Click chemistry-inspired design, synthesis, and molecular docking studies of biscoumarin derivatives using carbon-based acid catalyst

Article abstract of DOI:10.1002/jhet.4045

A green and eco-benign synthesis of biscoumarin derivatives using carbon sulfonic acid, a solid support catalyst has been described. The reaction involved a one-pot two-component reaction of 4-hydroxycoumarin and aldehyde using carbon sulfonic acid involv

Full text of DOI:10.1002/jhet.4045

Received: 18 February 2020
DOI: 10.1002/jhet.4045
Revised: 18 May 2020
Accepted: 22 May 2020
A R T I C L E
Click chemistry-inspired design, synthesis, and molecular
docking studies of biscoumarin derivatives using
carbon-based acid catalyst
Dinesh K. Agarwal1 | Ayushi Sethiya2 | Pankaj Teli2 | Anu Manhas3
|
Jay Soni2 | Nusrat Sahiba2 | Prakash C. Jha4 | Shikha Agarwal2
Pradeep K. Goyal1
|
1Department of Pharmacy, B. N.
Abstract
University, Udaipur, Rajasthan, India
2Synthetic Organic Chemistry Laboratory,
Department of Chemistry, Mohan Lal
Sukhadia University, Udaipur, Rajasthan,
India
3School of Chemical Sciences, Central
University of Gujarat, Gandhinagar,
Gujarat, India
4School of Applied Material Sciences,
Central University of Gujarat,
Gandhinagar, Gujarat, India
A green and eco-benign synthesis of biscoumarin derivatives using carbon sul-
fonic acid, a solid support catalyst has been described. The reaction involved a
one-pot two-component reaction of 4-hydroxycoumarin and aldehyde using
carbon sulfonic acid involving Knoevenegal-Michael condensation. A series of
aromatic (bearing electron withdrawing and releasing group) and hetero-
aromatic aldehydes has been converted to biscoumarins with excellent isolated
yields. The reaction is in compliance with green principles, that is, inexpensive
catalyst, easy to prepare, nontoxic, easy handling, reusable up to five recycle
runs, easy separation, short reaction time, no need of time consuming column
purification, high yielding, and so on. The synthesized catalyst and biscoumarin
derivatives were well characterized by spectral analysis. The molecular modeling
studies showed that the designed molecular scaffolds (3a-j) showed outstanding
interaction with methylenetetrahydrofolate reductase (MTHFR) and cytochrome
P450 3A4 (CYP3A4) proteins. It was noticed that 3f (−17.55 kJ/mol) and 3d
(−26.23 kJ/mol) showed the highest docking score against CYP3A4 and MTHFR
proteins, respectively.
Correspondence
Shikha Agarwal, Synthetic Organic
Chemistry Laboratory, Department of
Chemistry, Mohan Lal Sukhadia
University, Udaipur, Rajasthan 313 001,
India.
Email: shikha_urj@yahoo.com
Funding information
Council of Scientific and Industrial
Research, India, Grant/Award Numbers:
09/172(0088)2018-EMR-I, 09/172(0099)
2019-EMR-I; UGC-MANF, Grant/Award
Number: MANF-2018-19-RAJ-91971
1 | INTRODUCTION
and so on.1–12 Furthermore, they have varied applications
such as fluorescent brighteners, agrochemicals, effective
Synthetic and naturally occurring biscoumarin derivatives
are of considerable interest in synthetic and medicinal
chemistry (Figure 1). They are highly potent due to their
hydrogen bonding property via two OH groups and also
exhibit various biological activities like anticoagulant, ure-
ase inhibitory, antioxidant, anti-leshmanial, α-glucosidase
inhibitor, anti-inflammatory, antifungal, antibacterial,
enzymatic inhibition activity, HIV integrase, anticancer,
laser dyes, polymer synthesis, WLED display, additives in
food and cosmetics, and so on.13–17
Knoevenagel, Pechmann, Perkin, Reformatsky,
Michael, and Wittig reactions are the most important
synthetic methods for the synthesis of biscoumarin
derivatives.
In synthetic organic chemistry, heterogeneous catalysis
has opened new era for the progressive green and eco-benign
J Heterocyclic Chem. 2020;1–16.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

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AGARWAL ET AL.
FIGURE 1 Synthetic and naturally available coumarin-based drugs
synthesis. Significant advancements have been achieved in
modern organic chemistry by replacing conventional acid
catalysts with pollution free, recyclable and eco-benign
solid acid catalysts. Solid acid catalysts play a profound
role in organic synthesis as they are recyclable, ease of
workup, corrosion free, immiscible in routine organic sol-
vents, easy recovery from the products, selective synthesis,
and so on. Recently, carbon based solid acid catalyst,18,19
that is, carbon sulfonic acid has attracted scientists because
of its increased acidity, selectivity, high stability, easy
separation of products, no corrosion of equipments, easy
recovery and recyclability, and so on. This catalyst contains
many functional groups and is found to be completely
insoluble in various solvents like water, methanol, and eth-
anol. It has been reported for various organic transforma-
tions like quinazolinones, spirooxindoles, thiazolidines,
tetrahydropyranyl protection/deprotection of alcohols
and phenols, biofuel production,20–27 and so on. The suit-
ability of this catalyst and exhaustive literature survey
for the synthesis of coumarin derivatives inspired us to
search the applicability of this catalyst for the synthesis
of biscoumarins. The literature studies showed their
synthesis using different methods such as catalyst-free
microwave-assisted organic synthesis,28 [PSebim][OTf],29
propane-1,2,3-triyl tris(hydrogen sulfate),30 phospho sul-
fonic acid,31 W-doped ZnO nanocomposite,32 choline
hydroxide,33 o-benzenedisulfonimide,34 P4VPy-CuO-NPs,35
sulfonated rice husk ash,36 piperidine,37 magnetite-
containing sulfonated polyacrylamide,38 CuO-CeO2
nanocomposite,39 Montmorillonite K10ꢀNi0-Mont,40
taurine,41 VB1,42 cerric ammonium nitrate,43 HY-
Zeolite,44 FeNi3-ILs nanoparticles,45 and so on and
high yields were obtained. A comprehensive review on
the synthesis of biscoumarin derivatives has recently
been published46 and it was found that the reported
methods have their own merits coupled with endure
drawbacks, that is, costly, tedious work up procedures,
formation of toxic by-products, use of toxic solvents,
and so on. In lieu of all these drawbacks, an highly effi-
cient, simple, mild, cheap and demandable protocol
has been developed for the synthesis of biscoumarin
derivatives method using carbon sulfonic acid as a
robust catalyst under ambient conditions (water:etha-
nol, 1:1 ratio) at 80ꢁC (Scheme 1).

AGARWAL ET AL.
3
SCHEME 1 General
reaction for the synthesis of
biscoumarin
R
CHO
OH
O
Carbon-SO3H catalyst
OH
O
HO
+
Stirred at 80o C
10 - 35 min
O
R
H2O : EtOH (1:1)
O
O
4-Hydroxycoumarin
(1)
O
Aldehyde
(2a-j)
Biscoumarin
(3a-j)
TABLE 1 Prediction of biological activity by PASS online
program for biscoumarin derivatives (selective)
the irreversible reduction of 5,10-methylenetetrahydrofolate
to 5-methyl-tetrahydrofolate that is indirectly involved in
the biosynthesis of monophosphates and purines.51 This
target is believed to be essential for the investigation of anti-
cancer drugs.52
Pa
Pi
Activity
0.929 0.004 Methylenetetrahydrofolate reductase
(NADPH) inhibitor
Nowadays, Coumarin moiety is widely used as a pre-
cursor for the synthesis of various biologically active
scaffolds.53–57
0.918 0.003 Monodehydroascorbate reductase (NADH)
inhibitor
0.854 0.003 P-benzoquinone reductase (NADPH) inhibitor
0.867 0.020 CYP2C12 substrate
0.821 0.003 Antiviral (HIV)
2 | RESULTS AND DISCUSSION
0.823 0.025 Ubiquinol-cytochrome-c reductase inhibitor
0.736 0.005 CYP2A4 substrate
2.1 | Characterization of carbon-based
catalyst
0.696 0.006 Cytochrome-b5 reductase inhibitor
0.651 0.023 Oxidoreductase inhibitor
0.580 0.020 CYP2A6 substrate
The solid acid catalyst prepared from glycerol by in situ
carbonization and sulphonation was fully characterized
by FT-IR, SEM, XRD, and TGA techniques. As per FT-IR
spectrum of the carbon-SO3H catalyst, the two absorption
bands at 1548 and 1023 cm−1 due to the presence of sym-
metric and asymmetric stretching of sulfonyl group
assured the formation of catalyst. The peak at 1187 cm−1
is due to SO3H group. The absorption band at 1696 cm−1
is related to carbonyl functional group of COOH. The
absorption bands emerged at range 3000 to 3700 cm−1 is
due to O-H stretching vibrations (including SO3H,
COOH, and adsorbed water). The peak at 3738 cm−1 is
due to adsorbed water and at 3615 cm−1 is due to OH
group of COOH group, 3015 cm−1 is related to bonded
OH of SO3H group (Figure 2).
0.564 0.005 CYP2A5 substrate
0.546 0.003 HIV-1 integrase (30-processing) inhibitor
0.562 0.020 CYP2A1 substrate
0.478 0.032 Cytochrome P450 stimulant
Note: Pa means probability to be active and Pi mean probability to
be inactive. If Pa > 0.71 then molecule is expected to show that
activity.
The protein Cytochrome P450 3A4 (CYP3A4) and
methylenetetrahydrofolate reductase (MTHFR) were
selected to conduct molecular docking studies on the basis
of literature47,48 and PASS online prediction (Table 1).
CYP3A4 pertaining PDB ID 4D75 is responsible for var-
ious oxidation reactions and is known as a xenobiotic-
metabolizing enzyme in human beings.49 The inhibition of
this enzyme is helpful in the treatment of HIV infection.50
Moreover, MTHFR having PDB ID 6FCX is concerned with
The morphology of the sample was investigated with
scanning electron microscopy (SEM). The SEM image of
catalyst exposed a nonuniform structure of sulfonated
carbon and specified agglomerate structure of particles
(Figure 3).

4
AGARWAL ET AL.
FIGURE 2 FT-IR spectrum of synthesized carbon based sulfonic catalyst
To our delight, the characterization of catalyst was in
accordance with the previously reported papers. As a part
of our quest to find a green protocol, we studied its cata-
lytic activity for the synthesis of biscoumarin. Initially we
carried out the reaction of 4-OH Coumarin 1 (5 mmol)
and benzaldehyde (2.5 mmol) 2a with 5 mg of catalyst
under solvent-free condition at room temperature. It was
noteworthy that after 80 minutes, 65% yield was isolated.
To accelerate the reaction, catalyst loading was succes-
sively increased (Table 2, Entry 2-8) and it was observed
that increase in amount of catalyst reduced the reaction
time and improved the yields. About 30 mg of catalyst
was found to be appropriate for the transformation and
additional increase in amount of catalyst did not increase
the yields. Although we got excellent yield in solvent-free
condition but with solid aldehydes yield was not good
and it took more time so we also examined the effect of
solvents by varying solvents and H2O:EtOH (1:1) was
found ideal for the reaction (Table 2, Entry 9-11). The
effect of temperature was also studied by performing the
reaction at 80ꢁC and 100ꢁC (Table 2, Entry 12-14). It was
interesting to note that in H2O:EtOH (1:1) excellent yield
(97%, 3a) was obtained in just 10 minutes.
FIGURE 3 FE-SEM Image of carbon-SO3H catalyst
The thermogravimetric analysis was carried out in
order to identify the thermal stability of catalyst and
found that it was stable upto 300ꢁC as first loss occurred
due to absorbed water and second loss occurred at 150ꢁC
to 200ꢁC, owing to the loss of sulfonic groups19
(Figure 4).
The XRD pattern displayed two broad and weak dif-
fraction peaks at 2θ = 15ꢁ to 30ꢁ and 40ꢁ to 50ꢁ, that are
attributed to amorphous carbon19,27 (Figure 5). To com-
pare with the structural findings, the SEM finding is in
analogy to the XRD pattern.
With the optimal conditions in hand, we next
explored the generality and scope of this reaction. For
this, a variety of aryl aldehydes having electron with-
drawing and electron donating groups were scrutinized.
It was found that all the synthesized compounds (3a-j)

AGARWAL ET AL.
5
400.0
350.0
300.0
250.0
200.0
150.0
100.0
50.0
25.00
20.00
15.00
10.00
5.00
5.000
4.500
4.000
3.500
3.000
0.00
50.0
100.0
150.0
Temp Cel
200.0
250.0
FIGURE 4 TGA-DTA curve of synthesized carbon-SO3H catalyst
FIGURE 5 The XRD pattern of
synthesized carbon-solid catalyst
gave high to excellent (89%-98%) yields irrelevant to
nature of the substituents whether electron withdrawing
and electron releasing (Table 3).
to 1444 and 1345 cm−1, respectively. Besides this, resonat-
ing signal at δ 8 to 11 ppm was endorsed to the OH pro-
1
ton in H NMR spectra. But OH resonating signals of
The current study has numerous advantages over the
previous reported methods viz. reusability and recyclabil-
ity of catalyst, cost-effective; avoid the use of toxic sol-
vents, excellent yields, high atom economy, high
E-factor, and less reaction time. The structures of all the
derivatives (3a-j) were confirmed by FT-IR, 1H NMR.
The FT-IR spectrum showed a broad absorption at
3058 cm−1 due to OH stretching frequency. The vibra-
tional modes of C O and C O groups appeared at 1702
some compounds was broadened or disappeared due to
the interaction with the aqueous DMSO-d6 as a polar and
hydrogen bond acceptor solvent. The methine proton
became visible as a singlet near to δ 6.7-5.5 ppm. Further-
more, in the 13C NMR spectra, the signals at δ 167 to
162 and δ 38 to 32 ppm were related to carbonyl and
methine carbon atoms. The supposed mechanism for the
synthesis of biscoumarin derivatives was shown in
Scheme 2. The solid acid carbon-SO3H catalyst increased

6
AGARWAL ET AL.
TABLE 2 Typical optimization of
the reaction conditions for the
preparation of bis(4-hydroxycoumarin)
derivatives
Entry
1.
Catalyst (mg)
Solvent
Temp.
RT
Time (min.)
Yield (%)
No reaction
65b
70b
75b
80b
88b
90a
90a
82b
85b
92a
97a
-
5
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
EtOH
200
80
60
60
60
50
45
45
45
45
45
10
10
2.
RT
3.
10
15
20
25
30
35
30
30
30
30
35
RT
4.
RT
5.
RT
6.
RT
7.
RT
8.
RT
9.
RT
10.
11.
12.
13.
H2O
RT
H2O:EtOH (1:1)
H2O:EtOH (1:1)
H2O:EtOH (1:1)
RT
80ꢁC
80ꢁC
97a
Note: Reaction conditions: Benzaldehyde (2.5 mmol), 4-OH coumarin (5 mmol).
aThe yields are related to the isolated products.
bThe yields are related that reaction is not completed.
TABLE 3 Synthesis of bis(4-hydroxycoumarin) derivatives using carbon-SO3H as catalyst
Entry
Aldehyde
C6H5
Product symbol
Time (min.)
Yield (%)
Observed (m.p.ꢁC)
Literature (m.p.ꢁC)
230 to 23241
217 to 21941
221 to 22334
22934
258 to 25944
201 to 20441
196 to 19841
245 to 24841
210 to 21243
210 to 21743
1
3a
3b
3c
3d
3e
3f
10
25
30
35
35
30
15
15
15
30
97
98
91
90
92
92
89
93
94
96
231 to 232
213 to 215
220 to 221
230 to 231
260 to 261
201 to 202
200 to 201
240 to 241
211 to 212
220 to 221
2
2-Cl C6H4
3
2-Me C6H4
3-NO2 C6H4
3,4-(OCH3)2 C6H3
2-NO2 C6H4
2-Furyl
4
5
6
7
3g
3h
3i
8
4-OCH3 C6H4
3-OH C6H4
3-Br C6H4
9
10
3j
The suitability of this procedure was demonstrated by comparing the protocol with the previously reported protocols (Table 4).
the electrophilic character of carbonyl carbon of aldehyde.
Then Knoevenagel condensation occurred between one
molecule of 4-hydroxycoumarin and activated aldehyde to
form intermediate I. This intermediate I underwent Michael
addition with next molecule of 4-hydroxycoumarin and
furnished the desired product (Scheme 2).
able to bind in the active site of the respective protein
(Table 5). It was obvious from the Table 5, that 3f
showed highest docking score of −17.55 kJ/mol
followed by 3d, 3a, 3b, 3c, 3g (Figure 6). On analyzing
the 3D orientation of the docked compounds, it was
noticeable that all the compounds bound well within
same pocket (Figure 7).
From the generated 2D and 3D interaction plots
(Figure 8 and Figure S1), it was found that among the
docked six molecules, 3f and 3d showed H-bonding inter-
action with the amino acid Arg 212. Besides, in 3a and
3c, the interaction with Arg212 was seen in hydrophobic
form. Moreover, among all the molecules, a common
hydrophobic interaction was observed with Arg105 and
2.2 | Docking assessment
2.2.1 | 4D75
After assessment of docking results with 4D75 protein,
it was perceived that out of 10 compounds, only 6 were

AGARWAL ET AL.
7
TABLE 4 Comparative study of the present method with the reported methods
Catalyst
S.No.
1.
Catalyst
loading
Solvent
H2O
Condition
Reflux
Time (min)
35 to 85
Yield (%)
84 to 96
75 to 98
Reference
Taurine
0.20 mmol
10 mol%
41
43
2.
Ceric Ammonium
Nitrate
H2O
RT, Stirring
360 to 480
3.
4.
o-Benzenedi
sulfonimide
50 mol%
0.5 mol%
H2O
Reflux
25 to 30
180
74 to 91
90 to 95
34
58
ZIL@CuO
Solvent-free
ball milling
(600 rpm)
5.
HAP/ Fe3O4Nps
Fe3O4@B(HSO4)3
-
80 mg
0.03 wt%
-
-
100ꢁC
15 to 100
15 to 30
90 to 180
23-Oct
85 to 95
80 to 90
82 to 92
93 to 98
93 to 97
89 to 98
59
6.
-
80ꢁC
60
7.
Ethylene glycol
Toluene
Toluene
H2O-EtOH
90ꢁC
61
8.
Cu-Ni-Ag
50 mg
50 mg
30 mg
90ꢁC
62
9.
Cu-Ni or Cu-Ni-Ag
Carbon-SO3H
90ꢁC
16 to 30
25-Oct
62
10.
Stirring (80ꢁC)
Present work
SCHEME 2 Mechanistic pathway for the synthesis of biscoumarin using C-SO3H as a catalyst
Hem601, which is considered as the crucial interaction.49
As per the meticulous literature studies, it was found that
Roussel et al., Yano et al., Jayakanthan et al., and Manuu
et al. also performed the docking studies on CYP3A4.
They showed that the interaction of the inhibitor with
Arg 212 of CYP3A4 is considered as a key residue for the
inhibition of the enzyme.63–66 Thus, we can conclude that
based on the docking score and presence of crucial

8
AGARWAL ET AL.
TABLE 5 Docking scores of the selected hits with 4D75 protein
Molecules
Docking scorea
−17.55
Match scorea
−20.51
Lipo scorea
−11.67
Ambig scorea
−5.60
Clash scorea
07.83
Rot scorea
7.00
Matchb
27
3f
3d
3a
3b
3c
3g
−16.71
−17.38
−09.20
−7.23
04.69
7.00
27
−08.84
−11.63
−11.83
−8.68
10.89
7.00
20
−08.49
−10.78
−13.55
−4.82
08.26
7.00
24
−07.37
−10.38
−12.44
−5.73
08.77
7.00
26
−05.21
−08.49
−13.64
−4.07
08.58
7.00
21
Note: Match score: contribution of interacting groups, Lipo score: lipophilic-contact area contribution, Ambig score: Lipophilic-hydrophilic
ambiguous contact area, Clash score: clash penalty contribution, and Rot score: entropy contribution of ligand conformation.
akJ/mol.
bNumber of matches.
FIGURE 6 Graphical
representation of the six docked
molecules within the binding pocket of
4D75 protein
noticed that 3d showed the highest docking score of
−26.23 kJ/mol followed by 3e, 3f, 3i, 3j, 3a, 3g, 3h, 3b, 3c
(Figure 9). Further, on analyzing the 3D orientation of
the docked compounds, it was observed that apart from
four compounds (3e, 3a, 3b, 3i), remaining compounds
were docked within the same pocket of the protein
(Figure 10). Also, the molecule 3a, 3b, and 3i bound in
second pocket and 3e bound in the third pocket
(Figure 10). Depending on the number of molecules
docked, the respective pocket of the protein chain is
named as Pocket 1 (six molecules), Pocket 2 (three mole-
cules), and Pocket 3 (one molecule).
On scrutinizing the 2D interaction plots (Figure 11
and Figure S2) of the docked compounds in the Pocket
1, it was found that in all molecules, greater than 3 H-
FIGURE 7 Pictorial representation of all the ligands docked
within the same active site of 4D75 protein
bonding interactions were reported with the interaction
with amino acid Tyr197 and His201 being the common
interactions, 3f and 3d can be considered as the potent
inhibitors of CYP3A4 protein.
one. Moreover, number of other H-bondings and hydro-
phobic interactions were also witnessed (Figure 11 and
Figure S2). In case of Pocket 2, it was observed that the
three molecules, showed common H-bonding with
Leu301 and Ala233. Apart from these interactions, num-
ber of other H-bonding and hydrophobic interactions
were reported (Figure S3). Therefore, based on the dock-
ing score and population of the docked compounds
within the site of the protein, out of 10 molecules 3d and
2.2.2 | 6FCX
From the docking outcome of 6FCX, it was demonstrated
that all the 10 molecules showed binding interaction with
the respective protein (Table 6). From the Table 6, it is

AGARWAL ET AL.
9
FIGURE 8 2D interaction plots of
the top scored docked ligands (3f and
3d) within the binding pocket of 4D75
protein
TABLE 6 Docking scores of the selected hits with the 6FCX protein [Color table can be viewed at wileyonlinelibrary.com]
Molecules
Docking scorea
−26.23
Match scorea
−24.28
Lipo scorea
−11.76
−11.49
−06.86
−11.73
−13.13
−11.66
−10.42
−11.41
−13.82
−10.58
Ambig scorea
−10.59
Clash scorea
8.01
Rot scorea
7.00
Matchb
24
3d
3e
3f
−21.30
−21.67
−12.08
8.74
9.80
21
−20.84
−23.78
−07.88
5.29
7.00
24
3i
−20.78
−17.88
−07.96
2.99
8.40
21
3j
−20.51
−16.81
−11.04
8.07
7.00
23
3a
3g
3h
3b
3c
−20.04
−15.65
−07.84
2.70
7.00
20
−20.02
−21.67
−09.82
9.49
7.00
22
−19.94
−20.78
−08.74
7.19
8.40
25
−18.93
−15.18
−06.62
4.28
7.00
20
−17.50
−18.87
−08.00
7.56
7.00
26
Note: Match score: contribution of interacting groups, Lipo score: lipophilic-contact area contribution, Ambig score: Lipophilic-hydrophilic
ambiguous contact area, Clash score: clash penalty contribution, and Rot score: entropy contribution of ligand conformation.
The different colors in the table represents the three binding pockets of interaction of molecule with protein. Black with binding pocket 1,
Red with binding pocket 3, and Green with binding pocket 2.
akJ/mol.
bNumber of matches.
3f can be considered as potent molecules for inhibiting
the activity of the MTHFR enzyme. The interactions pat-
tern found in docking studies are in accordance with the
literature. The importance of interaction of inhibitor with
His201 to inhibit the enzyme was also revealed by
Nagaranjan et al.67

10
AGARWAL ET AL.
2.3 | Green chemistry matrices for a
reaction
XRD analysis was done by X-Ray diffractometer
(RikaguMiniflex) and SEM was performed on Nova nano
SEM 450. The TG/DTA analysis was done by
TG/DTA7300 of EXSTAR. The purity of derivatives was
examined by thin layer chromatography (TLC) eluting
with hexane:ethylacetate in (1:1) ratio.
When green chemistry matrices68,69 was calculated, it was
accomplished that the reaction has low Environment-
factor (E-factor
=
0.044), high atom economy
(AE = 95.72%), high process mass intensity (PMI = 1.865)
and high reaction mass efficiency (RME = 92.9%), with
excellent eco-score (88.5). These values confirmed that the
synthesis is eco-benign and highly efficient.
3.1 | General procedure for the synthesis
of biscoumarin derivatives
In a round bottomed flask of 50 ml, a mixture of 4-OH
coumarin (5 mmol) and aromatic aldehyde (2.5 mmol)
with 30 mg of catalyst in H2O:EtOH were taken and
stirred at 80ꢁC for an appropriate time. The progression
of the reaction was screened by TLC. Then, the crude
was dried to remove the solvent and dichloromethane
was added and filtered to recover the catalyst. The
acquired solid mass was dried and washed with ethanol
to remove impurities. The desired products (3a-j) were
achieved in high to excellent yields (89%-98%) in a less
span of time (10-30 minutes). The recovered catalyst was
dried in oven and again used for the next reaction.
3 | EXPERIMENTAL
All chemicals were purchased from Sigma-Aldrich, Loba-
Chemie, Alfa Aesar, Spectrochem, and used without fur-
ther purification. Melting points were ascertained in open
capillary tubes and were uncorrected. The IR spectra
were recorded in KBr pellets on a Bruker FT-IR spec-
trometer. The 1H NMR (500 MHz) and 13C NMR
(500 MHz) spectra of synthesized derivatives were
scanned on a Bruker Advance NEO 500 MHz spectrome-
ter using tetramethylsilane (TMS) as an internal standard
and DMSO and CDCl3 as a solvent. The mass spectra
were recorded on a Waters Xevo G2-S QT spectrometer.
3.2 | Synthesis of carbon-based catalyst
C-SO3H
To synthesize carbon-based catalyst, we took a mixture of
glycerol (20 g) and concentrated sulfuric acid (80 g) and
these were gently heated from ambient temperature to
180ꢁC to 200ꢁC for 20 minutes, to assist in situ partial
carbonization and sulfonation. The reaction mixture was
allowed to remain at that temperature for about 20 to
40 minutes (until foaming ceased) to achieve the polycy-
clic aromatic carbon compound. The crude product was
allowed to kept at room temperature and washed with
hot water under agitation until the wash water demon-
strated a pH = 7 value. The partially crystalline product
FIGURE 9 Graphical representation of the 10 docked
molecules within the binding pocket of 6FCX protein (black color
for the ligands docked in the pocket 1, green color for pocket 2, and
red color for pocket 3)
FIGURE 10 Pictorial
representation of all the ligands docked
within the different active site of 6FCX
protein

AGARWAL ET AL.
11
FIGURE 11 2D interaction plots
of the top scored docked ligands (3d and
3f) within the binding pocket 1 of 6FCX
protein
was filtered and dried in an oven at 120ꢁC for 2 hours
until it was moisture-free to acquire the glycerol-based
carbon catalyst (9.42 g).21
selected protein files of 4D75 and 6FCX were prepared in
the Receptor Preparation Wizard of the FlexX70,71 module
of LeadIT 2.1.8 program.72 The preparation involved the
addition of the polar hydrogen atoms, assigning of the
atom-type and removal of the crystallographic water. The
selection of active site for 4D75 was based on the known
experimental inhibitor (PK9) with the defined radius of
6.5 Å around the inhibitor. On the other hand, for 6FCX,
the FlexX70,71 module of LeadIT70 automatically per-
ceived the binding site present in the protein. Therefore,
all the binding sites were docked independently in order
to inquest the interaction pattern. To optimize the
ligands, cofactors and residues, Protossmodule77 of
LeadIT 2.1.8 program was employed. It also assigns the
appropriate tautomers and protonation state in the active
site of the macromolecule chain. Default docking and
chemical parameters were used to deal with the steric
clashes. Docking calculations were performed via default
hybrid entropy and enthalpy based docking scheme. To
search for the best docking pose, a maximum of 50 poses
per ligand were requested. The docked interactions were
reported in the form of 2D-interaction plot generated via
PoseView78 widget of LeadIT 2.1.8 program.72
3.3 | Methodology for molecular docking
To perform molecular docking calculations, FlexX70,71
module of LeadIT 2.1.8 program was used.72 This mod-
ule, make use of incremental construction based algo-
rithm70 to assemble the ligand incrementally within the
active site of the protein chain. Thus, give flexibility to
the compounds chosen for conducting docking. Further-
more, this module estimated free binding energy (ΔG) of
the docked ligand-protein complexes by utilizing the
modified Böhm's scoring function.73 Ten synthesized
biscoumarin compounds were selected. These selected
compounds were converted to SYBYL mol2 file format74
and were assembled as hit library. The selected molecules
were modified for the correction of the atoms, bond
types, add hydrogen atoms, assign formal charges using
Accelrys discovery studio version 4.075 and energy of
ligands is minimized by CHARMm force field.76 The

12
AGARWAL ET AL.
3.4 | Screening and reusability of
catalyst
further reuse, there was increase in reaction time and the
yield decreased (Figures 12 and 13).
The carbon-SO3H catalyst was insoluble in the dic-
hloromethane (DCM). The reaction mixture was filtered
to separate the catalyst. The recycled catalyst was washed
with EtOH and dried in oven for further use. The
recycled catalyst can be used to fifth run. For the reac-
tion, there was no loss in catalytic activity of catalyst upto
first three runs and was confirmed by the IR spectra.
However, there was slight decrease in the yield of prod-
uct for next fourth run. After fifth run of catalyst, on
3.5 | Spectral characterization of
synthesized biscoumarin derivatives
3.5.1 | 3,30-(Phenylmethylene)bis
(4-hydroxy-2H-chromen-2-one) (3a)
White solid; 97% Yield; m.p. 231ꢁC to 232ꢁC; IR
(max/cm−1) 3857, 3738 (OH), 3064 (sp3,C H), 1702, 1652
(C O), 1605, 1560, 1495 (C C aromatic), 1345 to 1097
(C O), 953 to 756 (sp2 C H); 1H NMR (500 MHz,
CDCl3) δ 6.11 (s, 1H, CH), 7.22 to 7.42 (m, 9H, Ar-H),
7.64 to 7.65 (m, 3H, Ar-H), 7.89 (d, J = 5 Hz, 1H, Ar-H),
8.05 (dd, J = 12.9 Hz, 8.3 Hz, 2H, Ar-H), 10.03 (s, 1H,
OH), 11.54 (s, 1H, OH);13C NMR (500 MHz, DMSO-d6) δ
167.05, 163.83, 151.89, 140.00, 130.44, 127.54, 126.29,
123.58, 122.21, 120.01, 117.06, 102.52, 46.03, 36.43; MS
(m/z): 412.09 (M+).
110
100
90
80
70
60
50
40
30
20
10
0
3.5.2 | 3,30-((2-Chlorophenyl)methylene)
bis(4-hydroxy-2H-chromen-2-one) (3b)
Fresh I Run II Run III
Run Run
Catalytic efficiency
IV V Run VI
Run
White solid; 97.5% Yield; m.p. 213ꢁC to 215ꢁC; IR (max/
cm−1) 3738, 3612 (OH), 2977 (sp3 C H), 1641 (C O),
FIGURE 12 The catalytic efficiency of recovered catalyst
FIGURE 13 The FT-IR spectrum of recovered catalyst of third run with the fresh catalyst

AGARWAL ET AL.
13
1597, 1556, 1491 (C C aromatic), 1345 and 1091 (C O),
748 to 954 (sp2 C H), 660 (Cl); 1H NMR (500 MHz,
DMSO-d6) δ 6.32 (s, 1H, CH), 7.17 (dd, J = 8.10, 0.55 Hz,
2H, Ar-H), 7.27 (m, 2H, Ar-H), 7.32 (m, 2H Ar-H), 7.58
(m, 2H Ar-H), 7.90 (dd, J = 8.5 Hz, 1.5 Hz, 2H), 10.56
(broad, 2H, OH); 13C NMR (500 MHz, DMSO-d6) δ
166.13, 165.25, 154.39, 152.05, 133.78, 128.8, 127.66,
124.89, 123.75, 117.34, 115.99, 114.77, 104.58, 52.63,
35.22. MS (m/z): 446.5 (M+).
7.348 (d, J = 8 Hz, 2H, Ar-H), 7.90 (dd, J = 7.5 Hz,
1.5 Hz, 2H, Ar-H), 8.25(br, 2H, OH), 13C NMR (500 MHz,
DMSO-d6) δ 166.85, 165.90, 152.52, 132.99, 130.87,
128.23, 124.97, 124.41, 116.67, 115.66, 115.37, 105.49,
103.96, 35.69; MS (m/z): 472.12 (M+).
3.5.6 | 3,30-((2-Nitrophenyl)methylene)
bis(4-hydroxy-2H-chromen-2-one) (3f)
Yellow; 92% Yield; m.p. 230ꢁC to 231ꢁC; IR (max/ cm−1
)
3.5.3 | 3,30-(o-Tolylmethylene)bis
(4-hydroxy-2H-chromen-2-one) (3c)
3738 (OH), 2977, 2716 (sp3C H), 1650 (C O), 1558,
1518, 1445 (C C aromatic), 1501 (N-O stretching) 1606
1
(NO2), 1349, 1095 (C O), 951-671 (sp2 C H); H NMR
Cream solid; 91% Yield; m.p. 220ꢁC to 221ꢁC; IR (max/
cm−1) 3739 (OH), 2975 (sp3 C H), 1702 and 1652 (C O),
1605, 1560, 1495, 1444 (C C aromatic), 1345 to 1097
(C O), 953 to 756 (sp2 C H);1H NMR (500 MHz, CDCl3)
δ 2.08 (s, 3H), 6.07 (s, 1H, CH), 7.16 to 7.21 (m, 3H, Ar-
H), 7.33 to 7.41 (m, 5H, Ar-H), 7.62 (t, J = 10 Hz, 2H, Ar-
H), 8.03 (dd, J = 24 Hz, 4 Hz, 2H, Ar-H), 11.0 (s, 1H),
11.46 (s, 1H); 13C NMR (500 MHz, DMSO-d6) δ 166.13,
165.25, 154.39, 152.05, 133.78, 128.8, 127.66, 124.89,
123.75, 117.34, 115.99, 114.77, 104.58, 35.22, 19.6. MS
(m/z): 426.11 (M+).
(500 MHz, DMSO-d6) δ 6.35 (s, 1H, CH), 7.28 (dd,
J = 9 Hz, 2.5 Hz, 2H Ar-H), 7.34 (t, J = 10 Hz, 2H Ar-H),
7.59 (m, 2H, Ar-H), 7.86 (dd, J = 9 Hz, 1.5 Hz, 2H, Ar-H),
8.09 (m, 2H, Ar-H), 9.28 (br, 2H, OH); 13C NMR
(500 MHz, DMSO-d6) δ 168.5, 167.8, 166.4, 164.8, 152.6,
151.3, 146.5, 143.3, 131.8, 124.8, 122.1, 121.9, 116.8, 114.2,
104.7, 35.5; MS (m/z): 457.08 (M+).
3.5.7 | 3,30-(Furan-2-ylmethylene)-bis-
(4-hydroxy-2H-chromen-2-one) (3g)
Black-brown; 88% Yield; m.p. 201ꢁC; IR (max/ cm−1
)
3.5.4 | 3,30-((3-Nitrophenyl)methylene)
bis(4-hydroxy-2H-chromen-2-one) (3d)
3859, 3738 (OH), 2978 (sp3 C H), 1652 (C O), 1604,
1559, (C C aromatic), 1341, 1087(C O), 641 to 946 (sp2
C H); 1H NMR: (500 MHz, DMSO d6) δ 6.10 (s, 1H,
CH), 6.31 (m, 1H, Ar-H), 6.35 (dd, J = 8.5 Hz, 1.5 Hz,
1H), 7.34 to 7.37 (m, 2H, Ar-H), 7.38 to 7.39 (m, 2H,
Ar-H), 7.49 (t, J = 1 Hz, 1H, Ar-H), 7.60 to 7.64 (m, 2H,
Ar-H), 7.96 (dd, J = 8 Hz, 1.5 Hz, 2H, Ar-H), 9.80 (br,
2H, OH); 13C NMR: (500 MHz, DMSO d6) δ 165.32,
164.21, 152.94, 152.10, 141.35, 131.93, 123.85, 123.70,
117.77, 115.90, 110.14, 105.92, 102.53, 54.83, 31.44. MS
(m/z): 402.36 (M+).
Yellow colored; 90% Yield; m.p. 230ꢁC to 231ꢁC; IR
(max/ cm−1) 3863, 3736 (OH), 2974, 2698 (sp3 C H),
1689 (C O), 1602, 1555, (C C aromatic), 1093 (C O),
1599, 1546, 1501 (N-O stretching), 660 to 939 (sp2 C H);
1H NMR (500 MHz, DMSO-d6) δ 6.38 (s, 1H, CH), 7.29
(t, J = 7.5 Hz, 2H Ar-H), 7.33 (d, J = 8 Hz, 2H Ar-H), 7.58
(m, 2H, Ar-H), 7.84 (dd, J = 7.5 Hz, 0.5 Hz, 2H, Ar-H),
8.07 (m, 2H, Ar-H), 8.41 (br, 2H, OH); 13C NMR
(500 MHz, DMSO-d6) δ 169.5, 166.8, 167.4, 164.8, 153.6,
152.3, 147.5, 144.3, 132.8, 125.8, 124.1, 122.9, 117.8, 116.2,
104.7, 36.5; MS (m/z): 457.08 (M+).
3.5.8 | 3,30-((4-Methoxyphenyl)
methylene)bis(4-hydroxy-2H-chromen-
2-one) (3h)
3.5.5 | 3,30-((3,4-Dimethoxyphenyl)
methylene)bis(4-hydroxy-2H-chromen-
2-one) (3e)
Light yellow; 93% Yield; m.p. 240ꢁC; IR (max/cm−1) 3739
(OH), 2938, 2834, 2792 (sp3 C H), 1669.77 (C O), 1594,
1502, (C C aromatic), 1346, 1088, (C O), 1020 (OCH3),
756 to 952 (sp2 C H); 1H NMR: (500 MHz, CDCl3) δ 3.76
(s, 3H, CH3), 6.05 (s, 1H, CH), 6.85 (d, J = 8.1 Hz, 2H, Ar-
H), 7.12 (dd, J = 6.5 Hz, 0.5 Hz, 2H, Ar-H), 7.41 (m, 4H,
Ar-H), 7.63 (t, J = 10 Hz, 2H, Ar-H), 8.05 (dd, J = 10 Hz,
1.5 Hz, 2H, Ar-H), 11.32 (s, 1H, OH), 11.49 (s, 1H, OH),
13C NMR: (500 MHz, CDCl3) δ 168.26, 164.66, 163.57,
White solid; 92% Yield; mp 260ꢁC to 261ꢁC; IR
(max/cm−1) 3872, 3740 (OH), 2926, 2604 (sp3 C H), 1663
(C O), 1606, 1559, 1501 (C C aromatic), 1344, 1095
(C O), 760 to 952 (sp2 C H); 1H NMR (500 MHz,
DMSO-d6) δ 6.31 (s, 1H), 7. 03 (t, J = 8.5 Hz, 2H Ar-H),
7.17 (dd, J = 8 Hz, 5 Hz, 2H, Ar-H), 7.33 (m, 2H, Ar-H),

14
AGARWAL ET AL.
159.43, 151.46, 131.81, 126.63, 125.95, 123.86, 122.38,
117.63, 114.03, 104.78, 55.28, 35.54; MS (m/z):
442.11 (M+).
30 minutes made this protocol a user-friendly approach
for the synthesis of biscoumarins. In order to establish
the biological potency, molecular docking was performed
against CYP3A4 and MTHFR protein. The in silico stud-
ies revealed that the synthesized compounds showed
good interaction with both the proteins and it was found
that 3f and 3d form a stable binding interaction with
CYP3A4 and MTHFR enzymes. Thus, we may conclude
that 3d and 3f compounds showed good inhibitory activ-
ity against the selected proteins.
3.5.9 | 3, 30-((3-Hydroxyphenyl)
methylene)-bis-(4-hydroxy-2H-chromen-
2-one) (3i)
Cream color solid; 94% Yield; m.p. 211ꢁC to 212ꢁC; IR
(max/ cm−1) 3739 (OH), 2978 (sp3C H), 1647 (C O),
1604, 1560, 1498, 1446 (C C aromatic), 1347 to 1066
(C O), 956 to 755 (sp2 C H); 1H NMR (500 MHz,
DMSO-d6) δ 6.30 (s, 1H, CH), 6.69 (m, 2H, Ar-H), 7.05
(dd, J = 8.7, 2.4 Hz, 2H, Ar-H), 7.39 (m, 2H, Ar-H), 7.42
(m, 2H Ar-H), 7.65 (m, 2H), 7.96 (dd, 12.4 Hz, 6.4 Hz,
2H), 9.74 (broad, 3H, OH); 13C NMR (500 MHz, DMSO-
d6) δ 163.83, 162.39, 154.39, 152.02, 131.02, 127.8, 126.66,
124.89, 122.75, 116.34, 114.99, 113.97, 104.58, 55.83,
35.12; MS (m/z): 411.09 (M+).
ACKNOWLEDGMENTS
The authors are thankful to Head, Department of Phar-
macy, B. N. University for providing necessary laboratory
facilities. The authors duly acknowledge Department of
Chemistry and Department of Physics, University College
of Science, MLS University, Udaipur for synthesis and
characterization of catalyst. The authors would also like
to acknowledge Sophisticated Analytical Instrumentation
Facility, Chandigarh, India, and Material Research Cen-
tre, Malviya National Institute of Technology Jaipur
(MNIT, Jaipur) for carrying out the spectral analysis.
3.5.10 | 3, 30-((3-Bromophenyl)
methylene)-bis-(4-hydroxy-2H-chromen-
2-one) (3j)
CONFLICT OF INTEREST
The authors confirmed that this article has no conflict of
interest.
Cream color solid; 96% Yield; m.p. 220ꢁC to 221ꢁC; IR
(max/ cm−1) 3739 (OH), 2978 (sp3C H), 1652 (C O),
1602, 1554, 1494 (C C aromatic), 1344 to 1087 (C O),
949 to 754 (sp2 C H), 668 (Br);1H NMR (500 MHz,
DMSO-d6) δ 6.32 (s, 1H, CH), 7.15-7.20 (m, 2H Ar-H),
7.27 to 7.34 (m, 6H, Ar-H), 7.58 (t, J = 7 Hz, 2H, Ar-H),
7.95 (m, 2H, Ar-H), 9.48 and 9.99 (broad, 2H, OH);13C
NMR (100 MHz, DMSO-d6) δ 166.26, 164.39, 152.26,
135.48, 131.92, 131.62, 131.51, 131.29, 130.79, 130.01,
129.17, 128.15, 125.90, 123.91121.36, 118.51, 115.70,
103.27, 35.92.; MS (m/z): 491.29 (M+).
ORCID
Shikha Agarwal https://orcid.org/0000-0003-2946-0409
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In summary, we have demonstrated a click chemistry-
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How to cite this article: Agarwal DK, Sethiya A,
Teli P, et al. Click chemistry-inspired design,
synthesis, and molecular docking studies of
biscoumarin derivatives using carbon-based acid
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