Design, synthesis and biological evaluation of novel 4-hydroxybenzene acrylic acid derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.12.063

A series of 4-hydroxybenzene acrylic acid derivatives were designed and synthesized based on the ferulic acid of natural active ingredients. The tested compound 5a, 5f and 6a have significant anti-inflammatory activity with suppression rates of 45.29%, 44.75% and 24.11%, respectively, compared with that of indomethacin, and their cardiac toxicity was not observed. The structure-function relationship shows that the p-hydroxyl group on the α-position benzene ring, particularly if acetylated, contributes to the considerable anti-inflammatory activity; that the carboxyl group on the double bond, if esterified, also contributes to the anti-inflammatory activity; that the p-methylsulfonyl group on the other benzene ring, whose introduction is due to the COX-2 selectivity, also contributes to anti-inflammatory activity surprisingly.

Full text of DOI:10.1016/j.bmcl.2010.12.063

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1549–1553
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of novel 4-hydroxybenzene
acrylic acid derivatives
Jin-Long Mao a, Xiang-Kai Ran b, , Jing-Zhen Tian a, Bo Jiao c, Hong-Lei Zhou a, Li Chen d, Zhen-Guo Wang e
⇑
a School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
b School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Road, Jinan 250100, Shandong Province, China
c School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
d Qilu Hospital, Shandong University, 107, Western Culture Road, Jinan 250012, China
e School of Information, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 4-hydroxybenzene acrylic acid derivatives were designed and synthesized based on the ferulic
acid of natural active ingredients. The tested compound 5a, 5f and 6a have significant anti-inflammatory
activity with suppression rates of 45.29%, 44.75% and 24.11%, respectively, compared with that of indo-
methacin, and their cardiac toxicity was not observed. The structure–function relationship shows that the
Received 16 October 2010
Revised 28 November 2010
Accepted 15 December 2010
Available online 23 December 2010
p-hydroxyl group on the a-position benzene ring, particularly if acetylated, contributes to the consider-
able anti-inflammatory activity; that the carboxyl group on the double bond, if esterified, also contributes
to the anti-inflammatory activity; that the p-methylsulfonyl group on the other benzene ring, whose
introduction is due to the COX-2 selectivity, also contributes to anti-inflammatory activity surprisingly.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ferulic acid
4-Hydroxycinnamic acid
NSAIDs
Anti-inflammatory
Cardiac toxicity
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the
most widely used drugs, having anti-inflammatory, analgesic, and
antipyretic effects. There are more than 50 kinds of NSAIDs on the
market, of which the main products include aspirin, diclofenac,
ibuprofen, naproxen, indomethacin and so on, but gastrointestinal
disorders and cardiovascular risks remain to be the most common
side effects in those who use these drugs long-term.1 The newly
developed cyclooxygenase (COX-2) inhibitors obviously reduce
the incidences of ulcers and hemorrhages, being effective as the
relief of pain and inflammation. On the other hand, they increase
the incidence of cardiovascular risk.2
anti-inflammatory and anti-cancer activities by acetylation of the
hydroxyl group of the ferulic acid (Fig. 2, 2a).5,6 Mou et al. revealed
that compounds similar to a-phenylcinnamic acid (Fig. 2, 2b) had
powerful vasodilatory activity, in addition to displaying a certain
degree of potassium-channel activation, and were promising for
prevention and treatment of hypertension.7
4-Hydroxybenzene acrylic acid derivatives of formula (Fig. 1, 1)
are on the basis of ferulic acid of natural active ingredients, introduc-
ing the cyclooxygenase and lipoxygenase structure–activity group.
The compound (Fig. 1), 5a is one of the typical derivatives, its struc-
ture is characterized by two benzene rings being ‘cis’ to each other
Ferulic acid, which derived from 4-hydroxybenzene acrylic acid
(para-hydroxycinnamic acid), is the main active ingredient of angel-
ica and white peony root, both of which are traditional Chinese her-
baceous drugs. The ferulic acid has not only anti-inflammatory and
antibacterial effects, but lowers lipid levels significantly in the
serum, prevents thrombosis, and advances coronary artery disease,
however, no obvious toxicity is observed. Sodium ferulate, the
sodium salt of ferulic acid, is to treat cardiovascular and cerebrovas-
cular diseases and to prevent thrombosis.3 The efficacy of sodium
ferulate in the treatment of focal cerebral infarction was about
83.3% in a 36 case clinical trials.4 Liu et al. found that better
across the unsaturated bridge in the
a- and b-position of the deriv-
atives, The benzene ring in the -position has the methylsulfonyl or
a
aminosulfonyl group, and the benzene ring in the b-position has the
p-hydroxyl group, which form para-hydroxy styrene structure with
unsaturated double bond, and which furthermore form para-
hydroxybenzene acrylic acid with the carbonyl group.
In the compounds of formula (1), para-hydroxystyrene deriva-
tives (Fig. 2, 2c) have excellent activities.8,9 The p-hydroxyl group
on the ring is essential for activity as an inhibitor of PGS, and lack
of it exhibits a striking loss of anti-inflammatory activity and a de-
crease in PGS inhibitory activity. The double bond of the styrene
has a conjugated system combined with an arachidonic acid, which
enhances the activity, and saturation of the double bond decreases
the activity. The methylsulfonyl group on the other benzene ring is
due to the COX-2 selectivity.10 Furthermore, these compounds also
⇑
Corresponding author. Tel.: +86 531 88382378; fax: +86 531 82169408.
E-mail address: maojinlong@gmail.com (X.-K. Ran).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.063

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J.-L. Mao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1549–1553
Figure 1. Ferulic acid and the new derivatives designed.
Scheme 2. Synthesis of substituted benzaldehydes. Reagents and conditions: (a)
CH3COCl, alcohol, 80 °C, 1 h, 4a 91% (mp 77–78 °C); (b) methyl sulfate, 10%NaOH
solution, reflux, 2 h, 4b 78% (mp 42–43 °C), 4e 94% (mp 43–44 °C), 4g 82% (mp 60–
61 °C); (c) cinnamic acid, SOCl2, 80 °C, 3 h, 4c 85% (mp 89–90 °C); (d) Br2, methanol,
rt, 3 h, 4d 65% (mp 123–124 °C), 4f 86.5% (mp 163–164 °C).
Figure 2. Active p-hydroxycinnamic acid derivatives reported.
represent strong 5-LOX inhibitory effect.11,12 Dual inhibitors of the
COX-2 and 5-LOX pathways may provide safer NSAIDs, and the
simultaneous modulation of them may reduce the cardiovascular
risk of COX inhibitors.13–15
For the synthesis of p-hydroxybenzene acrylic acid derivatives,
substituted phenylacetic acids are condensated with substituted
Scheme 3. Perkin condensation of phenylacetic acids with benzaldehydes.
benzaldehydes to give a-phenylcinnamic acid derivatives through
the amine-catalyzed Perkin condensation.16,17
A mixture of 3, 4a, acetic anhydride, and triethylamine was heated
to 140 °C and then acidified, filtered and dried, gave 5a as a
off-white solid, and 5a was also obtained by condensated 3 with
vanillin in the similar conditions. If 5a was hydrolyzed in the
solution of sodium hydroxide, then the acetyl was eliminated
and 5b was achieved. Compound 5c was achieved from 3 and 4b
in the similar conditions.
If the 3 was first esterified, gave ethyl 4-methylsulfonypheny-
lacetate, and then condensated with vanillin, but somehow 6a or
6b can not be obtained. Therefore, 6b was first achieved by ester-
ification of 5a or 5b in ethanol catalyzed by concentrated sulfuric
acid, subsequent treatment with acetic anhydride, ultimately
yielded 6a. Compound 6f was obtained by esterification of 5a in
methanol similar to 6b. Compounds 5h and 5i were obtained from
treatment of 5a and 5c at appropriate temperature and basic con-
4-Methylsulfonylphenylacetic acid (3) is an important interme-
diate, prepared by the way as shown in Scheme 1. It was carried
out by converting acetophenone to phenylacetic acid through the
Willgerodt rearrangement.18,19 4-Methylmercaptoacetophenone
(3a) was prepared by acidation of thioanisole on the para-position
through the Friedel–Crafts reaction, then oxidized to 4-methylsulf-
onylacetophenone (3b).20–22 A mixture of 3b, sulfur, and morpho-
line was refluxed for 10 h, and then treated with sodium hydroxide
for 10 hours, finally acidified, gave the 4-methylsulfonylphenylace-
tic acid.23
The synthesis of substituted benzaldehydes is depicted in
Scheme 2. Acylation of vanillin with acetyl chloride gave 4a.24
Similarly treatment with cinnamic acid and thionyl chloride yielded
4c. Alkylation of vanillin with dimethyl sulfate in alkaline conditions
gave 4b.25 Bromination of 4-hydroxybenzaldehydes with bromine
in methanol at low temperature yielded 4d and 4f,26,27 which was
followed by treatment with dimethyl sulfate to give 4e and 4g.
The synthesis of (E)-2-(4-methylsulphonylphenyl)-3-(3-meth-
oxyl-4-acetoxylphenyl) acroleic acid (5a) is shown in Scheme 3.
ditions. Other
a-phenylcinnamic acid derivatives were accom-
plished by the amine-catalyzed Perkin condensation of
phenylacetic acids with benzaldehydes according to the corre-
sponding methods as shown in Scheme 4.
In order to observe the activity of methylsulfonyl group of the
a-position benzene ring and the p-hydroxyl group of the b-position
benzene ring, no methylsulfonyl group of 9a, 9b, 9c and no
p-hydroxyl group of 9d were synthesized. 9a was obtained from
phenylacetic acid and vanillin by a procedure similar to 5a, then
hydrolyzed in the solution of sodium hydroxide gave 9b, and then
methylated with dimethyl sulfate in alkaline conditions gave 9c.
Compound 9d was obtained from 3 and benzaldehyde by a
procedure also similar to 5a.
Based on the ferulic acid, a series of 4-hydroxybenzene acrylic
acid derivatives (Table 1) were designed and synthesized, and 26
of them were not reported in literatures. These compounds were
determined by spectra, and they are the (E)-isomers, bearing a
a
,b-double bond of acrylic acid bridging the two aromatic rings
Scheme 1. Synthesis of 4-methylsulfonylphenylacetic acid (3). Reagents and
conditions: (a) AlCl3, CH3COCl, CHCl3, rt, 2 h, 3a 90.0% (mp 80–81 °C); (b) H2O2,
H3PO4, CH3COOH, reflux, 3 h, 3b 96% (mp 126–127 °C); (d) (i) S, morpholine, 130 °C,
10 h; (ii) NaOH solution, 85 °C, 10 h, 3 52% (mp 135–136 °C).
in a cis-position. The (Z)-isomers have not been obtained.
Ketcham et al. reported that the triethylamine-catalyzed phen-
ylacetic acids with benzaldehydes in acetic anhydride, afforded

J.-L. Mao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1549–1553
1551
Table 1
Structure and melting point of compounds designed
Compd
R1
R2a
R3
R4
R5
Mp (°C)
Formula (1)
O
5a
CH3O
H
H
SO2CH3
225–226
CH3C-O
5b
5c
CH3O
CH3O
HO
CH3O
H
H
H
H
SO2CH3
SO2CH3
222–223
232–233
O
5d
5e
CH3O
CH3O
H
H
H
SO2CH3
SO2CH3
250–251
220–221
O
H
CH3O
O
5f
H
H
H
H
H
H
SO2CH3
SO2CH3
213–214
219–220
CH3C-O
5g
HO
O
5h
5i
CH3O
CH3O
H
H
Na
Na
SO2CH3
SO2CH3
197–199
251–253
CH3C-O
CH3O
O
6a
CH3O
H
CH2CH3
SO2CH3
129–130
CH3C-O
6b
6c
CH3O
CH3O
HO
CH3O
H
H
CH2CH3
CH2CH3
SO2CH3
SO2CH3
178–179
163–164
O
6d
CH3O
H
CH2CH3
SO2CH3
171–173
O
6e
6f
CH3O
CH3O
H
HO
CH3O
H
CH2CH3
CH3
SO2CH3
SO2CH3
134–135
170–171
O
7a
H
Br
H
SO2CH3
210–212
CH3C-O
O
7b
CH3O
Br
H
SO2CH3
224–226
CH3C-O
Scheme 4. Synthesis of target compounds. Reagents and conditions: (a) Ac2O, Et3N,
130–140 °C, 3 h; (b) NaOH solution, 80 °C, 0.5 h; (c) alcohol, 98% H2SO4, 90 °C, 5 h;
(d) Ac2O, 130–140 °C, 3 h; (e) NaOH solution, 30 °C, 0.5 h.
7c
7d
8a
8b
H
CH3O
H
HO
HO
HO
HO
Br
Br
Br
Br
H
H
SO2CH3
SO2CH3
SO2CH3
SO2CH3
216–218
225–227
110–111
171–172
CH2CH3
CH2CH3
CH3O
O
‘trans-isomer’ of
a-phenylcinnamic acids, but in about half of the
8c
8d
9a
H
Br
Br
H
CH2CH3
CH2CH3
H
SO2CH3
SO2CH3
H
103–105
148–150
205–207
CH3C-O
condensations reported none of the ‘cis-isomer’ has been ob-
tained.16 The ‘trans-isomer’ had a lower solubility and a higher
melting point than the ‘cis-isomer’ in each pair. The ‘trans-isomer’,
which was ambiguous as it may refer to the structure of cinnamic
acid in his literature, and which was just corresponding to the (E)-
isomer rather than the (Z)-isomer, was precisely the structure of
two aromatic rings in a cis-position of double bond. The structure
can be proved by the data that the melting point of compound
O
CH3O
CH3O
CH3C-O
O
CH3C-O
9b
9c
9d
CH3O
CH3O
H
HO
CH3O
H
H
H
H
H
H
H
H
H
186–188
228–229
229–230
SO2CH3
R2 = OR , in Figure 1, formula (1).
a
2
0
(I),
a-phenylcinnamic acid, ‘trans-isomer’ was 172–173 °C in his
literature, which was matched with the ‘cis-isomer’ (172–173 °C)
in the other literature.28 The compound 9b synthesized by the
reaction system has a melting point of 186–188 °C, also reported
as the (E)-isomer.29
In addition, it is quite possible to perform analysis of the
structure by the 1H NMR. The isolated hydrogen of the double bond
(Ph–CH@C–Ph) in the
a-phenylcinnamic acid has a displacement
in the (E)-isomer is larger than in the (Z)-isomer, its displacement
is about 7.95 (D2O) or 7.80 (DMSO), single for the (E)-isomer more
than 7.08 (D2O), single for the (Z)-isomer.30,31 About these target
compounds, the isolated hydrogen have a similar displacement
about 7.85 (DMSO) in 5a by the 2D NMR of HMQC analysis as
shown in Figure 3, 7.74 (DMSO) in 5b (deacetylated from 5a),
7.85 (CDCl3) in 6b (esterified from 5a), 7.87 (CDCl3) in 6f (esterified
from 5a), and 7.56 (D2O) in 5h (the salt of 5a), which are very close
to the data of the (E)-isomer.32
Stereochemistry of double bond in these compounds can also be
determined spectroscopically. The displacement of olefinic proton
is 7.87 (CDCl3), and the methyl esters is 3.82 (CDCl3) in 6f.33 The
correlation between olefinic proton and methyl ester in 6f (esteri-
fied from 5a) typically reveal two benzene rings being ‘cis’ to each
other and the stereochemistry of the (E)-isomer by the 2D NMR of
NOESY analysis as shown in Figure 4.
The anti-inflammatory activity of compounds were tested
through a xylene-induced ear edema mouse model method.34 Kun-
ming mice, consisting of both males and females, each weighing
Figure 3. 2D NMR of HMQC analysis of 5a.
18–22 g, are divided into groups of 10 at random. The tested com-
pounds and indomethacin which are made into suspensions using
5‰ CMC-Na are administered orally to the dose group and the po-
sitive control group, respectively, while the base control group is
treated with only 5‰ CMC-Na. One hour later after administration,

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J.-L. Mao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1549–1553
as its absence in 5e and 9d is associated with decreased suppres-
sion rates of 10.60% and 17.49% at a dose of 300 mg/kg, respec-
tively, when compared with the 15.92% and 44.75% of 5c and 5f
at the same dose, respectively. (2) Acylation of the p-hydroxyl
group significantly improves anti-inflammatory activity, as the
suppression rate of 5a is 45.29% at a dose of 300 mg/kg, while that
of 5b is only 9.97%. (3) When the same p-hydroxyl group is alkyl-
ated to a methoxy in 5c, the suppression rate of 15.92% is higher
than that of the untreated 5b, but not as high as that of the acety-
lated 5a. (4) Esterification of the carboxyl group on the double
bond, also on the incorporated ferulic acid, improves anti-inflam-
matory activity, as exemplified by the suppression rate of 34.62%
of 6b, compared with that of 5b. (5) When bromine is introduced
into the structure, anti-inflammatory activity will be lost, as shown
in 8c. (6) If the methylsulfonyl group (–SO2CH3) on the p-position
of the ring, which is not derived from ferulic acid and which has
been proved by the diaryl heterocyclic inhibitors to impart selec-
tive inhibition effects on cyclooxygenases, is removed, some anti-
inflammatory activity is retained as is shown by 21.86% of 9a,
but it is clearly lower than that of 5a.
Figure 4. 2D NMR of NOESY analysis of 6f (esterified from 5a).
Table 2
Anti-inflammatory activity of the test compounds
In the cardiac toxicity experiments, the groups are adminis-
tered orally every other day, a total of six times.35 Compounds
are treated similarly to anti-inflammatory activity. The growth
and behavior of mice is observed, such as condition of hair coat,
eating, and activities. All the mice anesthetized with sodium pen-
tobarbital are killed by cervical dislocation at the 12th day, atria
are isolated immediately after death, and are washed in phosphate
buffered saline, and the left ventricular fragments are prepared for
electron microscopy. The myocardial lesion is evaluated by exam-
ination on the pathologic changes of transverse and longitudinal
sections of the whole ventricle between the groups. There is no
tangible results for toxicity signs, such as reducing of activities,
decreased eating, loose fur, loss of hair and so on between the
control group and the dose groups (Table 3). The spectra of myo-
cardial tissue are also no significant difference or abnormal
changes in the groups.
Compd
Dose
(mg/kg)
Mice
Ear swelling
levels
Suppression rates
(%)
Base control
Indometacin
5a
—
9
22.36 3.30
14.08 3.94**
10.87 1.79**
14.68 4.16*
17.41 4.82
12.35 3.22**
15.01 2.45**
17.14 2.51*
21.14 3.7
—
100
300
150
75
300
150
75
300
300
300
300
300
75
10
10
10
10
10
10
10
9
10
10
10
10
10
10
10
37.03
45.29
26.12
12.38
44.75
32.87
23.34
9.97
15.92
10.60
24.11
34.62
0
5f
5b
5c
5e
6a
6b
8c
9a
9d
18.74 1.82*
16.70 2.63
15.74 1.43**
15.35 4.26*
20.97 2.77
17.47 3.29*
18.45 2.81*
300
300
21.86
17.49
In conclusion, a series of 4-hydroxybenzene acrylic acid deriva-
tives of formula (1) were designed and synthesized, the presented
compound 5a, 5f and 6a have significant anti-inflammatory activity
with suppression rates of 45.29%, 44.75% and 24.11%, respectively,
compared with that of indomethacin. The structure–function
Results are expressed in mean SD, significance levels.
*
P <0.05.
**
P <0.01, as compared with the base control group. Experiments were completed
in twice.
relationship shows that the p-hydroxyl group on the a-position ben-
zene ring, particularly if acetylated, contributes to the considerable
anti-inflammatory activity; that the carboxyl group on the double
bond, if esterified, also contributes to the anti-inflammatory activ-
ity; that the p-methylsulfonyl group on the other benzene ring,
whose introduction is due to the COX-2 selectivity, also contributes
to anti-inflammatory activity surprisingly.
The cardiac toxicity of the tested compounds are not observed,
and the spectra of myocardial tissue are no significant difference
and abnormal changes between the dose group and the base con-
trol group. The NSAIDs, especially such as rofecoxib and celecoxib,
are associated with risk of cardiovascular events, which is a long
slow process. The mechanism of action for the potential risk is still
uncertain. To establish a feasible model for exact experiments of
these compounds is difficult in short periods of time, but cardiac
toxicity is not observed, it is possibly matched with anti-inflamma-
tory and cardiovascular activity of these derivatives.
Table 3
Cardiac toxicity of the test compounds
Compd
Dose*
(mg/kg)
Mice
Toxic
deaths
Toxic
signs
Myocardial
lesions
Base control
Indometacin
5a
6a
—
10
10
10
10
1/10
0/10
0/10
1/10
NTSa
NTS
NTS
NTS
NTS
NTS
NTS
NTS
100
150
150
NTS: no tangible symptoms.
a
Single, every other day, a total of six times.
50 lL of xylene is applied to both sides of right ears of the mice,
while left ears are left untreated as control. Another hour later after
swelling is induced, mice were killed and each of the two auricles
from a mouse is fetched with an 8 mm punching device and
weighed. The anti-inflammatory activity of each tested compound
is assessed through the suppression rate of ear swelling level.
The structure–function relationship, as revealed by the anti-
inflammatory activity from animal experiments associated with
the test compounds (Table 2), may be summarized as follows.
(1) The p-hydroxyl group with pharmacological activity
proposed by 4-hydroxystyrene derivatives, contributes to activity,
Acknowledgments
This work was supported by the Natural Science Foundation of
Shandong Province (Project Z2008C05), and by the Major State
Basic Research Development Program of China (973 Program
2007CB512601). The authors wish to express their gratitude to
Zhan Chen who works in the School of Foreign Languages of

J.-L. Mao et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1549–1553
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