Benzothiazolopyridine compounds: Facial synthesis, characterization, and molecular docking study on estrogen and progesterone receptors

Article abstract of DOI:10.1016/j.molstruc.2021.130792

In this work, a convenient and efficient procedure for the synthesis of 1-amino-2- (benzo [d] thiazol-2-yl)-3-aryl-3-hydro-benzo [4, 5] thiazolo [3, 2-a] pyridine-4-carbonitrile derivatives (6a-f) was studied. This synthesis was catalyzed by piperidine in an ethanol medium under ultrasonic irradiation at room temperature. The obtained results were compared with the conventional reflux method. Compared to the reflux method, ultrasonic irradiation provided several privileges such as shorter reaction time, cleaner reactions, and higher yields. By using the ultrasound technique, the reaction time was reduced from 50- 480 min to 80–200 min and the product yields improved from 10 -71% to 30–90% compared to the reflux method. Molecular docking studies of synthetic compounds (ligands) were carried out with some vital targets in the breast cancers, such as estrogen receptor-α (ERα) and progesterone receptors A and B (PRA and PRB). The main aim of this evaluation was to predict the activity of ligands against ERα, PRA, and PRB. The docking results show that all ligands have favorable interactions with receptors in terms of binding free energy.

Full text of DOI:10.1016/j.molstruc.2021.130792

Journal of Molecular Structure 1243 (2021) 130792
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Revised
Benzothiazolopyridine compounds: Facial synthesis, characterization,
and molecular docking study on estrogen and progesterone receptors
Mohammad Ali Shirania, Mohammad Hassan Malekia, Parvin Asadib, Mohammad Dinaria,∗
a Department of Chemistry, Isfahan University of Technology, Isfahan 84156, 83111, Iran
b Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, a convenient and efficient procedure for the synthesis of 1-amino-2- (benzo [d] thiazol-
2-yl)-3-aryl-3-hydro-benzo [4, 5] thiazolo [3, 2-a] pyridine-4-carbonitrile derivatives (6a-f) was studied.
This synthesis was catalyzed by piperidine in an ethanol medium under ultrasonic irradiation at room
temperature. The obtained results were compared with the conventional reflux method. Compared to the
reflux method, ultrasonic irradiation provided several privileges such as shorter reaction time, cleaner
reactions, and higher yields. By using the ultrasound technique, the reaction time was reduced from 50-
480 min to 80–200 min and the product yields improved from 10 -71% to 30–90% compared to the
reflux method. Molecular docking studies of synthetic compounds (ligands) were carried out with some
vital targets in the breast cancers, such as estrogen receptor-α (ERα) and progesterone receptors A and B
(PRA and PRB). The main aim of this evaluation was to predict the activity of ligands against ERα, PRA,
and PRB. The docking results show that all ligands have favorable interactions with receptors in terms of
binding free energy.
Received 11 March 2021
Revised 5 May 2021
Accepted 26 May 2021
Available online 30 May 2021
Keywords:
Benzothiazolopyridine
Ultrasonic irradiation
Molecular docking
© 2021 Elsevier B.V. All rights reserved.
Introduction
activity has emerged as a useful method in developing many med-
ical drugs [15].
Breast cancer is one of the most commonly diagnosed cancer
and the second leading cause of cancer death worldwide in women
[1]. On average, the incidence of breast cancer increases at a rate of
0.5 percent per year [2]. Based on different clinical and histologi-
cal features, breast cancer is divided into several categories. The
main classification is based on histopathological features and cel-
lular receptors, such as estrogen receptors (ER) [3, 4], progesterone
receptors (PR) [5], and epidermal human growth factor receptors
[6-8]. ER and PR subtypes are the most common breast cancers.
About 75% of breast cancers express estrogen receptors (ER+) and
also progesterone receptor is expressed in 65% of breast cancers
(PR+) [9]. These receptors are targeted for designing the drugs and
treatment of various types of breast cancer [9-12].
The biological properties present in the thiazole and pyridine-
based heterocyclic compounds lead to great attention to these
compounds in the biological study [16, 17]. Pyridine is present in
the skeleton of more than 7000 known drug compounds [18]. The
pyridine derivatives can be used as a medicine in iron overload
disease, an antioxidant, an analgesic, or psychological antagonist
drugs, and many other biological features [19-25]. In the 1950s, the
use of several 2-aminobenzothiazoles as a central muscle relax-
ant was studied. After discovering their properties as a Glutamate
neurotransmission inhibitor, many biologists turned their attention
to these compounds [26]. Benzothiazole and thiazole interactions
with diverse biological receptors have been significant in discov-
ering compounds with extensive therapeutic [27-31]. The thiazole
and benzothiazole-based compounds have many biological proper-
ties such as antidiabetic, anticonvulsant, antidepressant, anticancer,
antiviral, antimicrobial [32-39].
Over the years, efforts to discover different drugs have been fo-
cused on the synthesis and design of small molecules [13]. Nowa-
days, a wide range of small molecules based on heterocyclic sys-
tems have been studied and evaluated to discover new drugs, and
many heterocyclic-structured nuclei are considered privileged scaf-
folds [14]. In recent years, the concept of privileged structure-
The synthesis of benzothiazole and pyridine derivatives is a sig-
nificant part of today’s synthetic debate. A classical method for
the synthesis of benzothiazole-based compounds is the reaction
of ortho-amino thiophenol with an aldehyde [40], acyl chloride
[41], carboxylic acid [42], ester [43], or nitrile [44] substitutions.
Pyridine compounds can be synthesized by Hanch-like methods,
∗
Corresponding author.
E-mail address: dinari@iut.ac.ir (M. Dinari).
https://doi.org/10.1016/j.molstruc.2021.130792
0022-2860/© 2021 Elsevier B.V. All rights reserved.

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
namely Knoevenagel condensation, followed by Michele addition
and an intramolecular cyclization at high temperatures [45, 46].
Sonochemistry is a different organic synthesis trend that is a ro-
bust, environment-friendly, safe, and inexpensive method [47-50].
The synthesis procedure based on this method can provide milder
conditions have less reaction time, high chemical reactivity, high
yields, less material wastage, and leads to high purity products
rather than other classical methods [51, 52]. However, ultrasonic
synthesis in various organic compounds has not been thoroughly
investigated; it can be used in various organic syntheses [53, 54].
This study aimed to synthesize benzothiazolopyridine based
compounds using homogeneous and heterogeneous catalysts by
driving force of ultrasonic irradiation and mild condition. In addi-
tion, the activity of synthesized compounds against the estrogen
and progesterone hormone receptors as crucial targets in breast
cancer was predicted.
2-(benzo[d]thiazol-2-yl)−3-phenylacrylonitrile
(5a). FT-IR
(KBr)
(ν/cm−1); 3054, 3016, 2213, 1589, 1583, 1490; 1HNMR (400 MHz,
d6-DMSO) δ (ppm) 8.45 (s, 1H), 8.25 – 8.18 (m, 1H), 8.16 – 8.07
(m, 3H), 7.68 – 7.57 (m, 4H), 7.54 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H);
13CNMR (101 MHz, d6-DMSO) δ (ppm) 163.1, 152.8, 148.3, 134.3,
132.4, 132.3, 130.2, 129.2, 127.1, 126.4, 123.2, 122.5, 116.1, 105.5;
mp ( °C) 120–122.
2-(benzo[d]thiazol-2-yl)−3-(4-methoxyphenyl)acrylonitrile (5b). FT-
IR (KBr) (ν/cm−1); 3010, 2981, 2937, 2219, 1589, 1563, 1511, 1428;
1HNMR (400 MHz, d6-DMSO) δ (ppm)8.31 (s, 1H), 8.17 – 8.13 (m,
1H), 8.13 – 8.09 (m, 2H), 8.06 – 8.03 (m, 1H), 7.57 (ddd, J = 8.3,
7.2, 1.3 Hz, 1H), 7.49 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.20 – 7.13 (m,
2H), 3.87 (s, 3H); 13CNMR (101 MHz, d6-DMSO) δ (ppm) 163.7,
162.7, 152.9, 147.7, 134.1, 132.6, 127.0, 126.0, 124.9, 122.9, 122.4,
116.6, 114.9, 101.9, 55.7; mp ( °C) 144–146.
2-(benzo[d]thiazol-2-yl)−3-(3-nitrophenyl)acrylonitrile
(5c). FT-IR
Experimental
(KBr) (ν/cm-1); 3066, 3027, 2227, 1600, 1531, 1346; 1HNMR
(400 MHz, d6-DMSO) δ (ppm) 8.97 (t, J = 2.0 Hz, 1H), 8.63 (s, 1H),
8.51 (ddd, J = 8.6, 1.7, 0.9 Hz, 1H), 8.43 (ddd, J = 8.4, 2.3, 1.0 Hz,
1H), 8.26 – 8.22 (m, 1H), 8.16 – 8.11 (m, 1H), 7.91 (t, J = 8.1 Hz,
1H), 7.62 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.56 (ddd, J = 8.4, 7.2,
1.3 Hz, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm) 162.6, 152.7,
148.0, 145.8, 135.7, 134.5, 133.8, 130.7, 127.2, 126.6, 126.1, 124.5,
123.4, 122.6, 115.4, 108.3; mp ( °C) 203–205.
Reagents and materials
All materials purchased from Acros, Sigma Aldrich and Merck,
were used without any more purification.
Characterization and instrumentation
Bruker Avance 400 MHz spectrometer (Germany) was used to
record the 1H NMR, and 13CNMR spectra had been run on the
Bruker Avance 100 MHz spectrometer. FT-IR spectra of solids were
recorded in the spectral range between 4000 and 400 cm−1 on
Jasco-680 (Japan). Preparation of compounds was performed by a
MISONIX ultrasonic liquid processor, XL- 2000 SERIES, USA. The
elemental analyses (C, H, N, S) were obtained from a Carlo ERBA
Model EA 1108 analyzer. All reactions were monitored by thin-layer
chromatography. Merck TLC-silica gel-f 454 nm 60 sheets were
used.
2-(benzo[d]thiazol-2-yl)−3-(4-chlorophenyl)acrylonitrile (5d). FT-IR
(KBr) (ν/cm−1); 3066, 3014, 2219, 1587, 1492; 1HNMR (400 MHz,
d6-DMSO) δ (ppm) 8.45 (s, 1H), 8.23 – 8.19 (m, 1H), 8.15 – 8.09
(m, 3H), 7.71 (d, J = 8.6 Hz, 2H), 7.61 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H),
7.54 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H); 13CNMR (101 MHz, d6-DMSO)
δ (ppm) 162.9, 152.8, 146.9, 136.9, 134.3, 131.8, 131.2, 129.4, 127.2,
126.4, 123.2, 122.5, 115.9, 106.1; mp ( °C) 145–147.
2-(benzo[d]thiazol-2-yl)−3-(4-nitrophenyl)acrylonitrile
(5e). FT-IR
(KBr) (ν/cm−1); 3077, 3041, 2223, 1594, 1525, 1344; 1HNMR
(400 MHz, d6-DMSO) δ (ppm) 8.60 (s, 1H), 8.46 – 8.41 (m, 2H),
8.33 – 8.28 (m, 2H), 8.26 – 8.22 (m, 1H), 7.66 – 7.60 (m, 1H), 7.57
(td, J = 7.7, 7.3, 1.3 Hz, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm)
162.5, 152.7, 148.6, 145.7, 138.3, 134.5, 131.1, 127.3, 126.7, 124.1,
123.4, 122.6, 115.4, 109.2; mp ( °C) 174–176.
General procedure for the synthesis of benzothiazolopyridine
derivatives
Preparation of 2-(benzo[d]thiazol-2-yl)acetonitrile (3)
2-(Benzo[d]thiazol-2-yl)acetonitrile was synthesized according
to the reported procedure [55]. First, 20 mmol of malononitrile
(1.32 g) with 1 ml of glacial acetic acid was added to a solution of
10 mmol of 2-aminothiophenol (1.04 ml) in 8 ml of ethanol, and
it was stirred for 12 h at room temperature. Finally, the resulting
yellow crystalline solid was separated with filter paper and washed
with 300 ml of distilled water, and the pure product was obtained
with a 91% yield.
FT-IR (KBr) (ν/cm−1); 3054, 2954, 2248; 1HNMR (400 MHz, d6-
DMSO) δ (ppm) 8.18 (dd, J = 8.4, 1.1 Hz, 1H), 8.09 (dd, J = 8.1,
0.6 Hz, 1H), 7.60 (ddd, J = 8.2, 7.2, 1.4 Hz, 1H), 7.53 (ddd, J = 8.5,
7.2, 1.3 Hz, 1H), 4.81 (s, 2H); 13CNMR (101 MHz, d6-DMSO) δ (ppm)
160.6, 152.2, 135.1, 126.6, 125.6, 122.6, 122.4, 116.6, 22.4; Elemental
Analysis for C9H6N2S (%) C, 61.72; H, 3.32; N, 15.98; S, 18.31; mp (
°C) 98–100.
2-(benzo[d]thiazol-2-yl)−3-(4-hydroxyphenyl)acrylonitrile (5 g). FT-
IR (KBr) (ν/cm−1); 33,458, 2216, 1606, 1566, 1437; 1HNMR
(400 MHz, d6-DMSO) δ (ppm) 10.81 (s, 1H), 8.37 (s, 1H), 8.26 (dd,
J = 8.1, 1.5 Hz, 1H), 8.21 – 8.09 (m, 3H), 7.67 (ddd, J = 8.3, 7.2,
1.4 Hz, 1H), 7.59 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.17 – 7.03 (m, 2H);
13CNMR (101 MHz, d6-DMSO) δ (ppm) 164.4, 162.4, 153.4, 148.5,
134.5, 133.5, 127.5, 126.4, 123.9, 123.3, 122.8, 117.3, 116.8, 101.3; mp
( °C) 227.
2-(benzo[d]thiazol-2-yl)−3-(3, 4-dimethoxyphenyl)acrylonitrile (5 h).
FT-IR (KBr) (ν/cm−1); 3062, 3012, 2948, 2917, 2210, 1583, 1515,
1436; 1HNMR (400 MHz, d6-DMSO) δ (ppm) 8.20 – 8.16 (m, 1H),
8.10 – 8.04 (m, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.9,
2.2 Hz, 1H), 7.59 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.51 (ddd, J = 8.3,
7.3, 1.3 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H);
13CNMR (101 MHz, d6-DMSO) δ (ppm) 163.6, 152.9, 152.6, 148.7,
148.0, 134.1, 127.0, 126.0, 125.6, 124.9, 122.9, 122.3, 116.8, 112.5,
111.8, 101.8, 55.8, 55.5; mp ( °C) 155–157
Preparation of 2-(benzo[d]thiazol-2-yl)−3-arylacrylonitrile (5)
To
a
prepare
2-(benzo[d]thiazol-2-yl)−3-phenylacrylonitrile,
to
solution containing 0.5 mmol of 2-(benzo[d]thiazol-2-
yl)acetonitrile (3) and 0.5 mmol of aldehyde in 4 ml of ethanol,
piperidine (20mol%) was added, and the reaction was performed
under ultrasound irradiation at room temperature. After the com-
pletion of the reaction in 20 min (monitored by TLC), water was
added to the reaction mixture, and the obtained product was
separated using filter paper.
Preparation of 1-amino-2-(benzo[d]thiazol-2-yl)−3-aryl-3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile
(6)
Method A: To a solution containing 0.5 mmol of compound 3
(0.087 g) and 0.5 mmol of aldehyde in 4 ml of ethanol, 20 mol%
2

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
Table 1
Reaction optimization results for the synthesis of 6a.
Entry
Catalyst
Solvent
Time (min)
Temperature
Yield (%)
1
–
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
600
300
300
300
120
140
100
90
RT (28 C)
0
º
2
CuO (10 mol%)
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
3
ZnO (10 mol%)
0
4
Al2O3 (10 mol%)
0
5
K2CO3 (10 mol%)
62
51
71
83
89
84
58
86
75
Trace
41
Oily
47
6
Triethylamine (10 mol%)
Piperidine (10 mol%)
Piperidine (15 mol%)
Piperidine (20 mol%)
Piperidine (25 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
Piperidine (20 mol%)
7
8
9
90
10
11
12
13
14
15
16
17
100
180
90
Reflux (78 C)
º
40
60
RT
RT
RT
RT
C
C
º
º
90
240
130
–
Methanol
THF
Ethanol
180
Table 2
Synthetic derivatives under ultrasound and reflux methods.
3

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
Scheme 1. Synthesis of benzothiazolopyridine compounds.
4

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
Table 3
Docking results of ligand molecules at ERα, PRA and PRB receptor chains.
Complexes
ꢀG(kcal/mol)
Complexes
ꢀG(kcal/mol)
Complexes
ꢀG(kcal/mol)
(R) 6a+ERα
(S) 6a+ERα
(R) 6b+ERα
(S) 6b+ERα
(R) 6d+ERα
(S) 6d+ERα
(R) 6e+ERα
(S) 6e+ERα
−9.80
−8.26
−8.87
−9.32
−8.47
−7.84
−8.09
−9.18
(R) 6a+PRA
(S) 6a+PRA
(R) 6b+PRA
(S) 6b+PRA
(R) 6d+PRA
(S) 6d+PRA
(R) 6e+PRA
(S) 6e+PRA
−8.86
−9.07
−8.27
−8.87
−8.77
−8.47
−9.58
−9.74
(R)6a+PRB
(S) 6a+PRB
(R) 6b+PRB
(S) 6b+PRB
(R) 6d+PRB
(S) 6d+PRB
(R) 6e+PRB
(S) 6e+PRB
−8.49
−9.06
−8.78
−11.79
−8.73
−10.65
−8.66
−9.32
Scheme 2. The proposed mechanism for the synthesis of compound 6.
(compound5), 0.6 mmol of compound 3 was added to the reac-
tion and exposed to ultrasound irradiation at room temperature.
After the completion of the reaction, the resulting precipitate was
filtered and recrystallized from hexane: ethyl acetate (3:1).
Method B: To the solution containing 1.1 mmol of compound 3
and 0.5 mmol of aldehyde in 4 ml of ethanol, 20 mol% of piperi-
dine was added and exposed to ultrasonic waves at room temper-
ature. Work-up is as described for method 1.
1-amino-2-(benzo[d]thiazol-2-yl)−3-phenyl-3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile (6a). FT-IR (KBr)
(ν/cm−1); 3440, 3355, 2181, 1637, 1454; 1HNMR (400 MHz, d6-
DMSO) δ (ppm) 8.44 (s, 2H), 8.04 (dd, J = 8.4, 1.0 Hz, 1H), 7.94
(dd, J = 8.1, 1.5 Hz, 1H), 7.84 (dd, J = 8.8, 0.9 Hz, 1H), 7.78 (dd,
J = 7.8, 1.3 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.39 – 7.20 (m, 7H),
4.82 (s, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm) 168.7, 152.6,
150.8, 145.1, 142.9, 137.0, 131.2, 129.0, 127.5, 126.9, 126.6, 126.3,
124.6, 124.1, 123.5, 123.4, 121.4, 120.3, 118.6, 116.4, 86.5, 80.1, 44.0;
Elemental Analysis for C25H16 N4S2 (%); C, 68.31; H, 3.72; N, 12.60;
S, 15.10; mp ( °C) 216–218.
Fig. 1. FT-IR spectrum of compound 6a.
1-amino-2-(benzo[d]thiazol-2-yl)−3-(4-methoxyphenyl)−3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile (6b). FT-IR (KBr)
(ν/cm−1); 3326, 3129, 3062, 2950, 2892, 2184, 1643, 1454; 1HNMR
piperidine was added, and the reaction was performed under ul-
trasonic waves, After 20 min without separation of the product
5

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
Fig. 2. 1HNMR (400 Hz) spectrum of the compound 6a in d6-DMSO.
Fig. 3. 13 CNMR (400 Hz) spectrum of the compound 6a in d6-DMSO.
6

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
Fig. 4. Predicted 2D binding model using computational molecular docking for the complexes a) (R) 6a + ERα b) (S) 6e + PRA c) (S) 6b + PRB.
(400 MHz, d6-DMSO) δ (ppm8.40 (s, 2H), 8.03 (dd, J = 8.5, 1.1 Hz,
1H), 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.78 (dd,
J = 7.9, 1.4 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.32 – 7.24 (m, 4H),
6.92 – 6.86 (m, 2H), 4.75 (s, 1H), 3.68 (s, 3H); 13CNMR (101 MHz,
d6-DMSO) δ (ppm) 168.8, 158.6, 152.6, 150.3, 145.0, 137.1, 134.9,
131.2, 127.7, 126.8, 126.3, 124.54, 124.1, 123.4, 123.3, 121.4, 120.2,
118.7, 116.3, 114.3, 86.9, 80.5, 55.0, 43.3; Elemental Analysis for
C26H18 N4OS2 (%); C, 66.84; H, 3.80; N, 11.77; S, 13.80; mp ( °C)
212–215.
1-amino-2-(benzo[d]thiazol-2-yl)−3-(3-nitrophenyl)−3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile
(6c). FT-IR
(KBr)(ν/cm−1); 3465, 3417, 3102, 2925, 2857, 2184, 1639, 1527,
1459,1347; 1HNMR (400 MHz, d6-DMSO) δ (ppm) 8.54 (s, 2H), 8.21
(t, J = 2.1 Hz, 1H), 8.15 – 8.09 (m, 1H), 8.06 (d, J = 9.4 Hz, 1H),
7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.90 – 7.83 (m, 2H), 7.80 (dd, J = 7.9,
1.4 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 – 7.40 (m, 2H), 7.35 –
7.24 (m, 2H), 5.14 (s, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm)
168.4, 152.6, 151.8, 148.1, 145.4, 145.0, 137.0, 133.4, 131.1, 130.8,
127.0, 126.4, 124.8, 124.1, 123.6, 123.4, 122.6, 121.5, 121, 120.3,
7

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
118.4, 116.5, 85.5, 78.8, 43.1; Elemental Analysis for C25H15N5O2S2
Results and discussion
(%); 61.79; H, 3.22; N, 13.90; S, 14.04; mp ( °C) 222–224.
Synthesis and characterization
1-amino-2-(benzo[d]thiazol-2-yl)−3-(4-chlorophenyl)−3H-
Synthesis
of
1-amino-2-(benzo[d]thiazol-2-yl)−3-aryl-3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile (6d). FT-IR (KBr)
(ν/cm−1); 3403, 3064, 2960, 2196, 1646, 1467; 1HNMR (400 MHz,
d6-DMSO) δ (ppm) 8.46 (s, 2H), 8.03 (dd, J = 8.5, 1.1 Hz, 1H),
7.95 (td, J = 7.9, 1.2 Hz, 1H), 7.85 (td, J = 8.2, 1.0 Hz, 1H), 7.79
(dd, J = 7.9, 1.4 Hz, 1H), 7.49 – 7.39 (m, 6H), 7.34 – 7.25 (m, 2H),
4.88 (s, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm) 168.5, 152.6,
151.1, 145.2, 141.8, 137.0, 132.1, 131.1, 129.0, 128.5, 126.9, 126.4,
124.7, 124.0, 123.5, 123.4, 121.5, 120.3, 118.5, 116.4, 86.1, 79.5, 43.3;
Elemental Analysis for C25H15ClN4S2 (%); C, 63.29; H, 3.15; N,
12.02; S, 13.45; mp ( °C) 210–214.
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitril (compound 6) can
be carried out by applying two methods:
Method A was involved in performing a reaction between 1eq
of compound 3 and 1 eq of aldehyde until the completion of the
reaction. Then without separation of compound 5, compound 3
was added to the reaction mixture. Method B was including a re-
action between 2 eq of compound 3 and 1 eq of aldehyde. A sum-
mary of the reaction can be observed in scheme 1.
As shown in Table 1, initially It is focused on evaluating differ-
ent catalysts for the model reaction of compound 3 and compound
5a under ultrasonic irradiation in ethanol. At first, a reaction per-
formed without any catalyst, and it was not feasible (entry 1). Then
the activity of several catalysts, such as CuO, Al2O3, ZnO, K2CO3,
triethylamine, and piperidine was studied (entries 2–7). From the
results, it was cleared that piperidine was the best catalyst among
those examined. When 10, 15, and 20 mol% of piperidine were
used, the yields were 71, 83, and 89, respectively (entries 8–10).
So, 20 mol% of piperidine was suitable and more excess did not
increase the yields. To assess the effect of ultrasound irradiation,
the reaction was performed under both ultrasonic irradiation and
reflux method. This study shows that the reaction under ultrasonic
irradiation provides high efficiency and shorter reaction time com-
pared to the thermal method. The ultrasound technique reduced
reaction time from 180 min to 90 min and improved the yield from
58 to 89 (entries 9, 11). To study the effect of temperature, two re-
1-amino-2-(benzo[d]thiazol-2-yl)−3-(4-nitrophenyl)−3H-
benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile (6e). FT-IR (KBr)
(ν/cm−1); 3473, 3397, 3070, 2925, 2863, 2192, 1637, 1515, 1459,
1342; 1HNMR (400 MHz, d6-DMSO) δ (ppm) 8.53 (s, 2H), 8.22
(d, J = 8.7 Hz, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.3 Hz,
1H), 7.85 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 7.9, 1.3 Hz, 1H), 7.72 –
7.64 (m, 2H), 7.52 – 7.40 (m, 2H), 7.30 (dt, J = 15.0, 7.4 Hz, 2H),
5.09 (s, 1H); 13CNMR (101 MHz, d6-DMSO) δ (ppm) 168.3, 152.6,
151.9, 150.0, 146.9, 145.4, 137, 131.1, 128.0, 126.9, 126.4, 124.8,
124.4, 124.0, 123.6, 123.4, 121.5, 120.3, 118.30, 116.6, 85.5, 78.5,
43.5; Elemental Analysis for C25H15N5O2S2 (%); C, 62.15; H, 3.07;
N, 14.39; S, 13.41; mp ( °C) 238–240.
actions were performed at 40 and 60 C under ultrasonic irradia-
º
tion (entries 12–13). It was observed that the higher temperatures
had no superiority to room temperature (RT). Subsequently, some
reactions were perused to test the effect of solvent. Examined sol-
vents, such as water, methanol, and tetrahydrofuran, exhibited no
advantage to EtOH (entries 14–16). The results of the optimization
are presented in Table 1.
1-amino-2-(benzo[d]thiazol-2-yl)−3-(2,6-dichlorophenyl)−
3Hbenzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile (6f). FT-IR (KBr)
(ν/cm−1); 3444, 3426, 3060, 3048, 2981, 2896, 2190, 1644, 1438;
1HNMR (400 MHz, d6-DMSO) δ (ppm) 8.81 (s, 1H), 8.17 (dd,
J = 8.5, 1.1 Hz, 1H), 8.08 (dd, J = 8.1, 1.6 Hz, 1H), 7.98 – 7.94 (m,
1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.55 (tt, J = 8.6, 1.6 Hz, 3H),
7.51 – 7.34 (m, 4H), 6.06 (s, 1H); 13CNMR (101 MHz, d6-DMSO) δ
(ppm) 168.2, 152.8, 152.3, 146.8, 137.2, 135. 0, 131.1, 130.1, 127.0,
126.4, 124.5, 123.5, 123.5, 123.3, 121.4, 120.2, 117.7, 115.8, 84.1,
75.4, 40.7; Elemental Analysis for C25H14 Cl2N4S2 (%) C, 59.17; H,
2.61; N, 10.98; S, 12.70; mp ( °C) 235–237.
One reaction was scrutinized using method B, depicted in
Scheme (1). Compared with method A, the obtained yield from this
method was less and reaction time was longer (entry 17).
To further investigate the ultrasound technique’s effect, some
derivatives were synthesized using several aldehydes under ultra-
sound irradiation and the conventional reflux method. Reaction
under ultrasonic irradiation showed a preference in yield and reac-
tion time. The results obtained from both ultrasonic irradiation and
reflux technique are given in Table 2. Also, reactions with aldehy-
des, including the electron donor group, gave low yield for a long
time.
Molecular docking
Protein 3D structures of ERα (PDB ID-1 × 7R) in the form of
co-crystalline structure with Genistein ligand and PR’s 3D structure
(PDB ID-1A28) in the form of co-crystalline heterodimer structure
of PRA and PRB with progesterone hormone as ligand were ob-
tained from the protein data bank. All water molecules and other
inessential species were removed, and original ligands were ex-
tracted from protein structures with Discovery Studio visualizer
software [56].
a) For reactions where the yield was low or no product was ob-
tained, method B (in scheme 1) was tried and the yield did not
improve in any of them.
b) The intermediate formed in the first step (5f) could not be iso-
lated and identified; its spectral data are not available.
The 3D structures of synthesized ligands were drawn using
gauss view 6, and the structure of compounds was optimized us-
ing Gaussian software (version 09) with density functional theory
(DFT) B3LYP and basic sets 6–311 G ++ (p, d). For both the re-
ceptors and ligands PDBQT file, which stores atom types, partial
charges, and atomic coordinates, was performed by AutoDockTools-
1.5.6.
There are no confirmed mechanisms for the synthesis
of 1-amino-2-(benzo [d] thiazol-2-yl)−3-aryl-3H-benzo [4,5]
thiazolo[3,2-a]pyridine-4-carbonitril.
A proper suggested mech-
anism is shown in scheme 2. At first, the reaction proceeds
between 2-(benzo [d] thiazol-2-yl) acetonitrile (3) and aldehyde
by Knoevenagel condensation to 2-(benzo[d]thiazol-2-yl)−3-
phenylacrylonitrile (5). Then Michael’s addition of 3 to 5 followed
by intramolecular cyclization leads to final product 6.
Molecular docking was performed with AutoDock 4 [57]. In all
three directions, the grid box was considered large enough to allow
the ligand to rotate freely to obtain the most stable conformation
in the complex structure. Finally, the interactions were displayed
by Discovery Studio visualizer software.
In the FT-IR spectrum of 1-amino-2-(benzo[d]thiazol-2-yl)−3-
phenyl-3H-benzo[4,5]thiazolo[3,2-a]pyridine-4-carbonitrile
(6a),
the absorption peaks have appeared at 3440, and 3355 cm−1
corresponds to symmetric and asymmetric stretching vibrations
8

M.A. Shirani, M.H. Maleki, P. Asadi et al.
Journal of Molecular Structure 1243 (2021) 130792
−1
PRO696, VAL729, ALA779, PRO780, ILE699 make many Pi-Alkyl in-
teractions. VAL698 creates a pi-sigma interaction, and the TRP765
is stacked with the aromatic ring via Pi-Pi interaction (Fig. 4c).
–
of N H bond. The emerged band at 2281 cm
is related to the
stretching vibration of the nitrile group. The bands at 1454 and
1637 cm−1 can be assigned to the stretching vibrations of C = C
(Fig. 1).
The 1HNMR (400 Hz) spectrum of 1-amino-2-(benzo[d]thiazol-
4. Conclusions
2-yl)−3-phenyl-3H-benzo[4,5]thiazolo[3,2-a]pyridine-4-
carbonitrile is shown in Fig. 2. The peak at 8.44 ppm (m) is
related to the hydrogens of the NH2 group. The dd peak at
8.04 ppm (a) is correlated to the hydrogen at the ortho position
of the nitrogen in the thiazole ring. The peak at 7.94 ppm can
be given to the hydrogen denoted by the letter (d). The dd peak
at 7.78 ppm (l) is associated with the hydrogen at the ortho
position of the nitrogen in the thiazolidine. The multiple peaks at
7.20–7.48 ppm are correlated to aromatic hydrogen. The singlet
peak at 4.82 ppm (h) is related to the aliphatic hydrogen in the
dihydropyridine ring.
In summary, the ultrasonically assisted method promoted an
effective way to prepare compounds based on benzothiazolopy-
ridine, i.e., 1-amino-2- (benzo [d] thiazol-2-yl) −3-aryl-3H-benzo
[5,4] thiazole [3,2-a] pyridine-4-carbonitrile. Furthermore, the re-
action also can be carried out under thermal conditions. The ul-
trasonic irradiation afforded several superiorities involving shorter
reaction time, cleaner reaction, and high yields. The purpose of
molecular docking on Estrogen and progesterone receptors was to
predict the activity potential of ligands against vital hormone re-
ceptors in breast cancer. The computational molecular docking be-
tween ligands (R and S enantiomers of 6a, 6b, 6d, and 6e) and all
three receptors showed favorable interactions in terms of binding
free energy.
The 13CNMR (400 Hz) spectrum of 1-amino-2-(benzo[d]thiazol-
2-yl)−3-phenyl-3H-benzo[4,5]thiazolo[3,2-a]pyridine-4-
carbonitrile in d6-DMSO is shown in Fig. 3. The peak at 44 ppm
(i) is related to the aliphatic carbon. The peak at 80.1 ppm marked
with the letter (n) is associated with the sp2 carbon attached to
the nitrile group. The emerged peak at 86.5 ppm (h) is allocated
to the sp2 carbon attached to the thiazole ring. The appeared
peak at 116.4 ppm (o) is related to the nitrile group. The peak
at 168.7 ppm (p) can be associated with the common carbon
between the thiazole and the dihydropyridine ring. Other aromatic
carbons and sp2 carbon (w) attached to the NH2 group have
appeared in the range of 118.6 to 152.6 ppm.
CRediT author statement
Mohammad Ali Shirani: Software, Visualization, Writing- orig-
inal draft preparation, Conceptualization, Validation, Formal analy-
sis, and Writing - Review & Editing.
Mohammad Hassan Maleki
preparation, and Formal Analysis.
Parvin Asadi : Software, Writing- Original draft preparation,
‎: Software, Writing- Original draft
‎
and Formal Analysis.
Molecular docking
Mohammad Dinari: Supervision, Project administration, Con-
ceptualization, Validation, Investigation, Resources, and Writing -
Review & Editing.
Molecular docking is an effective manner to evaluate several
ligand structures in drug design [58]. Docking studies were per-
formed to evaluate the interactions of various synthetic ligands (6a,
6b, 6d, and 6e) with ERα, PRA, and PRB receptors. The molecules
contain chiral carbon and are in the form of a racemic mixture,
so the docking process was implemented for both R and S enan-
tiomers.
Declaration of Competing Interest
None.
Supplementary materials
The molecules, receptors, and docking results are listed in
Table 3. According to the theoretical results of this study, all of
the selected ligands have the potency to interact with all three re-
ceptors and all interactions are energetically desirable. ERα shows
the highest tendency to form bonds with compound 6a (ꢀG=
−9.8 kcal/mol). PRA shows the highest binding affinity with 6e
(ꢀG= −9.74 kcal/mol) and PRB shows the highest reactivity with
6b (ꢀG= −11.79 kcal/mol). As shown in Fig. 4, 2D diagrams of the
mentioned complexes interactions are explained. Other compounds
show binding free energy in the range of −7.84 to −10.65 kcal/mol.
The interaction diagrams are depicted in Figures S27- 50.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130792.
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