A rapid synthesis of 2-substituted 1,2,3- triazole-1-oxide derivative starting from 4-(methyl)isonitrosoacetophenone and its Ni(II) complex: Characterization, DNA binding and cleavage properties

Article abstract of DOI:10.1016/j.molstruc.2016.09.066

An efficient route, not including any metal salt as a catalyst, for the synthesis of a new 2-substituted 1,2,3- triazole-1-oxide is reported in this paper. The title compound has been synthesized via reacting 4-(methyl)isonitrosoacetophenone with hydrazine hydrate and dipyridyl ketone in high yield under mild reaction condition. The structure of the new 1,2,3-triazole-1-oxide has been characterized via single crystal X-ray and spectral studies. The 1:1 ratio reaction of the 1,2,3-triazole 1-oxide ligand with nickel(II) chloride gives the mononuclear complex [Ni(L)(DMF)(Cl)₂] which is hexa-coordinated within an octahedral geometry. Characterization of the 1,2,3-triazole compound and its Ni(II) complex with FTIR, ¹H and ¹³C NMR, UV–vis, TGA and elemental analysis also confirm the proposed structures for the compounds. The interactions of the compounds with Calf thymus DNA (CT-DNA) have been investigated via UV–visible spectra and viscosity measurements. The results suggested that both ligand and Ni(II) complex bind to DNA in electrostatic interaction and/or groove binding with a slight partial intercalation. DNA cleavage experiments have been also investigated by agarose gel electrophoresis in the presence and absence of an oxidative agent (H₂O₂). Both 1,2,3-triazole 1-oxide ligand and nickel(II) complex show nuclease activity, which significantly depends on concentrations of the compounds, both in the presence and absence of an oxidative agent. DNA binding and cleavage affinities of the Ni(II) complex is stronger than that of the 1,2,3-triazole 1-oxide ligand.

Full text of DOI:10.1016/j.molstruc.2016.09.066

Journal of Molecular Structure 1129 (2017) 142e151
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
A rapid synthesis of 2-substituted 1,2,3- triazole-1-oxide derivative
starting from 4-(methyl)isonitrosoacetophenone and its Ni(II)
complex: Characterization, DNA binding and cleavage properties
,
Ramazan Gup a *, Oktay Erer a, Nefise Dilek b
a Department of Chemistry, Science Faculty, Mugla Sıtkı Koçman University, 48100 Mugla, Turkey
b Department of Physics, Arts and Sciences Faculty, Aksaray University, 68100 Aksaray, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2016
Received in revised form
21 September 2016
Accepted 22 September 2016
Available online 23 September 2016
An efficient route, not including any metal salt as a catalyst, for the synthesis of a new 2-substituted
1,2,3- triazole-1-oxide is reported in this paper. The title compound has been synthesized via reacting
4-(methyl)isonitrosoacetophenone with hydrazine hydrate and dipyridyl ketone in high yield under mild
reaction condition. The structure of the new 1,2,3-triazole-1-oxide has been characterized via single
crystal X-ray and spectral studies. The 1:1 ratio reaction of the 1,2,3-triazole 1-oxide ligand with nickel(II)
chloride gives the mononuclear complex [Ni(L)(DMF)(Cl)2] which is hexa-coordinated within an octa-
hedral geometry. Characterization of the 1,2,3-triazole compound and its Ni(II) complex with FTIR, 1H
and 13C NMR, UVevis, TGA and elemental analysis also confirm the proposed structures for the com-
pounds. The interactions of the compounds with Calf thymus DNA (CT-DNA) have been investigated via
UVevisible spectra and viscosity measurements. The results suggested that both ligand and Ni(II)
complex bind to DNA in electrostatic interaction and/or groove binding with a slight partial intercalation.
DNA cleavage experiments have been also investigated by agarose gel electrophoresis in the presence
and absence of an oxidative agent (H2O2). Both 1,2,3-triazole 1-oxide ligand and nickel(II) complex show
nuclease activity, which significantly depends on concentrations of the compounds, both in the presence
and absence of an oxidative agent. DNA binding and cleavage affinities of the Ni(II) complex is stronger
than that of the 1,2,3-triazole 1-oxide ligand.
Keywords:
1,2,3-triazole-N-oxide
Oxime
Hydrazine
Nickel(II) complex
DNA binding
DNA cleavage
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
compounds with attractive physico-chemical properties [17,18].
The nitrogen atoms of the 1,2,3-traizole ligands can participate in
Heterocycles containing five-membered rings such as triazole,
imidazole, pyrrole, pyrazole, etc., often play an important role in
various biochemical processes. Among them triazole derivatives
can be ideal drug candidate since they are non-toxic, mostly water
soluble and highly stable compounds [1e3]. They have been
intensively investigated for many years due to their interesting
biological properties, such as antifungal and antibacterial [4e6],
anti-nociceptive [7], anti-inflammatory [8], antiviral [9], antitu-
berculosis [10,11], anticancer [12e14] and HIV protease inhibitors
[15,16]. Therefore, the synthesis of 1, 2, 3-triazole based heterocy-
cles is the corner stone of drug chemistry because of their broad
biological activities. They can also act as N-donor ligands capable of
interaction with various metal ions, creating coordination
metal coordination while additional coordination sites can be
readily introduced into 2-, 4- or 5- substituents [19e22].
Because of their importance, a number of methods have been
developed for the synthesis of 1,2,3-triazole and 1,2,3-triazolium 1-
oxide derivatives. The widely used method for the synthesis of
1,2,3-triazole is the copper(I)-catalyzed azide-alkyne cycloaddition,
called ‘click chemistry’, to give 1,4-disubstituted 1,2,3-triazoles in
very high yields under mild conditions. This metal-catalyzed re-
action discovered independently by Meldal [23] et al. and Sharpless
et al. [24] and improved by Huisgen [25,26]. The other common
approach to obtain the 1,2,3-triazoles, especially N2-substituted-
1,2,3-triazole, is the oxidative cyclization of various hydrazones
[27,28]. In the case of the aroylhydrazone-oxime, the oxidative
cyclization reaction usually leds to the 1,2,3-triazolium 1-oxides
[29e32]. Here we present a new simple one-pot method for the
synthesis of the 2-substitue 1,2,3-triazole 1-oxide compounds. We
also report an account on synthesis, characterization of nickel(II)
* Corresponding author.
E-mail address: rgup@mu.edu.tr (R. Gup).
http://dx.doi.org/10.1016/j.molstruc.2016.09.066
0022-2860/© 2016 Elsevier B.V. All rights reserved.

R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
143
complex having N,N,N-1,2,3-triazole 1-oxide ligand moiety and
investigation of the DNA binding and cleavage activities of both
ligand and its nickel complex.
absolute ethanol (15 mL) with stirring. The reaction mixture was
refluxed for 2 h, and then the resulting green precipitate was
filtered off, washed with absolute ethanol and small amount of cold
water, and then dried in vacuum. The crystals, unsuitable for X-ray
diffraction, were obtained upon diffusion of the ethyl ether into the
DMF solution after 3 weeks. Yield: 76%; M.p.: 277 ꢁC. UV (DMF, nm);
270 and 348; FT-IR (KBr, cmꢀ1) 3429, 3112 (triazole), 3031, 2942,
(CeH), 1643 (C]O), 1605 and 1498 (C]N), 1189 (CeN), 947 (NeO);
Analysis (%calculated/found) for C23H24Cl2N6NiO2 C: 50.59/50.92,
H: 4.43/4.48, N:15.39/15.44, Cl: 12.98/12.69, Ni: 10.75/10.24.
2. Experimental section
2.1. Material and methods
All the reagents and solvents were of reagent-grade quality and
purchased from commercial suppliers. All aqueous solutions were
prepared with deionized water, which had been passed through a
Millipore Milli-Q Plus water purification system. Calf thymus DNA
(CT-DNA) was purchased from Sigma- Aldrich. pBR322 DNA was
purchased from Fermantas. 1H and 13C NMR spectra were recorded
on a Bruker 400 MHz spectrometer in DMSO_d6 with TMS as the
internal standard. IR spectra were recorded on pure solid samples
with a Thermo-Scientific, as KBR pellets. The electronic spectra of
the ligands and complexes were recorded on a PG Instruments
T80 þ UV/Vis Spectrophotometer. Carbon, hydrogen and nitrogen
analyses were carried out on a LECO 932 CHNS analyzer and nickel
content was determined via atomic absorption spectroscopy using
the DV 2000 Perkin Elber ICP-AES. Mass spectra were recorded on a
Waters Xevo TQ-S UPLC-MS/MS spectrometer. Room temperature
magnetic susceptibility measurements were carried out on
powdered samples using a Sherwood Scientific MK1 Model Gouy
Magnetic Susceptibility Balance. The thermogravimetric analysis
2.4. X-ray diffraction study
Crystallographic data were recorded on a Bruker Smart Breeze
CCD diffractometer using MoKa radiation (
l
¼ 0.71073 Å) at
T ¼ 296(2) K [36]. Absorption corrections by multi-scan were
applied [36,37]. Cell refinement was carried out using Bruker SAINT
and data were reduced by using Bruker SAINT [36]. The structure
was solved using SHELXS97 [38] and refined using SHELXL2014
[39] by full-matrix least-squares on F2 against ALL reflections. The
weighted R-factor wR and goodness of fit S are based on F2. The
threshold expression of F2 > 2sigma(F2) is used only for calculating
R-factors. All estimated standard deviations (e.s.d.’s) are calculated
using the full covariance matrix. The cell e.s.d.’s is taken into ac-
count individually in the estimation of e.s.d.’s in distances, angles,
and torsion angles; correlations between e.s.d.’s in cell parameters
are only used when they are defined by crystal symmetry. Molec-
ular graphics were drawn ORTEP-3 [40] and PLATON [40], and the
material for publication prepared using WinGX [41]. All non-
hydrogen atoms were refined anisotropically and hydrogen atoms
were added according to the theoretical model. A summary of the
experimental details and selected results for the title compound are
given in Table 1. The fractional atomic coordinates are given in
Table S1 and also the selected bond distance, bond angles, and
torsion angles are given in Table 2.
was carried out in dynamic nitrogen atmosphere (20 mL minꢀ1
)
with a heating rate of 20 ꢁC minꢀ1 using a Perkin Elmer Pyris 1 TGA
thermal analyzer at Mugla Sitki Kocman University. Crystallo-
graphic data were recorded on a Bruker Smart Breeze CCD area-
detector diffractometer in Science and Technology Application
and Research Center at Aksaray University, Turkey. 4-
methylisonitrosoacetophenone
[33,34]
and
4-
methylisonitrosoacetophenone hydrazone [35] were synthesized
as described in previously reported methods.
2.2. Synthesis of 2-(di(pyridin-2-yl)methyl)-4-(p-tolyl)-2H-1,2,3-
triazole 1-oxide (L)
2.5. DNA binding
2.5.1. Electronic absorption titrations
Dipyridyl ketone (10 mmol, 0.184 g) dissolved in absolute
ethanol (30 mL) was added drop wise to a solution of 4-
methylisonitrosoacetophenone hydrazone (10 mmol, 0.177 g) in
absolute ethanol (20 mL) with a catalytic amount of glacial acetic
acid at room temperature. The reaction mixture was refluxed for
further 4 h. Then, the reaction mixture was filtered, and the filtrated
was allowed at room temperature for crystallization of the 1,2,3-
triazole 1-oxide compound. After 4 days, the cream crystals suit-
able for X-ray diffraction were formed, collected by filtration,
washed with small amount of diethyl ether and then dried in
vacuum. The ligand is soluble in common organic solvents and
insoluble in water.
All the experiments involving the interaction of the complexes
with CT-DNA were carried out in water buffer containing 5 mM tris
[tris(hydroxymethyl)aminomethane] and 50 mM NaCl, and
adjusted to pH 7.3 with HCl. The solution of CT-DNA in the buffer
gave a ratio of UV absorbance of 1.8e1.9:1 at 260 and 280 nm,
indicating that the CT-DNA was sufficiently free of protein [42]. The
CT-DNA concentration per nucleotide was determined spectro-
photometrically by employing an extinction coefficient of
6600 Mꢀ1 cmꢀ1 at 260 nm [43]. An appropriate amount of the
compound was dissolved in a solvent mixture of 1% DMF and 99%
triseHCl buffer. Absorption titration experiments were performed
by maintaining the compound concentration as constant (25
while the concentration of the CT-DNA gradually increased within
6.25e50 M.
mM)
Yield 85%; Mp 175e176 ꢁC; UV (DMF, nm) 268 and 324; IR (KBr,
cmꢀ1) 3149 (triazole), 3043, 2947 (CeH), 1588 and 1525 (C]N),
m
1188 (CeN), 945 (NeO); 1H NMR (DMSO_d6, ppm)
d 2.34 (s, 3H),
7.31 (d, 2H AreH), 7.35 (m, 2H, Py-H), 7.45 (m, 2H, Py-H), 7.49 (s, H
CeH), 7.65 (d, 2H, AreH), 7.85, (m, 2H, Py-H), 8.40 (s, H, CH]N),
8.60 (m, 2H, Py-H); 13C NMR (DMSO_d6, ppm) 155, 149, 144 (C]N),
139, 137, 129.5, 126, 125, 123.5, 123.6, 113 (AreC), 66 (CeN), 21
(CH3). Analysis (% calculated/found) for C20H17N5O C: 69.96/70.24,
H: 4.99/4.98, N: 20.40/20.43.
2.5.2. Viscosity measurements
Viscosity experiments were carried out using an Ubbelodhe
viscometer at room temperature. The viscosity of CT-DNA solution
(25
mM) was measured in the absence and presence of increasing
amounts of the compound (6,25e50
m
M) in tris-HCl buffer (10 mM
triseHCl-NaCl; pH ¼ 7.6) containing %5 DMF solution. Flow time
2.3. Synthesis of Ni(II) complex ([Ni(L)(DMF)Cl2])
was measured three times via a digital stopwatch. Viscosity values
1/3
were presented as (
h
/h0
)
versus concentrations of [complex]/
A solution of 1 mmol NiCl2$6H2O (0.2377 g) in EtOH (10 mL) was
[DNA] [44,45] where
h was the viscosity value for DNA in presence
added to a hot solution containing 1 mmol ligands (0.343 g) in
of the compounds and h0 was the viscosity value of CT-DNA alone.

144
R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
Table 1
3. Results and discussion
Crystal data and structural refinement details.
3.1. Synthesis and characterization
Chemical formula
C20H17N5O
Formula weight (amu)
Crystal form, color
Crystal size (mm)
Crystal system
Space group
a (Å)
345.40
In this study a new 1,2,3-triazole-N-oxide ligand was synthe-
sized in a one-step reaction of 4-(methyl)isonitrosoacetophenone
hydrazone with di(2-pyridyl)ketone in presence of a catalytic
amount of acetic acid as illustrated in Scheme 1. We suggest that
the partly environment-friendly reaction proceeds via an inter-
mediate asymmetric azine compound which quickly undergoes
cyclization in the presence of catalytic amount of acetic acid to
produce 1,2,3-triazole 1-oxide compound in high yield under mild
conditions. The crystal structure of the 1,2,3-triazole 1-oxide was
defined by using single crystal X-ray diffraction analysis corre-
sponding to the proposed formula of the compound, which is also
supported by FTIR, UVeVis, 1H NMR, 13C NMR and elemental
analysis. The Ni(II) complex was synthesized by the reaction of the
1,2,3-triazole-N-oxide ligand with nickel(II) chloride in ligand to
nickel ratio of 1:1. The nature of bonding and geometry of the Ni(II)
complex was deduced from elemental analysis, FTIR and UVeVis
spectroscopies, magnetic susceptibility measurement and thermal
gravimetric analysis techniques.
yellow, colourless
0.980 ꢂ 0.740 ꢂ 0.450
Triclinic
P-1
8.9288(2)
9.9399(3)
10.6983(3)
70.003(1)
89.542(1)
72.276(1)
844.98(4)
2
1.358
0.71073
0.088
296(2)
28.43
b (Å)
c (Å)
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
V (Å3)
Z
Dx (g/cm3)
l
m
(MoKa) Å
(MoKa) mmꢀ1
T (K)
q
max
q
2.30
min
h
k
l
ꢀ11e11
ꢀ13e13
ꢀ14e14
20762
4275
3781
237
0.0490
0.1207
1.012
Number of reflections measured
Number of independent reflections
Number of reflections [I > 2
Number of parameters
R
The electronic spectra of the ligand and Ni(II) complex were
taken in dimethylformamide. The free ligand shows bands at 268
and 324 nm. These bands are due to aromatic nature of the 1,2,3-
triazole-N-oxide ligand. The Ni(II) complex on the other hand
shows a band at 270 nm and a shoulder at 348 nm probably due to
s(I)]
Rw
S
2(F2o) þ (0.1040P)2
p-p* and n-p* transitions [46,47]. Unfortunately, the expected
Weighting scheme,
1/[s
P ¼ (F2o þ 2F2c)/3
weak ded transition in the visible region for the complex cannot be
detected even with concentrated solution. It may be lost in the low
energy tail of the charge transfer transition. The observed magnetic
moment (meff) is 2.92 BM for the nickel complex and is consistent
with its octahedral geometry (Fig. 1) [48].
(
(
D
Dr
/
s
)
0.041
max
)max, (Dr
)
min
(eÅꢀ3
)
0.286, ꢀ0.245
Measurements
Structure determination
Refinement
Treatment of hydrogen atoms
Bruker Smart Breeze
direct method (SHELXS-97)
full matrix l.s. (SHELXL-2014)
geometric calculation
1H NMR of the 1,2,3-triazole-N-oxide ligand exhibits bands be-
tween 7.30 and 8.60 ppm due to the pyridine ring protons. The
observed doublet-doublet peaks, resembling an AB pattern of two
distorted doublets, at 7.31 and 7.65 ppm belong to 1,4-disubstitue
benzene protons side of the compound. The characteristic signal
of triazole ring appears at 8.60 ppm whereas the methine proton,
adjacent to N3 atom (Fig. 3), appears as a singlet at 7.49 ppm. The
movement of this absorption to lower frequency can be explained
by an inter-molecular hydrogen bond between this hydrogen atom
with acceptor N1 atom. The absence of the OH proton signal in-
dicates the deprotonation of the hydroxyl proton and subsequent
formation of 1,2,3-triazolium salt. The 1H NMR spectral assign-
ments of the 1,2,3-triazol 1-oxide ligand are also supported by the
13C NMR spectrum. The characteristic chemical shifts for the azo-
methine groups are observed at 155, 149 and 144 ppm. The
chemical shifts for the carbon atoms of the aromatic rings are
recorded between 113 and 139 ppm. In the 13C NMR spectra of the
2.6. Chemical nuclease activity
pBR322 plasmid DNA was used for all cleavage activities. In a
typical experiment, 7 l plasmid DNA (50 ng/ l) was mixed with
different concentrations of complexes (10, 25, 50, 75 and 100
dissolved in DMF) to determine optimum activation concentration.
l H2O2 (5 mM) was added to mixture to oxidize the reactant.
Finally, the reaction mixture was diluted with the Tris buffer
(100 mM Tris, pH: 8) to a total volume of 30 l. After that reaction
mixtures were incubated at 37 ꢁC for 2 h. Samples (20
l) were then
loaded with 4 l loading dye (0.25% bromophenol blue, 0.25%
xylene cyanol, 30% glycerol, 10 mmol EDTA) on a %1 agarose gel
containing 1 g/mL of EtBr. The gel was run at 100 V for 3 h in TBE
m
m
mM
5
m
m
m
m
m
buffer and photographed under UV light.
Table 2
Selected bond lengths (Å), bond angles (ꢁ) and torsion angles (ꢁ).
Bond lengths
Bond angles
Torsion angles
O1eN5
N3eN4
N3eN5
N3eC6
N4eC13
N5eC12
N1eC1
N1eC5
N2eC7
N2eC11
1.275(1)
1.335(1)
1.359(1)
1.462(1)
1.340(1)
1.337(2)
1.333(1)
1.342(2)
1.333(1)
1.342(2)
N4eN3eN5
N4eN3eC6
N5eN3eC6
N3eN4eC13
O1eN5eC12
O1eN5eN3
C12eN5eN3
C1eN1eC5
C7eN2eC11
N3eC6eC7
N3eC6eC1
112.18(9)
127.43(9)
119.31(9)
104.68(9)
132.0(1)
121.5(1)
106.5(1)
117.1(1)
116.6(1)
110.51(8)
110.82(8)
N5eN3eN4eC13
C6eN3eN4eC13
C6eN3eN5eO1
N4eN3eN5eC12
C6eN3eN5eC12
C6eC1eN1eC5
N4eN3eC6eC7
N5eN3eC6eC7
N4eN3eC6eC1
N5eN3eC6eC1
N1eC1eC6eN3
ꢀ2.1(1)
C2eC1eC6eN3
N1eC1eC6eC7
C2eC1eC6eC7
N3eC6eC7eN2
C1eC6eC7eN2
N3eC6eC7eC8
C1eC6eC7eC8
C19eC14eC13eN4
C15eC14eC13eN4
C19eC14eC13eC12
C6eC1eC2eC3
77.6(1)
ꢀ170.0(1)
ꢀ9.2(2)
130.1(1)
ꢀ46.3(1)
ꢀ32.7(1)
91.5 (1)
149.0(1)
ꢀ86.9(1)
3.0(2)
ꢀ177.3(1)
ꢀ176.5(1)
175.5(1)
1.7(1)
170.7(1)
ꢀ174.8(1)
105.8(1)
ꢀ61.4(1)
ꢀ19.1(2)
173.78(9)
ꢀ106.0(1)

R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
145
Scheme 1. Schematic diagram showing the synthesis of the 1,2,3-triazole-N-oxide ligands. i, NH2NH2, room temperature; ii, di(2-pyridyl) ketone, EtOH, AcOH, reflux 4 h.
Fig. 1. Proposed structure for the Ni(II) complex.
ligand, the signals at 66 and 21 ppm are assignable to the CeN and
CH3 groups, respectively.
n
(CeH) aliphatic,
n
(C]N),
n
(CeN) and
n
(NeO) groups, respectively.
Upon coordination of Ni(II) ion, the vibration bands of
n(C]N)
The IR spectra of the 1,2,3-triazole n-oxide compound show
sharp stretching vibration peaks at 3149, 3043, 2947, 1588 and
bounds are observed at 1605 and 1498 cmꢀ1 indicating the
involvement of these groups in the complex formation. Further-
more, in the IR spectra of the Ni(II) complex a new absorption
1525, 1188 and 945 cmꢀ1 due to
n(CeH) triazole, n(CeH) aromatic,
Fig. 2. TGA curve of the nickel(II) complex.

146
R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
appears at 1643 cmꢀ1 due to stretching vibration of the carbonyl
group of the coordinated dimethylformamide. The magnetic mea-
surement, elemental analysis and FT-IR data indicate that the 1,2,3-
triazole n-oxide compound act as a neutral N,N,N-tridentate ligand
coordinating through two pyridine nitrogen atoms and one triazole
nitrogen atom, and the structure proposed for the nickel(II) com-
plex is given in Fig. 1.
Temperature stability of the nickel(II) complex was conceived by
using thermogravimetric (TG) method carried out from 20 to
865 ꢁC (Fig. 2). TG curve exhibits mass losses in three steps. The first
step occurs within the temperature range 130e264 ꢁC, which cor-
responds to the removal of two chloride ions and one dime-
thylformamide molecule, with a mass loss of 23.40% (calcd:
23.81%). The subsequent steps (264-865 ꢁC) correspond to the
removal of the organic part of 1,2,3-triazole 1-oxide ligand, leaving
metal oxide as a residue.
the molecule are within expected ranges, and similar to the other
studies [49e52]. The all chelate rings of molecule are essentially
planar. The dihedral angle between A (N1/C1eC5) and B (N2/
C7eC11) planes is 80.64 (4)ꢁ. These two rings are close to
perpendicular. The dihedral angle between A and C (N3eN5/C12,
C13) planes is 63.07 (4)ꢁ. The dihedral angle between B and C
planes is 78.27 (5)ꢁ. The dihedral angle between C and D (C14eC19)
is 3.64 (10)ꢁ. These rings are almost in the same plane. The O1 atom
lies below 0.026 (2) Å from C plane. The C6 atom lies below 0.197
(2) Å and 0.053 (2) Å from C and B planes, respectively. Also, the C6
atom lies above 0.120 (2) Å from A plane. The C14 atom lies above
0.036 (2) Å from C plane. The C13 and C20 atoms lie above 0.043 (2)
and 0.024 (3) Å from D plane, respectively.
The H atoms were positioned geometrically with CeH ¼ 0.93 Å
(aromatic), CeH ¼ 0.96 Å (methyl), CeH ¼ 0.98 Å (for C6) and
constrained
to
ride
on
their
parent
atoms,
with
U
iso(H) ¼ 1.2Ueq(Caromatic, C6) and Uiso(H) ¼ 1.5Ueq(Cmethyl).
As can be seen from the packing diagram (Fig. 4), inter-
molecular CeH … hydrogen bonds (Table S2) link the mole-
3.2. Description of the crystal structures
p
cules and these hydrogen bonds may be effective in the stabiliza-
tion of the crystal structure. In this interaction, the N1 atom acts as
an acceptor and C6 atom acts as a donor.
Crystal structure was obtained for the 2-(di(pyridin-2-yl)
methyl)-4-(p-tolyl)-2H-1,2,3-triazole 1-oxide and it is discussed
below. The selected geometric parameters are listed in Table 1. The
new 1,2,3-triazole compound crystallized in the triclinic P-1 space
group. The crystal structure is shown in Fig. 3 with atom-
numbering scheme, and the selected bond lengths and bond an-
gels are summarized in Table 2. The N3eC6 bond length is 1.462(1)
Å corresponding to CeN single bond length, whereas the other CeN
bond lengths range from 1.333(1) to 1.342(2) Å which are between
the CeN single (1.471 Å) and double (1.273 Å) bonds and similar
with the reported 1,2,3-triazole compounds (1.309e1.339 Å)
[49,50] Similarly, the N3eN4 and N3eN5 distances are 1.335(1) and
1.359(1) Å, respectively, which are half way between being a single
(NeN) and a double (N]N) [51,52]. These observed bond lengths
indicate that the synthesized 1,2,3-triazole has resonance struc-
tures. The O1eN5 bond distance is 1.275(1) Å which is shorter than
a half bond character, surprisingly. Since there are opposite charges
on side to side N5 and O1 atoms of the 1,2,3-triazole compound, the
possible ionic interaction beside covalent interaction may be reason
of this observed bond length. The other bond lengths and angles in
3.3. Binding studies
3.3.1. Electronic absorption titrations
Electronic absorption spectroscopy is one of the most widely
used techniques to monitor the interaction of metal complexes
with DNA. Metal complexes can bind to DNA through both covalent
and/or non-covalent interactions [49,50]. In covalent interactions a
nitrogen donor atom from the nucleotide binds to the metal com-
plexes or it is replaced the labile group of complexes, while non-
covalent interactions occur via intercalative, electrostatic and
groove binding. Hypochromism results from the contraction of
DNA in the helix axis, as well as from the change in conformation
on DNA. On the other hand, hyperchromism in absorption bands
indicate minor groove binding, unwinding of DNA double helix,
simultaneous exposure of the DNA bases and damage to the DNA
double helix [53e56].
Fig. 3. An ORTEP drawing of molecular structure with the crystallographic numbering scheme. Thermal ellipsoids are drawn at % 50 probability levels.

R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
147
270 and 348 nm for Ni(II) complex can be attributed p-p* and n- p*
transitions, respectively. With increasing concentration of CT-DNA,
for the ligand, the hyperchromism in the peak at 268 nm reaches as
high as 38.8% with as small bothochromism of 2 nm. The nickel (II)
complex also exhibits an evident hyperchromism of about 50.5% at
270 nm and red shift of 2 nm. A strong hyperchromic effect in p-p*
transition was observed for the Ni(II) complex suggesting that it has
higher propensity for DNA binding than the 1,2,3-triazole ligand.
The absorption spectra of both 1,2,3-triazole 1-oxide ligand and its
Ni(II) complex exhibits hyperchromism upon addition of CT-DNA
which is suggestive of a conformational change of the DNA
duplex [57]. Hyperchromic effect may also be due to the electro-
static interaction between positively charged N (5) atom of the
triazole moiety of the compounds and negatively charged phos-
phate backbone at the periphery of the double helix DNA [42,43].
On the other hand, during this interaction the repulsion can take
place between the negatively charged O (1) atom of the compounds
and negatively charged phosphate group of CT-DNA which prob-
ably diminishes the force of the electrostatic interaction as well as
DNA binding abilities of the compounds. Structurally, electrostatic
binding may not be one of the binding mode, since the 1,2,3-
triazole 1-oxide ligand has planar area and extended system,
thereby leading to penetration and binding within DNA base pairs.
Nevertheless, the complete intercalation of the compounds be-
tween a set of adjacent base pairs is impossible probably due to the
strong attraction and repulsion between positively (N5) and
negatively (O1) charged atoms of the compounds with negatively
charged phosphate, yet some partial intercalation can be proposed
[58e60]. The existing 1,2,3-triazole 1-oxide ligand and its Ni(II)
complex may bind to DNA by groove binding since they have many
hydrogen bonding cites which may form hydrogen bonds with DNA
double helix. On the other hand, the existing compounds bearing
methyl group can also bind to DNA via a van der Waals interaction
between methyl group of the 1,2,3-triazole 1-oxide ligand and DNA
base thymine.
Fig. 4. A packing diagram for molecule, projected along a direction. Hydrogen bonds
are indicated by dashed lines.
The absorption spectra of the ligand and its Ni(II) complex
The binding constant, Kb, was determined by using the equation,
[DNA] ∕ (εa e εf) ¼ [DNA] ∕ (εo e εf) þ 1 ∕ Kb (εo e εf), where [DNA]
is the concentration of DNA in base pairs, εa, εf and εo correspond to
(25
(6.25e50
observed at 268 and 323 nm for 1,2,3-triazole 1-oxide ligand and
mM) in the presence of different concentrations of CT-DNA
mM) are shown in Figs. 5 and 6. The absorption peaks
Aobsd/[M], the extinction coefficient of the complexes and the
Fig. 5. Absorption spectral traces of the 1,2,3-triazole-N-oxide ligand with increasing concentration of CT-DNA.

148
R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
Fig. 6. Absorption spectral traces of the nickel(II) complex with increasing concentration of CT-DNA.
extinction coefficient of the complex in the fully bound form,
respectively, and Kb is the intrinsic binding constant. The ratio of
the slope to intercept in the plot of [DNA] ∕ (εa e εf) versus [DNA]
gives the value of Kb and for complex. The binding constant (Kb)
values of 2.5 ꢂ 10 Mꢀ1 for the ligand and 3.0 ꢂ 103 Mꢀ1 for the Ni(II)
complex suggest that the complex has slight higher affinity to DNA
than that of the ligand. These lower values also indicated partial
intercalative binding and/or surface binding of the complexes to
DNA.
3.3.2. Viscosity measurements
To understand the nature of the interaction between the com-
pounds and DNA, viscosity measurements were also performed.
Viscosity parameter is important as it sensitive to the change in
length of DNA strands and provides valuable information for any
conformational change. A strong intercalation of the ligand leads to
lengthening of DNA helix as base pairs are separated to accom-
modate the binding ligand, leading to an increase in viscosity of the
DNA solution. In contrast, electrostatic interaction, groove binding
or partial intercalation leads to only minor changes in the viscosity
[61,62]. The binding modes of the 1,2,3-triazole 1-oxide ligand and
nickel(II) complexes to DNA are further confirmed via viscosity
measurement carrying out by keeping [DNA] ¼ 25 mM and varying
the concentrations of the 1,2,3-triazole-1-oxide and its Ni(II)
complexes, DAPI or EB. The results are shown in Figs. 7 and 8. The
EB and DAPI have been used as references. As it can be seen from
these Figures, ethidium bromide (EB), being a well-known DNA
intercalator between DNA base pairs and thus lengthening the DNA
double helix, increases the relative viscosity of DNA sharply
whereas the viscosity of double strand DNA remains almost un-
changed in the case of DAPI, minor groove binding agent [60,63].
Here, the relative viscosity of DNA solutions slightly increases
upon increasing the amounts of 1,2,3-triazole-N-oxide ligand while
it is almost unchanged in the case its nickel(II) complex. The results
indicate electrostatic and/or groove binding nature of Ni(II) com-
plex and also partial intercalative nature of 1,2,3-triazole 1-oxide
ligand, which is also in agreement with the result of absorption
spectra. This situation may be related to the molecular structures of
the compounds. The 1,2,3-triazole 1-oxide has planar geometry,
Fig. 7. Effect of increasing amounts of the 1,2,3-triazole 1-oxide ligand, DAPI and EB on
the relative viscosity of calf thymus DNA at room temperature.
Fig. 8. Effect of increasing amounts of the Ni(II) complex, DAPI and EB on the relative
viscosity of calf thymus DNA at room temperature.
and easily penetrate into DNA base pairs binding to DNA probably
through a stacking interaction between the aromatic chromophore
of the ligand and the base pairs of DNA. On the other hand, the
nickel(II) complex has been proposed to have an octahedral

R. Gup et al. / Journal of Molecular Structure 1129 (2017) 142e151
149
Fig. 9. Agarose gel electrophoresis of pBR322 plasmid DNA by different concentrations of the 1,2,3-triazole-1-oxide ligand (L) in the presence and absence of hydrogen peroxide.
Lane 1: [L] (200
Lane 6: [L] (200
m
m
M) þ DNA þ H2O2, Lane 2: [L] (100
m
M) þ DNA þ H2O2, Lane 3: [L] (75
m
M) þ DNA þ H2O2, Lane 4: [L] (50
m
M) þ DNA þ H2O2, Lane 5: [L] (25
m
M) þ DNA þ H2O2,
M) (10
m
M) þ DNA, Lane 7: [L] (100
m
M)) þ DNA, Lane 8: [L] (75 M) þ DNA, Lane 9: [L] (50
m
m
M) þ DNA, Lane 10: [L] (25
m
M) þ DNA.
Fig. 10. Agarose gel electrophoresis of pBR322 plasmid DNA by different concentrations of the Ni(II) complex [Ni(L)(DMF)Cl2] in the presence and absence of hydrogen peroxide.
Lane 1: [Ni(L)(DMF)Cl2] (200 M) þ DNA þ H2O2, Lane 3: [Ni(L)(DMF)Cl2] (75 M) þ DNA þ H2O2, Lane 4: [Ni(L)(DMF)Cl2]
M) þ DNA þ H2O2, Lane 2: [Ni(L)(DMF)Cl2] (100
(50 M) þ DNA þ H2O2, Lane 6: [Ni(L)(DMF)Cl2] (200 M) (10 M) þ DNA, Lane 7: [Ni(L)(DMF)Cl2] (100 M)) þ DNA, Lane 8:
M) þ DNA þ H2O2, Lane 5: [Ni(L)(DMF)Cl2] (25
[Ni(L)(DMF)Cl2] (75 M) þ DNA, Lane 10: [Ni(L)(DMF)Cl2] (25 M) þ DNA.
M) þ DNA, Lane 9: [Ni(L)(DMF)Cl2] (50
m
m
m
m
m
m
m
m
m
m
m
geometry that, in part, relieves the steric crowding of the coordi-
nated ligands. This steric structure of the nickel complex may
hinder the intercalation mode in between the base pair of DNA.
new heterocyclic compound incorporating 1,2,3-triazole 1-oxide
moiety in order to investigate its coordination behavior and DNA
interaction ability. The one-pot reaction was carried out in a yield of
85% in a single reactor by the interaction of 4-(methyl)iso-
nitrosoacetophenone, hydrazine hydrate, di-2-pyridyl ketone,
acetic acid in ethanol without using any metal salt as a catalyst. Its
coordination ability was tested with bio relevant Ni(II) ion which
occupies a six coordinated octahedral environment surrounded by
the two pyridyl nitrogen atoms and one nitrogen atom of the 1,2,3-
triazole ring of N,N,N-tridentate ligand, two chloride ions and one
dimethylformamide group. The results of electronic absorption ti-
trations and viscosity measurements indicate that both 1,2,3-
triazole 1-oxide ligand and its Ni(II) complex interact with CT-
DNA through the non-covalent binding mode possibly by the
electrostatic interaction and/or groove binding as well as the partial
intercalation. The compounds exhibit efficient nuclease activity in
the presence and absence of hydrogen peroxide which has
dependence on the concentration of compound. The results also
indicate that the chemical nuclease activity of the nickel complex is
nakedly higher than that of its 1,2,3-triazole 1-oxide ligand prob-
ably due to its higher DNA binding affinity.
3.4. Cleavage studies
The chemical nuclease activities of the compounds have been
studied by using pBR322 plasmid in TBE buffer at 37 ꢁC in the
presence and absence of oxidizing agent under similar physiolog-
ical conditions. When pBR322 is conducted by electrophoresis, the
fast migration will be observed for the supercoiled form (Form I). If
only one DNA strand is cleaved, the form I will relax to produce a
slower-moving nicked circular from (Form II). If both strands are
cleaved, a linear form (Form III) that migrates at a rate between that
of Form I and Form III will be produced. Figs. 9 and 10 exhibit the
results of gel electrophoretic separations of pBR322 plasmid
induced by an increasing concentration of the compounds
(25e200 mM) in the presence and absence of hydrogen peroxide.
The results show that both ligand and its Ni(II) complex behave as a
chemical nuclease activity by nicking Form I into Form II and Form
III in the presence and absence of hydrogen peroxide. The
increasing concentrations of the compounds led to a gradual
diminish in the band intensity of Form I, while partly increasing in
the band intensities of Form II and Form III progressively suggesting
double-strand DNA breaks. The results also indicate that the nickel
complex exhibits better and different DNA cleavage affinity from
1,2,3-triazole 1-oxide ligand. It converts mostly the supercoiled
DNA to nicked and linear DNA even in the low concentrations
Acknowledgements
We thank the Scientific Research Projects Foundation of Mugla
Sıtkı Koçman University for financial support of this work (BAP No:
13-169).
Appendix A. Supplementary data
(50
the presence of hydrogen peroxide, with 100
complex is found to completely cleave Form I to Form II and Form III
(Fig. 10, lane 2) and at the 200 M concentration of the Ni(II)
m
M) both in the presence and absence of an oxidative agent. In
mM the nickel(II)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.09.066.
m
complex, the plasmid DNA is almost degraded into indistinguish-
able small fragments. In the absence of hydrogen peroxide the
nickel(II) complex also shows effective nuclease activity. With the
increase of the Ni(II) complex concentration, the intensity of the
supercoiled DNA band is found decrease gradually while those of
nicked and linear DNA bands increase apparently (Fig. 10, lanes 6-
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