Novel aldehyde and thiosemicarbazone derivatives: Synthesis, spectroscopic characterization, structural studies and molecular docking studies

Article abstract of DOI:10.1016/j.molstruc.2016.07.013

In this study our purpose is that, synthesis and characterization of compounds containing the aldehyde and thiosemicarbazone groups and comparison of the theoretical results with the experimental results. The structures of all synthesized compounds were e

Full text of DOI:10.1016/j.molstruc.2016.07.013

Accepted Manuscript
Novel aldehyde and thiosemicarbazone derivatives: Synthesis, spectroscopic
characterization, structural studies and molecular docking studies
Tuncay Karakurt, Hakan Tahtaci, Nuriye Tuna Subasi, Mustafa Er, Erbil Ağar
PII:
S0022-2860(16)30684-6
10.1016/j.molstruc.2016.07.013
MOLSTR 22716
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 27 January 2016
Revised Date: 7 July 2016
Accepted Date: 7 July 2016
Please cite this article as: T. Karakurt, H. Tahtaci, N.T. Subasi, M. Er, E. Ağar, Novel aldehyde and
thiosemicarbazone derivatives: Synthesis, spectroscopic characterization, structural studies and
molecular docking studies, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.07.013.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
NOVEL ALDEHYDE AND THIOSEMICARBAZONE DERIVATIVES: SYNTHESIS,
SPECTROSCOPIC CHARACTERIZATION, STRUCTURAL STUDIES AND
MOLECULAR DOCKING STUDIES
Tuncay Karakurta,*, Hakan Tahtacib, Nuriye Tuna Subasic Mustafa Erd and Erbil Ağare
aDepartment of Chemical Engineering, Faculty of Engineering and Architecture, Ahi Evran
University, 40100, Kırşehir, Turkey
bDepartment of Polymer Engineering, Faculty of Technology, Karabük University, 78050
Karabük, Turkey
cDepartment of Food Engineering, Faculty of Engineering and Architecture, Ahi Evran
University, 40100, Kırşehir, Turkey
dDepartment of Chemical Engineering, Faculty of Engineering, Karabük University, 78050
Karabük, Turkey
eDepartment of Chemistry, Faculty of Arts and Sciences, Ondokuz Mayıs University, 55139
Samsun, Turkey
*Corresponding author. Tel.: +90 5444571796, Fax: +90 386 280 38 01
E-mail address: tuncaykarakurt@gmail.com (T. Karakurt)
1

ACCEPTED MANUSCRIPT
Abstract
In this study our purpose is that, synthesis and characterization of compounds
containing the aldehyde and thiosemicarbazone groups and comparison of the theoretical
results with the experimental results. The structures of all synthesized compounds were
1
elucidated by IR, H NMR, 13C NMR, elemental analyses techniques. The structure of
compound (4) (C9H8N4O2S) was also elucidated by X-ray diffraction analysis. In addition, the
1
theoretical IR spectrum, H NMR and 13C NMR chemical shift values, frontier molecular
orbital values (FMO) of these molecules were analyzed by using Becke-3- Lee-Yang-Parr
(B3LYP) method with LanL2DZ basis set. Finally, molecular docking studies were performed
on synthesized compounds using the 4DKI beta-lactam protein structure to determine the
potential binding mode of inhibitors.
Keywords: Aldehyde; Thiosemicarbazone; NMR; B3LYP; Beta-lactam
2

ACCEPTED MANUSCRIPT
1. Introduction
Although recently, there were significant increases in the number of compounds
having various biological activities their use has been rather limited because of the emergence
of drug resistance to these compounds and their various side effects. For these reasons,
chemists have been made a great effort to the development of compounds with biological
activity that will be used in pharmaceutical chemistry. Due to having wide-spectrum
biological activity of thiosemicarbazone derivatives that synthesis studies made, interest on
these compounds has been considerably increased in the pharmaceutical sector at the present
time. Supraventricular or ventricular (cardiac arrhythmia) disorders in which the
thiosemicarbazone derivative of 3-amino-2-pyridine carboxaldehyde (triapin) [1] that is used
as among the rhythm regulators in the treatment is known to be a new third generation anti-
arrhythmic (rhythm regulators) [2].
Thiosemicarbazones and semicarbazones due to be a small molecule widely used in
the treatment of antiviral, anticancer and antiparasital disease. More recently, it has been
found that they are highly effective antiparasital compounds against trypanasoma cruzi
parasites that cause especially Malaria and Cagas diseases. Generally, thiosemicarbazones
show this effect by causing the inhibition of cysteine proteases in this type of parasites and
derivatives [3-6]. In higher electroshock applications aryl semicarbazones are known to cause
antiepileptic effects on the central nervous system [7-12].
In other study menthone derivatives of thiosemicarbazone and semicarbazones were
determined to have anti-HIV activity in an interesting way [13].
In another study of the thiosemicarbazones it was determined that salicyaldehyde
thiosemicarbazones act as a pharmacophore (play regulatory role against certain amino acid
protein) by forming dicyclic chelates with binding metal ions [14]. A study made on hydroxy
derivatives of thiosemicarbazone and semicarbazones lower toxic effects and higher
anticancer effects of the hydroxy semicarbazone were drown attention and this type of
compounds have been shown to act as a ribonucleotide reductase (RR) inhibitors [15, 16].
The biological activity of thiosemicarbazones is due to the aldehyde and ketone
functional groups in their structure [17]. It is emphasized with current research in recent years
that complex structures of thiosemicarbazone derivatives have antibacterial, antifungal,
antiviral and antitumoral [18, 19]. Also the copper complex of thiosemicarbazones was
determined to have quite high antimicrobial activity especially to a group Streptococcus
3

ACCEPTED MANUSCRIPT
which cause tonsillitis [20]. It is indicated in studies that acetylacetone thiosemicarbazone and
their metal complexes are effective against to Staphylococcus aureus, Staphylococcus
epidermidis from G(+) bacteria and Escherichia coli and Pseudomonas aeruginosa from G(-)
bacteria [19]. Furthermore, such molecules are reported to be effective against to human
cancer cells in the literature [21].
Nowadays, beta-lactam antibiotics are the most commonly used antibiotic derivatives.
The most important source of resistance against to beta-lactam antibiotic derivatives of
Enterobacteriaceae family is beta-lactamase enzymes secreted by the bacteria. Beta-
lactamase enzymes are synthesized by mostly gram-negative bacteria, they are believed to be
derived from penicillin binding protein due to having similar sequence analyzes and they
cause resistance to antibiotics with beta-lactam ring. At the present time there are many
identified beta-lactamase enzymes [22]. Beta-lactam antibiotics show their effects by
inhibiting the transpeptidase and carboxypeptidases which are responsible for peptidoglycan
synthesis and stopping the cell wall [23]. All beta-lactam antibiotics show their effects by
binding to target protein which is called penicillin-binding protein (PBP), responsible for the
peptidoglycan synthesis in bacterial cell walls on bacterial cytoplasmic membranes. Since
peptidoglycan cannot be synthesized, cell wall structure is broken in bacteria whom penicillin
binding proteins are inhibited by beta-lactam antibiotics. This situation caused to the loss of
osmotic resistance of bacteria and death [24]. Staphylococcus aureus is the most important
pathogen which synthesizes beta-lactamase in gram-positive bacteria. Staphylococcus aureus
enzymes are under the control of plasmid and they can pass through the sensitive cells by
means of bacteriophages. In case of gram-negative bacteria beta-lactamases are located in the
periplasmic space between the outer membrane and cytoplasmic membrane. In gram-negative
bacteria, beta-lactamase enzymes are synthesized under the chromosome or plasmid control
[25].
In the light of this important data which have been achieved with the literature survey
considering that the thiosemicarbazones are biologically active compounds, synthesis of the
thiosemicarbazone derivatives expected to show positive activity was carried out (Scheme 1).
All of the synthesized compounds are original and their structures were clarified by elemental
analysis and spectroscopic methods (FT-IR, NMR). Besides this, the other aim is that; in
order to support the experimental studies of the synthesized compound to examine
theoretically IR, NMR, UV spectra, potential energy distribution of the vibration frequency
(PED) and the frontier molecular orbital (FMO). Additionally, the structures of (4) and (5)
compounds were compared with the ligands of well-known antibacterial targets. Trial docking
4

ACCEPTED MANUSCRIPT
studies with this enzyme suggested that the crystal structure 4DKI of beta-Lactamase from S.
aureus as most appropriate target of the (4) and (5) compounds.
Scheme 1.
5

ACCEPTED MANUSCRIPT
2. Experimental
2.1. Materials and methods
The reactions were carried out under a nitrogen atmosphere using standard Schlenk
techniques. The 1H NMR and 13C NMR spectra of the compounds were recorded in DMSO-d6
using an Agilent NMR VNMRS spectrometer at 400 MHz and 100 MHz, respectively.
Chemical shift values are given in ppm (δ) with tetramethylsilane (TMS) as internal standard.
The IR spectra were measured in ATR using a Bruker Optics Alpha FT-IR. The mass spectra
were measured with a Thermo TSQ Quantum Access Max LC-MS/MS spectrometer equipped
with ethyl alcohol and chloroform as solvents. Elemental analyses were performed on a
LECO 932 CHNS (Leco-932, St. Joseph, MI, USA) instrument and the results were within ±
0.4% of the theoretical values. Melting points were recorded on a Thermo Scientific IA9000
series apparatus and were uncorrected. All of the chemicals were obtained from Sigma
Aldrich Chemicals. Theoretical calculations of this study were done by using Gaussian 09
[26] and Gaussview 5.0 [27] package programs. In this study Density Functional Theory
(DFT)[28] method is chosen because theoretical calculations of test results which we have
done for the analyzed molecules gave the closest value to the experimental results. B3LYP
hybrid functional which is one of the most commonly used exchange-correlation functionals
that contain Becke’s three-parameter exchange function [29-31] and Lee, Yang and Parr’s
correlation functionals [32] was used in DFT calculation. The LanL2DZ [33-35] base
set, which gave the closest value to our experimental results as well and is widely used for
large molecules, was selected. Veda4 [36] software was used for PED analysis of the
vibration frequency. Molecular docking studies were performed by using Autodock Vina [37]
and Discover studio Visualizer 4.5 [38] programs.
2.2. General procedure for the synthesis of 4,4'-((2,3-bis((4-formyl-2,6-
dimethoxyphenoxy)methyl)but-2-ene-1,4-diyl)bis(oxy))bis(3,5-dimethoxybenzaldehyde) (4)
In a two-necked flask, 4-hydroxybenzaldehyde (3) (0.02 mol) and KOH (0.02 mol)
were dissolved in absolute ethanol (100 mL) and the solution was stirred for 30 minutes at
room temperature. 1,4-dibromo-2,3-bis(bromomethyl)but-2-ene (2) (0.005 mol) was dissolved
6

ACCEPTED MANUSCRIPT
in absolute ethanol (50 mL) and added drop by drop to this solution at room temperature with
the assistance of a dropping funnel. The mixture was then refluxed and stirred for 8-10 h. The
progress of the reaction was monitored by TLC at appropriate time intervals. After
completion of the reaction, the solution was filtered and the solid matter was obtained. It was
washed with deionized water, ethanol and diethyl ether, respectively. The solid matter was
recrystallized from DMF-EtOH, 1:2). The synthesized compound was dried with P2O5 in a
vacuum oven. The physical properties and spectral data of the obtained product are listed
below.
This compound was obtained as white crystals, yield 3.26 g (81%), mp 178-179 °C
(from DMF-EtOH, 1:2; IR (ATR, cm-1): 3062 (Ar-CH), 2976, 2939 (Aliph. CH), 2839–2737
(CHO), 1684 (C=O), 1583, 1495 (CH=CH), 1117 (–OCH3), 1322, 1264, 1223 (=C–O–C); 1H
NMR (400 MHz, DMSO-d6, δ ppm): 3.73 (s, 24H, O–CH3), 4.69 (s, 8H, O–CH2), Ar-H [7.17
13
(s, 8H)], 9.85 (s, 4H, CHO); C NMR (100 MHz, DMSO-d6, δ ppm): 56.39 (O–CH3), 68.61
(O–CH2), Ar-C [106.87 (CH), 132.27 (C), 141.63 (C), 153.83 (C)], 137.48 (-C=C-), 192.33
(C=O). MS: m/z 826.97 (M+Na, 100). Anal. Calcd. for C42H44O16: C, 62.68; H, 5.51. Found:
C, 62.59; H, 5.59.
2.4. General procedure for the synthesis of (2E,2'E)-2,2'-((((2,3-bis((4-((E)-(2-
carbamothioylhydrazono)methyl)-2,6-dimethoxyphenoxy)methyl)but-2-ene-1,4-diyl)bis
(oxy))bis(3,5-dimethoxy-4,1-phenylene))bis(methanylylidene))bis(hydrazine
carbothioamide) (5)
Compound (5) was synthesized according to a method given in the literature [39]. In a
round-bottomed flask, compound (4) (0.0025 mol) and thiosemicarbazide (0.015 mol) were
heated to 140 °C without solvent in an oil bath and stirred for 1 h. After the completion of the
reaction, DMF (20 mL) was added to the reaction content and dissolved. Water was then
added to the solution and a solid precipitated. The solution was filtered and the solid was
obtained. The solid was washed with warm water and absolute ethanol to remove excess
thiosemicarbazide and impurities. The solid was recrystallized from DMF/ethanol (1:1). The
synthesized compound was dried with P2O5 in a vacuum oven. The physical properties and
spectral data of the obtained product are listed below.
This compound was obtained as gray solid, yield 2.08 g (76%), mp 230 °C (decomp.)
(from DMF-EtOH, 1:1); IR (ATR, cm-1): 3259–3156 (NH2), 3162 (–NH–), 3042 (Ar-CH),
2944 (Aliph. CH), 1577 (CH=CH), 1518 (C=N), 1323, 1273, 1233 (=C–O–C), 1123 (–
OCH3); 1H NMR (400 MHz, DMSO-d6, δ ppm): 3.71 (s, 24H, O–CH3), 4.58 (s, 8H, O–CH2),
7

ACCEPTED MANUSCRIPT
Ar-H [7.04 (s, 8H)], 7.93 (s, 4H, CH=N), 8.07 (s, 4H, NH2), 8.19 (s, 4H, NH2), 11.40 (s, 4H,
–NH); 13C NMR (100 MHz, DMSO-d6, δ ppm): 56.45 (O–CH3), 68.82 (O–CH2), Ar-C
[104.85 (CH), 130.20 (C), 138.07 (C), 153.82 (C)], 137.53 (-C=C-), 142.69 (CH=N), 178.17
(C=S).
MS: m/z 1098.19 (M+, 100). Anal. Calcd. for C46H56N12O12S4: C, 50.35; H, 5.14; N, 15.32
Found: C, 50.44; H, 5.28; N, 15.25.
3. Crystal structure determination
X-ray diffraction data of crystal was collected with a Bruker AXS APEX CCD [40]
diffractometer by using MoKα beam. Structure solving of the crystal was obtained by using
direct methods with the SHELXT-2014 [41] program. In solving process, refinement process
was carried out with SHELXL-2014 [42] program which uses full matrix the least squares
method to determine the positions of atoms other than hydrogen. Isotropic refinement was
performed in order to become more sensitive position of atoms in the first stage of the
treatment and for the determination of missing atoms. As a result of refinement process, the
absence of missing atoms other than hydrogen was observed and an anisotropic refinement
was performed. Hydrogen atoms were determined at the next stage of refinement. Hydrogen
atom positions were obtained geometrically according to the overlap method. When placing
hydrogen atoms geometrically an aromatic C-H bond length was fixed at 0.93 Å, methylene (-
CH2) bond length at 0.97 Å and methyl (-CH3) bond length at 0.96 Å. After the process of
structure solving and refinement, ORTEP-3 [43] program was used for molecular drawings,
WinGX [44] and MERCURY [45] programs were used for the calculations.
4. Results and discussion
Compound (2) was synthesized according to a method given in the literature [39]. In the
first part of the study, 4,4'-((2,3-bis((4-formyl-2,6-dimethoxyphenoxy)methyl)but-2-ene-1,4-
diyl)bis(oxy))bis(3,5-dimethoxybenzaldehyde) (4) was obtained in good yield (81%) from the
reaction of 4-hydroxy-3,5-dimethoxy benzaldehyde (3) with 1,4-dibromo-2,3-
bis(bromomethyl)but-2-ene (2) in the presence of KOH and absolute alcohol (Scheme 1). In
the second part of the study, thiosemicarbazone derivative (5) having the role of target
compound was synthesized in high yield (76%) by a condensation reaction of (4,4'-((2,3-
bis((4-formyl-2,6-dimethoxyphenoxy)methyl)but-2-ene-1,4-diyl)bis(oxy))bis(3,5-dimethoxy
benzaldehyde) (4) with thiosemicarbazide (Scheme 1).
8

ACCEPTED MANUSCRIPT
4.1. X-ray structure analysis of crystal (4)
The structure of compound (4) (C42H44O16) was supported by X-ray diffraction analysis.
The structural parameters of the crystal and the details of data collection and refinement
process are given in Table 1. Molecule’s ORTEP diagram drawing with experimental 40%
probability ellipsoids and input molecule used in Gaussian 09 program are given Fig. 1.a The
optimized structures of the molecules (4) and (5) that obtained from theoretical calculations
are shown in Fig. 1.b-c.
(a)
(b)
9

ACCEPTED MANUSCRIPT
(c)
Fig. 1.
Table 1. Data collection and refinement values of compound (4)
Chemical formula
C42H44O16
Formula weight
804.77 (a.k.b)
Temperature
293 K
Wavelength
MoKα, 0,71073 Å
Crystal system
Monoclinic
Space group
I2/a
Diffractometer/measurement
Bruker AXS APEX CCD / ω-scan
Unit cell parameters
a
14.740(12)Å
b
16.500(14)Å
c
16.591(14)Å
α
90°
β
102.369(6)°
γ
90°
Volume
3940.5(6)Å3
Z
4
Calculated density
ꢀ
1.357 gr cm-3
0.105 mm-1
F(000)
1696
crystal size (mm)
Theta range for data collection
Index ranges
0.44x 0.22x 0.16
2.99°- 28.35°
-19≤h≤18, -22≤k≤21, -22≤l≤22
Measured reflections
Independent/
47846
4910
Observed reflections [I>2σ(I)]
Absorption correction
Weighting scheme
3352
Integration (X-RED32)
w=1/[σ2(ꢀꢁꢂ)+(0.0692P)2+4.0624P] P=(ꢀꢁꢂ+2ꢀꢃꢂ)/3
R int
0.0539
Refinement method
Full-matrix least-squares on F2
10

ACCEPTED MANUSCRIPT
Goodness–of–fit on indicator(S) 1.045
R, wR
0.0566, 0.1349
0.004(8)
0.67, -0.22
Extinction coefficient
(∆σ)max, (∆σmin) (e/ Å3)
The compound (4) has non-planar dimethoxybenzaldehyde rings (A(C1-C6) ring and
B(C14-C19) ring). Dihedral angle between A and B rings is 79.15o (9). In similar molecule
this angle was observed as 76.43o (8) in the literature [46]. The molecular structure of (4) is
shown in Fig. 1.a The asymmetric unit contains half a molecule and the complete molecule is
generated by a crystallographic 2-fold axis with direction at 1/2-x,y,-z. The molecule exists in
a Z configuration with respect to the two carbon C11=C12 bonds [1.329 (3) Å]. This bond
length was found to be shorter than C-C bond length of the molecule. In the literature this
length was observed as 1.332(6) Å [47], 1.335(5) Å [47] and 1.318(6) Å) [48]. Likewise,
while bond lengths of C11-C10, C12-C13, C10-O4 and C13-O5 were observed as 1.506(3),
1.505(3), 1.445(2) and 1.445(2) Å, respectively. In the literature these bond lengths were
given as 1.504(3), 1.502(3), 1.434(3) and 1.451(3) Å [49].
The experimental and the calculated bond length and bond angles of the crystal (4) are
shown in Table 2.
Table 2. Experimental and theoretical parameters belonging to compound (4)
Bond length(Å)
O5-C14
O5-C13
O4-C10
O4-C8
Exp.
Cal.(DFT)
1.383
1.498
1.498
1.382
1.386
1.458
1.395
1.459
1.394
1.459
1.392
1.458
1.253
1.252
1.361
1.511
1.513
1.420
1.426
1.422
1.370(2)
1.445(2)
1.445(2)
1.365(2)
1.364(3)
1.427(3)
1.359(3)
1.425(3)
1.362(2)
1.426(3)
1.367(3)
1.421(3)
1.176(3)
1.195(3)
1.329(3)
1.506(3)
1.505(3)
1.394(3)
1.406(3)
1.397(3)
O6-C15
O6-C16
O8-C21
O8-C22
O3-C6
O3-C7
O1-C1
O1-C9
O7-C19
O2-C4
C11-C12
C11-C10
C12-C13
C14-C21
C14-C15
C8-C6
11

ACCEPTED MANUSCRIPT
C8-C1
1.398(3)
1.384(3)
1.385(3)
1.387(3)
1.382(3)
1.479(3)
1.420
1.402
1.407
1.402
1.409
1.476
C6-C5
C1-C2
C15-C17
C18-C20
C18-C19
Bond Angles(o)
C14-O5-C13
C10-O4-C8
C15-O6-C16
C21-O8-C22
C6-O3-C7
C1-O1-C9
C12-C11-C10
C11-C12-C13
O5-C14-C21
O5-C14-C15
O1-C1-C2
C5-C3-C2
C2-C3-C4
C1-C2-C3
115.5(1)
116.5(1)
117.4(2)
117.9(2)
117.5(2)
117.5(2)
123
120.4
119.1
118.4
118.5
118.4
118.4
123.6
123.1
117.8
122.9
124.4
120.8
119
123.3(2)
118.2(2)
121.6(2)
125.0(2)
121.5(2)
120.3(2)
118.9(2)
119.7
Intermolecular C-H…O and intramolecular C-H…O hydrogen bonds were observed in
the crystal. The molecules are bonded to each other with these interactions. It was observed
that intermolecular C-H…O hydrogen bonds of crystal (4) formed the Rꢂꢂ(30) closed ring
according to the symmetry center. C20 atoms in the bond formed for the crystal acts as a
hydrogen bond donors to O2 atom which is at 1-x,1-y,-z position by means of H20 atom (Fig.
2). C10-H10…O3 intramolecular hydrogen bond was observed to form the S(6) closed ring.
The data related to the hydrogen bonds are given in Table 3.
Symmetry operation operators that allow the crystal to repeat itself in the 3-dimensional
space are shown in Fig. 3 (yellow circle = inversion, purple line = sliding plane, green line =
2-axis rotation, brown line = 2-screw axis of symmetry processor).
12

ACCEPTED MANUSCRIPT
Fig. 2.
Table 3. Hydrogen bond geometry for compound (4) C23H25N3OS single crystal (Å, °)
D-H···A
C20- H20···O2i
D-H
H···A
D···A
D-H···A
162(3)
0.86 (3)
0.82(2)
2.28(3)
1.93(2)
3.11(2)
2.65(3)
C10- H10···O3
146(2)
Symmetry codes: i = 1-x,1-y,-z
Fig. 3.
13

ACCEPTED MANUSCRIPT
4.2. IR studies
Molecule (4) containing 24 atoms has C1 symmetry point group and 300 fundamental
vibration frequency while the molecule (5) has C1 symmetry point group and 384
fundamental vibration frequency. In this study, all calculations of the vibration frequency,
supported by potential energy distribution (PED) analysis, were done by using
DFT(B3LYP/LanL2DZ) basis set. Experimental and calculated spectra are shown in Fig. 4-5.
To match the calculation results with the experimental results for each frequency value is
multiplied by the scale value 0.961 [50].
Analyzing the IR spectral data of these compounds the most significant spectral data
for compound (4) is CHO (fermidublet) absorption band of an aldehyde which is observed at
between the ranges of 2839–2737 cm-1. In the literature experimentally this band was
observed as 2724-2894 cm-1 [51], 2796-2894 [47] and 2875-2756 cm-1, respectively [52]. This
vibration was calculated theoretically in the range of 2856–2850 cm-1 with 100-98% PED
contribution which consist of pure C-H modes. Accordingly, because the molecule is
symmetrical C=O absorption bands that bearing an important and specific bands in such
compounds was observed experimentally at 1684 cm-1. In the literature this band was
observed at 1672 [51], 1671-1656 [52] and 1698 cm-1 [47]. Theoretically it was calculated at
between the range of 1603-1600 cm-1 with 67-58% PED contribution which consist of pure
C=O modes. -CH absorption band for the aromatic ring in the compound was observed at
3062 cm-1, C-O-C bands at 1322, 1264 and 1223 cm-1; it has been found that observation of
these values supported the proposed structure. These vibration modes were calculated
between the range of 3114-3094 and 1298-1294 cm-1.
14

ACCEPTED MANUSCRIPT
Fig. 4.
When IR spectral data of compound (5) analyzed, it was determined that C=O
absorption band of the aldehyde functional group used in the synthesis of these compounds
was completely disappeared and instead of this the band of azomethine group (C=N) was
appeared at frequency of 1577 cm-1. This calculated value is given as 1601 cm-1 in the
literature [53]. This vibration was calculated at between the range of 1605-1592 cm-1 with 14-
11% PED contribution that consist of pure C=N modes.
Another important data that proved the formation of thiosemicarbazone derivatives (5)
is that observation of -NH2 symmetric and asymmetric absorption bands at between the range
of 3259–3156 cm-1 and –NH absorption band at 3162 cm-1. Observed symmetric and
asymmetric vibration frequencies of -NH2 group are given at 3330–3450 and 3150–3270 cm-1
[54], and the -NH vibration frequency is given as 3262 cm-1 in the literature [55]. These
vibration modes have been calculated as in the range 3602-3600 cm-1 with 97% PED
15

ACCEPTED MANUSCRIPT
contribution that consist of pure -NH2 modes and as between the range of 3476-3475 cm-1
with 88% PED contribution that consist of pure -NH modes, respectively.
Fig. 5.
4.3. NMR studies
GIAO (Gauge-Independent Atomic Orbital) [56, 57] method was used to determine
the NMR chemical shifts of molecule (4) and (5) and TMS (tetramethylsilane) was used as a
reference calculated 1H NMR and 13C NMR chemical shift values selected dimethyl sulfoxide
(DMSO) for TMS are 32.1 and 184.2 ppm for DFT/B3LYP/Lan2LDZ, respectively.
Experimental and calculated NMR spectra are shown in the Supplementary Material, Fig. S1,
S2.
1
The structure of the compound (4) was confirmed with the assistance of H NMR
spectroscopy. When analyzed the 1H NMR spectra of this compound, aldehyde group (CHO)
proton was observed at 9.85 ppm as a singlet that is corresponding to 4 protons. This chemical
shift value is specific for the aldehyde protons. This value is given as 10.05-10.18 and 10.83-
9.86 ppm in the literature. Calculated chemical shift value of this peak was obtained as 10.03
16

ACCEPTED MANUSCRIPT
ppm. Proton signals which belong to the -OCH2 and -OCH3 of this compound are recorded as
a singlet at 4.69 ppm corresponds to 8 protons and at 3.73 ppm corresponds 24 protons,
respectively. In the literature, proton signal of -OCH2 was observed as 4.23-4.53 [51] and
4.98-4.73 [52] ppm and proton signal of -OCH3 was observed as 3.70 [51] and 3.83 ppm [52].
Theoretically these two peaks were calculated between the range of 5.82-5.20 and 2.44-3.75
ppm. In compound 13C NMR spectrum, while -OCH2 carbon peak signal was recorded at
68.61 ppm as expected from sp3 hybridized carbon atoms, -OCH3 carbon bonded to the
aromatic ring was appeared at 56.53 ppm. In the literature, these two shift values were
observed at 56-65 [46] and 55.55 ppm [52], respectively. Theoretically, these peaks are
calculated at 73.10-71.95 and at 55.06-54.94 ppm. On the other hand, sp2 hybridized C=C and
C=O carbon signals were recorded as expected at 137.48 ppm and at 192.33 ppm,
respectively. These two values are calculated in the range of 138.87-136.77 and 199.36-
199.49 ppm.
The structure of the compound (5) which is a thiosemicarbazone derivative was
confirmed by 1H NMR spectrum. In 1H NMR spectrum of this compound it was observed that
aldehyde proton of (4) (CHO) occurring at about 9.85 ppm are replaced by the proton peak of
azomethine group (CH=N) which is appeared at 7.93 ppm. This value was calculated
theoretically as between the range of 9.86-9.85 ppm. On the other hand, while –NH proton
gains relatively acidic nature in this compound and it was appeared at about 11.40 ppm as a
singlet, the protons bonded to nitrogen atom (NH2) were observed at 8.07 and 8.19 ppm as a
singlet in spectral data although at first they seem to be equivalent protons. In the D2O-
exchangeable spectra of compound (5), disappeared the singlet belonging to -NH proton in
the 11.40 ppm and NH2 protons appeared at 8.07 and 8.19 ppm supported our suggested
structures. Observed CH=N and NH2 group protons are given in the literature at 10.06 and
8.57-7.56 ppm, respectively [58]. The peaks of -NH and NH2 protons were calculated in the
range of 7.72-7.59 and 4.70-4.62 ppm.
Chemical shifts of -NH and NH2 peaks were obtained as almost half of the
experimental results in the theoretical calculations. In this case, it is drown a conclusion that
there is a possible intermolecular hydrogen bond N-H…N in the molecule and free calculation
were done theoretically assuming that there is no hydrogen bond.
When analyze the 13C NMR spectrum of the compound, C=C, -OCH2 carbon atoms of
the molecule and aromatic carbon atoms were found to show great similarity with the spectral
data which is given in the molecule (4). However, in the molecule (5) the most significant and
different spectral data that belongs to the (C=S) group is appeared at about 178.17 ppm. This
17

ACCEPTED MANUSCRIPT
spectral data is quite specific value in the thiosemicarbazone derivatives, thiourea and
thioamides [59-62]. It is theoretically calculated as in the range of 186.3-185.80 ppm. On the
other hand, carbon signals of azomethine (C=N) group were recorded at 142.69 ppm and they
were calculated theoretically between the range of 147.27-148.87 ppm. Other spectral data
belonging to the carbon skeleton of the molecule completely confirms our proposed molecular
structure.
4.4. Frontier molecular orbital analysis
After obtaining stable structure and structural parameters of the molecule (4) and (5),
HOMO and LUMO energy values were analyzed and the hardness parameters were obtained
from these energies. How this property is changed with the effect of the different groups were
investigated.
The most important orbitals in a molecule are frontier molecular orbitals which are
called HOMO and LUMO. The energy difference between these two orbitals is a measure of
the chemical stability of the molecule and since it is a measurement of the electron
conductivity, it is a critical parameter determining the molecular electrical transport
properties. Therefore, this energy difference is largely responsible for the chemical and
spectroscopic properties of molecules [63].
The HOMO and LUMO of a molecule are significant for intermolecular interactions
[64], between the HOMO of the drug with the LUMO of the receptor and vice versa. Energy
gap between the interacting orbitals determines the stabilization of the intermolecular
interactions. Increasing HOMO energy and decreasing LUMO energy in the drug and receptor
molecule causes the more stabilizing interactions [65].
Calculations have been carried out in the gas phase, when the HOMO energy values
were calculated as -6.00 for the molecule (4) and -5.32 eV for the molecule (5). The LUMO
energy values were calculated as -2.12 eV for the molecule (4) and as -1.55 eV for the
molecule (5). The difference between this energy levels (ꢁEHOMO-LUMO) was calculated as
3.88 eV for the molecule (4), 3.77 eV for the molecule (5).
Nevertheless, the compound (5) has more stable interaction member with lowest
energy gap (3.77 eV) from compound (4), which may be explained the higher binding
interaction with binding site of Beta-lactam crystal structure.
The distributions and energy levels of the HOMO and LUMO orbitals and
corresponding density of state (DOS) of (4) and (5) structures are shown in the
Supplementary Material, Fig. S3.
18

ACCEPTED MANUSCRIPT
Molecular hardness parameters were obtained from finite difference formula proposed by
Paar and Pearson [66, 67], and they were calculated by using the operational definition of η:
η = 1/2 (IE-EA)
In this formula, IE shows the first ionization energy and EA shows the electron
affinity. Hardness value can provide the following approach by means of the highest occupied
molecular orbital energy (EHOMO) and the lowest unoccupied molecular orbital energy
(ELUMO):
η≈ 1/2(ELUMO- EHOMO
)
Some studies in the literature, the effect of hardness parameters on the charge transfer
are examined and in these studies it is indicated that small value of η corresponds to a more
powerful charge transfer interaction [68-70]. Calculated hardness values for the molecule (4)
and (5) are 3.88 and 3.77, respectively. Observing the calculated hardness value of molecule
(5) is smaller than the molecule (4) shows that charge transfer would be stronger in the
molecule.
4.5. Molecular docking studies
Beta-lactam crystal structure (pdb code: 4DKI) for the docking studies was provided
via Protein Data Bank (http://www.rcsb.org/pdb). Before the docking operation the water
molecules were removed from the structure 4DKI, hydrogen atoms and Gasteiger charges
were added. After these processes, docking was made to the target molecule binding site of
ligand (4) (Fig. 6(a)) and (5) (Fig. 6(c)). Autodock Vina was used for docking studies and
AutoDock Tools was used to create Docking input files. Receptor ligand interactions are
indicated by the Discover Studio Visualizer 4.5 software. The prediction of binding energy
(docking score) and RMSD values are obtained after molecular docking and computational
results are shown comparatively in Table 4.
Table 4. Affinity and RMSD values different conformations of compound (4) and (5).
Compound (4)
Distance from best mode
Compound (5)
Distance from best mode
Mode
Affinity
-6.3
RMSD 1.b.
0.000
Mode Affinity
RMSD 1.b.
0.000
1
2
3
4
5
6
7
1
2
3
4
5
6
7
-6.4
-6.3
-6.3
-6.2
-6.2
-6.1
-6.1
-6.3
49.217
1.067
1.261
-6.2
4.017
-6.2
1.603
2.902
3.692
-6.2
0.625
-6,1
1.666
7.677
-6.1
49.162
5.056
19

ACCEPTED MANUSCRIPT
8
9
-6.0
-6.0
49.230
47.242
8
9
-6.1
-6.0
4.054
4.170
The obtained docking results are stated as correct when the RMS value is smaller than
2 Ǻ [71]. RMSD value is the root mean square deviation from the determined structural
conformation of the ligand. In other words, it means that the deviation from the active site of
the ligand to interact and it is the most important criteria for the docking results. The binding
energy is the criteria that looked after the RMSD values. The reason of this priority is that the
molecule may also give lower binding energy with a place other than the active region.
Therefore, first looking at its proximity to the active site, and then looking at its binding
energy which is made in the active region. Docking results for the molecule 4, binding energy
that is corresponded to the lowest RMSD value is -6.2 kcal/mol and -6.3 kcal/mol for the
molecule 5.
(a)
20

ACCEPTED MANUSCRIPT
(b)
21

ACCEPTED MANUSCRIPT
(c)
22

ACCEPTED MANUSCRIPT
(d)
Fig. 6.
It was observed that ligands bonded to the substrate binding site of receptors with a
weak non-covalent interaction and they were bonded more specifically with hydrogen
bonding, van der Waals, π-π and π-alkyl interactions. As shown in Fig. 6(b, d) hydrogen
bonds were formed between SER403, LYS406, ASN442, SER462, GLN521 and O atoms for
ligand (4) at 1.96, 2.77/2.82, 2.27, 2.88 and 2.48/2.20/2.67 Å in length and for ligand (5)
between THR216, ARG241, TYHR165, MET375 and ASP275 with O and N atoms at 2.65,
2.31, 2.61, 2.63 and 3.48 Å in length, respectively. Furthermore, as shown in Fig. 6 (b, d)
while LEU603 was attached to the ligand (4) with π-sigma interaction, TYR446 with π-π
interaction and LYSB430 with π-alkyl interaction; TYR196, TYR373 and GLY374 were
attached to the ligand (5) with π-cation and amide-π interactions, respectively. According to
23

ACCEPTED MANUSCRIPT
the calculated binding affinity ligand (4) and (5) have been identified as inhibitor candidate
molecules for beta-lactam target structure. Consequently, these potential inhibitor compounds
which are found will be hoping for us to design drugs with high selectivity and have low side
effects in new studies that will be done in the future.
5. Conclusions
In this study, aldehydes and compounds containing thiosemicarbazone group were
synthesized easily with the applicable methods in high yield. The structures of all synthesized
compounds were clarified by various spectroscopic methods.
Among the synthesized compounds (4) and (5), single-crystal versions of compound
(4) was obtained. After the stable structures and structural parameters of these compounds
were calculated, their IR, NMR spectra, HOMO and LUMO energies and hardness parameters
of these energies were found.
The effect of aldehyde and thiosemicarbazone groups in the (4) and (5) on these
properties was investigated. Obtaining the smaller hardness value of (5) than molecule (4)
shows that there is a strong charge transfer in this molecule. At the same time, docking
simulation process was applied to obtain possible bonding patterns and conformation for
ligands (4) and (5). According to the calculated bonding affinities, all compounds in this study
were determined to be inhibitor candidates for the beta-lactamase target structure.
Supplementary data
CCDC– 1444663 contains the supplementary crystallographic data for the compound reported
in
this
paper.
This
data
can
be
obtained
free
of
charge
at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data
Center (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223–336033; e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgement
This study was supported financially by the Research Centre of Ahi Evran University (PYO-
MYO.4001.14.002).
24

ACCEPTED MANUSCRIPT
References
[1] Winder, P. Collins, D. Whelan, Effects of ethionamide and isoxyl on mycolic acid
synthesis in Mycobacterium tuberculosis BCG, Microbiology 66(3) (1971) 379-380.
[2] M. Spaniol, R. Bracher, H.R. Ha, F. Follath, S. Krähenbühl, Toxicity of amiodarone
and amiodarone analogues on isolated rat liver mitochondria, J. Hepatol. 35(5)
(2001) 628-636.
[3] D.C. Greenbaum, Z. Mackey, E. Hansell, P. Doyle, J. Gut, C.R. Caffrey, J. Lehrman,
P.J. Rosenthal, J.H. McKerrow, K. Chibale, Synthesis and structure-activity
relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against
Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi, J. Med.
Chem. 47(12) (2004) 3212-3219.
[4] R.A. Finch, M.-C. Liu, A.H. Cory, J.G. Cory, A.C. Sartorelli, Triapine (3-
aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of
ribonucleotide reductase with antineoplastic activity, Adv. Enzyme Regul. 39(1)
(1999) 3-12.
[5] H.R. Wilson, G.R. Revankar, R.L. Tolman, In vitro and in vivo activity of certain
thiosemicarbazones against Trypanosoma cruzi, J. Med. Chem. 17(7) (1974) 760-761
[6] X. Du, C. Guo, E. Hansell, P.S. Doyle, C.R. Caffrey, T.P. Holler, J.H. McKerrow,
F.E. Cohen, Synthesis and structure-activity relationship study of potent trypanocidal
thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain, J. Med.
Chem. 45(13) (2002) 2695-2707.
[7] P. Yogeeswari, D. Sriram, S. Mehta, D. Nigam, M.M. Kumar, S. Murugesan, J.
Stables, Anticonvulsant and neurotoxicity evaluation of some 6-substituted
benzothiazolyl-2-thiosemicarbazones, Il Farmaco 60(1) (2005) 1-5.
[8] J.P. Leach, Polypharmacy with anticonvulsants, CNS drugs 8(5) (1997) 366-375.
[9] S.a.J. Czuczwar, K. Przesmycki, Felbamate, gabapentin and topiramate as adjuvant
antiepileptic drugs in experimental models of epilepsy, Pol. J. Pharmacol. 53(1)
(2001) 65-68.
[10] S.J. Hays, M.J. Rice, D.F. Ortwine, G. Johnson, R.D. Schwarz, D.K. Boyd, L.F.
Copeland, M.G. Vartanian, P.A. Boxer, Substituted 2‐benzothiazolamines as sodium
flux inhibitors: Quantitative structure–activity relationships and anticonvulsant
activity, J. Pharm. Sci. 83(10) (1994) 1425-1432.
25

ACCEPTED MANUSCRIPT
[11] J. Mizoule, B. Meldrum, M. Mazadier, M. Croucher, C. Ollat, A. Uzan, J.-J.
Legrand, C. Gueremy, G. Le Fur, 2-Amino-6-trifluoromethoxy benzothiazole, a
possible antagonist of excitatory amino acid neurotransmission—I: anticonvulsant
properties, Neuropharmacology 24(8) (1985) 767-773.
[12] R.S. Chopade, R.H. Bahekar, P.B. Khedekar, K.P. Bhusari, R. Rao, A. Raghu,
Synthesis and Anticonvulsant Activity of 3‐(6‐Substituted‐benzothiazol‐2‐yl)‐6‐
phenyl‐[1, 3]‐xazinane‐2‐thiones, Arch. Pharm. 335(8) (2002) 381-388.
[13] V. Mishra, S. Pandeya, C. Pannecouque, M. Witvrouw, E. De Clercq, Anti‐HIV
Activity of Thiosemicarbazone and Semicarbazone Derivatives of (±)‐3‐Menthone,
Arch. Pharm. 335(5) (2002) 183-186.
[14] K.J. Duffy, A.N. Shaw, E. Delorme, S.B. Dillon, C. Erickson-Miller, L. Giampa, Y.
Huang, R.M. Keenan, P. Lamb, N. Liu, Identification of a pharmacophore for
thrombopoietic activity of small, non-peptidyl molecules. 1. Discovery and
optimization of salicylaldehyde thiosemicarbazone thrombopoietin mimics, J. Med.
Chem. 45(17) (2002) 3573-3575.
[15] S. Ren, R. Wang, K. Komatsu, P. Bonaz-Krause, Y. Zyrianov, C.E. McKenna, C.
Csipke, Z.A. Tokes, E.J. Lien, Synthesis, biological evaluation, and quantitative
structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide
as potential antitumor agents, J. Med. Chem. 45(2) (2002) 410-419.
[16] J. Patole, S. Padhye, M. Moodbidri, N. Shirsat, Antiproliferative activities of iron
and platinum conjugates of salicylaldehyde semi-/thiosemicarbazones against C6
glioma cells, Eur. J. Med. Chem. 40(10) (2005) 1052-1055.
[17] K. Hu, Z.-h. Yang, S.-S. Pan, H.-j. Xu, J. Ren, Synthesis and antitumor activity of
liquiritigenin thiosemicarbazone derivatives, Eur. J. Med. Chem. 45(8) (2010) 3453-
3458.
[18] F. Islam, A.S.M. Mohsin, J.A. Khanam, Hepatoprotective effect of acetone
semicarbazone on Ehrlich ascites carcinoma induced carcinogenesis in experimental
mice, A. Pac. J. of Trop. Biom. 3 (2013) 105-110.
[19] J.G. Da Silva, C.C. Perdigao, N.L. Speziali, H. Beraldo, Chalcone-derived
thiosemicarbazones and their zinc (II) and gallium (III) complexes: spectral studies
and antimicrobial activity, J. Coord. Chem. 66(3) (2013) 385-401.
[20] E. Pahontu, V. Fala, A. Gulea, D. Poirier, V. Tapcov, T. Rosu, Synthesis and
characterization of some new Cu (II), Ni (II) and Zn (II) complexes with salicylidene
26

ACCEPTED MANUSCRIPT
thiosemicarbazones: antibacterial, antifungal and in vitro antileukemia activity,
Molecules 18(8) (2013) 8812-8836.
[21] G. Ermut, N. Karali, İ. Çetin, M. Topçu, S. Birteksöz, Synthesis And
Chemotherapeutic
Activities
Of
5-Chloro-1h-Indole-2,3-Dione
3-
Thiosemicarbazones, Mar. Pharm. J. 17 (2013) 147-154.
[22] P.A. Bradford, Extended-spectrum β-lactamases in the 21st century: characterization,
epidemiology, and detection of this important resistance threat, Clin. Microbiol. Rev.
14(4) (2001) 933-951.
[23] S.Y. Essack, The development of β-lactam antibiotics in response to the evolution of
β-lactamases, Pharm. Res. 18(10) (2001) 1391-1399.
[24] F.M. Özsoy, O. Öncül, A. Yıldırım, A. Pahsa, Extended-spectrum beta-lactamases:
The clinical significance and bring its the problems, Flora, 6 (2001) 3-21.
[25] C.C. Sanders, β-lactamases of gram-negative bacteria: new challenges for new drugs,
Clin. Infect. Dis. 14(5) (1992) 1089-1099.
[26] R.A. Gaussian09, 1, MJ Frisch, GW Trucks, HB Schlegel, GE Scuseria, MA Robb,
JR Cheeseman, G. Scalmani, V. Barone, B. Mennucci, GA Petersson et al.,
Gaussian, Inc., Wallingford CT (2009).
[27] R. Dennington, T. Keith, J. Millam, GaussView, version 5, Semichem Inc., Shawnee
Mission, KS (2009).
[28] R. Ditchfield, W.J. Hehre, J.A. Pople, Self‐consistent molecular‐orbital methods. IX.
An extended Gaussian‐type basis for molecular‐orbital studies of organic molecules,
J. Chem. Phys. 54(2) (1971) 724-728.
[29] A.D. Becke, Density-functional exchange-energy approximation with correct
asymptotic behavior, Phys. Rev. A 38(6) (1988) 3098.
[30] A.D. Becke, A new mixing of Hartree–Fock and local density‐functional theories, J.
Chem. Phys. 98(2) (1993) 1372-1377.
[31] A.D. Becke, Density‐functional thermochemistry. III. The role of exact exchange, J.
Chem. Phys. 98(7) (1993) 5648-5652.
[32] C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-energy
formula into a functional of the electron density, Phys. Rev. B 37(2) (1988) 785.
[33] P.J. Hay, W.R. Wadt, Ab initio effective core potentials for molecular calculations.
Potentials for the transition metal atoms Sc to Hg, J. Chem. Phys. 82(1) (1985) 270-
283.
27

ACCEPTED MANUSCRIPT
[34] W.R. Wadt, P.J. Hay, Ab initio effective core potentials for molecular calculations.
Potentials for main group elements Na to Bi, J. Chem. Phys. 82(1) (1985) 284-298.
[35] P.J. Hay, W.R. Wadt, Ab initio effective core potentials for molecular calculations.
Potentials for K to Au including the outermost core orbitals, J. Chem. Phys. 82(1)
(1985) 299-310.
[36] M. Jamróz, J.C. Dobrowolski, Potential energy distribution (PED) analysis of DFT
calculated IR spectra of the most stable Li, Na, and Cu (I) diformate molecules, J.
Mol. Struct. 565 (2001) 475-480.
[37] O. Trott, A.J. Olson, AutoDock Vina: improving the speed and accuracy of docking
with a new scoring function, efficient optimization, and multithreading, J. Comput.
Chem. 31(2) (2010) 455-461.
[38] Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 4.5,
San Diego: Dassault Systemes, 2015.
[39] A.C. Cope, F. Kagan, Cyclic Polyolefins. XLII. 3, 3, 7, 7-Tetracarbethoxybicyclo
[3.3. 0] oct-1 (5)-ene and 3, 3, 7, 7-Tetracarbethoxycycloöctane-1, 5-dione, J. Am.
Chem. Soc. 80(20) (1958) 5499-5502.
[40] A. Bruker, APEX2, V2008. 6, SADABS V2008/1, SAINT V7. 60A, SHELXTL V6.
14, Bruker AXS Inc., Madison, Wisconsin, USA, 2008.
[41] G.M. Sheldrick, SHELXT–Integrated space-group and crystal-structure
determination, Acta Crystallographica Section A: Foundations And Advances, 71
(2015) 3-8.
[42] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Crystallogr. Sect.
C: Struct. Chem. 71(1) (2015) 3-8.
[43] L.J. Farrugia, ORTEP-3 for Windows-a version of ORTEP-III with a Graphical User
Interface (GUI), J. Appl. Crystallogr. 30(5) (1997) 565-565.
[44] L.J. Farrugia, WinGX suite for small-molecule single-crystal crystallography, J.
Appl. Crystallogr. 32(4) (1999) 837-838.
[45] C.F. Macrae, I.J. Bruno, J.A. Chisholm, P.R. Edgington, P. McCabe, E. Pidcock, L.
Rodriguez-Monge, R. Taylor, J.v. Streek, P.A. Wood, Mercury CSD 2.0–new
features for the visualization and investigation of crystal structures, J. Appl.
Crystallogr. 41(2) (2008) 466-470.
[46] M. Er, R. Ustabaş, U. Çoruh, K. Sancak, E. Vázquez-López, Synthesis and
Characterization of Some New Tetraaldehyde and Tetraketone Derivatives and X-ray
Structure of 1, 1'-(4, 4'-(2-(1, 3-bis (4-Acetylphenoxy) propan-2-ylidene) propane-1,
28