average
1
.930 Å) are mainly due to the different states of hybridization of nitrogen atom and/or the
ring strain [11] due to boat conformation of inner piperazine unit. The non-coordinating
perchlorate anions have a distorted tetrahedral structure, as indicated from their bond angles.
In cif check report, the low ratio (43%) of the Ratio of Observed to Unique Reflections might
be from the poor crystallinity of the complex.
The intermolecular Ni∙∙∙Ni separation is 7.547 (2) Å, a value which does not permit
any kind of bridging between the nickel atoms. Figure S1 shows the packing of the molecule
in a lattice, which is stabilized by the H-bonding interactions between the oxygen of the
anion with the piperazine ring hydrogen. The intramolecular hydrogen bonds are also

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4
observed between the amino groups and nearer perchlorate O atoms (2.267 Å), which help in
stabilizing the crystal structure.
The FT-IR spectrum of nickel(II) complexes (2 and 3) showed the broad peak at
-1
3
423–3450 cm is assigned to the phenolic ν(OH) group [12]. The ligands and complexes
-1
showed a sharp band in the region of 1620–1650 cm due to the presence of ν(C=N) [13].
The effective Schiff base condensation was confirmed by the disappearance of the ν(C=O)
-1
-1
peak at 1680 cm . All nickel(II) complexes showed a strong band around 1000–1100 cm
-
1
and a sharp band in the region around 625 cm is due to the antisymmetric stretch and
antisymmetric bend of the perchlorate ions respectively [14].
The absorption spectral data for Schiff base ligands and their complexes in DMF
*
solution shows the peaks in the UV region of 270 nm to 278 nm are obtained due to π → π
transition of coordinated ligands, broad and slightly intense bands between 384 and 396 nm
due to ligand–metal charge transfer associated with the nitrogen and oxygen donors [15]. The
visible spectra display the absorption bands below 670 nm assigned to the spin allowed d-d
8
transitions, which have a low-spin d nickel(II) ion in a square-planar environment [16].
Electron spray ionization (ESI) mass data of complex 2 (Figure S2) shows the
1
+
molecular ion peak at m/z 694.2 (5), which is assignable to [NiL +2ClO ] and the loss of
4
perchlorate ions as perchloric acid forms a base peak at m/z 493.3(100) due to the formation
1
+
of [NiL ] . In addition, few other intense peaks are obtained for 2 at m/z 375.3, 318.3 and
47.3. The ESI mass spectral data of the Schiff base nickel(II) complexes are in good
2
agreement with the proposed structure of mononuclear nickel(II) complexes.
The solution of 0.05 M mononuclear nickel(II) complexes (2 and 3) in sodium
perchlorate were acidified to pH 2 and titrated against standard NaOH solution. Titration with
base induces colour change of the solution from brown to green and also result in the
considerable change in absorption spectrum, as shown in Figure 2. In complex 2, the strong

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5
-1
-1
band at 337 nm (ε ꞊ 2836 M cm ) decreases, while a new band develops at 389 nm (ε ꞊
-
1
-1
4
2
047 M cm , limit value at pH 12). In the case of complex 3, the strong band at 338 nm (ε ꞊
-
1
-1
-1
-1
567 M cm ) decreases, while a new band develops at 390 nm (ε ꞊ 3489 M cm , limit
value at pH 12). The increase in absorbance (inset of Figure 3a and 3b) in d-d band and blue
shift of absorption band upon changing the pH (acidic to basic) of the mononuclear nickel(II)
complexes indicate that the colour and spectral changes are associated to the deprotonation
process and thus the molecular motion i.e. the change of the position of nickel atom from N4
compartment to N O compartment is achieved by varying the pH of the complex solution
2
2
[
5].
The electrochemical behaviour of the nickel(II) complexes have been studied using
-1
cyclic voltammetry in the potential range from ˗1.80 V to +1.80 V in DMF containing 10 M
-1
tetra(n-butyl)ammonium perchlorate (with scan rate 50 mV s ). The complex exhibits redox
wave on both the positive and the negative potential sides, corresponding to one electron
oxidation and reduction, respectively (Figure S3). The cyclic voltammograms of complexes
(1–3) show an irreversible reduction wave in negative potentials at -1.33V for 1, -1.30V for
2
, and -1.17V for 3 correspond to Ni(II)—Ni(I) reduction. The corresponding reversible
oxidation potential for Ni(II)—Ni(III) at 1.24V is observed for 1 and irreversible oxidation
potential for Ni(II)—Ni(III) at 1.19V for 2 and 0.98V for 3. The reduction and oxidation
2
1
potential for nickel complexes of L is observed at lower potential than L complex due to the
electron-withdrawing [17] substituent (Br) at the para position of the phenoxide oxygen in the
phenyl ring of complex 3 [18].
Addition of ligands or its nickel(II) complexes 1–3 (dissolved in DMF) to BSA results
in fluorescence quenching (up to 15% of the initial fluorescence intensity of BSA for bappz,
1
2
5
7% for L , 64% for L , 18% for 1, 68% for 2, 69% for 3) (Figure 3), due to the possible

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changes in secondary structure of BSA indicating the binding of the compounds to BSA [19].
According to Stern-Volmer quenching equation [20]:
I /I = 1+k  [Q] = 1 + K [Q]
0
q 0
SV
K = k 
SV
q 0
The calculated values of K and k for the interaction of the compounds with the BSA are
sv
q
given in Table 2 and indicate a good BSA binding propensity of the compounds with bappz
and its Schiff base complexes, out of which the complex 3 exhibiting the highest BSA
quenching ability. Using the Scatchard equation [21]:
(
I/I )/[Q] = nK- K(I/I )
0
0
2
It is obvious (Table 2) that the coordination of L to Ni(II) results in an increased K value for
BSA with complex 4 exhibiting the highest K value among the other complexes. The n
values of ligands and complexes vary with slight increase or decrease when coordinated to
Ni(II) in complexes 1–3 (Table 2) depending upon the availability of binding sites per
albumin.
Absorption titration experiments were performed with fixed concentrations of the
nickel(II) complexes (40 μM) while gradually increasing the concentration of DNA (0–10
o
mM) at 25 C. On addition of increasing amounts of DNA to the complexes 1–3, peak at 260
nm gradually increased with the hyperchromicity 60% for 1, hyperchromicity of 40% for 2
and hypochromicity of 36% for 3 suggesting the strong interaction between complex and
DNA. The isobestic point near 250 nm also proved the formation of the new complex
between DNA and complex. The spectrophotometric titration of the complex 3 is shown in
Figure 4 and other complexes are displayed in Figure S4. To compare quantitatively the
binding strength of all the nickel(II) complexes, the intrinsic binding constants K of all the
b
complexes with CT-DNA are determined according to the following equation [22]:
[
DNA]/(ε – ε ) = [DNA]/(ε – ε ) + 1/K (ε – ε )
a f b f b b f

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The K values obtained from the absorption spectral technique for the complexes 1–3
b
5
5
5
-1
were calculated as 1.63 (2) × 10 , 3.46 (2) × 10 and 6.44 (2) × 10 M respectively, which is
relevant to that of other typical groove binders and intercalators. The binding constants of the
1
nickel(II) complexes of bappz and L are relatively lower than that of the nickel(II) complex
2
2
of L , which may be due to the presence of electron-withdrawing group (Br) in L [23].
The emission spectrum of EB bound to DNA in the absence and presence of complex
3
is shown in Figure 5 and other complexes are displayed in Figure S5. The intensity of the
emission band at 596 nm of the DNA–EB system decreased (up to 90.12% of the initial EB–
DNA fluorescence intensity for 1, up to 93.48% for 2, up to 89.05% for 3) upon addition of
each complex 1–3 at diverse r values (Figure 5a) showing that each Ni(II) complex competes
with EB to bind with DNA. The KSV values of complexes (1–3) are calculated as 3.8 (3) ×
5
-1
5
-1
5
-1
1
0 M , 5.5 (2) × 10 M and 6.72 (3) × 10 M respectively and vary in the order: 3 > 2 > 1.
2
The KSV values illustrate that, the intercalary ability of Ni(II) complex of L ligand has a
1
better effect than L complex. As the quenching of fluorescence is too low the apparent DNA
binding constant (K ) of the nickel(II) complexes 1–3 cannot be determined. The presence
app
of 5-methyl (or bromo) salicylaldehyde groups and also the hydrophobic property of the rigid
ligand facilitate the DNA binding [24].
The conformational changes in the UV region of CT-DNA induced by the complexes
(1–3) were monitored by CD spectroscopy in buffer at room temperature, which show a
distinct change in the spectral band corresponding to the B-DNA conformation (Figure 6).
The nickel(II) complexes 1 and 2 exhibit groove binding interaction with large increase in
intensity of the DNA helicity, in its positive as well as negative band with a higher red-shift.
In complex 3 the ellipticity of the long wavelength positive band decreased in ellipticity of
the interaction progressed with a slight red shift in the wavelength maximum and moderate
changes also observed in the negative CD band at 245 nm indicates that intercalative

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interaction involved in binding process. The binding between nickel(II) complexes and CT-
DNA is due to the aromatic structure of ligands that provides planarity to the molecule.
Moreover, in terms of DNA interaction, it has been found that the complex 3 was more
effective when compared to other complexes because of higher K and K values and circular
b
sv
dichroism spectra.
The inhibition efficiencies of ligands and their nickel(II) complexes were tested
against four pathogenic bacteria species (Staphylococcus aureus, Bacillus subtilis,
Escherichia coli and Pseudomonas aeruginosa)) and two fungal species (Aspergillus niger
and Candida albicans) by Agar disc diffusion method. The solvent DMSO used as control
did not show any zone of inhibition [5]. The experimental result shown in Table S2 indicates
that all the complexes are having higher inhibition efficiency than the free ligands, which can
be explained on the basis of chelate formation [25]. Minimum inhibitory concentrations
(MICs) method (Table 3) was also used to determine the antibacterial activity of the
synthesized complexes. Ni(II) complex (MIC = 3.25-17.50 µg/mL) has a greater effect than
the effect of ligand against bacteria. Also, Ni(II) complex has been found to have high
antifungal activity towards A. niger (MIC = 8.25-11.5 µg/mL) and C. albicans (MIC = 7.50-
1
7
1.25 µg/mL) fungi as compared to ligands. The lowest MIC values 3.25 µg/mL and
.50 µg/mL observed for compound 3, with the bacteria S. aureus and fungus C. Albicans,
respectively being the most sensitive microorganism.
The minimum energy docked pose [26] of nickel(II) complex 1–3 (Figure S6)
revealed that the complexes snugly fitted into the curve contour of the targeted DNA in the
minor groove and is situated within G-C (~13.2Ǻ) region, and slightly bends the DNA in
such a way that a part of the planar aromatic Schiff base makes favourable stacking
interactions between DNA base pairs and lead to van der Waals interaction and hydrophobic
contacts with DNA functional groups that define the groove [27]. The resulting relative

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1
2
binding energy of docked ligands L , L , metal complexes 1–3 with DNA were found to be
˗310.67, ˗316.77, ˗247.24, ˗298.03, and ˗342.71, respectively, which is also in accordance
with our hypothesis that complex 3 is prominent DNA binder than that of other complexes.
1
The mononuclear nickel(II) complexes with bappz and its Schiff base ligands (L and
2
L ) were synthesized and characterised. The single crystal X-ray study confirms the structure
1
2
of ligands L , L and complex 1. The spectral and structural data give evidences for the
proposed coordination behaviour and geometries of the synthesized nickel(II) complexes.
The electrochemical study reveals that one quasi-reversible redox wave. The nickel ion in the
mononuclear complexes has been translocated between two non-equivalent coordinating
compartments of a ditopic ligand by varying the pH of the complex solution. All the
nickel(II) complexes (1–3) show good binding affinity to BSA protein and DNA giving
relatively high binding constants in the order 3 > 2 > 1. The computer-aided molecular
docking studies validate the interaction in the minor groove of DNA helix. All the nickel(II)
complexes showed good antimicrobial activity than their free ligands.
Supplementary Material
Crystallographic data in CIF format complex 1 have been deposited at the Cambridge
Crystallographic Data Centre, CCDC No. 889112. Copies of CIFs are available free of
charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: -/44-
1
223-336-033; email: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk). The mass
spectrum of complex 2 is given in the supplementary material.
Acknowledgements
The authors gratefully acknowledge the financial support by the Department of
Science and Technology, New Delhi (DST-SR/FT/CS-049/2009). The authors also
acknowledge the UGC for providing funds under UGC-BSR research fellowships in science.

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1
0
The authors thank the SAIF Central Drug Research Institute (CDRI), Lucknow for analyzing
the mass spectra.
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1
[
6] Synthesis of 1: To a solution of 1,4-bis(3-aminopropyl) piperazine (0.10 g, 0.49 mM) in
methanol (10 mL), Ni(ClO ) .6H O (0.19 g, 0.49 mM) in 10 mL of methanol was added
4
2
2
drop wise. The mixture was stirred well at room temperature and refluxed for about 2 h
resulted in light brown solution. The solution was concentrated, dried and recrystallized
in acetonitrile. Pale brown crystals of 1 were formed at the bottom of the vessel by slow
evaporation of the solvent after few days. The crystals were isolated by filtration, washed
with methanol and dried. Yield: 0.23 g (78%). m.p.: 174 °C (dec). Anal. Calcd. (%) for
C H Cl NiN O : C, 26.23; H, 5.28; N, 12.24. Found (%): C, 26.27; H, 5.24; N, 12.18.
10
24
2
4
8
−
1
-1
-1
FT-IR (ν, cm ) (KBr disc): 2867m, 2923br, 1630s, 1139s, 625s. λ , nm (ε, M cm ) in
max
DMF: 623 (520), 384 (12900), 278 (48006).
1
[
7] Synthesis of 2: To a solution of ligand (L ) (0.20 g, 0.46 mM) in methanol (10 mL),
Ni(ClO ) .6H O (0.17 g, 0.46 mM) in 10 mL of methanol was added drop wise. The
4
2
2
mixture was stirred well at room temperature and the content was refluxed for about 3 h.
The resultant brown solution was then concentrated to one third of its volume and washed
well with water, ethanol and ether and dried under vacuum. Yield: 0.27 g (74%). m.p.:
2
04 °C (dec.) Anal. Calcd. (%) for C H Cl NiN O : C, 44.98; H, 5.23; N, 8.07. Found
26 36 2 4 10
−
1
(
%): C, 44.87; H, 5.24; N, 8.12. FT-IR (ν, cm ) (KBr disc): 3450w, 3010s, 2867m,
-1
-1
2
923br, 1630s, 1225w, 1139s, 625s. λmax, nm (ε, M cm ) in DMF: 639 (329), 396
+
(
16005), 322 (16528), 272 (49504); ESI-MS in CH CN m/z (%): 247.3 (8) [C H N O] ,
3
14 21
3
+
+
1 +
3
18.3(22) [C H N O] , 375.3(10) [C H N NiO] , 493.3 (100) [NiL ] , 495.3 (40)
18 30 4 18 28 4
1
+ +
1
+
[
NiL +2H ] , 694.2(5) [NiL +2ClO ] .
4
[
8] Synthesis of 3: The complex 3 was synthesized using the same procedure as complex 2
2
1
using ligand L (0.20 g, 0.35 mM) instead of L with Ni(ClO ) .6H O (0.13 g, 0.35 mM)
4
2
2
in 10 mL of methanol. Yield: 0.23 g (70%). m.p.: 210 °C (dec.). Anal. Calcd. (%) for
C H Br Cl NiN O : C, 34.99; H, 3.67; N, 6.80. Found (%): C, 34.95; H, 3.74; N, 6.85.
24
30
2
2
4
10

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2
−
1
FT-IR (ν, cm ) (KBr disc): 3425br, 3017m, 2881m, 2958s, 1625s, 1224w, 1100, 626s.
-1
-1
λmax, nm (ε, M cm ) in DMF: 667 (76), 385 (9351), 268 (20788).
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all non-hydrogen atoms were refined anisotrophically by full-matrix least-square
procedures. Hydrogen atoms were added theoretically and refined with riding model
position parameters and fixed by isotropic thermal parameters.
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[
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Inorg. Chem. 41 (2002) 6161–6168.
[
[
[
16] K.-Y. Choi, Synthesis, properties and X-ray crystal structures of nickel(II) complexes
of a hexaazamacrotetracyclic ligand, J. Coord. Chem. 56 (2003) 481–491.
17] M.J. Ettinger, in: D.R. Lontine (Eds.), Copper proteins and copper enzymes, CRC,
Boca Raton, FL, 1984, pp. 175–229.
18] J. Manonmani, R. Thirumurugan, M. Kandaswamy, M. Kuppayee, S. Shanmuga
Sundara Raj, M.N. Ponnuswamy, G. Shanmugam, H.K. Fun, Synthesis of mononuclear
nickel(II) and copper(II) complexes using compartmental ligands: X-ray and
electrochemical studies, Polyhedron 19 (2000) 2011–2018.
[
19] (a) Y. Wang, H. Zhang, G. Zhang, W. Tao, S. Tang, Interaction of the flavonoid
hesperidin with bovine serum albumin: A fluorescence quenching study, J. Luminescence
1
26 (2007) 211–218. (b) V. Rajendiran, R. Karthik, M. Palaniandavar, H. Stoeckli-Evans,
V.S. Periasamy, M.A. Akbarsha, B.S. Srinag, H. Krishnamurthy, Mixed-ligand
copper(II)-phenolate complexes:ꢀ Effect of coligand on enhanced DNA and protein
binding, DNA cleavage, and anticancer activity, Inorg. Chem. 46 (2007) 8208–8221.
20] A. Tarushi, E. Polatoglou, J. Kljun, I. Turel, G. Psomas, D.P. Kessissoglou,
Interaction of Zn(II) with quinolone drugs: Structure and biological evaluation, Dalton
Trans. 40 (2011) 9461–9473.
[
[
21] S. Tsiliou, L.-A. Kefala, F. Perdih, I. Turel, D.P. Kessissoglou, G. Psomas, Cobalt(II)
complexes with non-steroidal anti-inflammatory drug tolfenamic acid: Structure and
biological evaluation, Eur. J. Med. Chem. 48 (2012) 132–142.

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[
22] R. Prabu, A. Vijayaraj, R. Suresh, L. Jagadish, V. Kaviyarasan, V. Narayanan, New
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[
[
23] E.J. Gao, L. Wang, M.C. Zhu, L. Liu, W.Z. Zhang, Synthesis, characterization,
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M(dmphen)(CO3)]·H2O [M = Pt(II), Pd(II)], Eur. J. Med. Chem. 45 (2010) 311–316.
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spectra of Au(III), Pt(II) and Pd(II) porphyrins with DNA at room temperature, Inorg.
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[
26] Molecular docking: The rigid molecular docking studies were performed using HEX
8
.0 software. The coordinates of complexes 1 was taken from its respective crystal
structure as a CIF file and was converted to the PDB format using Mercury software
http://www.ccdc.cam.ac.uk/). However, structure of the complexes 2 and 3 were
sketched by CHEMSKETCH (http://www.acdlabs.com) and converted to PDB format
from mol format by CHEMDRAW ULTRA 8.0
http://scistore.cambridgesoft.com/chemdraw). The crystal structure of the B-DNA
(
(

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dodecamer d(CGCGAATTCGCG) (PDB ID: 1BNA) was downloaded from the protein
2
data bank (http://www.rcsb.org./pdb). All calculations were carried out on an Intel
Pentium 4, 2.4 GHz based machine running MS Windows XP SP2 as operating system.
Visualization of the docked pose has been carried out using CHIMERA
(www.cgl.ucsf.edu/chimera).
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27] (a) V. Kettmann, D. Kostalova, H.D. Holtje, Human topoisomerase I poisoning:
docking protoberberines into a structure-based binding site model, J. Comput. Aided Mol.
Des. 18 (2004) 785–796. (b) S. Tabassum, A. Asim, F. Arjmand, M. Afzal, V. Bagchi,
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cleavage and antimicrobial activity, Eur. J. Med. Chem. 58 (2012) 308–316.
N
N
NH2
NH2
N
NH2
Ni
(ClO )
4 2
Ni(ClO ) .6H O
4
2
2
H N
2
N
X
X= CH / Br
3
1
C H OH
X
2
5
OH O
X
N
N
N
OH
OH
N
N
OH
X
Ni(ClO ) .6H O
4
2
2
Ni
(ClO4)2
OH
C2H5OH
N
N
X
N
X
CH3 L1
CH3
Br
2
3
L2
Br
X
Scheme 1

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Figure captions
Figure 1 OPTEP view of the molecular structure and atom labeling scheme of complex 1
Figure 2 Crystal packing diagram of complex 1
Figure 3 Plot of % relative fluorescence intensity at λem = 343 nm (I/I %) vs r (r =
0
[
compound]/[BSA]) for ligands and their Ni(II) complexes 1–3 in buffer solution (150 mM
NaCl and 15 mM trisodium citrate at pH 7.0)
–
5
Figure 4 Absorption spectra of complex 3 (10 M) in 5 mM Tris–HCl/20mM NaCl buffer
at pH 7.2 in the absence and presence of increasing amounts of DNA. Inset shows the least-
squares fit of [DNA]/ε -ε vs. [DNA] for the complex.
a
f
Figure 5 (a) Emission spectra of EB bound to DNA in the presence of nickel(II) complex 3
[EB] = 3.3 µM, [DNA] = 40 µM, [complex] = 0–25 µM, λ = 510 nm). Inset shows the
(
ex
plots of emission intensity I /I vs [DNA]/[complex]. (b) Plot of EB relative fluorescence
0
intensity at λ = 596 nm (I/I (%)) vs r (r = [compound]/[DNA]) for Ni(II) complexes 1–3 in
em
0
buffer solution (5 mM NaCl and 5 mM Tris–HCl at pH 7.4).
-5
Figure 6 Circular dichroism spectra of CT-DNA (10 ×10 M) in Tris–HCl (5 mM) (pH7.2)
-5
in the presence of increasing amounts of nickel complexes 1–3 (5 ×10 M).

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Table 1. Crystallographic data and structure refinement parameters for complex 1
1
Empirical formula
C H Cl N Ni O
10 24 2 4 8
Formula weight
457.94
296(2)
0.71073
Temperature (K)
Wavelength (Å)
Crystal system, space group
orthorhombic, Pbca
14.4352(11)
15.4172(12)
16.1779(13)
90
a (Å)
B(Å)
c (Å)
α (°)
β (°)
γ (°)
90
90
3
Volume (Å )
3600.4(5)
8, 1.690
-3
Z, calculated density (mg m )
-1
Absorption coefficient (mm )
F(000)
1.421
1904
Crystal size (mm)
0.18 ×0.15 ×0.12
2.31 to 25.50
Theta range for data collection (°)
Limiting indices, h,k,l
-17 ≤ h ≤ 17, -18 ≤ k ≤ 18,
19 ≤ l ≤ 19
-
Reflections collected / unique
Rint
21459/3355
0.0998
Data / restraints / parameters
3355/ 0 / 234
2
Goodness-of-fit on F
0.819
Final R indices [I > 2σ (I)]
R indices (all data)
R1 = 0.0523, wR2 = 0.1272
R1 = 0.1158, wR2 = 0.1575
0.629 and -0.499
-3
Largest difference peak and hole / e Å

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Table 2. The BSA binding constants and parameters (K , k , K, n) derived for ligands and
sv
q
their Ni(II) complexes (1–3)
-
1
-1 -1
-1
Compound
bappz
K (M )
k (M s )
q
K (M )
n
SV
3
4
4
3
4
4
11
12
12
11
12
5
5.2 (0.2) x10
5.5 (0.6) x10
7.6 (0.4) x10
6.1 (0.1) x10
4.5 (0.2) x10
8.9 (0.3) x10
5.2 (0.2) x10
5.5 (0.6) x10
7.6 (0.4) x10
6.1 (0.1) x10
4.5 (0.2) x10
1.20 (0.4) x10
0.1781
2.65
1
4
L
1.10 (0.2) x10
1.68 (0.1) x10
1.72 (0.1) x10
2
4
L
1.047
0.222
2.345
1.514
5
1
2
3
4
2.1 (0.4) x10
9.3 (0.4) x10
12
4
8.9 (0.03) x10

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Table 3 MIC (µg/ml) of nickel(II) complexes 1–3
Compound
Bacteria
Fungi
Gram-negative bacterium Gram-positive bacterium
A.niger
C.albicans
E.coli
P.aeruginosa
B.subtilis S.aureus
bappz
>50
>25
>50
>25
>50
>25
>50
>25
>25
9.50
6.25
2.25
>50
>25
>50
>25
1
L
2
L
>25
>25
>25
>25
>25
1
2
3
15.00
12.50
10.50
17.50
14.50
12.25
10.50
7.50
3.25
12.50
9.50
8.25
11.25
8.25
7.50

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Graphical abstract
The molecular structure of complex 1 was determined by X-ray crystallography. The
nickel ion in the mononuclear complexes has been translocated between two non-equivalent
coordinating compartments of ligand by varying the pH. Complexes (1-3) were able to bind
to DNA and protein in the order 3 > 2 > 1. Molecular docking studies validated the
intercalative mode of binding interaction.

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Highlights




The mononuclear nickel(II) complexes (1-3) were synthesized and characterized.
The molecular structure of complex 1 was determined by X-ray crystallography.
The position of Ni(II) atom from N to N O compartment is achieved by varying pH.
4
2
2
Complexes (1-3) were able to bind to DNA and protein in the order 3> 2> 1.

The ligands and their nickel(II) complexes exhibited good antimicrobial activity.