N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld surface analysis and molecular docking study

Article abstract of DOI:10.1080/07391102.2020.1819424

The compound N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide (8) was synthesized by the condensation of 3-methoxybenzoic acid (7) with N ¹-(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with a = 9.4694(10) ?, b = 9.4694(10) ?, c = 18.886(3) ?, α = 90°, β = 90°, γ = 90°. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule was investigated with theoretical calculations at the B3LYP/6-311 + G(d,p) levels. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. In addition, the title compound possesses marked inhibition against the proliferation of human colon cancer cell line HT-29 (IC₅₀ = 1.76 μM), human lung adenocarcinoma cell line A549 (IC₅₀ = 1.98 μM) and human gastric cancer cell line MKN45 (IC₅₀ = 2.32 μM), displaying promising anticancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity inhibiting PDB:3D15. Communicated by Ramaswamy H. Sarma.

Full text of DOI:10.1080/07391102.2020.1819424

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-
yl)amino]ethyl}-3-methoxybenzamide: design,
synthesis, crystal structure, antiproliferative
activity, DFT, Hirshfeld surface analysis and
molecular docking study
Pei Huang , Juan Zhao , Yan-Hong Gao , Ling-Xia Jin , Qin Wang , Xiao-Hu Yu ,
Xiao-Hui Ji & Jiu-Fu Lu
To cite this article: Pei Huang , Juan Zhao , Yan-Hong Gao , Ling-Xia Jin , Qin Wang , Xiao-
Hu Yu , Xiao-Hui Ji & Jiu-Fu Lu (2020): N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-
methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld
surface analysis and molecular docking study, Journal of Biomolecular Structure and Dynamics,
DOI: 10.1080/07391102.2020.1819424
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1819424
N-f2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethylg-3-methoxybenzamide:
design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld
surface analysis and molecular docking study
Pei Huang, Juan Zhao, Yan-Hong Gao, Ling-Xia Jin, Qin Wang, Xiao-Hu Yu, Xiao-Hui Ji and Jiu-Fu Lu
Shaanxi Key Laboratory of Catalysis, College of Chemical & Environment Science, Shaanxi University of Technology, Hanzhong, China
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
The compound N-f2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethylg-3-methoxybenzamide (8) was
Received 30 July 2020
Accepted 29 August 2020
1
synthesized by the condensation of 3-methoxybenzoic acid (7) with N -(2-chlorothieno[3,2-d]pyrimi-
din-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carb-
oxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then
condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined
and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with
KEYWORDS
Thieno[3,2-d]pyrimidine;
synthesis; X-ray diffraction;
antiproliferative activity;
Hirshfeld surface analysis
ꢀ
ꢀ
ꢀ
a ¼ 9.4694(10) Å, b ¼ 9.4694(10) Å, c ¼ 18.886(3) Å, a ¼ 90 , b ¼ 90 , c ¼ 90 . The optimized geometric
bond lengths and bond angles obtained by using density functional theory (DFT) have been com-
pared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of
the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule
was investigated with theoretical calculations at the B3LYP/6-311þ G(d,p) levels. A quantitative ana-
lysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld sur-
face analysis. In addition, the title compound possesses marked inhibition against the proliferation of
human colon cancer cell line HT-29 (IC50 ¼ 1.76 lM), human lung adenocarcinoma cell line A549
(
IC50 ¼ 1.98 lM) and human gastric cancer cell line MKN45 (IC ¼ 2.32 lM), displaying promising anti-
50
cancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity
inhibiting PDB:3D15.
1
. Introduction
activities with different biotargets and mechanisms (Heffron
et al., 2010; Sutherlin et al., 2010). For example, GDC-0941,
which is a potent, selective, orally bioavailable inhibitor of
PI3K, exerted antiprolifeative effects against an array of
human tumor cell lines (Folkes et al., 2008). Further optimiza-
tion of GDC-0941 led to several backup clinical candidates
with similar structures, such as GNE-477 (Heffron et al., 2010),
GNE-493 (Sutherlin et al., 2010), and GNE-490 (Sutherlin
et al., 2010). In view of these observations of thieno[3,2-
d]pyrimidine derivatives, and in continuation of our research
program on the development of novel potent antitumor
agents (Bravo-Altamirano et al., 2011; Ji et al., 2019; Lu, Jin,
et al., 2017; Lu, Zhou, et al., 2017), a novel 4-thieno[3,2-d]pyr-
imidine derivative N-f2-[(2-chlorothieno [3,2-d]pyrimidin-4-
yl)amino]ethylg-3-methoxybenzamide (8) was designed and
synthesized. The synthetic procedure for the title compound
is shown in Scheme 1. To determinate the molecular struc-
Cancer has become one of the most life-threatening diseases
to humans in the world for decades and has been the
second most leading cause of disease-related deaths (Farce
et al., 2004). Despite, enormous efforts to develop novel che-
motherapeutic strategies to treat cancer, it still remains one
of the major concerns worldwide. Most of the anticancer
drugs currently in clinical use are limited in their therapeutic
action due to their limited efficacy, non-specific toxicity, poor
tolerance and the resistance demanding the necessity for the
development of newer anticancer agents (D o€ rsam & Fahrer,
2
016; Liu et al., 2019).
Thienopyrimidine derivatives are an important class of
heterocyclic structures, and have received considerable atten-
tion in recent years due to their remarkable spectra of bio-
logical activities, such as antitumor (Heffron et al., 2010; Shi
et al., 2019; Sutherlin et al., 2010), antioxidant (Kotaiah et al., ture and spatial absolute conformation, the single crystal was
2
012), anti-inflammatory (Rizk et al., 2012), antimicrobial (El- grown and tested by X-ray single-crystal diffraction. In add-
Sayed et al., 2012), antiviral properties (Bassetto et al., 2016). ition, the biological tests suggested the compound displayed
Among these active compounds, thieno[3,2-d]pyrimidine excellent antiproliferative activities on the proliferation of
derivatives have been reported to show marked antitumor HT-29, A549 and MKN45 human cancer cell lines.
CONTACT Jiu-Fu Lu
jiufulu@163.com
Shaanxi Key Laboratory of Catalysis, College of Chemical & Environment Science, Shaanxi University of Technology,
Hanzhong, 723001, China
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2020.1819424.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
P. HUANG ET AL.
Scheme 1. Synthetic route of the title compound.
2
. Experimental section
slowly added to ice/water with vigorous stirring. The mixture
was then filtered to yield 18.9 g of 2,4-dichloro-thieno[3,2-d]pyr-
2.1. Physical measurements, chemicals, and reagents
15
ꢀ
imidine (4) as a white solid. Yield: 69.8%. m.p. 139–141 C (lit.
ꢀ
þ
Unless specified otherwise, all starting materials and reagents 138.8–139.3 C); MS (ESI) m/z(%): 205.1 [Mþ H] .
were obtained from commercial supplies without further
purification. All melting points ( C) were taken on a Beijing
Taike X-4 microscopy melting point apparatus and uncor-
rected. H NMR spectra were recorded on a Bruker Biospin
ꢀ
1
2
.2.3. Synthesis of N -(2-chlorothieno[3,2-d]pyrimidin-4-
yl)ethane-1,2-diamine (6)
1
To the mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine (8.0 g,
6
00 MHz instrument using TMS as the internal standard.
3
1
9.0 mmol) and MeOH (150 mL), ethane-1,2-diamine (11.7 g,
95.0 mmol) was added drop-wise at 0 C. The reaction mix-
Mass spectra were recorded on a Waters Quattro micro API
mass spectrometer (ESI, direct injection). All chemical shifts
were reported in ppm. Elemental analysis of the synthesised
compounds was carried out on a Carlo Erba 1108 analyser.
Crystal data were obtained on a Bruker P4 X-diffractometer.
ꢀ
ture then was stirred at room temperature for 7.5 h. After
completion of reaction as indicated by TLC, the mixture was
then filtered, washed with water and MeOH to yield 6.40 g of
1
N -(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6)
ꢀ
as a light yellow solid. Yield: 71.7%. m.p. >300 C. MS (ESI)
þ
2
.2. General procedure for synthesis of N-f2-[(2-
chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethylg-3-
methoxybenzamide (8)
m/z(%): 229.1 [M þ H] .
2
.2.4. Synthesis of N-f2-[(2-chlorothieno[3,2-d]pyrimidin-4-
2
.2.1. Synthesis of thieno[3,2-d]pyrimidine-2,4-diol (3)
yl)amino]ethylg-3-methoxybenzamide (8)
1
A mixture of methyl 3-amino-2-thiophenecarboxylate (50.5 g,
Under N2 atmosphere, a mixture of N -(2-chlorothieno[3,2-
d]pyrimidin-4-yl)ethane-1,2-diamine (2.0 g, 8.75 mmol), 3-
methoxybenzoic acid (1.46 g, 9.62 mmol), 1-[Bis(dimethylamino)
methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluoro-
phosphate (HATU, 6.64 g, 17.49 mmol) and triethylamine (2.65 g,
ꢀ
0
.32 mol) and urea (96.5 g, 1.6 mol) was heated at 190 C for
ꢀ
2
.5 h. Upon cooling to about 120 C, the reaction mixture
was poured into sodium hydroxide (1000 mL, 1 N) solution
and any insoluble material removed by filtration. The mixture
was then acidified with 2 M HCl and a large amount of white
solid was precipitated and filtered. The filter cake was dried
to give 49.60 g of thieno[3,2-d]pyrimidine-2,4-diol (3) as a
26.24 mmol) in dried N,N-dimethylformamide (20 mL) was
stirred at room temperature for 24 h. The reaction mixture was
diluted with 10% Na CO (100 mL), extracted by dichlorome-
2
3
ꢀ
19
ꢀ
white solid. Yield: 91.8%. m.p. 102–104 C (lit. 102.9 C). ESI-
MS m/z: 167.1 [M – H] ; H NMR (300 MHz, DMSO-d ) d: 6.93
thane three times (80 mL ꢁ 3). The combined organic extracts
–
1
6
was sequentially washed with 10% Na CO (60 mL ꢁ 3) and
2
3
(
(
d, J ¼ 5.2 Hz, 1H), 8.04 (d, J ¼ 5.2 Hz, 1H), 11.19 (s, 1H), 11.61
brine (60 mL ꢁ 3) and dried over anhydrous Na SO . After
2
4
s, 1H).
evaporation of the organic solvent, the residue was recrystal-
lized from ethyl acetate to afford 2.65 g of the title compound
ꢀ
1
2
A
1
.2.2. Synthesis of 2,4-dichlorothieno[3,2-d]pyrimidine (4)
mixture of thieno[3,2-d]pyrimidine-2,4-diol (22.2 g, d 8.61 (t, J¼ 5.5 Hz, 1H), 8.49 (t, J¼ 5.5 Hz, 1H), 8.17 (d,
32.0 mmol), phosphorous oxychloride (150 mL) and catalytic J¼ 5.3 Hz, 1H), 7.46–7.29 (m, 4H), 7.12–7.05 (m, 1H), 3.79 (s, 3H),
amount DMF (0.5 mL) was heated at reflux for 12 h and the 3.68–3.61 (m, 2H), 3.56–3.50 (m, 2H); MS (ESI) m/z(%):
in 83.5% yields. mp 242～244 C; H NMR (600MHz, DMSO-d )
6
þ
þ
reaction was monitored by TLC. The reaction mixture was 363.1[M þ H] , 385.1[Mþ Na] ; Anal. calcd for C16
H15ClN O S: C
4 2
concentrated under reduced pressure and the residue was 52.97, H 4.17, N 15.44; found C 53.08, H 4.23, N 15.56.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
ꢀ
Table 1. Hydrogen bond lengths (Å) and bond angles ( ).
cell line A549 and human gastric cancer cell line MKN45) by
D–HꢄꢄꢄA
d(D–H)
d(HꢄꢄꢄA)
d(DꢄꢄꢄA)
/DHA the MTT-based assay using sorafenib tosylate as a positive
#
1
2
N(4)-H(4)ꢄꢄꢄO(1)
0.86
0.86
2.12
2.14
2.912(5)
2.944(5)
152
156
control. Cells were grown in 96-well culture plates. The
#
N(3)-H(3)ꢄꢄꢄN(1)
tested compounds of various concentrations were added
Symmetry codes: (#1) y, -x þ 2, -z þ 1/4; (#2) -y þ 2, x-1, z-1/4.
ꢀ
into the plates at 37 C with 5% CO . After 72 h treatment,
2
the medium was removed. Cells were treated with 20 lL
Table 2. Geometric parameters of the title compound.
ꢀ
fresh MTT solution for 3ꢃ4 h at 37 C. The medium was
Bond lengths
X-ray
Bond angles
X-ray
replaced by 150 lL dimethyl sulfoxide and the absorbance
was measured on a microplate reader at 492 nm. The results
were expressed as IC50 (inhibitory concentration 50%) and
calculated by using the Bacus Laboratories Incorporated
Slide Scanner (Bliss) software.
C(1)-C(2)
C(1)-C(4)
C(1)-S(1)
C(2)-N(1)
C(3)-N(1)
C(3)-Cl(1)
C(4)-N(3)
C(4)-N(2)
C(7)-N(3)
C(8)-N(4)
C(9)-O(1)
C(9)-N(4)
C(9)-C(10)
C(10)-C(11)
C(10)-C(15)
C(12)-O(2)
C(16)-O(2)
1.380(5)
1.415(5)
1.719(4)
1.367(5)
1.309(5)
1.751(4)
1.335(5)
1.346(5)
1.453(5)
1.452(4)
1.238(5)
1.336(5)
1.492(5)
1.380(6)
1.384(5)
1.355(5)
1.435(5)
C(2)-C(1)-C(4)
C(2)-C(1)-S(1)
C(4)-C(1)-S(1)
N(1)-C(3)-N(2)
N(1)-C(3)-Cl(1)
N(3)-C(4)-N(2)
O(1)-C(9)-C(10)
N(4)-C(9)-C(10)
C(11)-C(10)-C(15)
C(3)-N(1)-C(2)
C(3)-N(2)-C(4)
C(4)-N(3)-C(7)
C(12)-O(2)-C(16)
118.4(4)
111.8(3)
129.7(3)
131.3(4)
114.8(3)
118.5(4)
121.1(4)
117.9(3)
119.5(4)
112.8(4)
116.0(4)
123.6(3)
117.6(4)
2.5. Dft calculations
Theoretical DFT analysis of 8 for its structure and reactivity
was done by using Gaussian 09 program package at DFT/
B3LYP/6-311 þ G(d,p) method/basis set (Becke, 1993; Frisch
et al., 2009; Lee et al., 1988). The geometry of 8 was opti-
mized and quantum parameters were computed. Frontier
molecular orbitals (FMO), molecular electrostatic potential
Torsion angles
N(3)-C(4)-N(2)-C(3)
N(4)-C(9)-C(10)-C(11)
C(7)-C(8)-N(4)-C(9)
178.8(4)
10.4(6)
ꢂ82.9(4)
(
3
MEP) and band gap were also computed at B3LYP/6-
11 þ G(d,p) method/basis set of theory.
2
.3. Crystal data structure determination
The yellow powder of the title compound was dissolved in
ethanol/ethyl acetate/tetrahydrofuran (1/1/1 by V/V/V). After
slowly evaporating the solvents for several days, some single
2
.6. Hirshfeld surface calculations
crystals suitable for X-ray analysis were obtained. A light yel- Crystal Explorer program 17.5 was employed to carry out the
low crystal (C H ClN O S) with dimensions of 0.20 mm ꢁ Hirshfeld surface analysis. It showed that the possible
1
6
15
4 2
0
.18 mm ꢁ 0.15 mm was selected for data collection which molecular packing and hydrogen bond interactions in the
was performed on a Bruker APEX-II CCD automatic diffract- structure (Turner et al., 2017). The structural input file was
ometer with a graphite-monochromatic Mo Ka radiation obtained in the CIF format. Hirshfeld surface distance from
(
k ¼ 0.71073 Å) by using the u and x-scan mode at 293 K. A the nearest nucleus inside and outside the surface was meas-
total of 8693 reflections were collected in the range of ured and represented by d and d , respectively, while a nor-
2
i
e
ꢀ
.40<h < 25.00 (index ranges: ꢂ11<h < 9, ꢂ11<k < 11, malized contact distance was represented as dnorm. White,
ꢂ22<l < 22) and 2975 were independent (R ¼ 0.032), of red and blue colors have been selected for the visualization
int
which 2429 observed reflections with I > 2r(I) were used in
the structure determination and refinements. The structure
was solved by direct methods with SHELXS-97 program
of dnorm
.
2
.7. Docking study
(
Sheldrick, 1997) and expanded by Fourier technique. The
non-hydrogen atoms were refined anisotropically. The hydro-
gen atoms bound to carbon were determined with theoret-
ical calculations and those attached to nitrogen and oxygen
were determined with successive difference Fourier synthe-
ses. The structure was refined by full-matrix Least-squares
To understand the binding mode of the novel 4-thieno[3,2-
d]pyrimidine derivative, docking analysis was performed by
AutoDock 4.2.6 using the default docking parameters (Morris
et al., 2009). The maps were generated by AutoGrid 4.2.6 with
a spacing of 0.375 Å. Compound 8 was docked with protein of
mouse Aurora A (Asn186->Gly, Lys240->Arg, Met302->Leu) in
complex with 1-(3-chloro-phenyl)-3-f[2-(thieno[3,2-d]pyrimidin-
2
techniques on F with SHELXL-97 (Sheldrick, 1997). The final
refinement gave the final R ¼ 0.038 and wR ¼ 0.066 (w ¼ 1/
2
2
2
2
2
[
r (F ) þ (0.010 P) þ 0.5337 P], where P ¼ (F þ 2 F )/3).
o
o
c
4
-ylamino)-ethyl]-thiazol-2-ylg-urea (PDB ID code: 3D15) at the
S ¼ 1.08, (D/r)
< 0.001, (Dq)
¼ 0.22 and (Dq)
¼
max
max
min
active site of the public domain crystal structure for an ana-
logue AK2. The results of docking was visualized with
PyMOL 1.8.
ꢂ3
ꢂ0.17 e/Å . The hydrogen bond data and geometric param-
eters of title compound are listed in Table 1 and Table 2,
respectively.
3. Results and discussion
2.4. In vitro antiproliferative activity test of the title
compound on HT-29, A549 and MKN45 cell lines
3.1. Description of the crystal structure of 8
The named compound 8 was evaluated for its in vitro anti- The synthetic route of the title compound in four steps with
1
proliferative activity against three cancer cell lines (human good yield was depicted in Scheme 1. The H NMR, MS,
colon cancer cell line HT-29, human lung adenocarcinoma elemental analysis and X-ray diffraction data for the product

4
P. HUANG ET AL.
4 2
Figure 1. Structure of the title compound (C16H15ClN O S) with all non-H atom-labelling scheme and ellipsoids drawn at the 30% probability level.
a
Table 3. In vitro anticancer activity test of the title compound on HT-29, biological activities about these derivatives are still underway
A549 and MKN45 cell lines.
in our laboratory and will be reported in the future.
IC50 IC50/(lmolꢄLꢂ1
)
Compound
HT-29
A549
MKN45
3
.3. Computational DFT studies
The title compound
Sorafenib Tosylate
1.76
3.81
1.98
2.62
2.32
3.58
The optimized geometry and electronic parameters (bond
lengths, bond angles, EHOMO, ELUMO) of compound 8 were
done using B3LYP/6-311 þ G(d,p) level of theory. The opti-
mized geometry and HOMO-LUMO orbitals of compound 8
are given in Figure 3. Obviously, the optimized structure
results are consistent with X-ray diffraction data. The global
energy minimum obtained by DFT of the structure optimiza-
a
Test MTT colourimetric assay in HT-29, A549 and MKN45 human cancer cell
lines. Each experiment was carried out in triplicate.
are in good agreement with the structure of the title com-
pound. According to X-ray analysis, compound 6 crystallizes
in tetragonal system, space group P4(3). As shown in Figure
1, the molecular structure of C H ClN O S, (1), consists of a
16 15 4 2
6
ꢂ1
tion is ꢂ1846.917254 Hartree (ꢂ4.849 ꢁ 10 kcalꢄmol ). And
the geometrical parameters such as bond length and bond
angles related to studied compound are presented in detail,
which are well replicated with the experimental data accord-
ing to X-ray single-crystal diffraction. It can be seen from the
results provided in Table 4. The minor deviations between
theoretical and experimental results are due to differences in
the molecular environment. It should be noted that XRD
results were obtained in the crystalline phase. On the other
hand, theoretical calculations were made in the gas phase
using Gaussian Program. Significantly, experimental and the-
oretically obtained geometric parameter values are very close
to each other (for example C3-N1 bond length values are
central pyrimidine ring which is significantly puckered to
assume a screw-boat conformation fused to a thiophene ring
with imino group and chlorine bonded at the C3 and C4
positions, respectively, around this fused-ring thieno[3,2-
d]pyrimidine moiety. The dihedral angle between the mean
planes of the thieno[3,2-d]pyrimidine and benzene ring
(
C(10)ꢃC(15)) is 4.264˚, which means the fused thieno[3,2-
d]pyrimidine ring and benzene ring (C(10)ꢃC(15)) are nearly
in the same plane. In the crystal, the average bond lengths
and bond angles of benzene rings and thieno[3,2-d]pyrimi-
dine are in normal ranges. The C(3)–N(1) (1.309(5) Å) and
C(3)–N(2) (1.321(5) Å) bonds are significantly shorter than a
normal single C–N bond (1.47 Å) and longer than a C ¼ N
bond (1.28 Å), indicating significant electron delocalization in
the thieno[3,2-d]pyrimidine ring system. On the other hand,
a mass of Intermolecular hydrogen bonds typed N–HꢄꢄꢄO and
N–HꢄꢄꢄN are found in the crystal structure of the title com-
pound (See Table 3), which play a major role in stabilizing
the molecule. Atoms O(1)#1 and N(1)#2 act as hydrogen-
bond donors, via H(4)–N(4) and H(3)–N(3), to generate the
supramolecular structure (Figure 2).
1
.309 (5) and 1.309, respectively).
To predict the molecular transitions, the frontier molecular
orbital (FMO) analysis was carried out by using the quantum
mechanical approach reported (Barakat et al., 2015; Sıdır
et al., 2010). EHOMO and ELUMO values give an estimate of the
inevitable charge exchange collaboration inside the studied
material. Dipole moment (l), electronegativity (v), hardness
(
5
g), electrophilicity (x) and softness (r) are recorded in Table
. The highest occupied molecular orbital energy determines
the electron-donating ability. However, the lowest unoccu-
pied molecular orbital energy provides the ability of a mol-
ecule to accept an electron (Sakthivel et al., 2018). The
3.2. Anticancer activity evaluation
In addition, the bioassay results showed the title compound corresponding EHOMO and ELUMO values were found to be
showed remarkable antiproliferative activity against HT-29, ꢂ6.513 eV and ꢂ1.722 eV, respectively. The significances of g
A549 and MKN45 cell lines with IC50 values of 1.76 lM, and r are evaluated both the reactivity and stability.
.98 lM and 2.32 lM, respectively, and thus it was slightly
The molecular electrostatic potential (MEP) was defined in
8
1
more potent than sorafenib tosylate (Table 3). Further struc- terms of total charge distribution of a molecule. The opti-
ture optimization may result in more active anticancer com- mized geometry at the B3LYP/6-311 þ G(d,p) level of theory
pounds. Further studies on structural optimization and was used to map the molecular electrostatic potential

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
4 2
Figure 2. A packing diagram of the title compound (C16H15ClN O S).
Figure 3. Left: the optimized geometry of 8 at the B3LYP/6-311 þ G(d,p) level of theory, Right: HOMO, LUMO, EHOMO, ELUMO and bandgap (DE).
surface (MEPS) of the compound 8 by Multiwfn (Lu & Chen, the N—HꢄꢄꢄO contacts and the nitrogen atoms (N1, N3, N4)
2
4
012) and VMD (Humphrey et al., 1996), as shown in Figure in the N—HꢄꢄꢄN, N—HꢄꢄꢄN and N—HꢄꢄꢄO contacts,
. It helps to investigate the interaction between molecules, respectively.
predict reaction sites and predict molecular property. The
The shape-index of the HS can visualize weak pꢄꢄꢄp stack-
electron density is essential for understanding the electro- ing interactions by the presence of adjacent red and blue tri-
philic or nucleophilic reactivity as well as non-bonding inter- angles. If there are no adjacent red and/or blue triangles,
actions (Hartwar et al., 2015) At the MEP surface, different then there are no pꢄꢄꢄp interactions. Figure 5(b) clearly sug-
colours represent the different electrostatic potential values. gests that there are pꢄꢄꢄp interactions in the titled compound.
Red and blue indicate electron-rich and electron-poor The intermolecular interactions appear as distinct spikes in
regions, and white indicates zero electrostatic potential.
the 2 D fingerprint plots are illustrated in Figure 6(a–i), which
are generated correspond to the Hꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄC/Cꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄN/
Nꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄS/Sꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄCl/Clꢄ ꢄ ꢄH, Cꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄC
and Cꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄC mutual effects (Mckinnon et al., 2004). To
3.4. Hirshfeld surface analysis
The Hirshfeld surface (HS) analysis of compound 8 was car- provide context, the complete fingerprint contour is dis-
ried out by using Crystal Explorer 17.5 to investigate the played in gray and blue areas showing separate contacts.
weak intermolecular interactions. Figure 5a presents 3D According to the fingerprint plots, the most important inter-
Hirshfeld surface and electrostatic potentials surface maps action is Hꢄ ꢄ ꢄH interactions accounting for 32.9% of the total
generated for compound 8. The white colour indicates area of the Hirshfeld surfaces. In the presence of a weak C—
medium proximity of out side atoms, and the red and blue Hꢄ ꢄ ꢄp interaction in the crystal, a pair of characteristic wings
colours indicate close or little proximity. Red spots on appear in the fingerprint plot delineated into Hꢄ ꢄ ꢄC/Cꢄ ꢄ ꢄH
Hirshfeld surface are related to the hydrogen bonding inter- contacts with a 13.2%. In addition, the proportions of Hꢄ ꢄ ꢄN/
actions. As shown in Figure 5(a), the red region on Hirshfeld Nꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄS/Sꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄCl/Clꢄ ꢄ ꢄH, Cꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄC
surface which is prominent above the oxygen atom (O1) in and Cꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄC interactions comprised 9.6%, 8.7%, 6.5%,

6
P. HUANG ET AL.
1
4.8%, 1.5% and 1.7% of the HS surface, respectively. The
The individual intermolecular interactions described above
results showed that van der Waals interactions, weak inter- can also be visualized by the different Hirshfeld surface represen-
molecular interactions and hydrogen bonding make the tations with the function dnorm plotted onto the surface. As
structure more stable (Zhou et al., 2019).
shown in Figure 7(a–f), Hꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄC/Cꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄO/
Oꢄ ꢄ ꢄH, Hꢄ ꢄ ꢄS/Sꢄ ꢄ ꢄH and Hꢄ ꢄ ꢄCl/Clꢄ ꢄ ꢄH interactions were revealed.
The Hirshfeld surface analysis provides a full understanding of
the intermolecular interactions in a facile and immediate way.
Table 4. Some selected experimental and theoretical geometric parameters
for Compound 8.
Geometric
parameters
Experimental
[X-ray diffraction]
Theoretical
[DFT/B3LYB]
3
.5. Docking study
C(1)-C(2)
C(1)-C(4)
C(1)-S(1)
C(2)-N(1)
C(3)-N(1)
C(3)-Cl(1)
C(4)-N(3)
C(4)-N(2)
C(7)-N(3)
C(8)-N(4)
C(9)-O(1)
C(9)-N(4)
C(9)-C(10)
C(10)-C(11)
C(10)-C(15)
C(12)-O(2)
1.380(5)
1.415(5)
1.719(4)
1.367(5)
1.309(5)
1.751(4)
1.335(5)
1.346(5)
1.453(5)
1.452(4)
1.238(5)
1.336(5)
1.492(5)
1.380(6)
1.384(5)
1.355(5)
1.435(5)
1.401
1.415
1.747
1.356
1.309
1.763
1.356
1.34
1.459
1.455
1.255
1.367
1.504
1.393
1.401
1.364
1.422
Docking study is a very important technique in structure-based
drug design. The method can estimate the conformation pat-
tern of binding within the target protein (Anderson, 2003;
Gilbert, 2004). Docking was performed by AutoDock 4.2.6 using
the default docking parameters. Firstly, compound 8 having
medical and pharmacological importance was optimized with
B3LYP/6-311 þ G(d,p) method/basis set and recorded as Protein
Data Bank (PDB) format. In second step, compound 8 was
docked with protein of mouse Aurora A (Asn186->Gly, Lys240-
>
Arg, Met302->Leu) in complex with 1-(3-chloro-phenyl)-3-f[2-
(
thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-ylg-urea (PDB
C(16)-O(2)
ID code: 3D15) at the active site of the public domain crystal
structure for an analogue AK2 (Dabrowska & Brylinski, 2006;
Dilly & Liegeois, 2016; Duan et al., 2003; Kang et al., 2016). The
active sites of protein PDB:3D15 were determined as HIS-214,
PHE-213, TYR-212, GLY-211, GLN-140, ILE-222, TRP-141, ARG-
Bond angles
C(2)-C(1)-C(4)
C(2)-C(1)-S(1)
C(4)-C(1)-S(1)
N(1)-C(3)-N(2)
N(1)-C(3)-Cl(1)
N(3)-C(4)-N(2)
O(1)-C(9)-C(10)
N(4)-C(9)-C(10)
C(11)-C(10)-C(15)
C(3)-N(1)-C(2)
C(3)-N(2)-C(4)
C(4)-N(3)-C(7)
C(12)-O(2)-C(16)
Torsion angles
N(3)-C(4)-N(2)-C(3)
N(4)-C(9)-C(10)-C(11)
C(7)-C(8)-N(4)-C(9)
118.4(4)
111.8(3)
129.7(3)
131.3(4)
114.8(3)
118.5(4)
121.1(4)
117.9(3)
119.5(4)
112.8(4)
116.0(4)
123.6(3)
117.6(4)
117.847
111.703
130.45
129.732
115.88
118.254
121.741
116.539
119.754
113.795
117.41
139, TYR-210 and PHE-146 active residues. The spacing of grid
boxes is 0.375 Å. The obtained docking result for compound 8-
PDB:3D15 was given in Figure 8. The binding was determined
with ꢂ5.78 kcal/mol energy (DG) and three active hydrogen
bonding. The inhibition constants for compound 8 and
PDB:3D15 interactions (Ki) was calculated as 57.96 lM. As
shown in Figure 8, the O1, H14, H15 atom in compound 8
docked well with the protein residues TRP-141, ARG-139 and
TYR-210 via H-bond, respectively.
123.788
118.63
178.8(4)
10.4(6)
ꢂ82.9(4)
179.346
24.807
ꢂ79.052
4. Conclusion
Table 5. Quantum chemical parameters of the investigated molecule using
DFT method.
A novel 4-thieno[3,2-d]pyrimidine derivative, named N-f2-[(2-
chlorothieno
[3,2-d]pyrimidin-4-yl)amino]ethylg-3-methoxy-
benzamide has been synthesized and its structure was
l (Debye) IP (eV)
2.7878 6.513
EA (eV)
1.722
v (eV)
g (eV)
x (eV) r (eV)
3.539 0.283
DFT
4.118
2.396
Figure 4. Molecular electrostatic potential surfaces (MESP, a.u.) of compound 8.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
Figure 5. (a) View of the three-dimensional Hirshfeld surface of compound 8 plotted over dnorm in the range -0.4862 to 1.3170 a.u.; (b) Hirshfeld surface of com-
pound 8 plotted over shape-index.
Figure 6. The full two-dimensional fingerprint plots for compound 8, showing (a) all interactions, and delineated into, (b) Hꢄ ꢄ ꢄH, (c) Hꢄ ꢄ ꢄC/Cꢄ ꢄ ꢄH (d) Hꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄH,
(
e) Hꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄH, (f) Hꢄ ꢄ ꢄS/Sꢄ ꢄ ꢄH, (g) Hꢄ ꢄ ꢄCl/Clꢄ ꢄ ꢄH, (h) Cꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄC, (i) Cꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄC. The d
i e
and d values are the closest internal and external distances (in Å) from
given points on the Hirshfeld surface contacts.

8
P. HUANG ET AL.
Figure 7. The Hirshfeld surface representations with the function dnorm plotted onto the surface for (a) Hꢄ ꢄ ꢄH, (b) Hꢄ ꢄ ꢄC/Cꢄ ꢄ ꢄH, (c) Hꢄ ꢄ ꢄN/Nꢄ ꢄ ꢄH, (d) Hꢄ ꢄ ꢄO/Oꢄ ꢄ ꢄH,
e) Hꢄ ꢄ ꢄS/Sꢄ ꢄ ꢄH and (f) Hꢄ ꢄ ꢄCl/Clꢄ ꢄ ꢄH interactions.
(
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work is supported by the team of syngas catalytic conversion of
Shaanxi University of Technology, the national natural science founda-
tion of China (project no. 21373132, 21603133, 21807068), project of
education department of Shaanxi province (20JK0565, 20JK0552),
Shaanxi provincial science and technology department project
(
2019JM471, 2020JM602), the project of Shaanxi University of
Technology(SLGKY2009), the Young Talent fund of University Association
for Science and Technology in Shaanxi, China (20180607).
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