Synthesis, crystal structure, DFT study, in vitro and in silico molecular docking of novel bis (aroyl selenourea) derivatives

Article abstract of DOI:10.1016/j.molstruc.2018.12.019

A new family of o-phenylenediamine substituted bis (aroyl selenourea) 1–3 were synthesised and characterised by spectroscopic methods and Single crystal XRD studies. The 1–3 showed that the synthesised compounds in crystallise in the monoclinic crystal sy

Full text of DOI:10.1016/j.molstruc.2018.12.019

Accepted Manuscript
Synthesis, crystal structure, DFT study, in vitro and in silico molecular docking of
novel bis (aroyl selenourea) derivatives
Moideen Musthafa, K.N. Aneesrahman, Balaji Perumalsamy, Thirumurugan
Ramasamy, Rakesh Ganguly, Anandaram Sreekanth
PII:
S0022-2860(18)31440-6
DOI:
https://doi.org/10.1016/j.molstruc.2018.12.019
MOLSTR 25956
Reference:
To appear in: Journal of Molecular Structure
Received Date: 2 November 2018
Revised Date: 30 November 2018
Accepted Date: 5 December 2018
Please cite this article as: M. Musthafa, K.N. Aneesrahman, B. Perumalsamy, T. Ramasamy, R.
Ganguly, A. Sreekanth, Synthesis, crystal structure, DFT study, in vitro and in silico molecular
docking of novel bis (aroyl selenourea) derivatives, Journal of Molecular Structure (2019), doi: https://
doi.org/10.1016/j.molstruc.2018.12.019.
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ACCEPTED MANUSCRIPT
Synthesis, crystal structure, DFT study, in vitro and in silico molecular docking of
novel bis (aroyl selenourea) derivatives
a
a
c
c
Moideen Musthafa, K.N.Aneesrahman, Balaji Perumalsamy, Thirumurugan Ramasamy,
*b
*a
Rakesh Ganguly, Anandaram Sreekanth
Abstract
A new family of o-phenylenediamine substituted bis (aroyl selenourea) 1-3 were
synthesised and characterised by spectroscopic methods and Single crystal XRD studies.
The 1-3 showed that the synthesised compounds in crystallise in the monoclinic crystal
system, and space group present is P 2/c, C 2/c and P 21/c. The computational studies of
1
-3 were performed with Density function theory (DFT) using B3LYP/ 6-31G (d, p) level
of theory. Molecular electrostatic potential map (MEP) and frontier molecular orbital
FMO) analysis were also carried out. Further molecular docking methods were used to
recognise the binding of the molecules towards the molecular target DNA (PDB ID:
BNA), BSA (PDB ID: 3V03) and human aromatase enzyme (PDB-ID: 3EQM). All
(
1
compounds were screened for their cytotoxicity against breast cancer cell lines (MCF-7)
and lung cancer cell lines (A549) under in vitro conditions. The compound 3 showed
overall good cytotoxic activity and especially towards MCF-7 (IC50
= 48.5 µM). AO/EB
and Hoechst 33258 staining methods were used to analyse morphological changes to
expose the mechanism of cell death.
Keywords: Bis (aroyl selenourea), Cytotoxicity, DFT, Docking, X-ray.
*
Corresponding Author E-mail address: sreekanth@nitt.edu; Tel: +91 431 2503642
Corresponding Author E-mail address: rganguly@ntu.edu.sg; Tel: (65) 6592-1698
Department of Chemistry, National Institute of Technology, Tiruchirappalli 620015,
*
a
India.
b
Division of Chemistry & Biological Chemistry, Nanyang Technological University,
Singapore 639798, Singapore.
c
National Centre for Alternatives to Animal Experiments (NCAAE), Bharathidasan
University, Tiruchirappalli 620 024, India.
1

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1. Introduction
Selenium (Se) is a necessary trace mineral that plays a variety of essential roles in
animal and human physiology. Unlike other elements which mainly act as cofactors or
structural scaffold, selenium is combined into the amino acid selenocysteine (Sec) in
selenium contain proteins. Selenium-containing compounds exhibited such as antioxidant
activities, antiviral properties, and anti-inflammatory actions. Selenium deficiency can lead
to conditions, such as increased cancer risk and a decrease in immunity. Se deficit can also
cause male infertility and several neurological conditions like Parkinson’s disease and
Alzheimer’s [1]. Deficiency of selenium causes a decline in glutathione peroxidase (GPx)
and Iodothyronine deiodinase (DIO) enzyme activity, which causes the accumulation of
hydrogen peroxide (H O ), leads to the damage of the thyroid gland [2] [3]. Hence the
2
2
study biological activity of selenium in the human body is of significant importance, which
helps us to develop a potential therapeutic agent in the prevention of diseases and is one of
the areas of growing interest. Several organoselenium compounds have been tested as
antioxidants, immunomodulators, and anticancer and antihypertension agents. The in vitro
studies on methyl selenic acid, methyl-selenocysteine, and SeMet, showed them to be
efficient as antitumorigenic agents in animals [4-6].
Based on the above facts we have synthesised bis (aroyl selenourea) with different
substituents at carbonyl groups shows that good antitumoral agents [7]. One side
substituted selenoureas less anti-cancer activity at the same time two sides substituted
selenoureas more cancer activity [8]. Indeed, cytotoxicity studies demonstrated that some
of the aroyl/acyl thioureas showed cytotoxic activity and their anti-proliferative effects
being dependent on the type/nature of the substituent on the aroyl/acyl thiourea attach
compounds [9]. Synthesised compounds were characterised using various spectroscopic
methods. Computational studies have been performed using DFT calculations to get further
bits of knowledge into the structural properties of the synthesised compounds, from which
we were able to perform MEP and FMO analysis, which allowed the calculation of HOMO
–
LUMO energy gap and interconnected parameters [10]. PASS test have been performed
to analyse the potential biological activity of synthesised bis (aroyl selenourea) [11]. All
the above facts have inspired us to estimate the molecular docking and the molecules were
evaluated against MCF-7 and A549 cancer cell lines under in vitro conditions to explore its
biological potential.
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2. Results and Discussion
2
.1. Synthesis
The bis (aroyl selenourea) derivatives 1-3 were prepared to taking on a reported
method [12] (Scheme 1). The pure crystals of 1-3 were obtained from recrystallisation in
1
13
EtOH. The synthesised compounds have been characterised by FT-IR, UV-Visible, H, C
NMR, CHNS and spectroscopic studies. Single crystal X-ray crystallographic studies
proved the structures of 1-3.
Scheme 1. Synthesis of bis (aroyl selenourea) 1-3
2
.2. Characterisation
Electronic spectra of 1-3 were recorded in DMF. The peaks corresponding to n →
π* and π → π* transitions were observed in the region of 303-305 and 248-256 nm. In the
−
1
FT-IR spectra of 1-3, the stretching frequencies of amide N−H appeared at 3398-3330 cm
−
1
region, and bis (aroyl selenourea) N−H bands appear in the regions of 3102-3283 cm . The
−
1
carbonyl stretching frequency of all compounds were observed at 1672-1676 cm while
−
1
1
that of v(C=Se) appeared at 1258-1286 cm . In the H NMR spectra of 1-3, there are three
different types of protons were observed, viz., NH (between C=Se and C=O) as a singlet at
12.14-12.70 ppm, NH (between phenyl and C=Se) at 9.14-9.59 ppm and aromatic protons
13
as multiplets between 6.61-7.77 ppm. The C NMR spectra of the 1-3 showed signals at
56.3-164.8 and 179.8-181.7 ppm, corresponding to C=O and C=Se respectively. The
1
signals observed at 112.0-146.1 ppm were assigned to the aromatic carbons in the bis (aroyl
selenourea) [13].
2.3. Single crystal X-ray crystallographic studies
Details of Crystal data collection is given in supporting information (Table 1), and
selected bond lengths and angles were shown in Tables 2-4. The 1-3 crystallise in the
monoclinic crystal structures, and space group present is P 2/c, C 2/c and P 21/c. All
molecules showed intramolecular hydrogen bonding interaction between selenocarbonyl
3

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attached N-H and carbonyl oxygen. Furthermore, carbonyl and selenocarbonyl groups are
in trans configuration around the C−N bond. Compound 1-3 crystal packing shows in
Figure 2.Table 2-4 show the bond lengths of C=Se of 1-3 1.829(4), 1.821(2), 1.821(3) (Å)
respectively. The Olex2-1.2 representations [14] of 1-3 including the atom-numbering
scheme are shown in Figure 1. Molecular structures of three compounds revealed that the
selenium atoms in all compounds have in the structures of 1-3.
Figure 1. Thermal ellipsoid plot (at 50% probability level) with atomic labelling of 1 (a), 2
(b) and 3 (c).
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Figure 2. Crystal Packing of 1 (a), 2 (b) and 3 (c).
Table 1. Crystallographic data and refinement parameters for (1-3)
1
2
3
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
C H O Se
C H N O S Se
C H N O Se
2
22
18
2
2
18 14
4
2
2
2
18 13
4
4
529.78 g/mol
103(2)
540.37 g/mol
103(2)
507.24 g/mol
250(2)
0.71073
0.71073
0.71073
Monoclinic
P 2/c
Monoclinic
C 2/c
Monoclinic
P 21/c
Space group
Unit cell dimensions
a (Å),
b (Å),
α
β
(°)
(°)
12.5676(8), 90
12.6160(8),
15.4855(15),90
16.5158(15),
122.730(3)
8.7839(7), 90
23.7248(18),
95.428(3)
105.1216(18)
c (Å),
γ
(°)
15.9051(9) , 90
2434.5(3)
9.4162(10),90
2025.9(3)
9.1673(7), 90
1901.9(3)
3
Volume (Å )
Z
4
4
4
3
1.552
1.772
1.772
Density Mg/m
Absorption coefficient
3.173
3.878
3.921
-
1
(
mm )
F(000)
1127
1064
996
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3
Crystal size (mm )
0.220 x 0.300 x
.420
0.080 x 0.100 x
0.100 x 0.140 x
0.160
0
0.140
Theta range for data
collection (°)
1.61 to 28.32
1.99 to 28.31
2.39 to 31.03
Index ranges
-16<=h<=15,
-19<=h<=20,
-22<=k<=22,
-12<=l<=5
-12<=h<=12,
-34<=k<=34,
-12<=l<=13
-
16<=k<=16,
14<=l<=21
-
Reflections collected
31236
15448
34647
Independent reflections 6065 (0.0669)
R(int)]
2518 (0.0569)
6056 (0.0423)
[
Completeness to
theta=27.50°
99.9%
99.6%
99.5%
Absorption correction
Max. and min.
transmission
Multi-Scan
Multi-Scan
Multi-Scan
0.5420 and 0.3490
0.7470 and 0.6130 0.6950 and 0.5730
Refinement method
Full-matrix least-
Full-matrix least-
Full-matrix least-
2
2
2
squares on F
squares on F
squares on F
Data / restraints /
parameters
6065 / 113 / 334
2518 / 0 / 127
6056 / 0 / 253
2
1.035
1.022
1.041
Goodness-of-fit on F
Final R indices
R1 = 0.0433,
R1 = 0.0277,
R1 = 0.0439,
[
I>2sigma(I)]
wR2 = 0.0961
R1 = 0.0747,
wR2 = 0.1071
wR2 = 0.0561
R1 = 0.0496,
wR2 = 0.0636
wR2 = 0.1006
R1 = 0.0648,
wR2 = 0.1084
R indices (all data)
Largest diff. peak and
1.189 and -0.547
0.736 and -0.452
1.489 and -0.853
-3
hole (e.Å )
Table 2. Selected bond lengths (Å) and Bond angles (°) for 1
Bond lengths (Å)
Se1-C8
C1-O1
1.829(4)
1.223(5)
Se2-C15
C1-N1
1.827(3)
1.382(5)
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C8-N1
C14-N3
C15-N4
C16-N4
1.388(4)
1.426(4)
1.383(4)
1.382(4)
C8-N2
C9-N2
1.316(5)
1.430(4)
1.328(4)
1.229(4)
C15-N3
C16-O2
Bond angles (°)
122.6(4) O1-C1-C2
O1-C1-N1
N1-C1-C2
121.9(4)
117.1(3)
118.3(3)
120.1(3)
120.7(3)
123.8(2)
122.0(3)
117.0(3)
125.1(3)
126.8(3)
115.5(4)
124.6(3)
120.0(3)
119.1(3)
116.4(3)
119.8(2)
121.0(3)
126.9(3)
125.9(3)
N2-C8-N1
N1-C8-Se1
C10-C9-N2
C9-C14-N3
N3-C15-Se2
O2-C16-N4
N4-C16-C17
C8-N2-C9
N2-C8-Se1
C14-C9-N2
C13-C14-N3
N3-C15-N4
N4-C15-Se2
O2-C16-C17
C1-N1-C8
C15-N3-C14
C16-N4-C15
Table 3. Selected bond lengths (Å) and bond angles (°) for 2
Bond lengths (Å)
Se1-C4
C4-N1
C5-O1
C6-S1
1.821(2)
1.336(3)
1.240(3)
1.724(3)
C1-N1
C4-N2
C5-N2
C9-S1
1.429(3)
1.388(3)
1.373(3)
1.700(3)
Bond angles (Å)
C1-C1-N1
N1-C4-Se1
O1-C5-N2
119.27(12)
124.83(18)
122.1(2)
C2-C1-N1
N1-C4-N2
N2-C4-Se1
120.4(2)
115.1(2)
120.10(17)
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N2-C5-C6
C5-N2-C4
118.3(2)
127.3(2)
O1-C5-C6
C4-N1-C1
119.6(2)
125.4(2)
Table 4. Selected bond lengths (Å) and bond angles (°) for 3
Bond lengths (Å)
Se1-C6
C5-O2
C6-N2
C7-N2
C13-N3
C14-O3
1.827(3)
1.227(4)
1.343(4)
1.408(4)
1.326(4)
1.221(4)
Se2-C13
C5-N1
1.821(3)
1.381(4)
1.377(4)
1.442(4)
1.390(4)
1.381(4)
C6-N1
C12-N3
C13-N4
C14-N4
Bond angles (Å)
O2-C5-N1
N1-C5-C4
123.2(3)
O2-C5-C4
N2-C6-N1
121.7(3)
114.3(3)
117.0(2)
117.2(3)
121.2(3)
125.8(2)
123.4(3)
114.6(3)
129.0(3)
128.3(3)
115.1(3)
128.6(2)
124.0(3)
118.6(3)
116.5(3)
117.7(2)
122.0(3)
129.9(3)
121.5(2)
N2-C6-Se1
C8-C7-N2
N1-C6-Se1
C12-C7-N2
C7-C12-N3
N3-C13-Se2
O3-C14-N4
N4-C14-C15
C6-N2-C7
C11-C12-N3
N3-C13-N4
N4-C13-Se2
O3-C14-C15
C6-N1-C5
C13-N3-C12
C14-N4-C13
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2
.4. MEP and Frontier Molecular analysis
.4.1 MEP analysis
MEP analysis gives an insight into the hydrogen bonding interactions, shape and
2
intermolecular interactions and reactivity sites [15, 16]. A comparative view of molecular
electrostatic maps is presented here which are Figure 3. MEP of 1-3 calculated using
-2
BL3YP/6-31G (d, p) basis set. The electrostatic potential lies in the range of -5.662e to
-2
-2
-2
-2
-2
+
5.662e , -5.697e to +5.697e ,-4.805e to +4.805 e for 1-3 respectively. As can be
seen in the MEP for all the three regions around carbonyl oxygens at 1-3 are red and hence
possess high electron density or in other words a site more exposed to electrophilic attack
[
17].
Figure 3. The MEP of 1, 2 and 3 calculated using B3LYP/6-31G (d, p) basis set. Negative
potential indicates red regions while positive potential indicates blue regions.
2.4.2. Frontier Molecular analysis
FMO’s of all three target compounds 1-3 (Figure 4) were calculated using DFT by
BL3YP/6-31G (d, p). The HOMO-LUMO energy gaps are 3.2814, 3.1592 and 3.3627 e.V
for compounds 1-3 correspondingly (Table 5). The HOMO-LUMO energies of all the
compounds are values follow the order of structural reactivity 3 > 1 > 2. This HOMO-
LUMO energy gap was explored to evaluate the critical chemical reactivity parameters like
softness, hardness (η), electronegativity (χ), the chemical potential (ꢀ), electron-affinity
(
A) and ionisation energy (I) [18, 19]. These properties have been defined as follows [20].
η = (I-A)/2 ꢀ= - (I-A)/2 χ = (I+A)/2
Where I and A were obtained from HOMO and LUMO energies as I = -EHOMO and
A = -ELUMO as per Janak theorem [21] and Perdew et al. [22]. Hardness (η) which is
directly related to stability was found to be 1.6407, 1.5796 and 1.6814e.v for 1-3
respectively. The chemical potential was found to be -3.4497,-3.5992, and -3.4729 for 1-3
9

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respectively. Parr et al. introduced a parameter like the global electrophilicity index (ω)
2
calculated by equation ω = ꢀ /η [23]. The corresponding values for compounds 1-3 are
7.2532, 8.2009 and 7.1732 e.V respectively. From Table 5, it is clear that all the above said
reactivity parameters of all the three compounds are more or less similar to each other,
suggesting their nearly similar behaviour in DNA, Protein and enzyme interaction study.
Figure 4. HOMO and LUMO representation of all the compounds 1, 2 and 3
Table 5. Calculated energy values for compounds (1-3) using B3LYP/6-31G (d, p) basis set
Parameter
Energy (au)
1
2
3
-6013.04147
4.8255
6658.74639
4.9977
-6013.04147
5.4058
Dipole moment (Debye)
EHOMO (eV)
-5.0904
-1.8090
3.2814
-5.1788
-2.0196
3.1592
-5.1543
-1.7915
3.3627
ELUMO (eV)
E
-
(eV)
HOMO LUMO
EHOMO-1 (eV)
ELUMO+1 (eV)
-5.3320
-1.4960
3.8359
-5.3380
-1.9747
3.3633
-5.2479
-1.3496
3.8983
E(HOMO-1)-(LUMO+1) (eV)
Hardness (η)
1.6407
1.5796
1.6814
1
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Chemical Potential (ꢀ)
-3.4497
3.4497
7.2532
-3.5992
-3.4729
3.4729
7.1732
Electronegativity (χ)
3.5992
8.2009
Electrophilicity index (ω)
2.5. Drug-likeness test
PASS define as Prediction of Activity Spectra for Substances.it is a valuable tool
that calculates the biological activity of a molecule[24]. It assesses the drug-likeness and
toxicities of molecules like carcinogenicity, teratogenicity, etc [25]. The calculation shows
that 95% according to LOOCV (leave-one-out-cross-validation) estimation and the
probabilities, Pa (Probable activity) and Pi (Probable inactivity) [26]. Their values are in-
between 0.000 to 1.000, and generally Pa + Pi is not equal to 1 as these probabilities were
calculated individually[27]. PASS test of the 1-3 have been carried out using online
software (http://www.pharmaexpert.ru/passonline), and the values were tabulated (Table 6
and S1-S2). The analysis of PASS result predicts that the 1-3 are having the potential for
Methylenetetrahydrofolate reductase (NADPH) inhibitor, Transcription factor STAT3
inhibitor, Apoptosis agonist. Hence the PASS test results suggesting the compelling nature
of 1-3 as an antitumor drug. Predominantly compound 3 shows good anticancer activity in
PASS test. The result shows that compound 3 has Pa value of 0.664. This activity mainly
shows that the activity of Transcription factor STAT3 inhibitor [28].
Table 6. PASS (Prediction Activity Spectra) of compounds 3 with Pa >0. 5
Pa
Pi
Activity
Pa
Pi
Activity
Malate oxidase
inhibitor
Complement factor
D inhibitor
0
0
0
0
0
.848
0.004
0.539
0.010
Transcription factor
STAT3 inhibitor
Sarcosine oxidase
inhibitor
Acrocylindropepsin
inhibitor
.664
.657
.632
.628
0.005
0.007
0.005
0.014
0.595
0.595
0.595
0.628
0.076
0.076
0.076
0.110
Chymosin inhibitor
Transcription factor
STAT inhibitor
Monodehydro
Saccharopepsin
inhibitor
Phobic disorders
treatment
ascorbate reductase
1
1

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(NADH) inhibitor
Chloride peroxidase
inhibitor
0
0
0
.588
.548
.550
0.028
0.007
0.018
Apoptosis agonist
0.549
0.597
0.510
0.038
0.109
0.011
PfA-M1
aminopeptidase
inhibitor
Ubiquinol-cytochrome-
c reductase inhibitor
5
Hydroxytryptamin
Taurine-2-oxoglutarate
transaminase inhibitor
e release inhibitor
2.6. Molecular docking with DNA, BSA and human aromatase enzyme
The compounds 1-3 were exposed to molecular docking with DNA (PDB ID:
BNA) [29], BSA (PDB ID: 3V03) [30] and human aromatase enzyme (PDB-ID: 3EQM)
1
using AutoDock 4.2 molecular docking software and visualised with Discover studio
software [24]. The DNA BSA and human aromatase enzymes were obtained from the
protein data bank website (https://www.rcsb.org/). The target molecules were selected
based on DNA, BSA interaction experiment study at the same time human aromatase
enzyme were selected according to the PASS result. The results of BSA DNA and human
aromatase enzyme docking parameters were listed in (Table 7-9), and the binding sites
showed in Figures (Figure 5 and S1-S3). The docking result suggested that compound 3
has the higher binding energy of DNA (-6.69 kcal/mol) and compound 2 shows that the
higher binding of BSA (-4.05 kcal/mol), but in the case of the human aromatase enzyme,
compound 3 (-5.47 kcal/mol) showed higher binding energy with inhibition constants Ki
(342.41 µM).
1
2

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Figure 5.(a) Molecular docked model of compound 3 with DNA dodecamer duplex of
sequenced (CGCGAATTCGCG) (PDB ID: 1BNA),(b) Molecular docked model of
2
compound 2 interaction with BSA (PDB ID: 3V03),(c) Best docked model of compound 3
interaction with human aromatase enzyme (PDB-ID 3EQM)
Table 7. Molecular docking parameters of compounds (1-3) with B-DNA (PDB ID:
1
BNA)dodecamer d(CGCGAATTCGCG)
2
Compound
No
Best Binding
Nucleotide residues involved in
interaction with compounds
Rotational
energy (ϚGb)
(kcal/mol)
-1.05
bonds
1
2
3
6
6
6
DA4 DA5 DA6
DA5 DG16 DA17
DG4 DA5 DA18
-3.24
-6.69
1
3

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Table 8. Molecular docking parameters of compounds (1-3) with BSA (PDB ID: 3V03)
Compound
No
Best Binding
Amino acid residues of Involved in
interaction with compounds
Rotational
energy (ϚGb)
bonds
6
(kcal/mol)
-2.16
1
2
3
SER104 LYS106 ASP107
ALA538 ARG412 LEU528 THR411
GLN203 PHE205
6
6
-4.05
-3.55
Table 9. Molecular docking parameters of compounds (1-3) human aromatase enzyme
(3EQM)
Compound
No
Best Binding
energy (ϚGb)
(kcal/mol)
-5.14
Inhibition
Constant
(Ki) (µM)
171.65
Amino acid residues of
Involved in interaction with
compounds
Rotational
bonds
1
2
3
6
6
6
ARG115 PHE430
-4.73
98.58
ALA306 CYS437
-5.47
342.41
ALA306 VAL370 PRO429
2
.7. In vitro cytotoxicity studies
.7.1. Cell Viability Test
The cytotoxic activities of 1-3 were investigated compared to the A549 and MCF-7
2
cancer cell lines using MTT assay after 24h of incubation. The inhibitory effect of 1-3 at
different concentration were measured regarding IC values. The observed IC reveal that
50
50
all the 1-3 exhibit different range of cytotoxicity against different cell types (Table 11 and
Figure 6 (a) and 6 (b)). In which all molecules 1-3 showing the moderate level activity
(
IC =100 to 150 µM). Interestingly, in the case of MCF-7 cell lines, each molecule
50
showed a different level of activity. Compound 1 showed a moderate level of activity
while 2 was not toxic/ less toxic (IC = >200 µM). Compound 3 showed the highest
5
0
activity among all result. The IC values of the compounds are displayed in Table 10.
5
0
Cytotoxicity of 1–3 were compared with that of recently reported selenourea compounds.
The cytotoxicity of the compounds were superior when compared to ethyl 4-(3-
hydroxyphenyl)-6-methyl-2-selenoxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (IC50
=
1
4

ACCEPTED MANUSCRIPT
4
52.2 µM) and the compound of ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-selenoxo-
,2,3,4-tetrahydropyrimidine-5-carboxylate (IC = 247.8 µM) against MCF-7 cancer cell
1
5
0
line [31]. As for the case of activity against A549 cancer cell line, the compound showed
less activity compared to the reported selenourea compounds.
Figure 6. (a) Cytotoxic effect of the 1-3 on MCF-7 cells after exposure for 24 h. (b).
Cytotoxic effect of the 1-3 on A549 cells after exposure for 24 h Data of (a) and (b) were
mean SD of three independent experiments with each experiment conducted in triplicate
Table 10.In vitro cytotoxicity assays for the compounds (1-3)
against different cancer cell lines in µM concentration
Compound
1
A549
120
MCF-7
169
2
3
148
152
19
>200
48.5
15
Cisplatin
2.7.2. Acridine orange (AO) and ethidium bromide (EB) staining
During apoptosis, the cells will undergo morphological changes which can be
traced with the help of AO/EB staining. In AO/EB staining AO is cell permeable while EB
is impermeable to the cell membrane. Since viable cell lines have a cell membrane, only
AO enter to the cell. We will get consistently green fluorescing nuclei with much-organised
structure. In the early apoptotic stage, the cells show that bright green patches are
1
5

ACCEPTED MANUSCRIPT
perinuclear chromatin condensation. In the late apoptotic stage, the cell blebbing and the
loss of membrane integrity starts to occur, giving an orange fluorescing nucleus with
condensed chromatin. For the case of necrosis, since it is not programmed cell death, the
fluorescence image will give an evenly orange fluorescing nucleus with no hint of
chromatin fragmentation.
From the AO/EB double-staining, the A549 cells treated with 1-3 for 24 hr of
incubation mostly underwent early apoptosis mode of cell death. A decidedly fewer in
necrosis mode of cell death also appeared in all type of samples Figure S4 and S5. From
the Figure, it is clearly stated that all the compounds induce apoptosis mode of cell death in
A549 cells. In the case of MCF-7 cells, all the 1-3 are inducing the apoptosis mode of cell
death except the 2; which is mostly having the live cells as seen in control Figure 7 -8. This
result is correlated with MTT assay since the compound 2 was having a lower cytotoxic
range than the other samples against MCF-7.
Figure 7. AO/EB staining of control and 1-3 treated MCF-7 cells. Live cells show green
colour, and apoptotic cells show an orange colour
Figure 8. Percentage of apoptosis and necrosis cells in control and compounds treated
MCF-7 cells (Data are mean% ± SD% of each triplicate)
1
6

ACCEPTED MANUSCRIPT
2
.7.3. Hoechst 33528 staining
To distinguish apoptosis, at an essential level, we incorporated Hoechst staining,
which uncovered the adjustments in cytology of the cell, with excellent reference to
cytoplasm and nucleus. Afterwards dealing with IC concentrations of the 1-3 for 24 h, the
5
0
A549 and MCF-7 cells were watched for cytological changes [32]. The interpretations
exposed that the early apoptotic topographies such as cell shrinkage, chromatin
condensation and fragmentation have seen mostly in treated cells and small numbers of
necrotic cells were also observed in Figure S6 Interestingly, in the case of 2, cells with
intact nuclei mostly appeared in MCF-7 cells Figure 9.
Figure 9. Hoechst 33258 Staining of MCF-7 treated cells contains apoptosis morphologies,
whereas control cells showed intact nuclei
2.7.4. Assessment of mitochondrial membrane potential (JC1 staining)
Mitochondrial film possible test was utilised here to identify changes in
mitochondrial function influenced by treatment. It uses the fluorescent cation JC-1, which
discharges red fluorescence when appropriated into the mitochondria of in good physical
shape cells with high mitochondrial potential. Cells experiencing apoptosis are never again
ready to appropriate the JC-1 cation into the mitochondria because of loss of membrane
potential thus cells fluoresce green [33]. The consequences of JC-1 recolouring of A549
and MCF-7 cancer cells treated with mixes at 12 hours incubation confirms the loss of
mitochondrial film potential Figure 10 and Figure S7. On account of 2 treated MCF-7 cells,
mitochondrial film potential was held as present in control Figure 10.
Figure 10. JC-1 staining of MCF-7 cells: Control shows cells with orange to red
fluorescence indicate high mitochondrial membrane potential. Treated cells emit green
1
7

ACCEPTED MANUSCRIPT
colour fluorescence indicates the loss of mitochondrial potential.
2.7.5. Annexin V-Cy3 Staining
An initial pointer of apoptosis is the fast chromosomal rearrangement and
aggregation of the film phospholipid phosphatidylserine from the cytoplasmic interface to
the extracellular surface [34]. The blend of Annexin V-Cy3 (produces red) and 6-CFDA
(transmits green) permits the separation between primary apoptotic cells (Annexin V
positive, 6-CFDA positive), necrotic cells (Annexin V positive, 6-CFDA negative), and
feasible cells (Annexin V negative, 6-CFDA positive). The outcomes acquired with
Annexin V restricting measure of control and treated cells are shown in Figure 11 and S8.
The aftereffect of Annexin V-Cy3 demonstrates that all the 1-3 specifically activate
apoptotic method of cell demise than putrefaction. It is significant that the compound 2
actuates a low number of apoptosis and necrotic impact in MCF-7 cells Figure 11.
Figure 11. MCF-7 breast cancer cells stained with annexin V-Cy3 and 6-CFDA. Control
and compounds treated cells after 24 hours incubation.
3. Experimental section
3.1. Synthesis of benzene-1, 2-diamine substituted bis (aroyl selenourea) 1-3
The resulting process prepared the 1-3. A solution of corresponding acid chloride in
acetone (25 mL) was added to potassium selenocyanate in acetone (25 mL). The reaction
o
mixture was refluxed for 45 minutes at 65 C. After cooling, benzene-1, 2-diamine dissolve
in acetone (25 mL) was added to it dropwise, and the resulting mixture was stirred for two
hours at ambient temperature. The solution was transferred into 0.1 M HCl (ca. 200 mL),
1
8

ACCEPTED MANUSCRIPT
and the resultant precipitate was filtered, washed with water and dried. The solid product
was filtered by recrystallisation from a methanol/dichloromethane mixture (1/2).
3.1.1. N, N’-((1,2-phenylene bis(azanediyl))bis(carbonoselenoyl))dibenzamide (1)
A solution of benzoyl chloride (0.6 mL, 5 mmol) in dry acetone (25 mL) was additional to
potassium selenocyanate (0.720 g, 5 mmol) in acetone (25 mL).
o
Yield: 1.18g, 78%. Pale yellow solid. m.p.: 162 C. Anal. Calc. for C H N O Se (%): C,
22
18
4
2
2
50.01; H, 3.43; N, 10.60; O, 6.06; Found: C, 49.88; H, 3.12; N, 10.33; O, 6.02 .UV-Vis
-1
(
DMF): λmax, nm 248, 304. FT-IR: ʋ, cm 3330, 3102 (N−H), 3005 (=C−H), 1672 (C=O),
1
1
286 (C=Se). H NMR (500 MHz, CDCl ): δ, ppm 12.70 (s, 1H, NH), 9.59 (s, 1H, NH),
3
1
3
7
.79 (d,J =7.5 3H), 7.55 (t, J =7.5,1H), 7.52 (t, J =7.05, 3H). C NMR (125 MHz, CDCl ):
3
δ, ppm 180.1 (C=Se), 164.8 (C=O), 132.5, 131.9, 129.3, 127.2, 126.9, 125.8, 125.4.LC-MS
−
=
532.5 [M − H] .
3.1.2.N,N’-((1,2-phenylenebis(azanediyl))bis(carbonoselenoyl))bis(thiophene-2-
carboxamide) (2)
A solution of thiophene-2-carbonyl chloride (0.6 mL, 5 mmol) in acetone (25 mL) was
additional to potassium selenocyanate (0.720 g, 5 mmol) in acetone (25 mL).
o
Yield: 1.06g, 76%. Pale yellow solid. m.p.: 155 C. Anal. Calc. for C H N O S Se (%):
18
14
4
2
2
2
C, 40.01; H, 2.61; N, 10.37; O, 5.92; S, 11.87;Found C, 39.88; H, 2.33; N, 10.19; O, 5.65;
-1
S, 11.57; UV-Vis (DMF): λmax, nm 256, 305. FT-IR: ʋ, cm 3405, 3283 (N−H), 3074
1
(
=C−H), 1674 (C=O), 1272 (C=Se). H NMR (500 MHz, CDCL ): δ, ppm 12.1 (s, 1H,
3
13
NH), 9.1 (s, 1H, NH), 7.79 (d,J =7.5 3H), 7.55 (t, J =7.5,1H), 7.52 (t, J =7.05, 3H). C
NMR (125 MHz, CDCL ): δ, ppm 179.8 (C=Se), 161.0 (C=O), 135.9, 134.3, 133.1, 130.9,
3
−
1
28.4, 128.2, 127.0.LC-MS = 543.9 [M − H] .
3.1.3.N,N'-((1,2-phenylenebis(azanediyl))bis(carbonoselenoyl))bis(furan-2-
carboxamide) (3)
A solution of furan -2-carbonyl chloride (0.5 mL, 5 mmol) in acetone (25 mL) was
additional to potassium selenocyanate (0.720 g, 5 mmol) in acetone (25 mL).
o
Yield: 1.20g, 79%. Pale yellow solid. m.p.: 165 C. Anal. Calc. for C H N OS (%): C,
2
1
16
2
2
66.99; H, 4.28; N, 7.44; S, 17.03. Found: C, 67.04; H, 4.41; N, 7.20; S, 16.92. UV-Vis
-1
(
DMF): λmax, nm 253, 303. FT-IR: ʋ, cm 3396, 3119 (N−H), 3019 (=C−H), 1676 (C=O),
1
1
258 (C=Se). H NMR (500 MHz, CDCL ): 0δ, ppm 12.4 (s, 1H, NH), 9.6 (s, 1H, NH),
3
1
3
7
.76 (m, 1H),7.62 (m, 1H), 7.48 (m, 1H), 7.36 (d, J =3.3, 1H) C NMR (125 MHz,
1
9

ACCEPTED MANUSCRIPT
CDCL ): δ, ppm 181.7 (C=Se), 156.3 (C=O), 147.5, 144.7, 134.6, 128.9, 127.6, 119.4,
3
−
1
13.2. LC-MS = 507.9 [M − H] .
3.2. Density Functional Theory study
The quantum chemical calculations have been carried using GAUSSIAN 09
software. The DFT method, using the basis set 6-31 G (d, p).The optimisation structures
were carried out varies parameters of molecules. The optimised molecules were used to
analyse molecular docking studies also.
3.3. Molecular docking studies
The structure of B-DNA (PDB ID: 1BNA), BSA (PDB ID: 3V03) and human
aromatase enzyme (PDB-ID 3EQM) were obtained from the Protein Data Bank
http://www.rcsb.org/pdb). Moreover, the structure of molecules were used from crystal
(
structures by converting the CIF file to PDB file. Docking studies have been done using
the AutoDock Tools (ADT) version 1.5.6 and AutoDock version 4.2.5.1 docking program
[
35]. The energy calculations were made using genetic algorithms. The outputs were
carried out discover studio for visual examination of the binding modes, binding energy
and hydrogen interactions of the compounds with Protein, DNA and human aromatase
enzyme.
3
.4. Cytotoxic properties
The detailed procedure for In vitro cytotoxicity studies were included in the
Supporting Information
. Conclusion
In this paper, we have described convenient syntheses and comprehensive
4
characterisation of three novel bis (aroyl selenourea) derivatives 1-3. Single crystal
analysis depicted that the synthesised compounds (1-3) crystallise in monoclinic crystal
system with P12/c1, C12/c1 and P121/c1 space group. DFT calculated the structural and
electronic properties of 1-3. HOMO-LUMO energy gap was considered which allowed the
calculation of reactivity related properties of molecules. Drug-likeness test predicted that
all compounds have anti-cancer activity. Compound 3 has a prominent cancer activity in
the PASS test result. In-silico molecular docking suggested that compound 3 has the higher
binding energy for DNA (-6.69 kcal/mol). Compound 2 showed the higher binding energy
of BSA (-4.05 kcal/mol), but in the case of the human aromatase enzyme, compound 3 (-
58.87 kcal/mol) has higher binding energy. In vitro cytotoxicity outcomes suggested that
the cytotoxicity activity of synthesised compounds were selective towards to different cell
2
0

ACCEPTED MANUSCRIPT
lines, in which compound 3 showed higher activity towards MCF7 (IC50
cell lines while compound 1 showed higher activity towards A549 (IC50
=
48.5 µM) cancer
120 µM) cancer
=
cell lines.AO/EB, Hoechst 33528, JC1 and Annexin V-Cy3 Stainings were performed to
analyse the mechanism of cytotoxicity; it is revealed that all molecules were able to induce
apoptosis in which molecules 3 showed the higher activity of apoptosis, especially in
MCF7 cell lines.
Acknowledgements
The author MM is thankful to MHRD, Govt. of India for providing Senior
Research Fellowship (SRF), National Centre for Alternative to Animal Experiments
(NCAAE) for providing help in the analysis of the samples. We are also grateful to
Nanyang Technological University (NTU), Singapore for the single crystal X-ray analysis.
Conflict of Interest
The authors declare no conflict of interest.
Electronic supplementary information (ESI) available:
The supplementary information includes NMR spectra of 1-3 and the methods, in
silico and in Vitro Biological evaluation studies were included in supporting information.
Crystallographic data for the structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as supplementary publication numbers
(
1566823, 1566808, and 1845637 respective for 1, 2 and 3). Copies of the data can be
obtained free of charge from the CCDC (12 Union Road, Cambridge CB2 1EZ, UK; Tel.:
44-1223-336408; Fax: + 44-1223-336003; e-mail: deposit@ccdc.cam.ac.uk ; Web site
+
http://www.ccdc.cam.ac.uk).Additional supporting information may be found online in the
Supporting Information section at the end of the article.
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Research highlights
1. Bis (aroyl selenourea) Derivatives 1-3 have been prepared and characterized by various
Spectroscopy techniques.
2
. 1-3 structures were confirmed by Single crystal XRD studies.
. Using DFT-based optimization of structures, theoretical calculations were done at the
DFT/B3LYP/6-311G (d, p) level of theory.
3
4
. Molecular docking studies revealed that these compounds exhibit good interaction with
BSA, DNA and human aromatase enzyme
5. All three compounds were carried out cytotoxicity activity
2
5