Synthesis of bis-coumarins over acetic acid functionalized poly(4-vinylpyridinum) bromide (APVPB) as a green and efficient catalyst under solvent-free conditions and their biological activity

Article abstract of DOI:10.1007/s13738-017-1247-1

Abstract: In this work, acetic acid functionalized poly(4-vinylpyridinum) bromide as a green and reusable catalyst was successfully tested on the synthesis of various bis-coumarins under solvent-free conditions. In addition, antioxidant and anti-inflammat

Full text of DOI:10.1007/s13738-017-1247-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-017-1247-1
ORIGINAL PAPER
Synthesis of bis‑coumarins over acetic acid functionalized
poly(4‑vinylpyridinum) bromide (APVPB) as a green efcient catalyst
under solvent‑free conditions their biological activity
Ehsan Noroozizadeh1 · Ahmad Reza Moosavi‑Zare2 · Mohammad Ali Zolfgol1 · Mahmoud Zarei1 · Roya Karamian3 ·
Mostafa Asadbegy3 · Siamak Yari3 · Seyed Hamed Moazzami Farida3
Received: 13 March 2017 / Accepted: 16 November 2017
© Iranian Chemical Society 2017
Abstract
In this work, acetic acid functionalized poly(4-vinylpyridinum) bromide as a green and reusable catalyst was successfully
tested on the synthesis of various bis-coumarins under solvent-free conditions. In addition, antioxidant and anti-infammatory
activities of the synthesized bis-coumarins were in vitro screened by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical
scavenging and formalin-induced edema model system, respectively. Antifungal activity was also evaluated against Fusarium
oxysporum. Results showed that the synthesized bis-coumarins studied possess strong antioxidant (IC50; 0.149 0.005 to
1.348 0.006 mg/ml) and anti-infammatory activities in comparison with ascorbic acid and diclofenac as positive controls,
respectively. Also, the compounds showed good inhibition activity against Fusarium oxysporum (58 1.4 to 100 0.0%).
For their biological activities, the synthesized bis-coumarins may be suggested to apply as biological agents for special use
in future.
Graphical Abstract
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-017-1247-1) contains
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Keywords Functionalized poly(4-vinylpyridinum) bromide ·
Bis-coumarin · Solvent-free · Anti-infammatory · Antioxidant
Introduction
Solvent-free reactions have been demonstrated to be as
an efcient technique for various organic transformations
instead of using harmful organic solvents. Solvent-free
conditions often lead to a remarkable decrease in reaction
times, increased yields, easier workup, matches with green
chemistry protocols and may enhance the regioselectivity
and stereoselectivity of reactions [1–5].
Reactive oxygen or nitrogen species (ROS or RNS) are
formed naturally in living cells have important roles in cell
signaling. However, high amount of these compounds are
hazardous to the cells and damage all major components,
including nucleic acids, polypeptides chains, and lipids in
cell membranes that play an important role in the develop-
ment of diseases such as infammation and other disorders
[6, 7]. Inflammation is a complex phenomenon involv-
ing interrelationships between diferent factors including
physical and chemical stimulants. ROS play a signifcant
role in the infammatory process. Antioxidants may act as
scavenger, reducing, quencher agents and/or activators of
cellular antioxidant enzymes to prevent the free radical
damages in biological systems [8, 9]. In this regard, several
natural or synthetic coumarins with various hydroxyl and
other substituents were found to inhibit lipid peroxidation
and to scavenge hydroxyl radicals and superoxide anions.
Hence, they can infuence processes involving free radical-
mediated injury as some plant phenolics and favonoids [10,
11]. Today, most of the bacteria and fungi showed resistance
to classical antibiotics, [12–14] and the discovery of active
compounds with novel mechanisms is a matter of urgency
[15, 16].
Fig. 1 Structure of acetic acid functionalized poly(4-vinylpyridinum)
bromide (APVPB)
antitumor [24, 25], anti-HIV10 [26] as well as agro-
chemicals [27] and analytical reagents [28] have been
represented. They have potential applications in various
biomedical including anticoagulants [22, 29, 30], anti-
oxidants [27], and also as non-ATP competitive inhibitor
of c-Me [31].
Several methods for the preparation of bis-coumarins
were reported. The majority of them have been carried
out by the knoevenagel reaction in the presence of various
acidic catalysts, such as sulfuric acid, phosphoruspentox-
ide, aluminum chloride, iodine, and trifluoroacetic acid
[32–34]. However, some of them suffer from drawbacks,
such as the use of volatile organic solvents, high cost, and
low yields. Therefore, it is highly desirable to develop
efficient and cost-effective catalysts and procedures
with high novelty for the preparation of these valuable
compounds.
Ionic liquids have received considerable interest as eco‐
friendly solvents, catalysts, and reagents in organic transfor-
mations due to their unique properties, such as low volatility,
non‐fammability, high thermal stability, negligible vapor
pressure, and the ability to dissolve a wide range of various
materials [35]. Among them, Brønsted acidic ionic liquids,
with useful characteristics of both solid acids and mineral
liquid acids, have been introduced to replace traditional min-
eral liquid acids, like sulfuric acid and hydrochloric acid, in
chemical procedures [36–51].
The preparation of heterocyclic compounds with
biological properties is very important. Nowadays cou-
marins, as a classification of the hetrocyclic compounds
containing oxygen hetro-atom, are completely introduced
due to their naturality [17–19], application as food addi-
tives, cosmetics [20], and optical brightening agents [21].
Moreover, their biological activities such as anticoagulant
[22] antibacterial [23], antifungal [23], antibiotic [24],
Scheme 1 Synthesis of bis-
coumarins catalyzed by APVPB
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Journal of the Iranian Chemical Society
Table 1 Efect of the catalyst amount and temperature on the reaction
Recently, we have introduced acid functionalized ionic
liquid, and applied them as organocatalysts for the prepara-
tion of 14‐aryl‐14H‐dibenzo [a,j]xanthenes [52], tetrahyd-
robenzo [b]pyrans [53], 2-aminobenzo[h] chromene [54],
4,4ʹ-(arylmethylene)- bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol)s [55].
between 4-hydroxycoumarin and 4-chlorobenzaldehyde
Entry
Amount of
Temp. (°C)
Time (min)
Yielda (%)
catalyst (mg)
1
2
3
4
5
6
7
3
5
7
10
7
7
70
70
70
70
50
90
110
40
25
15
15
30
15
15
55
70
92
92
45
92
92
Herein, in continuous of previous work on the prepa-
ration of Brønsted acidic ionic liquids and solid salts, we
would like to introduce acetic acid functionalized poly(4-
vinylpyridinum) bromide (APVPB) (Fig. 1) as an efcient
and reusable catalysts for the synthesis of bis-coumarins
by the condensation reaction of various aldehydes with
4-hydroxycoumarin at 70 °C under solvent-free conditions
(Scheme 1).
7
aIsolated yield
Biological activity
Experimental
Antioxidant capacity
Chemistry
Free radical scavenging activity of the compounds was
measured according to Mensor et al. [71]. In order to obtain
dilutions, diferent samples concentrations were prepared in
methanol (0.2–1 mg/ml), and 2.5 ml of each concentration
were added to 1 ml of alcohol solution of DPPH (0.3 mM).
The samples were frst kept in darkness at room temperature
for 30 min, and then bleaching of DPPH was read at 517 nm
against a blank (methanol). The inhibition in percent for
each concentration was calculated according to the follow-
ing formula:
All chemicals were purchased from Merck or Fluka Chemi-
cal Companies. The known products were identifed by
comparison of their melting points and spectral data with
those reported in the literature. Progress of the reac-
tions was monitored by TLC using silica gel SIL G/UV
254 plates. The H NMR (400–300 MHz) and 13C NMR
1
(100–75 MHz) were recorded on a BrukerAvance DPX
FT-NMR spectrometer (δ in ppm). Melting points were
recorded on a Büchi B-545 apparatus in open capillary
tubes.
[
]
DPPH free radical scavenging (%) = 1− (As−Ab)∕Ac × 100
where As is absorbance of the reaction mixture containing
2.5 ml of samples + 1 ml of DPPH, Ab is absorbance of the
reaction mixture containing 2.5 ml of samples + 1 ml metha-
nol, and Ac is absorbance of control sample containing 1 ml
of DPPH + 2.5 ml methanol. Also IC50 value, which repre-
sented the concentration of the sample that caused 50% inhi-
bition, was determined. Tests were carried out in triplicate
and ascorbic acid was used as a positive control.
General procedure for the preparation of bis‑coumarins
APVPB (7 mg) was added to a mixture of 4-hydroxycou-
marin (0.324 g, 2 mmol) and aryl aldehyde (1 mmol) in a
25-mL round-bottomed flask connected to a reflux con-
denser, and the resulting mixture was stirred magnetically
at 70 °C, and after that the reaction mixture was solidi-
fied, it was stirred with a small rod at same temperature.
After the reaction was completed, as monitored by TLC,
the reaction mixture was cooled to room temperature,
ethyl acetate (95%) (20 mL) was added to it, stirred and
refluxed for 3 min. Then, the mixture was centrifuged
for separation of the catalyst from the product and the
remaining starting materials. The solvent of the reaction
mixture was evaporated, and the precipitate (the crude
product) was purified by recrystallization from ethanol
(95%). In this work, the catalyst was recovered and reused
for 5 times without any significant changes in the yield
and the reaction time.
Animals
Mature Sprague Dawley rats (180–200 g) were obtained
from animal house of Bu-Ali Sina University, Hamedan,
Iran and were allowed to adapt themselves with their loca-
tion for 1 week. The rats were divided into three groups
as follows: group 1 as negative control (DMSO), group 2
as positive control (diclofenac treated) and group 3 as bis-
coumarin treated (C6). The animals, which have been bred in
our laboratory, were housed under standard conditions and
received a diet of commercial food pellets and water ad libi-
tum during the maintenance, but they were entirely fasted
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Journal of the Iranian Chemical Society
Table 2 Solvent-free synthesis
of bis-coumarin from aryl
aldehydes, 4-hydroxycoumarin,
and catalyzed by APVPB at
70 °C
Entry
C1
Product
Time (min)
15
Yielda (%)
Mp. °C (Lit.) [References]
92
257–260 (259–261) [57]
C2
C3
17
17
88
87
232–234 (230–232) [57]
275–277 (270–274) [57]
C4
C5
C6
12
13
12
92
89
94
205–207 (204) [59]
236–238 (234–236) [58]
238–240 (232–234) [58]
C7
C8
15
10
91
91
218–220 (224–226) [58]
268–270 (266–268) [58]
C9
15
18
86
87
262–264 (266–268) [58]
247–249 (246–248) [58]
C10
C11
10
17
90
89
262–264 (260–262) [57]
203–206 (197–201) [57]
C12
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Journal of the Iranian Chemical Society
Table 2 (continued)
Entry
C13
Product
Time (min)
10
Yielda (%)
94
Mp. °C (Lit.) [References]
210–212 (212–214) [58]
C14
20
82
230–232 (224) [61]
C15
C16
16
20
88
85
180–182 (178–180) [58]
188–190 (181.6) [60]
C17
20
85
265–268 (263–265) [58]
aIsolated yield
during the experiment period. Our studies were in accord-
ance with recognized guidelines on animal experimentation.
were added to cultivation medium. In order to make the con-
trol group, double-distilled water and DMSO were added
to the plates. After a 7-day incubation of fungus on cul-
ture medium containing samples, radial growth of fungal
mycelium was recorded. The following formula was used
for calculation of the inhibition rate (%):
Anti‑infammatory activity
Anti-infammatory activity was assessed as inhibition of
the formalin-induced edema by the synthesized coumarins.
Edema was induced in the feet rats by the intradermal injec-
tion of 0.1 ml 2% formalin. The tested compound (C6),
0.01 mM/kg body weight, was suspended in DMSO. The
rats were euthanized 15 min after formalin injection. The
diference between the weight of the injected and uninjected
paws of rats was measured for each animal, and changes
of paw weight were compared with that in control animals
(treated only with DMSO and diclofenac).
Inhibition rate (%) = (R − r∕R) × 100
where R is the radial growth of fungal mycelia on the control
plate and r is the radial growth of fungal mycelia on the plate
treated with bis-coumarin derivatives.
Results and discussion
Chemistry
Antifungal activity
At frst, acetic acid functionalized poly(4-vinylpyridinum)
bromide (APVPB) was prepared in three steps. Initially,
bromo ethyl acetate prepared according to previous literature
[56]. Then, to optimize the reaction conditions, a mixture
of 4-chlorobenzaldehyde (1 mmol) and 4-hydroxycoumarin
Antifungal activity of bis-coumarin derivatives was assessed
against Fusarium oxysporum cultivated in Potatoes Dextrose
Agar (PDA) medium. The samples bis-coumarin derivatives
(C1, C3, C7, and C17) in two concentrations (500–1000 ppm)
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Journal of the Iranian Chemical Society
Scheme 2 Proposed mechanism
for the synthesis of bis-cou-
marins
(2 mmol), as a model reaction, was stirred in the presence
of diferent amounts of APVPB at range of 50–110 °C under
solvent-free conditions. The respective results are displayed
in Table 1. As it can be seen in Table 1, 7 mg of APVPB was
sufcient to catalyze the reaction at 70 °C. In these reaction
conditions, the expected bis-coumarin was prepared in 92%
yield within 15 min (Table 1, entry 3).
To investigate the efcacy and the generality of the cata-
lyst, 4-hydroxycoumarin was reacted with various aromatic
aldehydes (benzaldehyde as well as aryl aldehyde contain-
ing electron-withdrawing groups, electron-donating groups,
and halogens), under the optimized reaction conditions
(Table 2). As it is shown in Table 2, all reactions proceeded
efciently to obtain the expected bis-coumarin derivatives in
high yields and in short reaction times. Therefore, APVPB
was a highly efcient and general catalyst for the synthesis
of bis-coumarins.
In a purposed mechanism which is shown in Scheme 2,
initially, the carbonyl group of aldehyde is activated by the
acidic moiety of APVPB and reacted with 4-hydroxycou-
marin to give I. Intermediate I is converted to II by the
elimination of one molecule of H2O. In the next step, II, as
a Michael acceptor, is activated by the catalyst, and reacted
with another molecule of 4-hydroxycoumarin to afford
III. At the end, III is converted to IV (the product) after
tautomerization.
To investigate the recyclability of APVPB, the reaction
of 4-chlorobenzaldehyde (2 mmol) with 4-hydroxycoumarin
(1 mmol) was performed using APVPB (7 mg) at 70 °C.
After the reaction was completed, the reaction mixture was
cooled to room temperature, ethyl acetate (95%) (20 mL)
Fig. 2 Condensation of 4-chlorobenzaldehyde with 4-hydroxycou-
marin in the presence of recycled catalyst
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Journal of the Iranian Chemical Society
Table 3 DPPH radical
scavenging activity (%) of
coumarins (C1–17) at diferent
concentrations and ascorbic acid
as standard
Compound
Concentration (mg/ml)
0.2 0.4
Average
0.6
0.8
1
C1
28.05 2.9a 34.16 1.6b 33.71 4.4b 41.15 2.4c 46.45 3.5c 36.70
32.22 2.3a 28.10 1.3a 28.43 3.8a 34.18 3.2a 37.09 1.2a 32.00
30.00 1.7a 34.14 2.2a 52.23 2.4b 61.47 1.3c 72.51 2.1d 50.07
28.16 1.2a 38.15 3.3b 49.56 1.8b 58.25 1.4c 66.21 2.7d 48.07
61.16 3.1a 62.02 1.6a 65.31 2.2a 65.17 3.7a 65.87 1.5a 63.89
66.91 4.1a 64.27 2.9a 73.82 1.9b 70.68 0.9b 71.31 1.1b 69.40
67.12 1.2a 65.22 3.1a 70.35 2.6b 72.51 2.2b 71.11 1.8b 69.26
64.80 3.2a 63.19 2.1a 62.97 1.6a 67.73 3.4a 67.41 1.1a 65.22
24.33 1.3a 26.41 0.8a 23.16 2.9a 36.52 1.7b 41.11 3.6b 30.31
32.43 3.3a 33.16 1.5a 43.52 1.3a 47.18 3.2a 52.23 3.1a 41.70
34.14 2.2a 38.25 1.2a 48.33 3.3b 55.21 2.8c 60.16 2.2d 47.22
16.11 0.8a 24.54 3.4b 21.27 0.9b 28.22 1.2c 40.43 1.8d 26.11
18.33 2.6a 23.13 2.4a 21.27 2.2a 21.17 3.1a 47.23 2.8b 26.23
24.53 1.2a 21.65 1.1a 27.32 0.6b 38.77 1.7c 46.43 1.2d 29.74
24.33 1.5a 33.41 0.8a 40.16 2.2a 49.52 3.6a 62.11 4.2a 41.91
27.33 1.7a 26.41 2.2a 25.16 1.7a 37.32 1.9b 41.24 1.6b 30.51
26.61 3.3a 29.31 3.4a 58.26 3.7b 57.22 3.2b 55.19 2.2b 45.32
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
Ascorbic acid 78.74 2.7a 80.26 3.4b 81.85 2.4b 80.31 1.1b 80.24 2.6b 80.28
Experiment was performed in triplicate and expressed as mean SD. Values within column with diferent
superscripts are signifcantly diferent (p < 0.05)
was added, stirred and refuxed for 2 min. Then, the resulting
mixture was centrifuged to separate of the nanocatalyst from
the product and remaining starting materials. The remained
catalyst was washed with hot ethyl acetate (10 mL) and dried
to use for the next run. Catalytic activity of APVPB was
restored within the limits of the experimental errors for 5
successive recycle runs (Fig. 2).
Antioxidant capacity
Coumarins and its derivatives are a very large class of com-
pounds, which are naturally found in plants [62]. They have
been attracted considerable attention due to their wide spec-
trum of pharmacological and biological activities such as
antifungal, antiviral, antibacterial, anti-infammatory, and
antioxidant capacities [63]. Antioxidants are very important
due to their role in the deleterious of free radicals [64, 65].
Our results showed that the synthesized coumarins showed
excellent dose-dependent (0.2–1 mg/ml) antiradical prop-
erties (26.10–69.40%) (Table 3). It has been reported that
in vitro antioxidant activity of phenolic compounds on a
molar basis is higher than that of vitamins E and C65, and
more antioxidant activity is refected in a lower IC50 value.
Vitamin C (ascorbic acid) as a synthetic antioxidant repre-
sented the IC50 value lowers than of the most of compounds
studied here (Fig. 3). The efectiveness of the compounds as
DPPH radical scavengers ranged in the following descending
order: ascorbic acid > C6 = C7 = C8 ≥ C5 > C17 > C3 ≥
C4 > C11 > C15 > C10 ≥.
Anti‑infammatory activity
The in vivo anti-infammatory activity of the compounds
was assessed by using the functional model of formalin-
induced rat paw edema (Table 4). Formalin-induced edema
is a nonspecifc infammation resulting from a complex
Fig. 3 Comparison of DPPH radical scavenging ability (IC50 Value)
of the studied coumarins and ascorbic acid as a positive control
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Journal of the Iranian Chemical Society
Table 4 Anti-infammatory
activity of a coumarin sample,
positive, and negative controls
Time (min)
Diameter (mm)
Coumarin sample
C6
Positive control
Diclofenac
Negative control
DMSO
Uninjected hind
Control rats
0
27.0 0.2
26.5 0.3
24.5 0.2
23.5 0.1
22.5 0.2
22.0 0.1
26.0 0.3
26.0 0.2
25.5 0.4
25.5 0.3
24.0 0.1
22.5 0.1
26.0 0.1
26.0 0.3
26.0 0.3
25.4 0.5
25.2 0.2
25.0 0.3
21.0 0.3
21.0 0.3
21.0 0.3
21.0 0.3
21.0 0.3
21.0 0.3
15
30
45
60
75
Experiment was performed in triplicate and expressed as mean SD
of diverse mediators [66]. The increase in diameter of the
paws reached about 6–7 mm of the diameter of the control
paw 15 min (0 min in table) after the injection of formalin
(Fig. 4). At higher dose, the diameter increased at the right
hind paw (26.5 0.3 mm) in comparison with the unin-
jected left hind paw (21.0 0.3 mm). As shown in Table 4,
compound C6 induced protection against formalin-induced
paw edema (5 mm). The reference drug, diclofenac, is a non-
steroidal anti-infammatory drug (NSAID) induced 3.75 mm
protection at an equivalent concentration. The sample was
the most potent (5 mm diameter), whereas DMSO as nega-
tive control had the lowest efect (1 mm). Our results indi-
cated that the studied compounds can be used to treat infam-
mation diseases.
Antifungal activity
The inhibition zone values were determined for some ran-
domly selected compounds synthesized here (C1, C3, C6, and
C17) against Fusarium oxysporum (Table 5). F. oxysporum is
a soil inhabitant that attacks its host by entering through the
root and grows in the plant xylem, eventually blocking the
vascular system. It prevents transport of water, and nutrients
can cause severe losses of crop and ultimately death of the
Table 5 Antifungal activity of some synthesized coumarin
Compound
Inhibition of radial growth of fungal
mycelium (%)
Concentration (ppm)
F. oxysporum
C1
500
1000
500
1000
500
1000
500
1000
–
60 3.2
100 0.0
86 2.8
100 0.0
78 2.3
100 0.0
58 1.4
91 1.2
NA
C3
C7
C17
DMSO
Fig. 4 a Increasing of diameter in formalin-injected right hind paw
(26.5 0.3 mm) in comparison with the uninjected left hind paw b
anti-infammatory activity of the coumarin, positive, and negative
controls
Experiment was performed in triplicate and expressed as mean SD
NA No active
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Journal of the Iranian Chemical Society
Fig. 5 Antifungal activity a
control (water distillation) b
coumarin treated
Acknowledgements We thank Bu-Ali Sina University, Sayyed Jama-
leddin Asadabadi University and Iran National Science Foundation
(INSF) (Grant Number: 940124) for fnancial support to our research
groups.
plants of great economic importance [67, 68]. It has been
shown that biological activity such as antimicrobial activ-
ity of a compound is attributed mainly to its major com-
ponents. However, today, it is known that the synergistic
or antagonistic efect of any compounds in minor percent-
ages has to be considered [69, 70]. Most of the old synthetic
fungicides usually are difcult to degrade and are toxic to
humans. Therefore, the searches for new compounds endo-
phytic fungi which are safe and more environmental friendly
were introduced to replace the synthetic fungicides. In this
research, it was determined that solvent DMSO as nega-
tive control had no antifungal activity against F. oxysporum
(Table 5). All samples showed excellent antifungal activity
(Fig. 5). Hence, the examined samples may be used to treat
plant diseases caused by F. oxysporum and also to increase
resistance in a wide variety of crop plants.
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In summary, we have reported acetic acid functionalized
poly(4-vinylpyridinum) bromide (APVPB) as a reusable,
stable, general and heterogeneous catalyst for the synthesis
of bis-coumarins under solvent-free conditions. Low tem-
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Journal of the Iranian Chemical Society
Afliations
Ehsan Noroozizadeh1 · Ahmad Reza Moosavi‑Zare2 · Mohammad Ali Zolfgol1 · Mahmoud Zarei1 · Roya Karamian3 ·
Mostafa Asadbegy3 · Siamak Yari3 · Seyed Hamed Moazzami Farida3
2
* Ahmad Reza Moosavi-Zare
Sayyed Jamaleddin Asadabadi University,
Asadabad 6541861841, Iran
moosavizare@yahoo.com
3
Department of Biology, Faculty of Science, Bu-Ali Sina
University, P. O. Box 65175/4161, Hamedan, Iran
1
Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 6517838683, Iran
1 3