Synthesis, characterization, anti-proliferative activity and chemistry computation of DFT theoretical methods of hydrazine-based Schiff bases derived from methyl acetoacetate and α-hydroxyacetophenone

Article abstract of DOI:10.1016/j.molstruc.2020.129086

In this study, the synthesized hydrazine Schiff bases belonging to methyl acetoacetate (1) and α-hydroxyacetophenone (2) were prepared by simple methods. In addition, FT-IR, UV–Vis, ¹H NMR, Mass spectra, along with melting point and conductivity measurements were used for the characterization of these compounds. The molecular structures of (1) and (2) were determined by single crystal X-ray diffraction technique. X-ray diffraction analysis reveals that (1)crystallizes in the orthorhombic system with Pca2₁ space group possessing a = 21.1032(12), b = 5.9061(3), c = 10.9717(7), β = 90° while compound (2) crystallizes in the monoclinic system with P2₁/c space group and a = 7.0386(14), b = 13.275(3), c = 15.071(3), β = 99.27(3)°. Also, theoretical studies were performed within the density functional theory (DFT) framework. Hydrazine compounds (1) and (2) were geometrically optimized using the B3LYP method with (6-311+G+ (d, p)) basis set. Calculated geometrical parameters exhibited a good agreement with experimental value. The optimized parameters from the DFT calculations were in line with experimentally measured Single Crystal X-ray Diffraction (SCXRD) results. The anticancer effects of the synthesized compounds were assayed using MTT assay against cancer cell lines K562 and MG63.

Full text of DOI:10.1016/j.molstruc.2020.129086

Journal of Molecular Structure 1225 (2021) 129086
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, characterization, anti-proliferative activity and chemistry
computation of DFT theoretical methods of hydrazine-based Schiff
bases derived from methyl acetoacetate and α-hydroxyacetophenone
Sakineh Parvarinezhad, Mehdi Salehi∗
Department of Chemistry, College of Science, Semnan University, P.O. Box 35195-363, Semnan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, the synthesized hydrazine Schiff bases belonging to methyl acetoacetate (1) and α-
hydroxyacetophenone (2) were prepared by simple methods. In addition, FT-IR, UV–Vis, 1H NMR, Mass
spectra, along with melting point and conductivity measurements were used for the characterization
of these compounds. The molecular structures of (1) and (2) were determined by single crystal X-ray
diffraction technique. X-ray diffraction analysis reveals that (1) crystallizes in the orthorhombic sys-
tem with Pca21 space group possessing a = 21.1032(12), b = 5.9061(3), c = 10.9717(7), β = 90° while
Received 1 March 2020
Revised 1 August 2020
Accepted 13 August 2020
Available online 14 August 2020
Keywords:
Crystal structure
Schiff base, Ligand
2, 4-Dinitrophenylhydrazine
DFT calculation
MTT assay
compound (2) crystallizes in the monoclinic system with P21/c space group and a = 7.0386(14),
b
= 13.275(3), c = 15.071(3), β = 99.27(3)°. Also, theoretical studies were performed within the density
functional theory (DFT) framework. Hydrazine compounds (1) and (2) were geometrically optimized us-
ing the B3LYP method with (6-311+G+ (d, p)) basis set. Calculated geometrical parameters exhibited a
good agreement with experimental value. The optimized parameters from the DFT calculations were in
line with experimentally measured Single Crystal X-ray Diffraction (SCXRD) results .The anticancer effects
of the synthesized compounds were assayed using MTT assay against cancer cell lines K562 and MG63.
© 2020 Elsevier B.V. All rights reserved.
1 Introduction
physiological activities [13–19]. Due to their importance in biolog-
ical processes, the hydrazines can serve as linkers for drug release
Schiff bases have been considered as privileged ligands in coor-
dination chemistry due to their simple preparation methods, di-
versity, and structural variability [1]. Moreover, the Schiff bases
and their complexes have been widely studied in various fields
including catalysis [2], material science [3], optoelectronic appli-
cations [4], medicinal chemistry [5], radiopharmaceuticals [6]. In
this regard, finding an alternative approach to enhance drug sta-
bility by changing the structural properties of these compounds
sounds crucial. On the other hand, hydrazones, which can form
an azomethine imine, are a major class of reagents in organic syn-
thesis due to their advantages such as accessibility, stability, and
different structure-dependent reactivity, and reaction conditions [7,
8]. Hdrazine Schiff bases are also a proper candidate in physio-
logical and biological studies due to their antimycobacterial, an-
titumor, cytotoxic, antiviral, and properties, they have also found
extensive applications in materials science [9–12]. These activities
are attributed to their crystallographic features as they form sta-
ble chelate compounds with transition metals which can catalyze
to enhance the therapeutic effects against cancer and decrease
the side effects [20]. The design, synthesis, characterization, and
structures of various hydrazine-based Schiff bases have been stud-
ied. These structures will certainly deliver useful information about
their coordination properties [21–25]. In the present study, two
Schiff base compounds were synthesized from hydrazine deriva-
tives with different ketones (Scheme 1). Their characteristics were
investigated through different physical and chemical methods. Fur-
thermore, DFT structural calculations as well as cytotoxicity assess-
ment towards cancer cell line of K562 and MG63 were discussed.
2. Experimental
2.1. Materials and physical measurements
All the chemicals and solvents were purchased from Aldrich and
Merck. A SHIMADZU UV-1650 PC spectrophotometer was used for
UV–Vis spectroscopy in ethanol. The FT-IR spectra were recorded
on FT-IR SHIMADZU spectrophotometer using KBr pellets at room
temperature in the wavenumber range of 4000–400 cm−1. The
melting point was determined in open capillaries on an elec-
∗
Corresponding author.
E-mail address: msalehi@semnan.ac.ir (M. Salehi).
https://doi.org/10.1016/j.molstruc.2020.129086
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
Scheme 1. Synthetic procedure for the preparation of hydrazine-based Schiff Bases (1) and (2).
trothermal 9100 apparatus. The molar conductivity values of the
solutions fell within the range observed for 1:1 electrolytes [26].
1H NMR spectra at room temperature was recorded in DMSO–
d6 using Varian - INOVA 500 MHz NMR spectrophotometer. The
Mass spectra was recorded on Agilent Technology (HP) 5973 Net-
work Mass Selective Detector. All theoretical studies were accom-
plished using density functional theory (DFT) in the Gaussian 09
program software. Cell lines were obtained from Pasteur Institute
of Iran (Tehran, Iran) and cell culture medium (RPMI 1640), fe-
tal bovine serum (FBS) and penicillin-streptomycin were purchased
from Gibco BRL (Life technologies, Paisley, Scotland). The culture
plates were obtained from Nunc (Roskilde, Denmark). MTT [3-
2.3. Crystal structure determination
Diffraction data were collected by the ω-scan technique, us-
ing graphite-monochromated MoK radiation (λ = 0.71073 A), at
˚
α
200 K (1) on Rigaku XCalibur four-circle diffractometer with EOS
CCD detector and at room temperature (2) on MAR345 dtb four-
circle diffractometer with MAR345 image plate detector. The data
were corrected for Lorentz-polarization as well as for absorption
effects [27]. Precise unit-cell parameters were determined by a
least-squares fit of the reflections of the highest intensity, cho-
sen from the whole experiment. The structures were solved with
SHELXT-2013 [28] and refined with the full-matrix least-squares
procedure on F2 by SHELXL-2013 [28]. All non-hydrogen atoms
were refined anisotropically, all hydrogen atoms were placed in
idealized positions and refined as ‘riding model’ with isotropic dis-
placement parameters set at 1.2 (1.5 for CH3) times Ueq of ap-
propriate carrier atoms. The crystals of (2) were of low quality,
therefore the diffraction data allowed only for determination of
the structure, but the R factors etc. are relatively high. Neverthe-
less, the geometry of molecule as well as intermolecular inter-
actions can be reliably determined. Table 1 shows the crystallo-
graphic data. Crystallographic data for the structural analysis has
been deposited with the Cambridge Crystallographic Data Centre,
Nos. CCDC - 1908139 – 1908141. Copies of this information may be
obtained free of charge from: The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK; e-mail: deposit@ccdc.cam.ac.uk, or www:
www.ccdc.cam.ac.uk.
ꢀ
(4, 5 -dimethyltiazol-2-yl)−2, 5-diphenyltetrazolium bromide] was
purchased from Sigma. Chem. Co. (Munich, Germany).
2.2. Synthesis of compounds (1) and (2)
2.2.1. General synthesis
The Schiff bases were synthesized through a general procedure.
Compounds (1) and (2) were prepared by the reaction of 2, 4-
dinitrophenylhydrazin (0.99 g, 0.5 mmol) with methyl acetoacetate
(0.058 g, 0.5 mmol) / α- hydroxyacetophenone (0.068 g, 0.5 mmol)
in DMSO (10 mL). The mixtures were then refluxed for 24 h. After
some days at room temperature, orange crystals were collected by
filtration, washed with a small amount of diethyl ether and dried
under pressure.
2.2.2. Compound (1)
2.4. Computational details
Methyl (Z)-3-(2-2, 4-dinitrophenyl)hydrazono)butanoate (1) Or-
ange crystals. Yield: 70%. Mol.Wt: 295.24 g/mol. M. p.: 166. ɅM
(DMSO) = 5.88 μscm−1. FT-IR: (KBr, cm−1): 3125(υN–H), 3118
(υ(C–H)), 3095 (υMethyle), 1613(υC=N), 1405, 1339(υNO2), 1055(υ
HN–N). UV–Vis: λmax (nm) (ε, M−1 cm−1) (EtOH): 249(30, 000),
390(46, 500), 432(43, 000).
The compounds (1) and (2) were theoretically studied (DFT)
and their atomic orbitals were examined to elucidate the chemical
phenomena and changes in the molecules. Theoretical studies were
conducted within density functional theory (DFT) framework using
B3LYP hybrid functional proposed by Becke [29, 30] and Lee, Yang
and Parr [31] and 6-311+G (d, p) basis set to geometrically opti-
mize the compounds (1 and 2) [32, 33]. Gaussview 5.0 was applied
to prepare the input files, while Gaussian09 software was utilized
for all the geometry optimization calculations at the B3LYP level
of theory [33]. The structures of the compounds were fully op-
timized with no constraint. The frequency calculations were also
carried out on the optimized structures to confirm that the op-
timized structures are real local minima on the potential energy
2.2.3. Compound (2)
(Z)-3-(2-(2,
4-dinitrophenyl)hydrazono)-3-phenylpropan-1-ol
(2) Orange crystals. Yield: 85%. Mol.Wt: 316.28 g/mol. M. p.: 188.
ɅM (DMSO)
3115(υN-H), 2984, 2489(υ(C-H)
1069(υ HN–N). UV–Vis: λmax (nm) (ε, M−1 cm−1) (EtOH): 243(350,
=
5.88 μscm−1
.
FT-IR: (KBr, cm−1): 3260(υO-H),
1614(υC=N), 1525, 1446 (υNO2),
)
000), 295(16, 300), 385(66, 300).

S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
3
Table 1
Crystal data, data collection and structure refinement.
Compound
(1)
(2)
Formula
C
11H12N4O6
295.24
C14H12N4O5
316.28
Formula weight
Crystal system
Space group
Orthorhombic
Pca21
Monoclinic
P21/c
˚
a(A)
21.1032(12)
5.9061(3)
10.9717(7)
90
7.0386(14)
13.275(3)
15.071(3)
99.27(3)
1389.8(5)
4
˚
b(A)
˚
c(A)
β(°)
3
˚
V(A )
1367.49(14)
4
Z
Dx(g cm−3
)
1.434
1.512
F(000)
612
656
μ(mm−1
)
0.119
0.118
Fig. 1. UV–Vis spectrum of compounds (1) and (2) in EtOH solutions (c = 10−5 M).
Reflections:
Collected
7277
2707 (0.029)
1867
8461
2395 (0.135)
1670
unique (Rint
)
structures of the compounds were determined by Single-Crystal X-
ray Diffraction (SCXRD)
with I>2σ(I)
R(F) [I>2σ(I)]
wR(F2) [I>2σ(I)]
R(F) [all data]
wR(F2) [all data]
Goodness of fit
0.051
0.124
0.123
0.302
0.081
0.163
3.2. Spectroscopic characterization of the compounds (1) and (2)
0.143
0.323
1.03
1.12
Several spectroscopic methods have been used to confirm the
synthesis of the compounds (1) and (2). FT-IR spectra can offer suf-
ficient information to clarify the bonding status of the compounds.
The FT-IR spectra of the Schiff base compounds are presented
in Figures S.1 and S.2 (Supplementary materials). FT-IR spectrum
of methyl acetoacetate exhibited two signals at around 1652 and
1631cm−1 which can be assigned to the stretching vibrations of the
C=O groups. Upon the formation of the azomethine groups in the
Schiff base Methyl(Z)-3-(2-2, 4- dinitrophenyl)hydrazono)butanoate
(1), these bands disappeared and a new intense band emerged at
1613 cm−1. This is the most characteristic band of the similar Schiff
base ligands and is indicative of the formation of the C=N band.
−3
˚
A
•
max/min ρ (e
)
0.27/−0.22
0.34/−0.29
surfaces. UV–Vis spectra and electronic transitions were computed
with the time-dependent DFT (TD-DFT) method at the B3LYP/ (6–
311 + G (d, p)) level.
2.5. Biological studies
2.5.1. Cell culture
Cells were cultured in the RPMI medium (RPMI1640, Sigma).
The medium was supplemented with 10% heat-inactivated fe-
tal calf serum (Sigma) and streptomycin (10 mg/mL)-penicillin
(5 μg/mL) was utilized as antibiotics at 37 °C under a humidified
atmosphere containing 5% CO2. The cells should have 80–90% con-
fluence before they are harvested and plated for the experiments.
The band at 3125 cm−1 can be attributed to the v(N H) stretch-
–
ing frequency for compound (1). Also, the band at 1055 cm−1 in-
dicates the HN–N vibration in the Schiff bases; another evidence
for the successful synthesis of this compound. In the case of (2)
α-hydroxyacetophenone, the signals at 1689 cm−1 are assigned
to the stretching vibrations of the C=O groups. Upon the forma-
tion of the azomethine groups in the Schiff base (Z)-3-(2-(2, 4-
dinitrophenyl)hydrazono)-3-phenylpropan-1-ol (2), these band dis-
appeared and a new intense one appeared at 1614 cm−1. Thus
band at 3260 cm−1 can be assigned to stretching vibration of OH
(υOH) in compound (2). The band at 3115 cm−1 can be related to
2.5.2. Assessment of cytotoxicity using MTT assay
The cell proliferation of 2, 4-dinitrophenylhydrazine, com-
pounds (1), (2), and 5-fluorouracil were determined in K562 (myel-
ogenous leukemia cancer) and MG63 (osteosarcoma cancer) cell
lines through the MTT assay. The harvested cells with a density of
1 × 103 cells/well were seeded in 96-well plates and cultured for
24 h. Three replica wells were used for all concentrations and con-
trol overnight. Then the media were removed and various amounts
of compounds (1) and (2) (2, 2.5, 5, 10, 15, 20, and 25 ng/mL) were
added to the wells. The plates were incubated in a humidified at-
mosphere 5% CO2 for 48 h. After treatments of the compounds, 20
μL of MTT Formosan precipitate (5 mg/mL) was added to each well
and incubated for an additional 4 h. Then, the culture medium of
the plate was removed and 100 μL of DMSO was added to dissolve
the MTT Formosan precipitate. The absorbance of samples in each
well was determined at 570 nm.
–
the v(N H) stretching frequency for compound (2) [8]. The band
at 1069 cm−1 can be also assigned to the HN–N vibration in the
spectra of the Schiff base (2).
The UV–Vis spectra of the compounds (1), (2) are depicted
in Figs. 1. The absorption spectra of the prepared compounds
were recorded in EtOH (10−5 M). In the UV–Vis spectrum of the
Schiff base compound (1), an intense peak at around 249 nm
can be assigned to the π →π∗ transitions of the aromatic rings.
The shoulder signal at 390 nm can be also attributed to the
π →π∗transitions of the azomethine groups while the peak at
432 nm is related to the n →π∗ transition.
In the electronic absorption spectra of the compound (2), an
intense peak at around 243 nm is indicative of the π →π∗ transi-
tions of the aromatic rings. The shoulder signal at 295 nm can be
also assigned to the π →π∗transitions of the azomethine groups.
On the other hand, the π →π∗ transitions of the azomethine
group showed a blue shift by about 95 nm. The peak at 385 nm
can be also attributed to the π →π∗ transition in the (C=N), which
blue-shifted by 47 nm compared to the compound (1) [25,34].
The synthesized compounds (1) and (2) were diamagnetic and
hence, NMR spectroscopy provided useful characterization data. In
the 1H NMR spectrum of the Schiff base compound (1) Figures
3. Results and discussion
3.1. Synthesis
Two new compounds were synthesized via reacting 2, 4-
dinitrophenylhydrazine with methyl acetoacetate, and α- hydrox-
yacetophenone in DMSO. All compounds were soluble in organic
solvents such as DMSO, MeOH, and EtOH. These compounds were
characterized by FT-IR, UV–Vis, 1H NMR, Mass spectra, melt-
ing point assessment, and conductivity measurement. The crystal

4
S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
Fig. 2. ORTEP view of 1, together with the numbering scheme. Ellipsoids are drawn at the 50% probability level; hydrogen atoms are represented by spheres of arbitrary
radii. Intramolecular hydrogen bond is shown as dashed blue line. (For interpretation of the references to color in this figure legend, the reader is referred to the web version
of this article.)
Table 2
˚
Selected geometrical parameters (A, °) with s.u.’s in parentheses. . Capital letters denote the
least-squares planes: A – nitrophenyl ring, B – nitro group at position 2, C – nitro group at 4,
–
–
–
D – the C
N
N=C C chain, and E – the terminal group: COOC (1) or phenyl ring (2).
(1)
(2)
N-O
1.218(5) 1.233(5) 1.222(5) 1.238(5)
1.232(7) 1.236(7) 1.225(8) 1.226(8)
–
C1 N7
1.356(5)
1.383(5)
1.282(5)
122.2(4) 123.5(4)
119.0(4)
116.2(3)
4.1(5)
1.361(8)
1.371(7)
1.286(7)
121.1(6) 120.9(7)
118.1(5)
118.5(5)
7.8(6)
–
N7 N8
N8-C9
O-N-O
–
–
C1 N7 N8
N7-N8-C9
A/B
A/C
4.0(7)
4.9(4)
B/C
5.6(8)
10.4(8)
A/D
8.0(2)
1.36(17)
1.89(17)
1.83(16)
D/E
68.8(3)
A/E
71.1(2)
Table. 3
S.3 (Supplementary materials), the signal above 10 ppm could be
˚
Hydrogen bond data for ligands (1) and (2) (A, °).
–
due to the protons of N H groups (a). The multiplets at around 7–
8 ppm could be assigned to the aromatic protons (b). Other signals
were also consistent with the proposed structure and attributed to
the experimental section. The signal above 3.5 ppm was due to the
D
H
O
D-H
H...O
D... O
D-H...O
(1)
2.02(6)
(2)
N7
H7
O22
0.86(5)
2.617(5)
126(5)
–
protons of O CH3 groups (c). The protons due to the CH2 groups
with appropriate intensity has also appeared at 3.4 ppm was con-
sistent with the obtained structures (d). The signal above 2 ppm
was due to the protons of CH3 groups (e).
N7
N7
H7
H7
O22
O11
0.86
0.86
2.00
2.18
2.617(7)
2.785(8)
128
127
In the 1H NMR spectrum of the Schiff base compound (2) Fig-
ures S.4 (Supplementary materials), the signal above 13 ppm was
the approximately planar fragments (cf. Table 2). The nitro groups
are almost slightly twisted with respect to the phenyl ring plane,
as can be expected for non-neighbouring groups. Molecules (2) are
in quite good approximation planar, while in molecule (1) due to
the presence of methylene group the terminal ether fragment is
–
due to the protons of N H groups (a). The multiplets at around 7–
8 ppm were due to the aromatic protons (b). The signal 6.5 ppm
–
was due to the protons of O H groups (c). The protons due to the
CH2 groups with appropriate intensity has also appeared at above
4 ppm was consistent with the obtained structures (d) [35]. The
Mass spectrum of Schiff base compounds, (1) and (2) Figures S.5,
6 (Supplementary materials) showed a molecular ion peak [M]+ at
m/z 296, 316 which corresponds to its proposed molecular formula,
respectively.
˚
relatively tilted. Table 3 show is Hydrogen bond data (A, °).
As can be seen in Fig. 4, this is the only important difference
between the molecules, the rest of the molecules are very simi-
lar. Intramolecular N H•••O hydrogen bonds (bifurcated in case of
–
(2)) additionally add for the stability of planar conformation. In the
crystal structures of (2) the principal role is played by π•••π in-
teractions, which connect molecules into dimers (interplanar dis-
3.3. Description of the crystal structures
˚
tances around 2.4 A), for which the UNI intermolecular potentials
ORTEP views of the molecules are shown in Figs. 2 and 3 se-
lected geometrical parameters are listed in Table 2. The conforma-
tion of the molecules can be described by dihedral angles between
have by far the highest absolute values, around −100 kJ/mol [36,
37]. In (1), due to the presence of methylene groups such a good
fit is not possible and therefore the highest potentials between

S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
5
Fig. 3. ORTEP view of 2, together with the numbering scheme. Ellipsoids are drawn at the 50% probability level; hydrogen atoms are represented by spheres of arbitrary
radii. Intramolecular hydrogen bond is shown as dashed blue line. (For interpretation of the references to color in this figure legend, the reader is referred to the web version
of this article.)
Fig. 4. A comparison of the shapes of molecules 1 (red) and 2 (blue). The nitrophenyl rings were fitted. (For interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.)
neighbours are almost two times smaller. Interestingly, the poten-
tials calculated for hydrogen- bonded pairs are even smaller, up to
−20 kJ/mol.
tained by B3LYP method for (1) and (2) compounds are more con-
sistent with investigational information.
3.4.2. Vibrational analysis
Frequency calculations were performed at this level of theory
which confirmed that the optimized structures belonged to the
minima on the potential energy surface. Fig. S1 shows the exper-
imental and calculated FT-IR spectra of compounds. Table 5 lists
the experimental vibrational wavenumbers and their correspond-
ing calculated values with the probable assignments.
3.4. Computational chemistry and density functional theory (DFT)
calculations
3.4.1. Computational molecular structure
All the DFT calculations, including the full geometry optimiza-
tions for Methyl (Z)-3-(2-2, 4-dinitrophenyl)hydrazono)butanoate
(1) and (Z)-3-(2-(2, 4-dinitrophenyl)hydrazono)-3-phenylpropan-1-
ol (2), were conducted using CIF as the experimental structure to
obtain the vibrational frequency from the basis set (i.e., 6-311+G
(d, p)). After optimizations, the geometric parameters of the com-
putational data (e.g. bending angles, the torsional angles, and the
bond lengths) were analyzed by Gaussview and compared with the
experimental data. The comparison of data showed slightly com-
puted larger bond length and angle as compared with the experi-
mental data. According to Table 4, the bond length and angles ob-
According to Table 5, the B3LYP method was more consistent
–
with the empirical data. The C H stretching vibration modes of
CH2 occur in the range of 2984–3095 cm−1 in compounds (2)
and (1), respectively. Meanwhile, the peaks in the range of 2977–
3102 cm−1 (B3LYP/6-311+G (d, p)) can be attributed to the C H
–
–
stretching vibration modes. The stretching vibration modes of C H
bonds of phenyl ring occurred at 3118 and 2489 cm−1 in com-
pounds (1) and (2), respectively; the B3LYP method showed the
mentioned peaks at 3237, 2977 cm−1, respectively. The experi-
–
mental N H stretching vibration mode of compounds (1) and (2)

6
S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
Table 4
˚
The most important geometric parameter including the bond length (A), the bond angles and the torsion angles (°) calculated in the base set 6–311+G(d, p).
Parameter
Length bond
–
X-ray
B3LYP/6–311+G(d, p)
1.284 1.016 1.225, 1.227 1.221, 1.242 1.360 1.206, 1.344
122.80 117.24 122.97 124.71
(1)
–
–
–
O
C=N H- N O(Ortho)N O(Para) C N C
1.282 0.860 1.222,1.238 1.218,1.233 1.356 1.170,1.296
Angels
118.71 116.20 122.24 123.54
(2)
–
–
H-N-N C=N- N O(Ortho) N O(Para)
Length bond
C=N
1.286
0.86
1.290
1.019
–
H
N
–
N
O(Ortho)
1.226,1.232
1.225,1.236
1.361
1.226,1.239
1.225,1.227
1.362
–
N
O(Para)
C-N
–
O
C
H
O
0.854
0.963
–
1.371
1.430
Angels
–
–
–
H
N
N
139.97
118.15
121.16
120.91
118.55
121.18
120.85
118.12
123.16
124.68
118.12
123.16
C=N
N
N-O(Ortho)
–
N
O(Para)
–
C=N
N
–
N
O(Ortho)
Table 5
with oscillator strengths of 0.0329 - 0.0531 eV and at 390 nm
which can be assigned to the π →π∗ transition in C=N. The π
→π∗ transition in C=N in (1) was observed at around 369 nm
with a bond energy of 3.355 eV and f = 0.5730 (orbital excita-
tion: HOMO→LUMO +1, 97% contribution). The TD-DFT calcula-
tions also confirmed the existence of a signal in this region. The
calculated wavelength is in good agreement with the experimental
value. Also, the maximum absorption by the electronic transmis-
sions of HOMO →LUMO occurred with the oscillation strength of
0.0899 and the band energy of 2.916 eV at a wavelength of 418
(n→π∗ transition in C=N). The spectrum obtained from TD-DFT
calculations in methanol showed the absorption band in the range
of 256–266 nm with a bond energy of 4.825–4.654 eV and oscil-
lator strengths of 0.0328–0.1057 the absorption band of 369 nm
with a bond energy of 3.356 eV and with oscillator strengths of
0.5670. In the case of DMSO solvent, TD-DFT computations exhib-
ited an absorption band at 257–273 nm with a bond energy of
4.822–4.531 eV and oscillator strengths of 0.0329–0.0472 as well
as an absorption band at 371 nm with a bond energy of 3.339 eV
and oscillator strength of 0.582. For (2), The UV–Vis spectrum in
EtOH showed a band at 243 nm which may be assigned to the
π →π∗ transition in the aromatic ring. The results calculated in
the same solvent indicated an absorption band at 274 nm with a
bond energy of 4.523 eV and oscillator strength of 0.0817. The band
at 295 nm can be assigned to the π →π∗ transition in C = N.
The calculated results indicated an absorption band at 305 nm
with a bond energy of 4.055 eV and f = 0.2037 (orbital excitation:
HOMO→LUMO+2 65%, HOMO-2→LUMO+1 25%, HOMO-2→LUMO
5% and HOMO-1→LUMO+1 2%). Moreover, the maximum absorp-
tion by the electronic transmissions of HOMO →LUMO with the
oscillation strength of 0.1238 and the energy of 2.653 eV was de-
termined at 467 nm. The spectrum obtained from TD-DFT calcu-
lations in MeOH solvent exhibited an absorption band at 274 nm
with a bond energy of 4.525 eV and f = 0.0870 and one at 305 nm
with a bond energy of 4.055 eV and f = 0.2046. The spectrum ob-
tained from calculations in DMSO showed two absorption bands;
one at 274 nm with a bond energy of 4.159 eV and f = 0.1231
and the other at 306 nm with a bond energy of 4.048 eV and
f = 0.2058. The calculated wavelength is in good agreement with
the experimental data. Polar solvents can affect the geometric
and electronic structure as well as the properties of the molecule
The important vibrational frequency of experimental and computational data
and vibrational modes using the B3LYP and experimental data in the base set
(6-311+G (d, p)).
Experimental
Calculated B3LYP/6-311+G (d, p)
Tentative assignment
(1)
–
υ (N H)
3125
3118
3480
3237
–
υ (C H)Ph
–
3095
3102
υ (C H)CH2
3083
3163,3133,3054
1791
υ (CH3)methoxy
υ (C=O)
1678
1613
1684
υ (C=N)
1405,1339
1594,1361
υ (NO2)
(2)
–
υ (O H)
3260
3115
3830
3436
–
υ (N H)
–
υ (C H)CH2OH
2984
3085
–
2489
2977
υ (C H)Ph
1614
1654,1648
1561,1359
υ (C=N)
υ (NO2)
1525,1446
can be observed at 3125 and 3115 cm−1; theoretical investiga-
tion showed wavenumbers higher than about 3480, 3436 cm−1
(for B3LYP method). The stretching vibration modes of C=N bonds
are indexed to the bands at 1684, 1654–1648 (for B3LYP method)
for compounds (1) and (2). The results showed that computa-
tional chemistry could properly reproduce the structure of the
compounds.
3.4.3. UV–Vis spectrum
TD-DFT calculations were also applied for a better descrip-
tion of the experimental UV–Vis signals. Using TD-DFT calcula-
tions, spectral characteristics such as maximum energy excitation,
and oscillation strengths can be calculated. Hence, only the single
transitions of absorption bonds with oscillation strengths (>0.03)
and wavelengths (>200) nm in the methanol, ethanol and DMSO
solvents for compounds (1) and (2) are shown in Table 6. The
UV–Vis spectrum of (1) in EtOH showed a band at 249 nm that
may be assigned to the π →π∗ transition in the aromatic ring.
The results calculated in the same solvent indicated the absorp-
tion band at 256–266 nm with a bond energy of 4.826–4.657 eV

S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
7
Table 6
Unique absorption bands with oscillation strengths (>0.03) and wavelength (>200) nm.
Solvent
λcal
f
Energy
(eV)
Combining configuration with
Assignment
absorption coefficient (>0.2)
(1)
Methanol
256
266
369
418
0.0328
0.1057
0.5670
0.0899
4.825
4.658
3.356
2.916
(66 ->78), 0.31365,
(73 ->78), 0.26661
(74 ->78), 0.37184,
(74 ->79), 0.33232
(77 ->79), 0.69710
(77 ->78), 0.69806
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π →π∗)C=
N
(n→π∗)C=
N
Ethanol
DMSO
CH2Cl2
CHCl3
256
266
369
418
0.0329
0.0531
0.5730
0.0913
4.826
4.657
3.355
2.962
(66 ->78), 0.30560,
(73 ->78), 0.28011
(74 ->79), 0.31916,
(76 ->79), 0.42568
(77 ->79) 0.69761
(77 ->78) 0.69859
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π →π∗)C=
N
(n→π∗)C=
N
257
266
371
420
0.0329
0.0527
0.582
4.822
4.650
3.339
2.951
(66 ->78), 0.32161,
(73 ->78), 0.25752
(75 ->79) 0.45556,
(76 ->79) 0.24338
(77 ->79) 0.69695
(77 ->78) 0.69789
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π →π∗)C=
N
0.0939
(n→π∗)C=
N
256
264
367
415
0.0292
0.0172
0.584
4.829
4.686
3.372
2.983
(66 ->78), 0.20499,
(73 ->78), 0.41844
(75 ->79) 0.33796,
(76 ->79) 0.50111n
(77 ->79) 0.70013
(77 ->78) 0.70130
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π→π∗)C=
N
0.0936
(n→π∗)C=
N
257
264
364
411
0.0151
0.0938
0.589
4.811
4.683
3.040
3.012
(73 ->79), 0.27768,
(73 ->78), 0.5644,
(75 ->79), 0.20658
(74 ->78) 0.36979,
(74 ->79) 0.27698
(77 ->79) 0.70180
(77 ->78) 0.70326
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π→π∗)C=
N
0.0946
(n→π∗)C=
N
n-Hexane
254
264
353
400
0.0171
0.0037
0.576
4.873
4.695
3.507
3.096
(76 ->79), 0.53489
(75 ->78) 0.43658,
(74 ->78) 0.30784,
(73 ->78) 0.34439,
(73 ->79) 0.21030
(77 ->79) 0.69969
(77 ->78) 0.70293
(π→π∗)aromatic ring
(π→π∗)aromatic ring
(π→π∗)C=
N
0.0950
(n→π∗)C=
N
(2)
Methanol
Ethanol
274
305
467
0.0870
0.2046
0.1238
4.525
4.055
2.653
(72 ->83), 0.24785,
(72 ->84), 0.36449,
(78 -> 83), 0.40988
(82 ->85), 0.56559
(82 ->83), 0.70432
(π→π∗)aromatic ring
(π →π∗)C=N
(n→π∗)C=N
274
305
467
0.0817
0.2037
0.1275
4.523
4.055
2.653
(72 ->83), 0.25448,
(72 ->84), 0.37694,
(78 ->83), 0.39531
(80 ->84), 0.47100,
(82 ->85), 0.28635
(82 ->83), 0.70432
(π→π∗)aromatic ring
(π →π∗)C=N
(n→π∗)C=N
DMSO
274
306,
468
0.1234
0.2058
0.1295
4.519
4.048
2.645
(72 ->83), 0.20858,
(78 ->84), 0.48644
(80 ->84), 0.35120,
(82 ->85), 0.56829
(82 ->83), 0.70422
(π→π∗)aromatic ring
(π →π∗)C=
N
(n→π∗)C=
N
CH2Cl2
275
304
462
0.0110
0.1684
0.1524
4.500
4.078
2.682
(73 ->83), 0.26312,
(73 ->84), 0.51304
(82 ->85), 0.57893
(82 ->83), 0.7036
(π→π∗)aromatic ring
(π →π∗)C=N
(n→π∗)C=N
CHCl3
274
305
465
0.0301
0.1925
0.1404
4.516
4.064
2.664
(73 ->83), 0.27439,
(73 ->84), 0.47440
(82 ->85), 0.57939
(82 ->83), 0.70439
(π→π∗)aromatic ring
(π →π∗)C=N
(n→π∗)C=N
n-Hexane
278
303
452
0.0092
0.1467
0.1719
4.457
4.091
2.742
(73 ->84), 0.49401
(82 ->85), 0.46224
(82 ->83), 0.70134
(π→π∗)aromatic ring
(π →π∗)C=N
(n→π∗)C=N

8
S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
Fig. 5. The molecular orbital plots for (1) and (2).
Table 7
Calculated excitation wavelengths (λcal/nm), major contribution and energy of ligands in ethanol solvent.
Transmission
λcal
Major contribution (>5%)
orbital distribution
Energy (eV)
(1)
–
HOMO → LUMO +1
HOMO → LUMO
369
418
97%
phenyl ring, C=N, N H, (NO2)
,
3.356
2.916
para
C=O and (CH3)
atoms
Ketone
ortho
97%
phenyl ring and (NO2)
atoms
ortho
(2)
HOMO→LUMO+2,
HOMO-2→LUMO+1,
HOMO-2→LUMO
HOMO → LUMO
305
467
97.%
phenyl ring, C=N and (NO2)
4.055
2.653
Ortho
–
99%
phenyl ring, N H, C=sN, (O)OH and
Para, Ortho
(NO2)
atoms
through their interaction with the dissolved molecule. Investiga-
tions on compounds (1) and (2) showed that of the solvent effect
is not significant. For the compound (1), the data obtained from
TD-DFT in n-Hexane were more consistent with the experimental
data. For the compound (2), the wavelengths in the polar solvent
were similar to the non-polar solvent. More information on the
calculated electronic spectroscopy data of compounds (1) and (2)
are presented in Table 6.
the (phenyl ring)hydrazine and (NO2)
atoms whereas, in HOMO-
ortho
2 → LUMO (5%) of (2), the orbital distribution is larger on the
(NO2) atoms [25].
para, ortho
The electronic spectra show the energies of compounds (1) and
(2) as 3.355 and 4.055 eV at the wavelengths of 369 and 305 nm,
respectively. These high energy gaps indicate a good consistency
as well as high chemical strength lower reactivity of the unit [39].
The compound (2) had the highest energy gap and higher chemical
rigidity as compared with the compound (1).
3.4.4. Frontier molecular orbital analysis
According to the frontier molecular orbital theory, HOMO and
LUMO are the most effective factors in the bioactivity. HOMO has
the priority to provide electrons, while LUMO can accept electrons.
Thus, the study on the frontier orbital energy can provide useful
information about the biological mechanism. Also, The difference
in energy between these two frontier orbitals can be used to pre-
dict the strength and stability of transition metal complexes, as
well as the colors they produce in solution [38].
3.5. Biological essays
3.5.1. Assessment of cytotoxicity using MTT assay
To further understanding on the mechanism of antiproliferative
activities of hydrazine, their inhibitory activities for CDK4, CDK2,
cyclin D, cyclin E proteins, and EGFR/ErbB-2 have been assessed.
Most anticancer drugs are focused on blocking the cell cycle in
the S or G2/M phases. It is well known that cisplatin usually in-
duces cell cycle arrest at the S phase, which signifies the inhibition
of DNA synthesis. The cell cycle distribution analysis of hydrazine
and their complexes showed that they could markedly increase the
cell death in S-phase or accumulation of the G1 population and in-
duce cell apoptosis by cyclin D1/CDK4 inhibitory activity and DNA
damage [40–42]. Moreover, hydrazines have demonstrated a potent
dual inhibitory effect on EGFR/ErbB-2 as well as inhibiting ErbB-2
over-expressing in human cancer cell lines [43].
Fig.
5 displays the molecular orbital of compounds while
Table 7 lists the calculated excitation wavelengths (λcal/nm) and
energy of compounds. The HOMO and LUMO are scattered on
–
phenyl ring atoms, C=N, NO2, and N H through various relations.
In HOMO → LUMO, the orbital distribution is larger on the phenyl
ortho
ring and (NO2)
atoms. For HOMO → LUMO +1 transitions
(97% Occupied volume of orbitals), the orbital distribution was
–
larger on the phenyl ring, C=N, N H, (NO2)
Ketone
,
C=O and
para
ortho
(CH3)
atoms of (1). In the case of (2), HOMO → LUMO orbital
In another research, Shp2 (a protein tyrosine phosphatase (PTP)
(PTPN11)) was inhibited by hydrazine (phenylhydrazonopyrazolone
sulfonate) indicating that hydrazine can positively regulate the
growth factor signaling in pediatric leukemia, juvenile myelomono-
cytic leukemia (JMML), and in myelodysplastic syndrome, acute
–
distribution is largely distributed on the phenyl ring, N H, C=N,
Para, Ortho
(O)OH and (NO2)
atoms; while in HOMO → LUMO +2
(65%), the orbital distribution mainly on the (phenyl ring)Ketone. For
HOMO −2→ LUMO +1 (25%), the orbital distribution is larger on

S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
9
Fig. 6. The anti-growth effect after the treatment with varying doses of compounds 2, 4-dinitrophenylhydrazine, (1) and (2), against cancer cell line in K562 (myelogenous
leukemia cancer) by the MTT as described in the experimental section. Data were normalized as a percentage of values of the control (p < 0.05).
Fig. 7. The anti-growth effect after the treatment with varying doses of compounds 2, 4-dinitrophenylhydrazine, (1) and (2), against cancer cell line in MG63 (osteosarcoma
cancer) by the MTT as described in the experimental section. Data were normalized as a percentage of values of the control (p < 0.05).
myeloid leukemia, and some solid tumors [44]. Furthermore, sul-
fonylhydrazone has been considered as a potent Phosphatidylinos-
itol 3-kinase (PI3K) inhibitor. As a regulator of intracellular signal-
ing pathways, PI3K signaling can be negatively regulated by PTEN,
which is overexpressed in the majority of human cancers as one of
the most commonly mutated proteins [45, 46]. N-benzoxazol-2-yl-
N’-1-(isoquinolin-3-yl-ethylidene)-hydrazine (EPH136) has shown
antitumor activity by DNA synthesis, RNA synthesis, and ribonu-
cleotide reductase [47]. Cell cytotoxicity of aroylhydrazone com-
plexes Ln(III) was examined by a standard MTT assay on hepato-
blastoma cells (HepG2) and human lung adenocarcinoma epithe-
lial cells (A549). These results suggested high anti-tumor activity
of the Ln(III) complexes through the necrotic mechanism and DNA
cleavage [48]. The MTT assay is a suitable approach to assess the
in vitro anticancer activity of the compounds. It is expressed as the
required concentration of compounds for 50% inhibition of cancer
cell viability (IC50) after 48 h [49–51].
dose-dependent against K562 and MG63 cell lines with approx-
imate IC50 values of 10, 2.5 and 5 ng/mL at 48 h, respectively.
Consequently, it has been suggested that the newly synthesized
compounds (1) and (2), showed anticancer activity toward K562
and MG63 cell lines. Detailed in vivo and in vivo tests of anti-
cancer efficacy of these compounds must be surveyed in the fu-
ture. Moreover, the compound (1) exhibits the highest cytotoxic
activity.
In this study, the Schiff’s base hydrazine derivatives were syn-
thesized from methyl acetoacetate and α-hydroxyacetophenone
with 2, 4-dinitrophenylhydrazine. The structures of the compounds
(1) and (2) were investigated by X-ray diffraction. Also, FT-IR, UV–
Vis, 1H NMR, Mass spectra, melting point assessments, and con-
ductivity measurements were conducted for sample characteriza-
tion. DFT calculations were used to study the optimized structure
of these ligands as well as their FT-IR, and UV–Vis spectra. The
spectroscopic data concerning compounds in the “Experimental”
section are in good agreement with the expected values. The anti-
cancer effects of the compounds were evaluated towards K562 and
MG63 using MTT assay. The synthesized compounds were screened
for dose-dependent in vitro of anticancer activities against myel-
ogenous leukemia cancer K562 and osteosarcoma cancer MG63.
Comparing the IC50 values revealed that both compounds (1) and
(2) had high cytotoxic activity against the K562 and MG63cancer
cells. These results suggest that compounds (1) and (2) may be
The synthesized compounds were screened for their in vitro cy-
totoxicity and growth inhibitory activities against different human
tumor cell lines including myelogenous leukemia cancer K562 and
osteosarcoma cancer MG63. 5-Fluorouracil is a common drug used
to treat gastric and colorectal cancers. The 5-Fluorouracil-treated
cells treated were considered positive control; while the untreated
ones were regarded as negative control [52]. As shown in Figs. 6
and 7, IC50 values of 2, 4-dinitrophenylhydrazine (1) and (2) were

10
S. Parvarinezhad and M. Salehi / Journal of Molecular Structure 1225 (2021) 129086
considered as a therapeutic agent in cancer treatment and man-
agement.
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Author contribution statement
SP. conducted most of the experiments. SP, analyzed the data
with the help of MS and prepared the manuscript under the
the supervision of MS. MS directed, designed, gave insight and in-
terpreted the spectroscopic data of the research project. AG. car-
ried out the X-ray analysis of this project. AK. did the Biological
study of this project. All authors have significant contribution on
conducting this research work and presenting the manuscript.
[17] S.N. Podyachev, B.M. Gabidullin, V.V. Syakaev, S.N. Sudakov, A.T. Gubaidullin,
W.D. Habicher, A.I. Konovalov, The role of preorganization of hydrazone moi-
eties on tetrathiacalix[4]arene platform for their conformational and binding
properties from the view of structural investigation, J. Mol. Struct. 1001 (2011)
125–133.
Declaration of Competing Interest
[18] Z.H. Chohan, M.A. Farooq, A. Scozzafavab, C.T. Supuran, Antibacterial Schiff
bases of oxalyl-hydrazine/diamide incorporating pyrrolyl and salicylyl moieties
and of their zinc(II) complexes, J. Enzyme Inhib. Med. Chem. 17 (1) (2002) 1–7.
[19] P. Crisalli, E.T. Kool, Importance of ortho proton donors in catalysis of hydra-
zone formation, Org. Lett. 15 (7) (2013) 1646–1649.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
[20] W.-L. Ye, Y.-P. Zhao, H.-Q. Li, R. Na, F. Li, Q.-B. Mei, M.-G. Zhao, S.-Y. Zhou,
Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for tar-
geted therapy of bone metastatic cancer, Sc. Rep. 5 (2015) 14614.
[21] H.H. Monfared, O. Pouralimardan, C. Janiak, Synthesis and spectral char-
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drazine. crystal structure of salicylaldehyde-2, 4-dinitrophenylhydrazone, Z.
Naturforschung 62 (5) (2007) 717–720 B.
Acknowledgments
We thank Semnan University for supporting this study. The au-
thors deem it necessary to appreciate Mrs. Anita Grzes´kiewicz,
Adam Mickiewicz University, Poznan, Poland, Mr. Ali Khaleghian,
Biochemistry Department, University of Medical Sciences, Semnan,
Iran, who generously helped us to flourish this research work.
[22] Ji.
Ning-Ning,
Shi
Zhi-Qiang,
1-Cyclopentylidene-2-(2,
4
dinitro-
phenyl)-hydrazine, Acta Cryst 64 (2008) o2141 E.
[23] Ji. Ning-Ning, Shi. Zhi-Qiang Shi, Zhao Ren-Gao, Zheng Ze-Bao, Li. Zhi-Feng,
Synthesis, crystal structure and quantum chemistry of a novel Schiff base N-(2,
4-dinitro-phenyl)-N’-(1-phenyl-ethylidene)-hydrazine, Bull. Korean Chem. Soc.
31 (2010) 4.
Supplementary materials
[24] H. Hongfei, L. Yaohua, A monoclinic polymorph with Z = 4 of (E)-2, 4-di-
hydroxyacetophenone 2, 4-dinitrophenylhydrazone N, Ndimethylformamide
monosolvate, Acta Cryst. (2011).
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129086.
[25] S. Parvarinezhad, M. Salehi, Sh. Kademinia, M. Kubicki, The structural study,
Hirshfeld surface analysis, and DFT calculations of ferrocenyl-hydrazine Schiff
base: a novel precursor for the selective preparation of Fe2O3 nanoparticles, J.
Mol. Struct. 1197 (2019) 96–107.
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