Synthesis and Evaluation of Coumarin-Resveratrol Hybrids as 15-Lipoxygenaze Inhibitors

Article abstract of DOI:10.1080/00397911.2014.979947

A series of coumarin-resveratrol hybrids, 3-arylcoumarin derivatives 3a-u, were synthesized through the intermolecular condensation reaction of various salicylaldehydes and phenylacetic acids in the presence of 1,4-diazabicyclo[2.2.2]octane under solvent-free conditions. All the synthesized compounds were screened for their inhibitory potency against soybean 15-lipoxygenase. Among them, three compounds (3c, 3j, and 3q) showed good enzyme-inhibitory activities. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.979947

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Synthesis and Evaluation of Coumarin-Resveratol
Hybrids as 15-Lipoxygenaze Inhibitors
Samira Rahmani-Nezhada, Leila Khosravania, Mina Saeedib, Kouros Divsalarc, Loghman
Firoozpourd, Yaghoub Pourshojaeia, Yaghoub Sarrafie, Hamid Nadrif, Alireza Moradif,
Mohammad Mahdavia, Abbas Shafieea & Alireza Foroumadicd
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medicinal Sciences, Tehran, Iran
b Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences,
Tehran, Iran
c Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of
Medicinal Sciences, Kerman, Iran
d Drug Design and Development Research Center, Tehran University of Medical Sciences,
Tehran, Iran
e Faculty of Chemistry, Mazandaran University, Babolsar, Iran
f Department of Medicinal Chemistry, Faculty of Pharmacy and Neurobiomedical Research
Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Accepted author version posted online: 11 Nov 2014.
To cite this article: Samira Rahmani-Nezhad, Leila Khosravani, Mina Saeedi, Kouros Divsalar, Loghman Firoozpour, Yaghoub
Pourshojaei, Yaghoub Sarrafi, Hamid Nadri, Alireza Moradi, Mohammad Mahdavi, Abbas Shafiee & Alireza Foroumadi (2014):
Synthesis and Evaluation of Coumarin-Resveratol Hybrids as 15-Lipoxygenaze Inhibitors, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.979947
To link to this article: http://dx.doi.org/10.1080/00397911.2014.979947
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Synthesis and Evaluation of Coumarin-Resveratol Hybrids as 15-Lipoxygenaze
Inhibitors
Samira Rahmani-Nezhad1, Leila Khosravani1, Mina Saeedi2, Kouros Divsalar3, Loghman
Firoozpour4, Yaghoub Pourshojaei1, Yaghoub Sarrafi5, Hamid Nadri6, Alireza Moradi6,
Mohammad Mahdavi1, Abbas Shafiee1, Alireza Foroumadi3,4
1Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medicinal Sciences, Tehran, Iran, 2Persian
Medicine and Pharmacy Research Center, Tehran University of Medical Sciences,
Tehran, Iran, 3Neuroscience Research Center, Institute of Neuropharmacology, Kerman
University of Medicinal Sciences, Kerman, Iran, 4Drug Design and Development
Research Center, Tehran University of Medical Sciences, Tehran, Iran, 5Faculty of
Chemistry, Mazandaran University, Babolsar, Iran, 6Department of Medicinal Chemistry,
Faculty of Pharmacy and Neurobiomedical Research Center, Shahid Sadoughi University
of Medical Sciences, Yazd, Iran
Corresponding author: Alireza Foroumadi, E-mail: aforoumadi@yahoo.com
Abstract
A series of coumarin-resveratrol hybrids; 3-arylcoumarin derivatives 3a-u, were
synthesized through the intermolecular condensation reaction of various salicylaldehydes
and phenylacetic acids in the presence of DABCO under solvent-free conditions. All the
synthesized compounds were screened for their inhibitory potency against soybean 15-
lipoxygenase. Among them, three compounds including 3c, 3j, and 3q showed better
enzyme-inhibitory activities.
KEYWORDS: Salicylaldehyde; 3-aryl coumarins; solvent-free; soybean 15-
lipoxygenase; DABCO
1

INTRODUCTION
Coumarin (2H-chromen-2-one) and its derivatives are one of the most important O-
heterocycles and extensively found in various bioactive natural and synthetic products.[1]
They are effective pharmacophores and widely used for the design and synthesis of novel
bioactive compounds.[2] Accordingly, different biological activities such as anticoagulants
and cardiovascular (warfarin),[3] and antimicrobial activities (novobiocin and
clorobiocin)[4] have been reported. They also possess anti-cancer,[5] anti- inflammatory
and antioxidant,[6] antiviral (inhibitor of HIV-1 protease and integrase),[7] and enzyme
inhibition effects.[8] At this juncture, 3-arylcoumarins have attracted lots attention due to
their precious biological properties.[9] Their anti-proliferative,[10] antioxidant,[11] and
monoamine oxidase A inhibitor activities[12] have been successfully reported in the
literature.
Various classic methods such as Perkin,[13] Pechmann,[14] Knoevenagel,[15] Wittig,[16] and
Kostanecki-Robinson reactions[17] have been used for the synthesis of 3-arylcoumarin
derivatives. One of the most common methods for the construction of 3-arylcoumarins is
based on the reaction 2-hydroxyacetophenones/2-hydroxybenzaldehydes with
phenylacetic acids. For this purpose, various catalysts or reagents such as 1,1-
carbonyldiimidazole,[18] cyanuric chloride/N-methyl morpholine,[19] and using two phase
system conditions[20] have been utilized. However, most of these methods suffer from
different limitations and disadvantages such as low yields of the products, use of
expensive and toxic reagents, formation of by-products and long reaction time. In view of
2

this, there is already a considerable demand for developing new synthetic approaches to
3-arylcoumarins.
In continuation of our efforts to develop efficient methods for the synthesis of novel
heterocyles as well as bioactive compounds;[21] herein, we report a simple, efficient, and
general method for the preparation of 3-aryl coumarins 3 as coumarin-resveratrol hybrids
through the reaction of salicylaldehydes 1 and phenylacetic acids 2 in the presence of
DABCO under solvent-free conditions (Scheme 1). Also, considering the ability of 3-aryl
coumarins to inhibit soybean LO,[18] all compounds were evaluated for their inhibitory
activity against soybean 15-lipoxygenase.
RESULTS AND DISCUSSION
Chemistry. Focusing on the efficiency of 1,4-diazabicyclo[2.2.2]octane (DABCO) as an
organocatalyst base in different organic transformations such as protection of
carbohydrates,[22] Heck reaction,[23] synthesis of isothiocyanates[24] and isoxazolines,[25]
alcohol oxidation,[26] and oxa-Michael-Henry reaction for the formation of 3-
nitrochromenes,[27] we decided to conduct the reaction in the presence of DABCO
(Scheme 1).
Initially, we selected the reaction of salicylaldehyde and phenylacetic acid as a model
reaction. Next, different conditions such as temperatures, solvents, and the amount of
DABCO were tested to obtain the optimal conditions (Table 1).
3

Different solvents such as EtOH, MeOH, toluene, THF, and DMF were examined. It was
found that using solvent-free conditions led to the best results in terms of reaction time
and yield. As shown in Table 1, the best yield (90%) was obtained for a molar ratio of
phenylacetic acid:salicylaldehyde:DABCO 1:0.5:3 (Table 1, Entry 5) at 180 oC. It should
be noted that lower temperatures gave the corresponding product in very low yield.
With the optimized reaction conditions, we conducted the reaction of a wide spectrum of
salicylaldehyde and phenylacetic acid derivatives under the optimized condition (Table
2). All substrates possessing electron-rich as well as electron-poor substituents underwent
DABCO- promoted reaction to afford the title compounds 3 in good yields (61-93%).
However, the best results were related to the salicylaldehyde series with no substituent
(Table 2, Entries 1-7).
The plausible mechanism for the formation of 3-aryl coumarins 3 have been shown in
Scheme 2. Initially, the acidic proton of phenacylacetic acid derivative 2 is captured by
DABCO to form the salt 4. Then, it would be attacked by hydroxyl group of
salicylaldehyde derivative 1 to afford the related ester 5 which was separated and
characterized during our investigations. Activation of methylene protons (6) in the
presence of DABCO followed by the intermolecular cyclization (7) and dehydration
gives 3-aryl coumarin derivatives 3.
Pharmacology
4

15-LOX inhibition assay. Inhibitory activity of the target compounds 3a-u on soybean
15-lipoxygenase was studied by the spectrophotometric assay method described in the
literature.[28] Quercetin was used as the reference compound and all results are
summarized in Table 3.
Among the tested compounds, compounds 3b, 3d, 3i, 3k, 3p, 3r, and 3s showed no
lipoxygenase inhibitory activity and other derivatives exhibited moderate activity. It
seems that 3-aryl coumarins bearing p-chlorophenyl at 3-position showed better activities
and the introduction of the methoxy groups to any positions of the synthesized
compounds did not improve inhibitory activity against soybean 15-lipoxygenase.
.
In conclusion, we developed a simple and efficient method for the synthesis of 3-aryl
coumarines via the reaction of salicylaldehydes and phenylacetic acids in the presence of
DABCO under solvent-free conditions. The advantages of this method compared to
previously reported methods include the use of safe base, solvent-free conditions,
elimination of toxic reagents and organic solvents, simple work-up, and high yield of
products. Also, all products were evaluated against soybean 15-lipoxygenase activities
and most of them showed moderate activity.
EXPERIMENTAL
All reagents and solvents were purchased from Merck. Melting points are uncorrected
and were determined with a Kofler hot-stage apparatus (Reichert, Vienna, Austria). 1H
and 13C NMR spectra were measured using 400 and 500 spectrometers in CDCl3;
5

chemical shifts (δ) are reported in ppm, coupling constant (J) values are presented in Hz.
The IR spectra were obtained on a Nicolet Magna FTIR 550 spectrophotometer
(potassium bromide disks). The elemental analysis was carried out using Elementar
Analysen system GmbH VarioEL.
Synthesis Of 3-Arylcoumarins; General Procedure
2-Hydroxy-3,4,5-trimethoxybenzaldehyde (1c) was synthesized from 2,3,4-trimethoxy
benzaldehyde according to the literature.[29] A mixture of salicylaldehyde derivative 1
(0.5 mmol), phenylacetic acid derivative 2 (1 mmol), and DABCO (3 mmol) was heated
at 180 ºC for the appropriate time (Table 1). After the completion of the reaction
(monitored by TLC), it was diluted with ice water and extracted with dichloromethane (3
× 15 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The crude product was recrystallized from ethanol to give pure
compound. All the products were characterized using 1H NMR, 13C NMR, and CHN
analysis.
Selected Data
6,7,8-Trimethoxy-3-(4-Nitrophenyl)-2H-Chromen-2-One (3s)
Yield: 72%, yellow crystals, mp 269-271 oC. IR (KBr): 1733 (C=O) cm-1. 1H NMR (400
MHz, CDCl3): δ = 3.91 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 6.74 (s,
1H, H5), 7.48 (d, J = 8.8 Hz, 2H, H2', H6'), 7.77 (s, 1H, H4), 8.43 (d, J = 8.8 Hz, 2H, H3',
H5'). 13C NMR (100 MHz, CDCl3): δ = 56.3, 61.6, 61.9, 103.7, 115.0, 123.0, 125.6,
6

130.0, 131.6, 133.7, 140.0, 141.0, 142.6, 145.9, 150.3, 160.0. Anal. calcd. for C18H15NO7:
C, 60.51; H, 4.23; N, 3.92. Found: C, 60.37; H, 4.41; N, 4.21.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website. Please
make the words “publisher’s website” a live DOI link.
ACKNOWLEDGMENTS
This research was supported by grants from the research council of Tehran University of
Medical Sciences and Iran National Science Foundation (INSF).
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13

Table 1. Investigation of various conditions for the reaction of salicylaldehyde and
phenylacetic acid
Entry Molar ratio phenylacetic acid:
salicylaldehyde: DABCO
Solvent Time
(min)
Temperature Yield (%)a
(°C)
1
1:1:1.5
1:1:2
_
120
120
110
100
90
180
55
65
65
75
90
10
5
2
_
180
3
1:0.5:2
1:0.5:2.5
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
_
180
4
_
180
5
_
180
6
_
90
140
7
_
90
110
8
_
90
r.t
0
9
EtOH
MeOH
DMF
THF
90
reflux
reflux
130
40
25
70
55
50
10
11
12
13
90
120
120
reflux
reflux
Toluene 120
aIsolated yields.
14

Table 2. Synthesis of 3-aryl coumarine derivatives 3
Entry
1
R
R'
Product 3 Time (min) Yield (%)a
H
H
90
90
81
88
85
93
86
91
79
74
78
75
80
78
80
67
61
65
63
3a
3b
3c
3d
3e
3f
2
H
3,4-diOMe
4-Cl
100
95
3
H
4
H
4-OMe
4-NO2
2,4-diCl
4-F
100
90
5
H
6
H
95
7
H
90
3g
3h
3i
8
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
3,4,5-triOMe
3,4,5-triOMe
3,4,5-triOMe
3,4,5-triOMe
H
115
120
115
120
110
120
110
115
120
120
120
9
3,4-diOMe
4-Cl
10
11
12
13
14
15
16
17
18
3j
4-OMe
4-NO2
2,4-diCl
4-F
3k
3l
3m
3n
3o
3p
3q
3r
H
3,4-diOMe
4-Cl
4-OMe
15

19
20
21
3,4,5-triOMe
3,4,5-triOMe
3,4,5-triOMe
4-NO2
2,4-diCl
4-F
115
120
115
72
65
70
3s
3t
3u
aIsolated yields.
16

Table 3. Structures and inhibition of soybean lipoxygenase (LO) at 100 µM for
coumarins 3a-u in comparison with Quercetin.
Entry
R
R'
Product 3 inhibition of
LO (%) at 100µM
1
H
H
18
3a
3b
3c
3d
3e
3f
2
H
3,4-diOMe
4-Cl
Noa
22
3
H
4
H
4-OMe
4-NO2
2,4-diCl
4-F
No
7.5
15
5
H
6
H
7
H
17.5
17
3g
3h
3i
8
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2-OMe
2,3,4-triOMe
2,3,4-triOMe
2,3,4-triOMe
2,3,4-triOMe
H
9
3,4-diOMe
4-Cl
No
23
10
11
12
13
14
15
16
17
18
3j
4-OMe
4-NO2
2,4-diCl
4-F
No
8
3k
3l
14.6
16
3m
3n
3o
3p
3q
3r
H
18.3
No
27
3,4-diOMe
R4-Cl
4-OMe
No
17

19
20
21
22
2,3,4-triOMe
2,3,4-triOMe
2,3,4-triOMe
Quercetin
4-NO2
2,4-diCl
4-F
6.2
3s
3t
12.7
21.6
100
3u
aNo activity.
18

Scheme 1. Synthesis of 3-arylcoumarins 3 in the presence of DABCO.
19

Scheme 2. Plausible mechanism for the preparation of 3-aryl coumarin 3.
20