Synthesis, characterization and crystal structures of two novel sulfa drug Schiff base ligands derived sulfonamide and molecular docking study

Article abstract of DOI:10.1016/j.molstruc.2018.12.002

The present paper reports the synthesis of two new sulfa drugs: based Schiff base N-(salicylidene) sulfadiazine = sal-sdzH (1) and N-(salicylidene) sulfathiazole = sal-stzH (2) derived from sulfonamide and substituted salicylaldehyde. These compounds were

Full text of DOI:10.1016/j.molstruc.2018.12.002

Accepted Manuscript
Synthesis, characterization and crystal structures of two novel sulfa drug Schiff base
ligands derived sulfonamide and molecular docking study
Mehdi Salehi, Maciej Kubicki, Masumeh Galini, Mahbobeh Jafari, Rahime Eshaghi
Malekshah
PII:
S0022-2860(18)31423-6
DOI:
https://doi.org/10.1016/j.molstruc.2018.12.002
MOLSTR 25939
Reference:
To appear in: Journal of Molecular Structure
Received Date: 31 July 2018
Revised Date: 11 November 2018
Accepted Date: 3 December 2018
Please cite this article as: M. Salehi, M. Kubicki, M. Galini, M. Jafari, R.E. Malekshah, Synthesis,
characterization and crystal structures of two novel sulfa drug Schiff base ligands derived sulfonamide
and molecular docking study, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2018.12.002.
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Graphical abstract
Two new Schiff base ligands were synthesized by the condensation of salicylaldehyde with
sulfonamide derivatives and characterized by physical methods. Molecular structures of
ligands were determined by single X-ray diffraction studies. The docking calculations were
performed to describe the mode of binding to DNA with the AutoDock program.

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Synthesis, characterization and crystal structures of two novel sulfa
drug Schiff base ligands derived sulfonamide and molecular docking
study
a,
b
a
a
Mehdi Salehi *, Maciej Kubicki , Masumeh Galini , Mahbobeh Jafari ,
a
Rahime Eshaghi Malekshah
a
Department of Chemistry, College of Science, Semnan University, Semnan, Iran
b
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
Abstract
The present paper reports the synthesis of two new sulfa drugs: based Schiff base N-
(salicylidene) sulfadiazine = sal-sdzH (1) and N-(salicylidene) sulfathiazole = sal-stzH (2)
derived from sulfonamide and substituted salicylaldehyde. These compounds were fully
1
characterized by elemental analysis, H-NMR, UV–Vis, and FTIR spectroscopy. The molecular
structures of both ligands were determined by single X-ray diffraction studies. The crystal
structures of ligand (1) are quite different probably due to using the sulfadiazine sodium salt in
the synthesis of these ligands. The crystal structures of ligand (2) are mononuclear and
monomeric, while the ligand (1) was found to be multinuclear and polymeric. Finally, the DNA
docking analysis revealed that the compounds have interactions with the minor groove through
hydrogen bonds bases and the backbone phosphates.
Keywords: Schiff base, Sulfadiazine, Sulfathiazole, Crystal structure, Mononuclear, Monomeric,
Multinuclear, Polymeric.
1
. Introduction

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Schiff bases are the compounds containing azomethine group (-HC=N-) – first reported by Hugo
Schiff – formed by the reaction of primary amines with a ketone or carbonyl compounds placed
under base catalysis, acid, or heat [1-3]. These compounds are used in the development of
coordination chemistry [4, 5] and numerous potential applications in various biological and
pharmacological fields [6-8]. In this regard, the sulfonamide and its derivatives containing group
–
SO NH– is known as the simplest molecule that belongs to sulfa drugs [9].
2
These simple compounds have a high potential in toxicological and pharmacological activities
when administered in the form of Schiff base ligands. This potential is attributed to the
2
exchanges of different functional groups without modification of the structural –SO NH–
feature. In the past, sulfur-containing compounds have long been used as drugs for diseases and
burn treatment [10]. Today, sulfonamides are used as antibiotics to treat infectious diseases, as
inhibitory agents against tumor cells [11], anti-thyroid [12], hypoglycaemic [13], diuretic [14],
and several other activities [15-18]. Thus, it seems worthwhile to continue investigations in this
area. Therefore, we were prompted to synthesize a series of Schiff base ligands (1) and (2)
derived from sulfonamide derivatives (scheme 1). In the present study, we describe the synthesis
of new Schiff base ligands obtained by the condensation of salicylaldehyde with sulfonamide
derivatives and characterize their structure by infrared spectra (IR), proton nuclear magnetic
1
resonance ( H-NMR), and visible spectra (UV–Vis). The crystal structures of both ligands were
characterized using the X-ray diffraction. Finally, the study was complemented by docking
calculations of compounds to DNA.

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Scheme 1. Synthetic procedure for the preparation of sulfa drug Schiff base ligands.
2
2
. Experimental
.1. Materials and methods
All the chemicals and solvents used in this work were of reagent grade and used without further
Purification FT-IR spectra (KBr pellets) were obtained on a FT-IR SHIMADZU (8400s)
-1
Spectrophotometer in the 4000–400 cm . UV-Vis spectra were recorded on a UV-1650 PC
1
SHIMADZU spectrophotometer in Methanol solutions. The H-NMR spectrum of the ligand was
obtained on a Bruker DRX-500 NMR Spectrometer using CD OD as solvent.
3
2
2
.2. Synthesis of the Schiff base ligands
.2.1. Synthesis of N (salicylidene) sulfadiazine (1).
A stirred methanolic solution (20 ml) of sulfadiazine sodium (1 mmol, 0.272 g) was added to the
methanolic solution solution (10 ml) of salicylaldehyde (1 mmol, 0.122 g). The mixture was
stirred at room temperature for 6 h and filtered and left standing at room temperature. By slow

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evaporation,
C H N Na O S2,C H N NaO SH. Yellow crystals. Mol. Wt.: 1127.11 g/moL. FT-IR: ν
max
orange
crystals
of
were
formed
after
one
week.
34
25
8
2
6
17 11
4
3
-1
−1
−1
cm (KBr): 1614 (s, C=N), UV–Vis: λ (nm) (ε, M cm ) (MeOH): 344(48100), 271(65200),
max
1
2
33(92200). HNMR (CD OD, 300MHz): 6.5(m, 11H), 8.8(s, 1H).
3
2
.2.3. Synthesis of N (salicylidene) sulfathiazole (2).
A stirred methanolic solution (20 mL) of Sulfathiazole (1 mmol, 0.255 g) was added to the
methanolic solution (10 mL) salicylaldehyde (1 mmol, 0.122 g), along with two drops of sulfuric
acid. Thereafter, the reaction mixture was refluxed for 16 h and filtered and left standing at room
temperature. By slow evaporation, orange crystals of were formed after one week.
-1
C H N O S . Orange crystals. Mol. Wt.: 359.42 g/moL. FT-IR: ѵ cm (KBr):1616 (s,
max
16
13
3
3
2
-1
-1
C=N). UV-Vis: λmax (nm) (ε.M cm ) (MeOH): 232 (92500), 275(104400), 345 (57600).
1
HNMR (CD OD, 300MHz): 6.71-7.96 (m, 10H), 8.82 (s, 1H).
3
2
.3. X-ray crystallography analyses
Diffraction data were collected by the ω-scan technique at room temperature (1) and at 130(1)K
2) on Rigaku SuperNova four-circle diffractometer with Atlas CCD detector and mirror-
monochromated CuK radiation (λ=1.54178 Å) in table 1. The data were corrected for Lorentz-
(
α
polarization as well as for absorption effects [19]. Precise unit-cell parameters were determined
by a least-squares fit of 16154 (1) and 7279 (2) reflections of the highest intensity chosen from
the whole experiment. The structure was solved with SIR92 [20] and refined with the full-matrix
2
least-squares procedure on F by SHELXL-2013 [21]. All non-hydrogen atoms were refined
anisotropically, hydrogen atoms in 2 were found in difference Fourier maps and isotropically
refined, in 1 hydrogen atoms were placed in idealized positions and refined as ‘riding model’

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with isotropic displacement parameters set at 1.2 (1.5 for OH groups). Hydrogen atoms were
localized at O atoms (rather than N ones) by scrutinizing the difference Fourier maps (Suppl.).
Table 1.
Crystallographic data for the structural analysis has been deposited with the Cambridge
Crystallographic Data Centre, Nos. CCDC-1535906 (1) and CCDC-1535906 (2). Copies of this
information may be obtained free of charge from: The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK. Fax: +44(1223)336-033, e-mail:deposit@ccdc.cam.ac.uk, or www:
www.ccdc.cam.ac.uk.
2
.4. Molecular docking of the complex with DNA duplex of sequence d
(
CGCGAATTCGCG) (PDB ID: 1BNA).
2
Molecular docking technique as an important computational tool has played essential roles in
understanding the drug and nucleic acid interactions for the drug design and discovery. Here, to
find the antitumor activity of componds, molecular docking studies were employed to identify
the principal binding site of the compounds to receptors. The crystalline structure of BNA, as a
receptor of docking studies, was downloaded from Protein Data Bank (ww.rcsb.org/pdb) with
PDB format. To coordinate compounds with DNA, structures of the compounds were converted
into pdb format from the crystal structures, CIF files, using Mercury 3.7 sofware. The molecular
dynamic simulation was carried out with AutoDock 4.2 using Lamarckian genetic algorithm (the
Scripps Research Institute, La Jolla, CA, USA). All water molecules were removed, followed by
adding polar hydrogen atoms, Kollman united atom type charges and Gasteiger partial charges to
BNA as a target using the AutoDock tools. Also, Pdbqt files for the receptors and compounds
were prepared with the use of utilities from AutoDock Tools. 4.2. A total of 100 runs were
carried out. In the docking analysis, the binding site was assigned across all of the minor and
major grooves of the DNA molecule, which was enclosed in a box with number of grid points in
x × y × z directions. Moreover, the grid box used for this purpose consisted of 74 × 64 × 117 Å
points with a grid-point spacing of 0.375 Å [22]. AutoGrid and AutoDock were run to generate
the grid map of compounds with the receptor and using parameter, respectively. After docking,
the 100 runs were clustered in the groups with root-mean-square deviation (RMSD) less than 1.0

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Ǻ. The clusters were ranked by the lowest energy representative of each cluster. Computational
docking analysis was accomplished to select the lowest binding energy conformation according
to the AutoDock scoring function. Then, the interactions of BNA with the compounds were
analyzed using UCSF Chimera and Accelrys Discovery Studio 2017 R2 Client.
3
3
. Results and discussions
.1. Synthesis
1
The new ligands were synthesized and characterized by FT-IR, H-NMR, UV-Vis, and X-Ray.
The ligands were quite stable at room temperature in the solid state and soluble in solvent hot
methanol. The spectroscopic data for the ligand in Table 2 are in good agreement with the
expected values.
Table 2.
3
3
.2. Spectroscopic characterizations of the ligands
.2.1. IR spectra
In order to clarify the mode of bonding on the ligand, some important IR spectral bands of these
ligands were presented in Table 2. The formation of the Schiff base ligands (1-2) is confirmed by
-1
the appearance of a strong band at around 1610-1620 cm , which was attributed to stretching
vibrations of the azomethine group and absence of the original aldehydic bond (-C=O) and NH
vibrations [23]. The IR spectra of the compounds 1 and 2 display absorption band around 3446
2
-1
and 3210 cm which is assigned to stretching vibrations of the hydroxyl. The IR spectra of these
ligands are very similar to each other. In both compounds, two bands appear at around 1310-
-1
-1
1
360 cm and 1120-1130 cm , which are indexed to [(S=O) asymmetric str] and [(S=O)
2 2
symmetric str], respectively. The peaks also support the formation of Schiff base ligands.
.2.2. UV–Vis spectra
3

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The electronic transition study of the ligands (1) and (2) were recorded at 200-500 nm using
methanol as the solvent (Figure 1 and Table 2). The electronic absorption spectrum of both
ligands showed bands in the range 230-250 and 270-280 nm, which can be assigned to the π→π*
transition of the aromatic rings and azomethine group, respectively [24]. The spectra also show
the other transitions in the range 340-350 nm, which can be indexed to n→π* transitions [25].
Fig. 1.
1
3
.2.3. H-NMR spectra
1
H-NMR spectra data of the ligands (1) and (2) are presented in Table 2, Figures 2 and 3.
1
1
CD OD was used as a solvent to measure the H-NMR spectra of both ligands. The H-NMR
3
spectra of both ligands show sharp singlet signals (s) at around 8.80 ppm, which is indexed to the
azomethine proton (-CH=N-). The aromatic protons appear in the appropriate region of 6.56-8.21
and 6.71-7.96 ppm in ligands (1) and (2), respectively. Also, the phenolic –OH proton signals in
both ligands and N-H proton of ligand (2) disappeared in the presence of D O, while the HOD
2
signal appeared in the region of 4.8 ppm.
Fig.s 2 -3.
3
.3. Description of the crystal structures
The perspective view of the polymeric ligand 1 is shown in Figure 4, while that of molecule 2 –
in Figure 5. Some geometrical data are listed in Table 3.
The crystal structure of 1 contains two symmetry-independent infinite polymeric chains. In one
of them repetitive part is 1:1 Na-ligand complex, which propagates through the consecutive
inversion centers and translations. The second polymer is built of two ligand molecules and two

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Na cations, which propagate by simple translation. The Na is 5-coordinated, and the geometry is
intermediate between trigonal bipyramid and tetragonal pyramid (τ parameter is almost exactly
0
.5 in each case, just between the ideal values of 0 and 1 for tetragonal pyramid and trigonal
bipyramid, respectively). The polymeric structure is built by consecutive Na and Na (NSO)
rings (cf. Figure 4). It might be noted that, despite the close similarity of the two polymers, they
differ in the orientation of SO oxygen atoms (cf. Table 3 and torsion angles). Overall
2
O
2
2
2
2
conformation of the ligands is similar, however, the dihedral angles between the terminal ring
planes differ significantly, probably this soft parameter can be changed in order to accommodate
the appropriate orientation of the chains. O-H···N intramolecular hydrogen bonds additionally
act towards more planar conformation of the azastilbene part of the molecule. In the crystal
structure the polymeric chains are joined only by weak van der Waals forces (Figure 5)
Overall conformation of 2 is quite similar to the ligands in 1 (Figure 6). In the crystal structure
additional intermolecular N-H···N hydrogen bonds connect molecules into centrosymmetric
dimers, which are further connected into three-dimensional network by means of weak
interactions, including some relatively directional C-H···π interactions. Hydrogen bond and
other weak interaction data are listed in table 4.
Table 3-4.
Fig. 4-6.
3
-4. Molecular docking study
Over the past several years, several studies have been conducted on Drug-DNA interactions.
Nucleic acids are the primary target molecule in living systems for most of the anticancer.
Interactions between small‐molecule substances and DNA can cause DNA damage in cancer
cells. Meanwhile, the feasibility of interacting with DNA is always determined by non-covalent

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modes such as electrostatic interactions, intercalation, or minor‐groove binding. Molecular
docking technique is frequently used to predict the drug-DNA interactions and the binding
orientation of small molecule drug for Structure-based drug design (SBDD). Hence, docking
plays a significant role in the rational design of drugs [26]. The negative values of the binding
energy of docked the compounds suggest that the compounds bind to DNA strands. Thus, the
binding free energy (ꢀGbinding) of the complex 1 and 2 was obtained - 9.90 and - 9.82,
respectively; with compound 1 showing a better binding ability compared to 2 (Table 5).
Table 5.
The shapes of the groove-binding molecules typically match the curve of the grooves, thus, a
perfect binding fit via interactions such as van der Waals contacts and hydrogen bonding. As can
be seen from Figure 7, the compounds 1 and 2 are located in the minor groove through hydrogen
bonds. Moreover, the resulting docking shows that the complexes 1 and 2 bind to the DNA
through the hydrogen bonds. The compound 1 has interactions with DC1 (2.61 Ȧ) and the
backbone phosphate (2.73, 2.63 and 2.18 Ȧ). In comparison, for compound 2, hydrogen bonds
were stabilized by three hydrogen bonds with base pairs: A66 (3.01 Ȧ), A118 (1.98 Ȧ), and
backbone phosphate (2.70 Ȧ). Among these interactions, intercalation is one of the most
important DNA-binding modes, which is related to the antitumor activity of the compound
(
Figure 8). Ultimately, there was a considerable preference of compound 2 for intercalation
binding of DNA, exhibiting the DNA cleavage capacity [27].
Fig. 7-8.
4
. Coclusions
We reported the synthesis and characterization series of new Schiff base ligands. The crystal
structures of both ligands were determined by X-ray crystallography. The crystal structures of

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ligands (1) are quite different because of using the sulfadiazine sodium salt in the synthesis of
these ligands. The ligands (1) and (2) were crystallized in triclinic and monoclinic space groups
P-1 and C2, respectively. The crystal structure of ligand (2) is mononuclear, while the ligand (1)
was described as multinuclear and polymeric. In the crystal structures, polymeric-like of ligand
(
1), each unit cell comprised four ligands bonded together with four sodium cations through the
sodium bridges. Each of the sodium cations coordinates to two Schiff base ligands of through
two SO group and three Schiff base ligands through three N groups. The compounds bind to
2
minor groove through hydrogen bonds. The result of this work revealed that compound 2 could
interactively bind between Bases of DNA.
5
. Acknowledgements
We thank Semnan University for supporting this study.
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Table 1. Crystal data, data collection and structure refinement
Compound
Formula
1
2
C H N NaO S
C H N O S
16 13
17
13
4
3
3
3
Formula weight
Crystal system
Space group
a(Å)
376.36
Triclinic
P-1
359.41
Monoclinic
P2 /c
1
5.97170(10)
18.5494(6)
16.0231(2)
b(Å)
9.07224(11)
c(Å)
α(°)
24.6690(6)
68.001(3)
10.97498(12)
90
β
(º)
87.684(2)
80.957(2)
2501.66(12)Å
6
102.4284(12)
γ(°)
90
1558.00(3)
4
3
V(Å )
Z
-3
D (g cm )
1.50
1.53
x
F(000)
1164
744
-
1
µ
(mm )
2.22
3.29
0
Θ
range ( )
75.52º
73.69º
Reflections:
Collected
21326
10128 (0.026)
9481
8524
3060 (0.025)
2949
unique (Rint)
with I>2σ(I)
R(F) [I>2σ(I)]
0.04
0.03
2
wR(F ) [I>2σ(I)]
0.01
0.08
R(F) [all data]
0.04
0.03
2
wR(F ) [all data]
0.12
0.08
Goodness of fit
1.008
1.046
-
3
max/min ∆
ρ
(e Å )
0.48/-0.37
0.36/-0.38

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Table 2. Spectroscopic data for ligands.
a
1
IR
H-NMR
UV-Vis: λmax (nm)
b
−1
−1 c
Compound
(δ, ppm )
(ε, M cm )
υ(
C=N)
υ(
N-H)
υ(
O-H)
υ s o
as( = 2)
υ s o
s( = 2)
1
616
3126
446
1616
118
210
1361
1307
1122
1126
6.56-8.2 (m, 11H, Ar), 344
(48100),
271
(
1)
2)
8.80 (s, 1H, CH=N)
(65200), 233 (92200)
3
(
6.71-7.96 (m, 10H,
Ar), 8.82 (s, 1H,
CH=N)
345 (57600), 275
(104400), 232 (92500)
3
3
a
b
c
KBr pellets, Solvent is CD OD. Solvent is methanol.
3
Table 3. Relevant geometrical data (Å, º) with s.u.’s in parentheses.
1
i
Na1-N1
Na1-N3
Na1-N7
Na1-O10
Na1-O10
S8-O9
2.5449(14)
2.4793(14)i
2.3856(13)
2.3372(12)
2.3820(13)
1.4378(11)
1.4635(11)
2.4877(14)
2.4648(14)
2.3912(13)
2.3404(12)
2.3940(14)
1.4368(11)
1.4648(11)
2.5073(14)
2.5031(14)
2.4123(13)
2.3230(12)
2.3378(13)
1.4354(11)
1.4624(11)
ii
S8-O10
C2-N1-C6
C2-N3-C4
116.74(13)
116.03(13)
116.88(13)
116.07(13)
115.96(12)
116.78(12)
C2-N7-S8-O9
173.66(13)
59.31(15)
-85.79(16)
151.93(15)
-178.64(13)
54.42(15)
-93.84(18)
28.11(8)
179.35(13)
-53.01(15)
-37.45(16)
-161.07(14)
C2-N7-S8-O10
C12-C11-S8-O9
C12-C11-S8-O10
A/B
52.74(12)
67.40(7)
85.63(7)
2
S1-C2
S7-O8
C2-S1-C5
C2-N6-S7-O8
C11-C10-S7-O8
A/B
1.7372(14)
1.4380(11)
90.80(7)
166.29(11)
34.49(13)
84.57(5)
S1-C5
S7-O9
C2-N3-C4
C2-N6-S7-O9
C11-C10-S7-O9
1.7389(16)
1.4441(10)
115.23(12)
35.58(13)
162.76(11)

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Table 4. Hydrogen bond data (Å, º).
D-H
D
H
A
H···A
D···A
D-H···A
1
O25A H25A N17A 0.82
O25B H25B N17B 0.82
O25C H25C N17C 0.82
1.89
1.91
1.89
2.623(3)
2.630(2)
2.599(2)
147
147
143
2
i
N3
H3
N6
N16
CgA
0.86(2) 1.98(2) 2.8373(17) 177.3(19)
0.99(3) 1.72(3) 2.6329(18) 152(2_
0.95(2) 2.61(2) 3.5360(17) 164.2(18)
0.97(2) 2.86(2) 3.7440(18) 152.2(16)
O24
C21
C23
H24
H21
H23
ii
iii
CgB
i
ii
iii
Symmetry code: 1-x,1-y,1-z; 2-x,1-y,1-z; 2-x,1/2+y,3/2-z.
Table 5. DNA docking results of the compounds 1 and 2 (Unit:kcal/mol)
1
2
*
Estimated Free Energy of Binding (kcal/mol)
-9.90
-9.82
Final Intermolecular Energy (kcal/mol)
vdW + Hbond + desolv Energy (kcal/mol)
Electrostatic Energy (kcal/mol)
Final Total Internal Energy (kcal/mol)
Torsional Free Energy (kcal/mol)
-12.10 -11.19
-9.40
-2.70
-1.32
+2.20
-1.32
-11.21
-0.01
-1.04
+1.37
-1.04
Unbound System's Energy (kcal/mol)

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Fig. 1. The electronic spectra of the free Schiff base ligand and the related complexes in
CH OH solution.
3
1
Fig. 2. H-NMR spectrum of (1) in CD OD.
3

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1
Fig. 3. H-NMR spectrum of (2) in CD OD.
3
Fig. 4. A perspective view of the polymeric chains in 1, symmetrical (A molecules, left) and
non-symmetrical (B and C molecules, right); ellipsoids are drawn at the 50% probability
level, hydrogen atoms are shown as spheres of arbitrary radii. Intramolecular hydrogen bond
is shown as dashed blue line.

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Fig. 5. Crystal structure of 1, as seen along y direction; different colours denote different
polymers.
Fig. 6. A perspective view of the molecule 2; ellipsoids are drawn at the 50% probability
level; hydrogen atoms are shown as spheres of arbitrary radii. Intramolecular hydrogen bond
is shown as dashed blue line.
(1)

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(2)
Fig. 7. Docking conformation and hydrogen bonding interactions of compounds 1 and 2.
1) (2)
(

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Fig. 8. Docking conformation and intercalation of the compounds 1 and 2.

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Highlights (for review)
ꢀ
The molecular structures of both compounds were determined by single X-ray
diffraction studies.
1
ꢀ
The crystal structures of compounds were determined by elemental analysis, H-
NMR, UV–Vis, and FTIR spectroscopy.
ꢀ
ꢀ
The molecular docking studies of these compounds with DNA.were investigated.
DFT of compound () were investigated.
J