Silica bonded N-(propylcarbamoyl)sulfamic acid (SBPCSA) as a highly efficient and recyclable solid catalyst for the synthesis of Benzylidene Acrylate derivatives: Docking and reverse docking integrated approach of network pharmacology

Article abstract of DOI:10.1016/j.bpc.2020.106443

A green approach has been developed for the synthesis of a series of benzylidene acrylate 3(a-p) from differently substituted aromatic/heterocyclic aldehydes and ethyl cyanoacetate in excellent yields (90–98%), and employing silica bonded N-(Propylcarbamoyl)sulfamic acid as a recyclable catalyst under solvent-free condition. The molecular structure of compounds 3b, 3d and 3i were well supported by single-crystal X-ray crystallographic analysis. The present protocol bears wide substrate tolerance and is believed to be more practical, efficient, eco-friendly, and compatible as compared to existing methods. In-silico approaches were implemented to find the biochemical and physiological effects, toxicity, and biological profiles of the synthesized compounds to determine the expected biological nature and confirm a drug-like compound. A molecular docking study of the expected biologically active compound was performed to know the hypothetically binding mode with the receptor. Also, reverse docking is applied to recognize receptors from unknown protein targets for drug-like compounds to explain poly-pharmacology and binding postures with different receptors.

Full text of DOI:10.1016/j.bpc.2020.106443

Journal Pre-proof
Silica bonded N-(Propylcarbamoyl)sulfamic acid (SBPCSA) as a
highly efficient and recyclable solid catalyst for the synthesis of
Benzylidene Acrylate derivatives: Docking and reverse docking
integrated approach of network pharmacology
Afroz Aslam, Mehtab Parveen, Mahboob Alam, Manuela Ramos
Silva, P.S. Pereira Silva
PII:
S0301-4622(20)30151-4
DOI:
https://doi.org/10.1016/j.bpc.2020.106443
BIOCHE 106443
Reference:
To appear in:
Biophysical Chemistry
Received date:
Revised date:
Accepted date:
8 June 2020
27 July 2020
27 July 2020
Please cite this article as: A. Aslam, M. Parveen, M. Alam, et al., Silica bonded N-
(Propylcarbamoyl)sulfamic acid (SBPCSA) as a highly efficient and recyclable solid
catalyst for the synthesis of Benzylidene Acrylate derivatives: Docking and reverse
docking integrated approach of network pharmacology, Biophysical Chemistry (2019),
https://doi.org/10.1016/j.bpc.2020.106443
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Silica bonded N-(Propylcarbamoyl)sulfamic acid (SBPCSA) as a highly
efficient and recyclable solid catalyst for the synthesis of Benzylidene
Acrylate derivatives: Docking and reverse docking integrated approach of
network pharmacology
Afroz Aslama, Mehtab Parveena*, Mahboob Alamb*, Manuela Ramos Silvac, P. S. Pereira
Silvac
a
Division of Organic Synthesis, Department of Chemistry, Aligarh Muslim University, Aligarh, 202002, India
b
Division of Chemistry and Biotechnology, Dongguk University, 123 Dongdae-ro, Gyeongju, Republic of Korea
c
CFisUC, Department of Physics, University of Coimbra, P-3004-516, Coimbra, Portugal
A b s t r a c t
A green approach has been developed for the synthesis of a series of benzylidene acrylate
3(a-p) from differently substituted aromatic/heterocyclic aldehydes and ethyl cyanoacetate in
excellent yields (90-98%), and employing silica bonded N-(Propylcarbamoyl)sulfamic acid as
a recyclable catalyst under solvent-free condition. The molecular structure of compounds 3b,
3d and 3i were well supported by single-crystal X-ray crystallographic analysis. The present
protocol bears wide substrate tolerance and is believed to be more practical, efficient, eco-
friendly, and compatible as compared to existing methods. In-silico approaches were
implemented to find the biochemical and physiological effects, toxicity, and biological
profiles of the synthesized compounds to determine the expected biological nature and
confirm a drug-like compound. A molecular docking study of the expected biologically
active compound was performed to know the hypothetically binding mode with the receptor.
Also, reverse docking is applied to recognize receptors from unknown protein targets for
drug-like compounds to explain poly-pharmacology and binding postures with different
receptors.
KeyWords: Heterogeneous Catalysts, Benzylidene Acrylates, DFT Calculation, Docking
studies, PASS, Reverse Docking.
*Corresponding author
E-mail address: mehtab.organic2009@gmail.com (MP); mahboobchem@gmail.com (MA)
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1. Introduction
Knoevenagel condensation is one of the most important reactions for C–C bond formation [1-
4]. From the viewpoint of green chemistry, this reaction is eco-friendly because its by-
product is water [5]. This reaction has been used to obtain fine chemicals and many other
useful compounds [6]. This reaction plays a key role in the synthesis of some bioactive
compounds [7, 8]. Also, the Knoevenagel reaction is one of the key steps in the preparation
of some medicines such as entacapone [9] and atorvastatin [10]. Because of the importance of
the Knoevenagel condensation of an aldehyde and malononitrile (or ethyl cyanoacetate) as a
basic and key step to obtain more important molecules, various methods, and catalysts have
been reported to promote this reaction [11-16].
The development of promoted organic reactions at room temperature under solvent-free
conditions is one of the important and challenging subjects in organic synthetic chemistry,
particularly from both economic and environmental points of view. Therefore, we aim to
develop an alternative method, more particularly with the application of novel, simple,
efficient, cost-effective, high-yield, and green methodologies. Solvent-free reactions are
gaining popularity because of the very easy set-up of reaction conditions. Moreover, the
grinding method with a solvent-free reaction offers the extra advantage, the reactions
complete within minutes rather than long hours as is the current practice. Faster reaction rates
coupled with low costs of running the reaction and without a need for employing special
techniques like microwaves, [17] reflux, [18], or sonication [19] make such reactions popular
in the industry. The work-up is very simple and does not require column chromatography and
the use of volatile organic solvents for purification. All the products are obtained in excellent
yields with high purity by just washing with water.
Recently, heterogeneous catalysts have attracted increasing interest due to economic and
environmental considerations [20-21]. The catalytic performance of supported metal
complexes as heterogeneous catalysts has been generally used in various chemical industries
[22]. Immobilization of catalysts on solid support improves their available active site,
stability, product separation, and recoveries, which are all factors important in the industry
[23]. Therefore, the use of supported and reusable catalysts in organic transformations has
economic and environmental benefits. Although supported catalysts are available on different
supports including charcoal, alumina, silica, and polymer, silica has many other advantages
such as no swelling, good mechanical and thermal stability, and ease of scalability [24].
Silica bonded N-(Propylcarbamoyl)sulfamic acid is a reusable silica-supported catalyst. This
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inexpensive and reusable catalyst can be easily handled and separated from the reaction
mixture, which contributes to make reactions cleaner, faster, and higher-yielding. The major
advantage of supported reagent is the reusability of the catalyst which makes the process
inexpensive. Moreover, it also contributes to the area of ―Green Chemistry‖. Applications of
synthetic compounds are always welcomed in the industrial and pharmaceutical sectors. The
pharmaceutical sectors have a strong desire to find new chemical entities from various
sources. Therefore, the identification of various lead compounds would be accompanied by
several approaches, until recently, the use of in Silico approach is cost and time effective and
especially when there are many restrictions and standardizations to conduct in-vivo studies
[25-28]. So, with the increase of computational study, computer-based activity has applied to
the assessment of the new drug with lower side effects [29]. Additionally, the molecular
docking has been done to know the way of binding of drugs with receptor residues, in case of
reverse docking; several receptors were allowed to interact with a single drug to establish the
pharmacological activity profile by inspecting the binding modes with the active sites of
amino acids of the protein [30].
In this context, heterogeneous catalysts have received prominent attention in organic
transformations on the ground of their remarkable ability to enhance faster rates of organic
reactions. In this repute, a heterogeneous supported catalyst can improve the synthetic
procedure by proposing the possibility of simple recovery, recycling, easy product
purification, isolation, and higher stability towards the reaction environment. Therefore, the
preparation of new supported catalysts with boosted efficiency is of significant interest,
herein, we report the synthesis of silica bonded N-(propylcarbamoyl)sulfamic acid (SBPCSA)
as a green, efficient and recyclable heterogeneous catalyst for the synthesis of benzylidene
acrylate derivatives. In comparison with the present reported methods of benzylidene acrylate
synthesis, our approach displays specific advantages and become more practical than existing
synthetic methodologies as it gives excellent yields (90–98%) within a minimum reaction
time and applicable to a broader substrate scope (electron-rich and electron-deficient).
Furthermore, to investigate the correlation between pharmacological activity and the
molecular properties of the synthesized compounds, cheminformatics software like
Molinspiration and PASS was applied in search of a lead compound.
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2. Material and methods
2.1. Materials
All the reagents were purchased from Merck and Sigma-Aldrich (India) as "synthesis grade"
and used without further purification. Melting points of all synthesized compounds were
determined on a Kofler apparatus and are uncorrected. Fourier transform-infrared (FT-IR)
spectra were recorded in the 400-4000 cm-1 wave-number range using a Perkin-Elmer (2000
FTIR) Spectrometer by the KBr pellet method. 1H NMR and 13C NMR spectra were recorded
on a Bruker Avance-II 400 MHz instrument in CDCl3 and DMSO-d6 solvent. The chemical
shifts (δ) are reported in ppm relative to the TMS as an internal standard and J values are
reported in Hertz. Mass spectra were recorded on a JEOL D-300 mass spectrometer.
Elemental analysis (C, H, and N) was conducted using a Thermo Scientific (FLASH 2000)
CHN Elemental Analyzer. Thin-layer chromatography (TLC) glass plates coated with silica
gel G254 (E-Merck) were used to check the purity of the reagent as well as the progress of
the reaction.
2.1. Preparation of the Silica Bonded N-(Propylcarbamoyl)sulfamic acid (SBPCSA)
The Silica Bonded N-(Propylcarbamoyl)sulfamic acid (SBPCSA) was synthesized by the
standard procedure as reported earlier in the literature [31].
2.2. General procedure for the synthesis of substituted benzylidene acrylate 3(a-p)
A mixture of aldehyde 1(a-p) (1.59 mmol), ethyl cyanoacetate (1.59 mmol) and silica bonded
N-(Propylcarbamoyl)sulfamic acid (SBPCSA) 200 mg was heated at 100°C with stirring for
the specified time (Table 8). After completion of the reaction (monitored by TLC), the
catalyst was filtered off washed with ethyl acetate, dried in the air, and reused. The organic
layer was evaporated under reduced pressure to get the products 3(a-p). The recrystallization
of products 3(a-p) was done using a mixture of methanol and chloroform (10:1). Scheme 1
Scheme 1 Synthetic scheme for the synthesis of benzylidene acrylate derivatives 3(a-p)
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Spectral Characterization
(3a) (E)-ethyl 2-cyano-3-(4-nitrophenyl)acrylate
Crystallize from chloroform-methanol as a colorless crystalline solid, Yield: 98%, M.P:
170C [lit. [32] M.P: 170-171C]; Anal. calc. for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38;
O, 25.99; Found: C, 58.50; H, 4.05; N, 11.34; O, 25.90; FTIR (KBr, υmax, cm-1): 3278,
1
(aromatic ═C─H), 3020 (alkene ═C–H), 2400, 2230 (C≡N), 1730 (C═O), 1660 (C═C); H
NMR (400 MHz, DMSO-d6, δ, ppm): 1.40 (t, 3H), 4.40 (q, 2H), 8.12 (d, 2H), 8.25 (d, 2H),
13
8.35 (s, 1H); C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 154.6 (C-3), 147.1 (C-
4'), 135.2 (C-1'), 131.5 (C-2' & C-6'), 123.8 (C-3' & C-5'), 118.7 (C≡N), 102.7 (C-2), 60.9
(CH2), 14.2 (CH3); MS (ESI) m/z: 246.06 [M+H]+•
(3b) (E)-ethyl 2-cyano-3-(4-fluorophenyl)acrylate
Crystallize from chloroform-methanol as a white crystalline solid, Yield: 97%, M.P: 82C
[lit. [33] M.P. 80-82C]; Anal. calc. for C12H10FNO2: C, 65.75; H, 4.60; F, 8.67; N, 6.39; O,
14.60; Found: C, 65.70; H, 4.55; F, 8.63; N, 6.34; O, 14.56; FTIR (KBr, υmax, cm-1): 3108
1
(aromatic ═C–H), 2993 (alkene ═C–H), 2845, 2221 (C≡N), 1719 (C═O), 1611 (C═C). H
NMR (400 MHz, DMSO-d6, δ, ppm): 8.19 (s, 1H, H-3), 8.01 (m, 2H), 7.18 (m, 2H), 4.37 (q,
2H), 1.38 (t, 3H). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1' & C-4"), 154.6 (C-3),
130.4 (C-2" & C-6"), 127.7 (C-1"), 116.9 (C≡N), 115.4 (C-3" & C-6"), 102.7 (C-2), 60.9
(CH2), 14.2 (CH3); MS (ESI) m/z: 219.07 [M+H]+•
(3c) (E)-ethyl 2-cyano-3-(4-hydroxy-3-methoxyphenyl)acrylate
Crystallize from chloroform-methanol as light brown solid, Yield: 96%, M.P: 99C [lit. [34]
m.p. 100C]; Anal. calc. for C13H13NO4: C, 63.15; H, 5.30; N, 5.67; O, 25.88; Found: C,
63.10; H, 5.25; N, 5.64; O, 25.84; FTIR (KBr, υmax, cm-1): 3300 (aromatic =C–H), 3040
1
(alkene =C–H), 2920, 2240 (C≡N), 1730 (C=O), 1590 (C=C); H NMR (400 MHz, DMSO-
d6, δ, ppm): 8.07(1H, s, =CH), 7.78(1H, s, H-2'), 7.33(1H, d, Ar-H), 6.93 (l H, d, Ar-H), 6.23
13
(l H, br.s, OH), 4.30 (2H, q, OCH2CH3), 3.91 (3H, s, OCH3), 1.33.(3H, t, OCH2CH3).; C
NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 154.6 (C-3), 149.9 (C-4"), 149.1 (C-3"),
128.8 (C-1"), 122 (C-2"), 117.9 (C≡N), 116.8 (C-5"), 111.9 (C-2"), 102.7 (C-2), 60.9 (CH2),
56.1 (OCH3), 14.2 (CH3); MS (ESI) m/z: 247.08 [M+H]+•
(3d) (E)-ethyl 2-cyano-3-(4-(dimethylamino)phenyl)acrylate
Crystallize from chloroform-methanol as an orange crystalline solid, Yield: 98%, M.P:
120C; [lit. [35] m.p. 119-121C] Anal. calc. for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47; O,
13.10; Found: C, 68.80; H, 6.55; N, 11.45; O, 13.06; FTIR (KBr, υmax, cm-1): 3080
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(aromatic═C─H), 2995 (alkene═C─H), 2208 (C≡N), 1701 (C=O)ester, 1927 (C═C), 1165
1
(C─O)ester; H NMR (400 MHz, DMSO-d6, δ, ppm): 8.07 (s, 1H, H─C═C─), 7.94 (d, 2H, Ar-
H), 6.70 (d, 2H, Ar-H), 4.36 (q, 2H, ─CH2─), 3.11 (s, 6H, ─CH3), 1.39 (t, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 154.6 (C-3), 150.3 (C-4'), 133.5 (C-2" & C-6"),
118.5 (C-1"), 116.1 (C≡N), 111.7 (C-3" & C-5"), 102.7 (C-2), 60.9 (CH2), 41.3 (2CH3), 14.2
(CH3); MS (ESI) m/z: 244.12 [M+H]+•
(3e) (E)-ethyl 3-(3-bromophenyl)-2-cyanoacrylate
Crystallize from chloroform-methanol as a white crystalline solid, Yield: 94%, M.P: 90C;
Anal. calc. for C12H10BrNO2: C, 51.45; H, 3.60; Br, 28.53; N, 5.00; O, 11.42; Found: C,
51.40; H, 3.55; Br, 28.50; N, 49.9; O, 11.40; FTIR (KBr, υmax, cm-1): 3031 (aromatic=C–H),
2985 (alkene=C–H), 2221 (C≡N), 1719 (C=O), 1611 (C=C). 1H NMR (400 MHz, DMSO-d6,
δ, ppm): 8.25 (s, 1H, H-3), 7.57 (s, 1H, H-2"), 7.54 (d, 1H, H-6"), 7.48 (d, 1H, H-4"), 7.29 (t,
1H, H-5"), 4.20 (m, 2H, CH2), 1.29 (d, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ, ppm):
162.1 (C-1'), 154.8 (C-3), 131.9 (C-6"), 131.3 (C-1"), 130.8 (C-4"), 129.9 (C-2"), 129.6 (C-
5"), 123.4 (C-3"), 116.9 (C≡N), 102.7 (C-2), 60.9 (CH2), 14.2 (CH3); MS (ESI) m/z: 278.99
[M+H]+•
(3f) (E)-ethyl 3-(4-chloro-3-nitrophenyl)-2-cyanoacrylate
Crystallize from chloroform-methanol as a shining orange crystalline solid, Yield: 96%, M.P:
180C; Anal. calc. for C12H9ClN2O4: C, 51.35; H, 3.23; Cl, 12.63; N, 9.98; O, 22.80 Found:
C, 51.30; H, 3.20; Cl, 12.59; N, 9.95; O, 22.76; FTIR (KBr, υmax, cm-1): 3104 (aromatic ═C–
H), 3047 (alkene=C–H), 2954 (–CH3), 2210 (C≡N), 1743 (C=O), 1657 (C=C). 1H NMR (400
MHz, DMSO-d6, δ, ppm): 8.36 (s, 1H, H-3), 8.07 (m, 1H, H-6"), 7.87 (d, 1H, H-2"), 7.70 (s,
1H, H-5"), 4.20 (m, 2H, CH2), 1.29 (d, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ, ppm):
162.1 (C-1'), 154.8 (C-3), 147.7 (C-3"), 135.1 (C-6"), 131.2 (C-1"), 129.6 (C-5"), 127.0 (C-
4"), 121.4 (C-2"), 116.3 (C≡N), 102.7 (C-2), 60.9 (CH2), 14.2 (CH3); MS (ESI) m/z: 280.03
[M+H]+•
(3g) (E)-ethyl 2-cyano-3-(2,3,4-trihydroxyphenyl)acrylate
Crystallize from chloroform-methanol as a light yellow crystalline solid, Yield: 95%, M.P:
210C; Anal. calc. for C12H11NO5; C, 57.83; H, 4.45; N, 5.62; O, 32.10 Found: C, 57.80; H,
4.40; N, 5.60; O, 32.05; FTIR (KBr, υmax, cm-1): 3400 (aromatic ═C─H), 2900 (alkene=C–
1
H), 2200 (C≡N), 1720 (C═O), 1600 (C═C); H NMR (400 MHz, DMSO-d6, δ, ppm): 8.52
(s, 1H, H-3), 7.49 (d, 1H, H-6"), 6.49 (d, 1H, H-5"), 5.35 (s, 3H, 3OH), 4.20 (m, 2H, CH2),
1.29 (d, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 149.3 (C-1" & C-
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4"), 142.1 (C-2"), 135.9 (C-3"), 123.8 (C-6"), 116.4 (C≡N), 110.5 (C-3), 109.8 (C-5"), 102.7
(C-2), 60.9 (CH2), 14.2 (CH3); MS (ESI) m/z: 249.06 [M+H]+•
(3h) (E)-ethyl 3-(4-chlorophenyl)-2-cyanoacrylate
Crystallize from chloroform-methanol as a white solid, Yield: 98%, M.P: 90C [lit. [32] m.p.
89-90 C]; Anal. calc. for C12H10ClNO2: C, 61.16; H, 4.28; Cl, 15.04; N, 5.94; O, 13.58
Found: C, 61.14; H, 4.25; Cl, 15.00; N, 5.90; O, 13.53; FTIR (KBr, υmax, cm-1): 3100
1
(aromatic ═C─H), 2850 (alkene=C–H), 2220 (C≡N), 1730 (C═O), 1610(C═C); H NMR
(400 MHz, DMSO-d6, δ, ppm): 1.40 (t, 3H), 4.40 (q, 2H), 7.59 (d, 2 H), 7.95 (d, 2H), 8.20
13
(s, 1H) C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 154.6 (C-3), 133.5 (C-4"),
132.6 (C-2" & C-6"), 130.2 (C-), 126.7 (C-3" & C-5"), 115.7 (C≡N), 102.7 (C-2), 60.9
(CH2), 14.1 (CH3); MS (ESI) m/z: 235.04 [M+H]+•
(3i) (E)-ethyl 3-(5-bromothiophen-2-yl)-2-cyanoacrylate
Crystallize from chloroform-methanol as a white crystalline solid, Yield: 97%, M.P: 110C;
Anal. calc. for C10H8BrNO2S: C, 41.97; H, 2.82; Br, 27.92; N, 4.89; O, 11.18; S, 11.21
Found: C, 41.90; H, 2.80; Br, 27.90; N, 4.84; O, 11.14; S, 11.20; FTIR (KBr, υmax, cm-1):
1
3086 (aromatic ═C─H), 2219 (C≡N), 1717 (C═O), 1599 (C═C); H NMR (400 MHz,
DMSO-d6, δ, ppm): 8.64 (s, 1H, H-3), 7.78 (d, 1H,), 7.26 (d, 1H,), 4.20 (m, 2H, CH2), 1.29
(d, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.0 (C-3), 140.4 (C-
2"), 136.4 (C-3"), 131.4 (C-4"), 118.9 (C-5"), 116.7 (C≡N), 93.5 (CH2), 60.9 (CH3), 14.2 (C-
6''); MS (ESI) m/z: 286.94 [M+H]+•
(3j) (E)-ethyl 2-cyano-3-(1H-pyrrol-2-yl)acrylate
Crystallize from chloroform-methanol as a light grey solid, Yield: 95%, M.P: 135C [lit. [32]
m.p. 135-137 C]; Anal. calc. for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73; O, 16.82 Found:
C, 63.13; H, 5.28; N, 14.65; O, 16.80; FTIR (KBr, υmax, cm-1): 3307 (aromatic ═C─H), 2206
1
(C≡N), 1695 (C═O), 1585 (C═C); H NMR (400 MHz, DMSO-d6, δ, ppm): 1.39 (t, 3H),
4.39 (q, 2H), 6.40 (dd, 1H), 6.90 (d, 1 H), 7.25 (d, 1H), 8.0 (s, 1 H), 10.05 (br. s, 1H, NH);
13C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 140.4 (C-3), 128.9 (C-6"), 118.3 (C-
2"), 117.9 (C≡N), 111.9 (C-3"), 108.2 (C-4"), 86.3 (C-2), 60.9 (CH2), 14.1 (CH3); MS (ESI)
m/z: 190.07 [M+H]+•
(3k) (E)-ethyl 2-cyano-3-(1H-indol-2-yl)acrylate
Crystallize from chloroform-methanol as a yellow solid, Yield: 96%, M.P: 160C [lit. [32]
m.p. 161-162 C]; Anal. calc. for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66; O, 13.32; Found:
C, 69.93; H, 5.00; N, 11.65; O, 13.20; FTIR (KBr, υmax, cm-1): 3325 (aromatic ═C─H), 2212
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1
(C≡N), 1697 (C═O), 1565 (C═C); H NMR (400 MHz, DMSO-d6, δ, ppm): 1.40 (t, 3H),
4.40 (q, 2H), 7.20-7.38 (m, 2H), 7.40-7.50 (m, 1H), 7.78-7.85 (m, 1H), 8.60 (s, 1H), 8.65 (s,
13
1 H), 9.45 (br. s,1H, NH); C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 140.4 (C-
3), 131.0 (C-5"), 128.2 (C-4"), 122.3 (C-2"), 121.7 (C-7"), 120.7 (C-9"), 119.8 (C-8"), 118.3
(C≡N), 111.1 (C-6"), 101.0 (C-3"), 86.4 (C-2), 60.9 (CH2), 14.2 (CH3); MS (ESI) m/z:
240.09 [M+H]+•
(3l) (E)-ethyl 2-cyano-3-(5-nitrofuran-2-yl)acrylate
Crystallize from chloroform-methanol as a light yellow crystalline solid, Yield: 97%, M.P:
170C; Anal. calc. for C10H8N2O5: C, 50.85; H, 3.41; N, 11.86; O, 33.87 Found: C, 50.84; H,
3.43; N, 11.82; O, 33.83; FTIR (KBr, υmax, cm-1): 3100 (aromatic ═C─H), 2900 (alkene ═C-
H), 2200 (C≡N), 1723 (C═O), 1635 (C═C); 1H NMR (400 MHz, DMSO-d6, δ, ppm): 8.22 (s,
1H, H-3), 7.94 (d, 1H, H-4"), 7.58 (d, 1H, H-3"), 4.20 (m, 2H, CH2), 1.29 (d, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.0 (C-3), 155.4 (C-2"), 153.8 (C-5"),
117.5 (C≡N), 118.2 (C-3"), 114.5 (C-4"), 93.5 (C-2), 60.9 (CH2), 14.2 (CH3); MS (ESI) m/z:
236.04 [M+H]+•
(3m) (E)-ethyl 2-cyano-3-(3-methylthiophen-2-yl)acrylate
Crystallize from chloroform-methanol as a brown solid, Yield: 98%, M.P: 110C; Anal. calc.
for C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; O, 14.46; S, 14.49; Found: C, 59.68; H, 5.00 N,
6.30; O, 14.43; S, 14.42; FTIR (KBr, υmax, cm-1): 3086 (alkene ═C-H), 2219 (C≡N), 1717
(C═O), 1599 (C═C), 1H NMR (400 MHz, DMSO-d6, δ, ppm): 8.64 (s, 1H, H-3), 7.97 (d, 1H,
H-5"), 7.33 (d, 1H, H-4"), 4.20 (m, 2H, CH2), 2.44 (s, 3H, CH3), 1.29 (d, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.0 (C-3), 154.4 (C-3"), 135.0 (C-5"), 131.8
(C-4"), 130.3 (C-2"), 117.2 (C≡N), 93.5 (C-2), 60.9 (CH2), 14.8 (CH3), 14.2 (CH3); MS (ESI)
m/z: 221.05 [M+H]+•
(3n) (E)-ethyl 3-(5-bromofuran-2-yl)-2-cyanoacrylate
Crystallize from chloroform-methanol as an orange crystalline solid, Yield: 95%, M.P:
130C; Anal. calc. for C10H8BrNO3: C, 44.47; H, 2.99; Br, 29.59; N, 5.19; O, 17.77; Fond: C,
44.43; H, 2.95; Br, 29.51; N, 5.13; O, 17.74; FTIR (KBr, υmax, cm-1): 3100 (aromatic ═C─H),
2900 (alkene ═C-H), 2200 (C≡N), 1723 (C═O), 1635(C═C); 1H NMR (400 MHz, DMSO-d6,
δ, ppm): 8.22 (s, 1H, H-3), 7.27 (d, 1H, H-3"), 6.78 (d, 1H, H-4"), 4.20 (m, 2H, CH2), 1.29
(d, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.0 (C-3), 154.2 (C-
2"), 122.5 (C-5"), 118.3 (C≡N), 113.8 (C-4"), 113.6 (C-3"), 93.5 (C-2), 60.9 (CH2), 14.2
(CH3); MS (ESI) m/z: 268.97 [M+H]+•
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(3o) (E)-ethyl 2-cyano-3-(5-methylfuran-2-yl)acrylate
Crystallize from chloroform-methanol as a yellow crystalline solid, Yield: 98%, M.P: 120C;
Anal. calc. for C11H11NO3: C, 64.38; H, 5.40; N, 6.83; O, 23.39; Found: C, 64.35; H, 5.7; N,
6.80; O, 23.33; FTIR (KBr, υmax, cm-1): 3200 (aromatic ═C─H), 2900 (alkene ═C-H), 2210
1
(C≡N), 1725 (C═O), 1620 (C═C); H NMR (400 MHz, DMSO-d6, δ, ppm): 8.22 (s, 1H, H-
3), 7.28 (d, 1H, H-3"), 6.43 (d, 1H, H-4"), 4.20 (m, 2H, CH2), 2.30 (s, 3H, CH3), 1.29 (d, 3H,
13
CH3); C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.8 (C-5"), 157.0 (C-3),
149.7 (C-2"), 126.6 (C-3"), 118.7 (C≡N), 108.5 (C-4"), 93.5 (C-2), 60.9 (CH2), 14.2 (CH3),
13.8 (s, 3H, CH3); MS (ESI) m/z: 205.07 [M+H]+•
(3p) (E)-ethyl 2-cyano-3-(furan-2-yl)acrylate
Crystallize from chloroform-methanol as a colorless solid, Yield: 96%, M.P: 91C [lit. [32]
m.p. 89-91C]; Anal. calc. for C10H9NO3: C, 62.82; H, 4.74; N, 7.33; O, 25.11; Found: C,
62.82; H, 4.74; N, 7.33; O, 25.11; FTIR (KBr, υmax, cm-1): 3100 (aromatic ═C─H), 2900
1
(alkene ═C-H), 2200 (C≡N), 1720 (C═O), 1630 (C═C); H NMR (400 MHz, DMSO-d6, δ,
ppm): 8.22 (s, 1H, H-3), 8.17 (d, 1H, H-2"), 7.65 (d, 1H, H-4"), 6.87 (d, 1H, H-3"), 4.20 (m,
13
2H, CH2), 1.29 (d, 3H, CH3); C NMR (100 MHz, DMSO-d6, δ, ppm): 162.1 (C-1'), 157.0
(C-3), 151.5 (C-2"), 143.7 (C-5"), 118.3 (C≡N), 112.7 (C-4"), 109.5 (C-3"), 93.5 (C-2), 60.9
(CH2), 14.2 (CH3); MS (ESI) m/z: 191.06 [M+H]+•
3. Experimental and Computational Methods
3.1. Crystal structure determination
A crystal of (E)-ethyl3-(5-bromothiophen-2-yl)-2-cyanoacrylate 3i suitable for an X-ray
diffraction study, with approximate dimensions of 0.55 mm × 0.40mm × 0.30 mm, was glued
on glass fiber and mounted on a Bruker Apex II diffractometer. The diffraction data were
collected at room temperature 293(2) K using graphite monochromated Mo Kα (λ= 0.71073
Å). The data reduction was performed with APEX II [36]. Lorentz and polarization
corrections were applied. Absorption correction was applied using SADABS [37].
The crystallographic structure was solved using direct methods (SHELXS-2014/7) [38]. The
structure refinement was carried out with SHELXL-2014/7 software [38]. The refinement
was made by full-matrix least-squares on F2, with anisotropic displacement parameters for all
non-hydrogen atoms. All the hydrogen atoms were located in a difference Fourier synthesis,
placed at calculated positions and then, included in the structure factor calculation in a riding
model using SHELXL defaults. The software MERCURY 4.0.0 [39] was used for figure
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plotting. PLATON [40] was used for structure analysis. Additional information to the
structure determination is given in Table 1. Atomic coordinates, thermal parameters, and
bond lengths and angles have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). Any request to the CCDC for this material should quote the full literature citation
and the reference number CCDC 1927055.
Table 1 Crystallographic data and structure refinement of compound (3i)
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
C10H8BrNO2S
286.14
293(2)
0.71073
Triclinic
̅
Space group
a (Å)
b (Å)
c (Å)
α (deg.)
β (deg.)
γ (deg.)
Volume (Å3)
6.985(2)
7.660(2)
11.866(4)
106.550(8)
102.465(8)
97.490(8)
581.6(3)
2
Z
Calculated density (g/cm3)
Absorption coefficient (mm–1)
F(000)
1.634
3.692
284
Crystal size (mm)
θ range for data collection (deg.)
Index ranges
0.55 0.40 0.30
3.052–27.166
–8<h<8, –9<k<9, –15<l<15
11654/2553 [R(int) = 0.0896]
99.9%
Full–matrix least-squares on F2
2553/0/137
Reflections collected/unique
Completeness to θ = 25.00º
Refinement method
Data/restraints/parameters
Goodness–of–fit on F2
Final R indices [I> 2σ(I)]
R indices (all data)
Largest diff. peak and hole (e Å – 3)
1.030
R =0.0338wR = 0.0756
R = 0.0512wR = 0.0812
0.514 and –0.363
3.2. Computational methods
All calculations presented in this work were performed with the GAMESS US package [41].
The experimental X-ray geometries of compounds 3b, 3d, and 3i (E-isomers) were optimized
in a vacuum within density functional theory (DFT) using B3LYP (Becke three-parameter
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Lee–Yang–Parr) for exchange and correlation, which combines the hybrid exchange
functional of Becke [42, 43] with the correlation functional of Lee, Yang, and Parr [44]. The
calculations were executed with an extended 6–311G(d,p) basis set. Tight conditions for
convergence of both the self-consistent field cycles and the maximum density and energy
gradient variations were imposed (10–5 atomic units).
The geometries of the Z-isomers were also optimized with the same level of theory. The
starting geometries of the Z-isomers used for the optimizations were obtained from the
optimized geometries of the E-isomers, performing a rotation of 180º around the C═C double
bond, in both compounds, with the aid of the software UCSF Chimera software package
version 1.8 [45].
At the end of each geometry optimization, we conducted a Hessian calculation to guarantee
that the final structure corresponds to a true minimum, using the same level of theory as in
the geometry optimization.
4. Computational profiling using in silico tools
4.1. Lipinski’s rule of five, bioactivity score and toxicity
Chemical structure of the synthesized compounds and their SMILES notation was obtained
using Chemdraw v.12. SMILES at the benzylidene acrylates were then provided to the online
Molinspiration software to compute various molecular properties and know the in-Silico
biological activity scores for drug targets including enzymes and nuclear receptors, kinase
inhibitors, GPCR ligands, and ion channel modulators. Partition coefficient (LogP),
Topological polar surface area (TPSA), hydrogen bond donors and acceptors, rotatable
bonds, number of atoms, molecular weight, and violations of Lipinski’s rule of five are
considered as a Molecular property of the chemical identities involving the evaluation of the
drug-likeness of the synthesized compounds [46]. The toxicity of the synthesized compounds
was also taken into consideration and calculated using the ProTOX online tool to help select
the best compound in the series [47].
4.2. PASS and Swiss target prediction online
The possible pharmacological activity of the synthesized benzylidene acrylates was
predicted using an online tool named Bioactivity score and Prediction of Activity Spectra for
Substances (PASS). The analyses of expected biological activities are based on probable
activity (Pa) and probable inactivity (Pi), where both Pa and Pi can have values ranging from
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0.000 to 1.000. The values of Pa> Pi and Pa> 0.700 were considered to indicate biological
activities
for
a
series
of
compounds
(Way2Drug;
http://www.pharmaexpert.ru/PASSonline/index.php). Probable targets for the synthesized
benzylidene acrylate were predicted by Swiss target prediction analysis, using
http://www.swiss target prediction.ch, a web server, based on measures of 2D and 3D
structures available in the database on the Swiss website.
4.3. Docking studies
Docking studies of the prepared compounds were carried out using PyRx [48] which is
screening software for Computational Drug Discovery. The PyRx software acts as an
AutoDock [48] interface that can be applied to screen a series of compounds against potential
drug targets at the same time. The three-dimensional crystal structures of proteins for
isoenzymes; COX-2(PDB: 1CX2) and COX-1 (PDB; 3KK6) were taken from the PDB
database and were used as receptors for docking studies. All protein-bound solvents and
heterocycles were removed from the structures using Discovery studio to be used for
subsequent steps of the docking steps. A series of sixteen synthesized compounds were drawn
using ChemDraw software and structures of the file were saved in SDF format after energy
minimization with an MM2 force field. These energy minimization structures of the
compounds were used for molecular docking in the PyRx virtual screening tool. The best
pose of the docking results based on the ranked dock scores was visualized using Discovery
studio and associated software [49, 50].
4.4. Reverse docking
The number of potential targets for the reverse docking will be required to complete the
reverse docking setup. For this operation, the mol2 file of the best-docked pose of the
compound of the synthesized series compounds was taken and uploaded on the PharmMapper
server for a ligand-based inverse screening resulting in 300 hits. Of them, only 30 best targets
were selected for reverse docking due to a lack of professional software. PharmMapper [51]
analysis is a highly efficient mapping methodology that has a high throughput capability and
detects potential target candidates from the database within a very short timeframe for
synthetic compounds. In reverse docking, 30 docking experiments were included separately
for the best pose ligand. A standard docking method reported in the literature was considered
to carry out inverse docking properly with the addition of Gasteiger atomic charges and
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default atom-types assignment. Visualization software was used to analysis of docking
results.
5. Results and Discussions
In the present study, a library of benzylidene acrylate derivatives 3(a-p) has been synthesized
by using environmentally benign heterogeneous catalyst SBPCSA under solvent-free
conditions. This protocol offers several advantages over other existing synthetic
methodologies in terms of yield and purity of products, operational procedures, reaction
times, catalyst stability, and recyclability. This synthetic scheme possesses diverse
applicability and is compatible with a range of functional groups (electron-donating/ electron-
withdrawing).
5.1 Chemistry
The synthetic pathways of a series of benzylidene acrylate 3(a-p) are shown in Scheme 1
respectively. Herein, the series was typically accessed via a nucleophilic addition between
ethyl cyanoacetate and appropriately substituted aromatic aldehydes 1(a-p) to yield target
benzylidene derivatives. All the compounds were obtained in excellent yields (90-98%) with
high purity. The structural elucidation of the synthesized compounds 3(a-p) was established
1
13
based on elemental analysis, FT-IR, H NMR, C NMR, and mass spectral analysis. The
analytical results for C, H, and N were within 0.3% of the theoretical values. The spectral
analysis has been in good corroboration with the expected structural framework of the
synthesized compounds. All the synthesized compounds showed the following characteristic
peak in the IR spectrum. All the compounds displayed a characteristic peak for C≡N and
C═O and C═C group, resonating at around 2200-2240 cm-1, 1695-1743 cm-1, and 1565-1927
cm-1, respectively. In the 1H NMR spectra, each compound shows a sharp singlet at around 
8.00-8.64 ascribed to the olefinic proton (H-3), 13C NMR spectra, a series of signals emerging
at around  101.0-162.1 are ascribed to aromatic carbons, peaks resonating at around  115.7-
118.7 correspond to the cyanide group. Finally, compounds (3a–3p) showed characteristic
molecular ion peaks in Mass spectra which were in good agreement with the proposed
structures.
1
In the present study, it was not possible to confirm geometry across C=C based on H NMR
analysis. To gain some insight into the influence of the electronic interactions on the
molecular geometry, we have performed quantum mechanical calculations of the equilibrium
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geometry of the free molecule. For this purpose, we choose compounds 3b and 3i for the DFT
study. Of the two possible geometrical isomers (E/Z) of the compound 3b and 3i E-isomer
was obtained as the sole product. It was found that in case of 3i the E-isomer is stabilized by
2.33 kcal mol-1 of energy than Z-isomer and the E-isomer of 3b is also more stable by 5.00
kcal mol-1 and this energy difference is satisfactory enough to suggest that during the
crystallization process, the E-isomer gets exclusively crystallized out from the solution.
5.2. Crystal structure
In Figure 1, we present the asymmetric unit of compound 3i with the corresponding atomic
labeling scheme. The molecular structure of compound 3i is planar with an E-configuration
about the C5═C6 double bond. The exception to planarity is the ethyl moiety, evidenced by
the torsion angle C8-O2-C9-C10 of 89.8(3)°.
Fig. 1. Asymmetric unit of compound (3i) with the ellipsoids drawn at the 50% probability
level, with the atomic labeling scheme.
The molecules of 3i are arranged in stacks approximately parallel to the (1 0 2) plane and
consisting of antiparallel molecules linked in pairs by C—H…O hydrogen bonds (see Table
(
)
(
)
( )
2, Fig. 2), forming rings with descriptors according to Etter’s
graph-set theory [52]. There is also one weak intramolecular C—H…Br hydrogen bond
linking molecules from adjacent planes. The formation of stacks consisting of antiparallel
molecules is a structural feature also present in 3b and similar compounds [53]. The distance
between the planes of two adjacent molecules (3.467 Å) is identical to the corresponding
distance in 3b.
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Table 2 H-bond geometry of (3i) (Å,º).
D—H...A
C3—H3...O1i
C5—H5...O1i
C10—H10A...Br ii
D—H H...A
D...A
(D—H...A)
145.0
0.93
0.93
0.96
2.48
2.52
3.07
3.282(3)
3.352(3)
4.021(4)
149.6
171.0
symmetry codes i:1-x, 1-y, 1-z; ii: -x, 1-y, 1-z.
Y
Fig. 2. Packing diagram of (3i) showing the layers approximately parallel to the (-1 2 0)
plane.
The structure of compounds 3b and 3d was also confirmed by single-crystal X-ray diffraction
and our data has a very good agreement with a previous report [54-55]. In Fig. 3 we present
the asymmetric unit of both compounds.
Fig. 3. Asymmetric unit of compound (3b and 3d) with the ellipsoids drawn at the 50%
probability level.
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5.3. DFT calculations
5.3.1. Optimized geometries
To evaluate the influence of the intermolecular interactions on the molecular geometries we
have performed DFT calculations of the equilibrium geometries of the free molecules starting
with the experimental X-ray geometries.
For both compounds 3b and 3i there is a good agreement between the experimental and
calculated geometries (see Figures 4, 5, and Tables 3,4) suggesting that the supramolecular
the aggregation has a small effect in the stabilization of the observed molecular geometries of
both compounds.
Fig. 4. Comparison of the molecular conformation of (3i), as established from the X-ray study
(red) with the DFT optimized geometry (blue) (Software used for visualization: VMD,
version 1.9.1, January 29, 2012 [54]).
Fig. 5. Comparison of the molecular conformation of (3b), as established from the X-ray
study (red) with the DFT optimized geometry (blue) (Software used for visualization: VMD,
version 1.9.1, January 29, 2012 [54]).
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Table 3 Comparison of selected geometrical parameters for (3i) as determined by X-Ray
diffraction and from DFT geometry optimizations in vacuum (Å,°).
Experimental
1.866(3)
1.698(3)
1.737(2)
1.201(4)
1.328(4)
1.472(4)
1.138(4)
113.4(2)
91.11(13)
117.7(2)
111.7(2)
130.2(3)
119.9(3)
89.8(3)
DFT (vacuum)
1.886
1.734
1.764
1.217
1.344
1.450
1.164
113.5
90.53
116.9
111.2
131.1
117.4
87.1
Br1—C1
S1—C1
S1—C4
O1—C8
O2—C8
O2—C9
N1—C7
S1—C1— C2
C1—S1— C4
C8—O2— C9
O2—C8—C6
C4—C5—C6
C5—C6—C8
C8—O2—C9—C10
C9—O2—C8—O1
-3.8(4)
-0.18
Table 4 Comparison of selected geometrical parameters for (3b) as determined by X-Ray
diffraction and from DFT geometry optimizations in vacuum (Å,°).
Experimental
(this study)
1.358(4)
DFT
(vacuum)
1.344
F1—C4
O1—C10
1.202(4)
1.313(3)
1.462(4)
1.136(4)
112.4(2)
116.3(3)
122.9(3)
132.0(2)
118.3(2)
178.1(3)
1.214
1.343
1.451
1.165
111.5
116.0
122.2
132.4
117.0
176.64
O2—C10
O2—C11
N1—C9
O2—C10— C8
C10—O2—C11
C3—C4—C5
C1—C7—C8
C7—C8—C10
C10—O2—C11—C12
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For the two compounds 3i and 3b, we have calculated the vacuum single-point energies of the
optimized geometries of both E and Z isomers to obtain the energy difference. For 3i the E-
isomer is more stable by 2.33 kcal mol-1 thus explaining the crystallization of this particular
form. The E-isomer of 3b is also more stable, by 5.00 kcal mol-1.
5.4. Optimization of reaction conditions
Initially, we focused our study to prove the optimized reaction conditions for the present
protocol regarding the choice of solvent, amount of catalyst, temperature of reaction and
investigating efficiency of various catalyst on a selected model reaction using p-
(N,N-dimethylamino) benzaldehyde (1d) and ethyl cyanoacetate (2) to establish the best
possible reaction conditions for the synthesis of benzylidene acrylate 3d. (Scheme 1)
5.4.1. Effect of different solvent
The effect of solvents on the reaction rate as well as the yield of product in the presence of
SBPCSA was studied. Solvents like methanol, ethanol, and isopropyl alcohol gave
unsatisfactory results. In acetic acid PEG 200, PEG 400 the reaction completed in 4h and
impure product was obtained in low yield. In acetonitrile and chloroform, the reaction did not
proceed. In solvent-free conditions the reaction produced the best results, requiring less time
for completion and giving excellent product yield. The results are summarized in Table 5.
Table 5 Effect of different solvents on the reactiona
Entrya
1
Solvent
CH3OH
Temperature
Timeb
4 h
Yieldc (%)
Reflux
62
CH3CH2OH
(CH3)2CHOH
CHCl3
Reflux
Reflux
Reflux
3.5 h
7 h
68
56
2
3
4
16 h
Trace
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CH3CN
PEG-200
Reflux
Reflux
Reflux
Reflux
100 C
17.5 h
3 h
Trace
Mixture
Mixture
Mixture
98
5
6
7
8
9
PEG-400
3.5 h
4 h
CH3COOH
Solvent-free
10 min
aReaction of N,N-dimethylaminobenzaldehyde (1.59 mmol) with ethyl cyanoacetate (1.59 mmol) in the
presence of 200 mg of catalyst.
bReaction progress monitored by TLC.
cIsolated yield.
5.4.2. Effect of different catalysts
To emphasize the efficiency of SBPCSA in comparison with other catalysts, the model
reaction was carried out with various catalysts such as 3-Aminopropyl-functionalized Silica
Gel, Mesoporous carbon nitride, Silica supported ammonium acetate, ZnCl2, NaHSO4–SiO2,
FeCl3, C/Co, Ni–SiO2 and Ni-Hydroxyapatite (Table 6). It is observed that when the reaction
was performed with C/Co, Ni–SiO2, and Ni-Hydroxyapatite it was completed after a long time
with a 70-80% yield (Table 6, entry 8, 9, 10). In a comparative study, the model reaction was
also carried out in NaHSO4–SiO2, FeCl3. The result showed that the reaction took a long time
for completion (more than 4 h) and that the products were obtained in very little amounts
(Table 6, entries 6, 7). Using zinc chloride, the reaction was completed in a relatively shorter
time, but with a moderate yield of the product (Table 6, entry 5). With 3-Aminopropyl-
functionalized Silica Gel, Mesoporous carbon nitride, Silica supported ammonium
acetate little good amounts of the products were obtained (Table 6, entries 2, 3, 4). When
SBPCSA was used as a catalyst, the reaction was completed in shorter reaction times, with an
excellent yield of the product (Table 6, entry 1).
5.4.3. Effect of loading of the Catalyst
The model reaction was performed using different loadings of catalyst in solvent-free
condition. To optimize the amount of catalyst used for the catalysis of the reaction to form
the desired product, we analyzed the reaction by varying the loading amount of catalyst in
model reaction from 0.10 g to 0.20 g and became steady with a further increase to 0.25 g.
Therefore, it was found that 200 mg of the catalyst was sufficient to give the desired products
in excellent yields. (Table 7, entry 6)
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Table 6
The influence of different catalysts on the model reaction under thermal solvent-free
condition
Entrya
Catalyst
Timeb
Yieldc (%)
SBPCSA
3-Aminopropyl-
functionalized Silica Gel
Mesoporous carbon
nitride
Silica supported
ammonium acetate
ZnCl2
NaHSO4-SiO2
FeCl3
C/Co
Ni-SiO2
Ni-Hydroxyapatite
10 min
1h
98
76
1
2
1.2 h
10 h
88
82
3
4
3 h
4 h
4.5 h
2 h
15 h
20 h
79
58
45
80
80
70
5
6
7
8
9
10
aReaction of N,N-dimethylaminobenzaldehyde (1.59 mmol) with ethyl cyanoacetate (1.59 mmol) in the
presence of 200 mg of catalyst.
breaction progress monitored by TLC,
cisolated yield.
5.4.4. Catalytic reaction
After the optimization of reaction conditions, the substrate scope of the (SBPCSA) catalyzed
synthesis of benzylidene acrylate derivatives was examined (Scheme 1). The results showed
that the reaction tolerated aromatic aldehydes with both electron-donating and electron-
withdrawing groups efficiently. The reactions with alicyclic and heterocyclic aldehydes also
gave satisfactory results (see Table 8).
Table 7 Effect of catalyst loading on the reaction
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Entrya
Catalyst loading
Timeb (min)
Yieldc
(mg)
100
15
10
10
10
10
10
65
76
86
88
90
98
1
2
3
4
5
6
120
140
160
180
200
aReaction of N,N-dimethylaminobenzaldehyde (1.59 mmol) with ethyl cyanoacetate (1.59 mmol) in the
presence of 200 mg of catalyst.
bReaction progress monitored by TLC.
cIsolated yield.
Table. 8 Scope of different substrates for the synthesis of acrylonitrile derivativesa
Entry
Substrate 1(a-p)
Product 3(a-p)
Timeb
(min)
Yieldc (%)
15
15
98
1
97
96
2
3
15
15
98
4
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20
15
94
96
5
6
15
95
7
20
98
8
20
20
97
95
9
10
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20
96
11
15
15
97
98
12
13
15
15
15
95
98
96
14
15
16
aReaction progress monitored by TLC. bIsolated yield. cCompounds characterized by their melting points.
5.4.5. Reaction Mechanism
A plausible mechanism for the synthesis of benzylidene acrylate derivative 3a is outlined in
Scheme 2. The mechanism seems to proceed via Knoevenagel condensation. The SBPCSA
catalyst activates aldehydic group (1a) by protic SBPCSA catalyst to form intermediate and
which facilitates the nucleophilic attack of ethyl cyanoacetate (2) to promote the formation of
C–C bond to yield intermediate. By the successive elimination of H2O molecule from
intermediate promoted by catalyst SBPCSA eventually yielded the target compound followed
by regeneration of the catalyst.
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Scheme 3 Plausible mechanistic pathway
5.4.6. Catalyst recycling
The catalyst recycling experiment was done using the model reaction of N,N-dimethyl
benzaldehyde, ethyl cyanoacetate, and 200 mg of the catalyst under the solvent-free condition
at a suitable temperature. After completion of the reaction, the catalyst was recovered by
extracting the mixture with ethyl acetate followed by filtration. The catalyst was then washed
with ethyl acetate and reused for subsequent cycles. The catalyst was found to retain its
activity for a minimum of seven reaction cycles (Fig. 8) displaying a high catalytic
performance with a very sound yield of the product.
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Fig. 8. Recyclability of the catalyst SBPCSA for the model reaction
5.5. Computational profiling
5.5.1. Molecular descriptors analysis, bioactivity score, and PASS analysis
Drug discovery is a time-consuming and costly process. The critical parameters that define
the nature of the drug and its potential of a compound have become easier to predict using
computational methods. The parameters associated with the discovery of drugs, such as
cLogP, solubility, molecular weight (MW), topological molecular polar surface area(TPSA)
under Lipinski's rule of 5, and toxicity were calculated using the Molinspiration software and
the ProTox online software. Lipinski's rule of five is a general rule that calculates important
parameters for compounds that show drugs in nature. A candidate of the synthesized
compound is likely orally active if the synthesized compound will have a molecular weight of
less than 500, partition coefficient (Log P) <5, a polar surface area less than 140Å2, hydrogen
bond donors less than 5 (OH and NH groups), hydrogen bond acceptors less than 10
(especially N and O), zero violations and a molecular weight less than 500 according to
Lipinski's rule. All the synthesized compounds mentioned in our research work follow the
rule of Lipinski and do not show any violation that indicates that all the compounds have
good bioavailability. In the case of toxicity, most of the proposed compounds are included in
class 4-6, which leads to the nature of intermediate toxic to non-toxic (Table 9). Descriptors
explained natures of the synthesized compounds are suitable foundations for an attempt to
discover drugs. Pharmacological activity is directly related to the beneficial effects of
chemical compounds in beings. Therefore, chemical compounds act as drugs that target the
protein, which is more common, such as enzymes, ion channels, and receptors. The
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bioactivity of the benzylidene acrylate derivatives was predicted using Molinspiration by
calculating the active score towards the GPCR ligand, Ion channel modulator, Kinase
inhibitor, nuclear receptor ligand, protease inhibitor, and enzyme inhibitor, as indicated in the
table. In most cases, the higher the bioactivity, the more likely it is that the derivatives being
studied will be active. For the candidate compound, if the bioactive score is greater than zero,
then the compound appears to be active, it is in range -0.50 to 0.00 then compound will be
moderately active while the compound will be inactive if there is a biological activity scores
less than-0.50. The biological activity scores for synthetic compounds are given in Table 10,
suggesting that some of the studied compounds are biologically moderately active and some
are inactive.
Table 9:
Lipinski rule of five and toxicity parameters for synthesized compounds 3(a-p)
Compd
Chemical
formula
Lipinski rule of 5
volume
TPSAd
(A˚2)
Rotatable
bonds
No.
violations
Toxicity
Class
MiLog
Pa
MW
HBDb HBAc
C12H10N2O4
C12H10FNO2
C13H13NO4
2.58
246.22
219.22
247.25
244.29
280.12
280.67
249.22
235.67
286.15
190.20
240.26
236.18
221.28
270.08
205.21
191.19
0
0
1
0
0
0
3
0
0
1
1
0
0
0
0
0
6
3
5
4
3
6
6
3
3
4
4
7
3
4
4
4
212.99
194.58
223.21
235.56
207.54
226.52
213.70
203.19
198.25
174.64
218.63
194.55
196.92
189.10
187.78
171.22
95.92
50.10
79.56
53.34
50.10
95.92
110.78
50.10
50.10
65.89
65.89
109.06
50.10
63.24
63.24
63.24
5
4
5
5
4
5
4
4
4
4
4
5
4
4
4
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5
5
6
5
5
4
4
4
4
4
4
4
4
4
4
4
3a
3b
3c
3d
3e
3f
2.79
1.96
2.73
3.41
3.19
1.42
3.30
3.28
1.60
2.91
1.78
2.72
2.63
1.92
1.70
C14H16N2O2
C12H10BrNO2
C12H9ClN2O4
C12H11NO5
3g
3h
3i
C12H10ClNO2
C10H8BrNO2S
C10H10N2O2
C14H12N2O2
C10H8N2O5
C11H11NO2S
3j
3k
3l
3m
3n
3o
3p
C10H8BrNO3
C11H11NO3
C10H9NO3
Class 1: fatal if swallowed (LD50 ≤ 5); Class 2: fatal if swallowed (5 < LD50 ≤ 50), Class 3: toxic if swallowed
(50 < LD50 ≤ 300), Class 4: harmful if swallowed (300 < LD50 ≤ 2000), Class 5: may be harmful if swallowed
(2000 < LD50 ≤ 5000), Class 6: non-toxic (LD50 > 5000)
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Table 10 Bioactivity score for benzylidene acrylate derivatives 3(a-p) calculated using the
Molinspiration software
Compd. GPCR
ligand
Ion
channel
modulator
-0.49
Kinase Nuclear Protease Enzyme
inhibitor receptor inhibitor inhibitor
ligand
-0.91
-0.89
-0.72
-0.69
-1.07
-0.83
-0.68
-0.91
-1.38
-0.96
-0.42
-1.38
-1.23
-1.38
-1.32
-1.45
-0.96
-0.94
-0.76
-0.71
-1.11
-0.88
-0.70
-1.02
-1.53
-1.03
-0.52
-1.40
-1.43
-2.04
-1.62
-1.84
-0.58
-0.60
-0.39
-0.42
-0.86
-0.66
-0.40
-0.67
-1.31
-0.78
-0.26
-1.51
-1.22
-1.97
-1.12
-1.37
-0.89
-0.94
-0.80
-0.73
-1.11
-0.94
-0.72
-0.97
-1.21
-1.25
-0.60
-1.54
-1.38
-1.67
-1.46
-1.72
-0.49
-0.47
-0.32
-0.35
-0.57
-0.52
-0.23
-0.49
-0.69
-0.34
-0.05
-0.81
-0.70
-1.08
-0.90
-0.96
3a
3b
3c
3d
3e
3f
-0.51
-0.47
-0.45
-0.62
-0.50
3g
3h
3i
-0.37
-0.50
-0.88
-0.63
3j
-0.40
3k
3l
-1.30
-1.00
3m
3n
3o
3p
-1.03
-0.96
-0.98
The biological activity of the compounds is the result of the interaction with a biological
object that considers the type, age, sex, etc. The pharmacological nature of the compounds
depends on the structural characteristics of the compounds, the biological object, and the
administration and dose of the compounds, including the experimental conditions. The PASS
online server is a very important tool to predict the biological activity of the compound when
experimentally determining drug bioactivity is a time-consuming and costly process, so the
use of PASS is generally very important. Also, it is useful to identify the most likely
compounds from a series of compounds available for proper screening. To determine which
screens are more suitable for specific compounds. In PASS analysis, the biological activities
are described qualitatively ("active; Pa" or "inactive; Pi"); in quantitative results. The
chemical identity acts as the drug that is recognized as "active" if the semi-effective
concentration is less than 10 μM. From Table 11, it has been found that most of the
compounds show enzymatic activity, generally with a low to high intensity and percentage
predicted using PASS and Swiss Target Prediction, respectively. In this table, activities of
derivative were predicted with Pa values in the range 0.578–0.936 to obtain the maximum
crystal gazing of biological potentialities.
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Table 11 PASS predicted activity score and Swiss Target Prediction (%) of benzylidene
acrylate derivatives 3(a-p)
Compd.
Pa
Pi
Pharmacological effects/
Swiss Target Prediction (%)
Mechanisms of action*
Skin irritation, inactive
Electrochemical transporter
Enzyme
6.7
26.7
6.7
0,936
0,826
0,820
0,811
0,811
0,811
0,811
0,792
0,796
0,782
0,774
0,777
0,770
0,754
0,784
0,746
0,738
0,744
0,724
0,711
0,787
0,743
0,741
0,723
0,889
0,842
0,840
0,761
0,774
0,752
0,753
0,753
0,749
0,738
0,722
0,721
0,003
0,007
0,003
0,005
0,018
0,018
0,018
0,005
0,010
0,004
0,003
0,010
0,013
0,005
0,038
0,011
0,007
0,030
0,016
0,021
0,012
0,006
0,005
0,019
0,004
0,005
0,023
0,005
0,025
0,004
0,007
0,008
0,009
0,009
0,004
0,008
3a
Prolyl aminopeptidase inhibitor
Aryldialkylphosphatase inhibitor
Cutinase inhibitor
Hydrolase
Toll-like and II-1 receptor
6.7
Saccharopepsin inhibitor
Family A G protein-coupled receptor 6.7
Acrocylindropepsin inhibitor
Chymosin inhibitor
Isomerase
6.7
26.7
6.7
Phosphodiesterase
Kinase
Antianginal
Membrane permeability inhibitor
Eye irritation, inactive
3-Carboxyethylcatechol 2,3-dioxygenase inhib
Fusarinine-C ornithinesterase inhibitor
GST A substrate
Antihypoxic
Ubiquinol-cytochrome-c reductase inhibitor
Arylsulfate sulfotransferase inhibitor
Antiprotozoal (Leishmania)
Polyporopepsin inhibitor
Acute neurologic disorders treatment
Protein-glutamate methylesterase inhibitor
Membrane permeability inhibitor
Antianginal
Electrochemical transporter
Enzyme
6.7
33.3
6.7
3b
3c
Centromere associated protein inhibitor
5-O-(4-coumaroyl)-D-quinate 3'-monooxygenase
Toll-like and II-1 receptor
Cytochrome P450
Protease
13.3
40.0
6.7
Feruloyl esterase inhibitor
Membrane permeability inhibitor
Aspulvinone dimethylallyltransferase inhibitor
Preneoplastic conditions treatment
Chlordecone reductase inhibitor
Insulysin inhibitor
Oxidoreductase
Lyase
46.7
Secreted protein
Family A G protein-coupled receptor 20.0
Kinase
6.7
6.7
6.7
Electrochemical transporter
Toll-like and II-1 receptor
Antiprotozoal (Leishmania)
Lipid metabolism regulator
Fibrinolytic
Linoleate diol synthase inhibitor
Cytoprotectant
Antianginal
Antieczematic
Mediator release inhibitor
TP53 expression enhancer
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Mucomembranous protector
CYP2C12 substrate
0,740
0,701
0,703
0,720
0,702
0,756
0,767
0,739
0,714
0,732
0,720
0,033
0,004
0,025
0,048
0,057
0,004
0,017
0,005
0,008
0,027
0,016
Sulfite oxidase inhibitor
NADPH peroxidase inhibitor
Insulysin inhibitor
Toll-like and II-1 receptor
Ligand-gated ion channel
6.7
6.7
3d
3e
Family A G protein-coupled receptor 6.7
Antianginal
Electrochemical transporter
Enzyme
6.7
26.7
6.7
Membrane permeability inhibitor
Fibrinolytic
Kinase
Primary active transporter
Cytochrome P450
Protease
6.7
33.3
6.7
Feruloyl esterase inhibitor
Prolyl aminopeptidase inhibitor
Centromere associated protein inhibitor
Aspulvinone dimethylallyltransferase inhibitor
Antihypoxic
0,872
0,861
0,846
0,776
0,725
0,712
0,706
0,005
0,005
0,003
0,041
0,006
0,008
0,054
Unclassified protein
Transferase
6.7
6.7
Ligand-gated ion channel
13.3
Family A G protein-coupled receptor 6.7
Antianginal
Electrochemical transporter
Enzyme
13.3
26.7
13.3
6.7
Mucomembranous protector
Cytochrome P450
Phosphodiesterase
Toll-like and II-1 receptor
Phosphatase
Skin irritation, inactive
GST A substrate
13.7
6.7
0,906
0,815
0,799
0,770
0,756
0,747
0,727
0,703
0,702
0,716
0,792
0,779
0,766
0,795
0,732
0,748
0,726
0,706
0,708
0,737
0,718
0,004
0,008
0,010
0,011
0,006
0,004
0,018
0,004
0,009
0,063
0,006
0,014
0,005
0,035
0,008
0,030
0,019
0,009
0,014
0,050
0,052
3f
Membrane permeability inhibitor
Acute neurologic disorders treatment
Antianginal
Protease
20.0
6.7
Isomerase
Enzyme
20.0
6.7
Eye irritation, inactive
Oxidoreductase
Phosphodiesterase
Kinase
5-O-(4-coumaroyl)-D-quinate 3'-monooxygenase
GST P substrate
20.0
6.7
Antiprotozoal (Leishmania)
Ubiquinol-cytochrome-c reductase inhibitor
Lipid metabolism regulator
Membrane permeability inhibitor
Antihypoxic
Family A G protein-coupled receptor 20.0
3g
Unclassified protein
Lyase
6.7
40.0
6.7
Aspulvinone dimethylallyltransferase inhibitor
Antiprotozoal (Leishmania)
Chlordecone reductase inhibitor
Feruloyl esterase inhibitor
Antianginal
Enzyme
Kinase
26.7
Apoptosis agonist
CYP2C12 substrate
Membrane integrity agonist
29