Synthesis, potential anti-inflammatory and analgesic activities study of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides

Article abstract of DOI:10.1016/j.bmcl.2017.06.002

A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed moderate COX-2 isozyme inhibitory effects (IC₅₀?=?0.47?μM and 1.63?μM, respectively) and COX-2 selectivity indexes (SI?=?11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2 isozyme active than the reference drug celecoxib.

Full text of DOI:10.1016/j.bmcl.2017.06.002

Accepted Manuscript
Synthesis, potential anti-inflammatory and analgesic activitiesstudy of
(S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides
Li-Ping Guan, Ya-Nan Xia, Qing-Hao Jin, Bing-Yu Liu, Si-Hong Wang
PII:
S0960-894X(17)30605-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.002
BMCL 25036
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
10 March 2017
15 May 2017
2 June 2017
Please cite this article as: Guan, L-P., Xia, Y-N., Jin, Q-H., Liu, B-Y., Wang, S-H., Synthesis, potential anti-
inflammatory and analgesic activities study of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
car boxamides, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2
017.06.002
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Synthesis, potential anti-inflammatory and analgesic
activities study of substituted 3,4-dihydroisoquinoline
2(1H)-carboxamides
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-
a*
a
a
a
b*
Li-Ping Guan , Ya-Nan Xia , Qing-Hao Jin , Bing-Yu Liu , Si-Hong Wang

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis, potential anti-inflammatory and analgesic activities study of (S)-N-
substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides
a*
Li-Ping Guan , Ya-Nan Xia , Qing-Hao Jin , Bing-Yu Liu , Si-Hong Wang
a
a
a
b*
a
Food and Pharmacy College, Zhejiang Ocean University Engineering Technology Research Center of Marine Biomedical Products, Zhejiang, Zhoushan
3
16022, P. R.China
b
Analysis and Test Center, Yanbian University, Jilin,Yanji, 133002, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were
designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among
the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95
Revised
Accepted
%
and 92.7 %, respectively) and analgesic effect (inhibition rate: 100 % and 100 %, respectively),
Available online
which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were
selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase
inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed
moderate COX-2 isozyme inhibitory effects (IC50=0.47 µM and 1.63 µM, respectively) and COX-2
selectivity indexes (SI=11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2
isozyme active than the reference drug celecoxib.
Keywords:
Isoquinoline-2(1H)-carboxamides
Anti-inflammatory
Analgesic
COX-1/COX-2
Inhibition assay
Traditional non-steroidal anti-inflammatory drugs (NSAIDs)
are widely used therapeutics for the inflammation and pain. But,
bleeding and pepticulcer are the main side effects of NSAIDs,
∗ Corresponding author. Tel.: +86-580-2555280; fax: +86-580-2554781;
E-mail: glp730@163.com (L.-P. Guan); shwang@ybu.edu.cn(S.-H.Wang)
1-3
1
1
such as, oxyphenbutazone, indomethacin and ibuprofen develop
the anti-inflammatory effects through non-selective inhibition of
both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
inhibitory activity in vitro. Abdelrahman et al. synthesized a
series of novel quinoline-2-carboxamides and evaluated in vitro
as dual COXs/LOX inhibitors. Two compounds exhibited the
best anti-inflammatory effects and showed the highest potency
and selectivity for COX-2 inhibitory activity.
4
,5
(
Fig 1). So, selective inhibition of COX-2 over COX-1 is
believed to reduce gastrointestinal side effects as a useful method
for treatment of inflammation in medicinal and organic
6
,7
chemistry. Hence, the development of efficient, new selective
COX-2 inhibitors is essential.
Figure 2 Chemical structures of non-selective NSAIDs
Figure 2. Nonselective COX inhibitors such as piroxicam and selective
COX-2 inhibitors (I-II) and the designed derivatives 2a-2s.
Several non-acidic nonselective COX inhibitors and
potential anti-inflammatory activity of COX-2 inhibitors has
been demonstrated with quinazoline ring, is an important moiety
in medicinal chemistry, such as piroxicam (nonselective COX)
inhibitors and tryptanthrin (COX-2 inhibitors: I, II) (Fig.2) with
Our research group has been studying with the chemical and
biological properties of heterocyclic compounds. Based on these
results, in this work, the ammonia reaction of ester was adopted,
a series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2
(1H)-carboxamide derivatives (2a-2s) was designed, synthesized
and evaluated their anti-inflammatory and analgesic effect in vivo
and COX-1 and COX-2 inhibition in vitro.
8
,9
selectivity indexes (SI) of 500, respectively. In addition, Abdel-
1
0
Aziz et al. also reported a new series of 2-substituted mercapto-
(3H)-quinazolinone showed anti-inflammatory and analgesic
activities in vivo, some compounds exhibited effective COX-2
——
4
—

*
*
*
*
*
*
The synthetic routes of the target derivatives are illustrated
in Schemes 1. Compound 1 was synthesized to underwent a
nucleophile substitution reaction with commercial compound (S)-
2h
2i
3.70±3.72
1.43±0.98
2.43±0.98
2.86±1.57
1.14±1.07
61.0
84.9
74.4
69.9
88.0
82.0
92.7
72.9
83.1
74.4
86.3
77.4
-
92.3
89.8
91.1
71.7
100
98.7
100
82.4
89.8
79.7
73.3
96.3
-
**
**
*
2j
1
-phenyl-1,2,3,4-tetrahydroisoquinoline at room temperature in a
good yield (95%). (S)-N-substitued-3,4-dihydro-isoquinoline-
(1H)-carboxamide derivatives (2a-2s) were obtained by stirring
2k
**
2l
*
**
2
2m
2n
1.71±1.8
*
*
**
compound 1 with the appropriate substituted aniline and
benzylamine in methylbenzene containing sodium hydride at
0.69±0.95
2.57±1.27
1.60±0.61
2.43±1.62
1.30±0.95
2.14±1.57
9.49±0.95
0.58±0.78
**
2o
o
10-120 C in 60-82 % yield. The structures of compounds 2a-2s
***
1
were confirmed by spectral data and high resolution mass
spectra. The IR spectra of the synthesized target derivatives 2a-2s
2p
*
*
**
**
2q
2r
-
showed absorption bands at 3221-3288 cm , 1710-1721 cm ,
1
-1
***
2s
-
610-1620 cm corresponding to -NH, -C=O stretching and -
1
1
control
1
C=N group, respectively. H-NMR showed appearance of the -
NH group as singlet signals at 6.46-6.71 ppm and the -CH group
Indomethacin
a
90.4
98.6
b
at 1 h of anti-inflammatory activity. % at 1 h of analgesic activity.
%
1
as singlet signals at 6.38-6.58 ppm. C-NMR spectra displayed
3
** p<0.01 *** p<0.001 compared with the PEG-200 (control) group
the appearance of the new peak at 153.38-157.49 ppm for the
O=C group.
12
Next, compounds 2a and 2n exhibited the most potent anti-
inflammatory activity and were further evaluated anti-inflamma-
tory activity after treatment with three low doses (10, 20 and 30
mg/kg) (Table 2). It should be noted that compounds 2a and 2n
showed to be able to decrease the ear edema in mice, and also
exhibited the anti-inflammatory effect in a dose-dependent
manner from 10 mg/kg to 30 mg/kg. Compound 2a displayed
anti-inflammatory activity with inhibition rate value 60.3%
which was better than that of indomethacin (51 %) at a dose of
1
0 mg/kg.
Table 2. The anti-inflammatory and analgesic activities of compounds 2a and
p at different doses in vivo.
2
Compound
Dose
mg/kg)
Anti-inflammatory
a
activity (%)
Analgesic activity
b
(%)
R:
(
2
2
2
a=H
2b=o-CH
2h=o-F
2n=2,6-Cl
3
2c=m-CH
2i= m-F
2o= o-Br
3
2d=p-CH
2j= p-F
2p= m-Br
3
2e=o-OCH
2k= o-Cl
2q= p-Br
3
2f=m-OCH
2l= m-Cl
3
1
0
60.3
69.6
g=p-OCH
m= p-Cl
3
2
2a
2
3
1
0
0
0
69.5
74.7
44.2
76.4
87.2
58.7
Scheme 1. Synthesis routes of target compounds 2a–2s.
2
p
2
3
0
0
51.7
61.2
51.0
b
63.7
80.2
73.7
Nineteen of the targeted compounds and indomethacin, as a
reference drug, were subjected to anti-inflammatory activity
studies in vivo monitoring xylene-induced ear edema model.
The anti-inflammatory effect of the synthesized compounds was
comparable to indomethacin (10 mg/kg) as reference drugs (Table
Indomethacin
a
10
1
3-15
%
at 1 h of anti-inflammatory activity. % at 1 h of analgesic activity.
Structure activity relationship (SAR) studies for the anti-
inflammatory activity of derivatives 2a-2s mentioned above in
Table 1) displayed that: (1) all compounds reduce the ear
inflammation not only with electron-donating substituent, but
also with electron-withdrawing substituent on phenyl ring, ear
edema (0.47-3.70). (2) For six electron-donor groups with the
1
). The percentage inhibition of anti-inflammatory) of the tested
compounds was measured after 1 h of treatment with xylene-
induced ear edema. All compounds showed ant-inflammatory
activity at a dose of 100 mg/kg administered intraperitoneally
before the inflammatory agent xylene with inhibition rate values
of 61-95 %. Among the synthesized compounds 2a and 2n, both
with no substituent (R:H) and with electron-withdrawing
substituent 2,6-dichloro on the phenly ring, showed the best anti-
inflammatory activity (inhibition rate: 95 % and 92.7 %,
respectively), which was greater than that or nearly equivalent to
that of indomethacin (90.4 %).
(
3 3
introduction of -CH and -OCH , it was obvious to afford the
excellent anti-inflammatory effects at the m-positions of the
phenyl ring as compounds 2c and 2f. In addition, the position of
the substituted greatly influenced anti-inflammatory effects, the
obtained data clearly revealed that the six compounds with –CH3
and-OCH
2
3
substituent are active in the order of: 2c > 2b > 2d and
f > 2e > 2g, respectively. (3) For nine with electron-
Table 1 . In vivo anti-inflammatory and analgesic activities of the designed
compounds (2a-2s)
withdrawing substituent with the introduction of F atoms (2h, 2i
and 2j), Cl atoms (2k, 2l and 2m), or Br atoms (2o, 2p and 2q),
which also exhibited the excellent anti-inflammatory activity at
the m-positions of the phenyl ring as compounds 2i, 2l and 2p.
The position of the halogen atom substituted greatly influenced
the anti-inflammatory effects. Compared with compounds with
different F-substituted positions on the phenyl ring, the order of
activity was m-F > p-F > o-F, and the order of activity observed
for Cl-substituted positions was m-Cl > p-Cl >o-Cl. The order of
activity for with different Br-substituted positions was m-Br > p-
Br > o-Br. But we found compound 2n with 2,6-dichlolo
substituent showed the best anti-inflammatory activity (92%). (4)
Compound
Anti-inflammatory activity
Ear edema Inhibition rate
Analgesic
b
activity (%)
a
(%)
*
*
*
*
**
**
**
**
2
2
a
0.47±0.79
2.32±2.44
1.29±0.72
2.53±2.64
95.0
75.6
86.4
73.3
82.0
85.9
74.7
100
82.4
99.2
93.8
81.5
94.6
93.6
b
2
c
2
d
*
**
2
2
e
1.71±1.1
*
*
**
f
1.34±0.89
2.40±1.72
**
2
g

Compounds 2r and 2s with N,N-diphenyl and N-benzyl
substituent displayed to be able to decrease the ear edema in
mice, by 86.3% and 77.4%, respectively. (5) It is worth
mentioning that the presence of no substituent on the phenyl ring
compound 2a showed the best anti-inflammatory activity, for this
This work was supported by Zhejiang Province Public
Technology Application Project (No. 2017C33131) and the
Science and Technology Program Project of Zhoushan City of
China (No. 2015C41015).
reason, it was difficult to determine
a structure-activity
relationship for the different substituent group attached to phenyl
ring.
The analgesic effect of the synthesized derivatives 2a-2s
1. Abdellatif, K.R.A.; Fadaly, W.A.A.; Azouz, A.A. Arch.
Pharm. Chem. Life Sci. 2016, 349, 801-807.
was evaluated in mice using the hot plate technique at 60 min
o
after intraperitoneal injection at 58
indomethacin as reference drugs.
C
comparable to
All compounds exhibited
2. Wallace, J.L.; McCafferty, D.M.; Carter, L.; McKnight, W.;
Argentieri, D. Gastroenterology 1993, 105, 1630.
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10 Abdel-Aziz, A.A.-M.; Abou-Zeid, L.A.; ElTahir, K.E.H.;
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12. The synthesis of (S)-N,1-diphenyl-3,4-dihydroisoquinoline-
2(1H)-carboxamide (2a): To a flask containing toluene (30
mL) and(S)-ethyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate (1 mmol, 3g) was heated at 110 °C under reflux
for 2 h. Then, substituted aniline (5 mmol) and NaH (1.6
mmol, 0.4 g) was added, the reaction mixture was heated at
16-18
potent analgesic activity at a dose of 100 mg/kg administered
intraperitoneally with inhibition rate values of 71.7-100 % (Table
1
). Compounds 2a, 2l, 2m and 2n exhibited the excellent
analgesic activity (inhibition rate: 100 %, 99.2%, 100%, 98.7%
and 100 %, respectively), which was nearly equivalent to that of
indomethacin (98.6 %). Moreover, we also found that
compounds 2c, 2f, 2i, 2l and 2p exhibited better analgesic effect
at the m-positions of the phenyl ring not only with electron-
donating substituent (2b-2g) but also with electron-withdrawing
substituent (2h-2m, 2o-2q) on phenyl ring. Interestingly, the
unsubstituted of the phenyl ring compound 2a exhibited the best
analgesic activity, and exhibited the anti-inflammatory effect in a
dose-dependent manner from 10 mg/kg to 30 mg/kg.
Compounds 2a and 2n exhibited the best analgesic and anti-
inflammatory effects were tested for their inhibitory activity
against ovine COX-1 and COX-2 (Table 3). The results displayed
that compounds 2a and 2n are weak inhibitors of COX-1
isozyme but exhibited moderate COX-2 isozyme inhibitory
effects (IC50=0.47 µM and 1.63 µM, respectively) and COX-2
selectivity indexes (SI=11.5 and 4.8). Furthermore, compounds
2
a was more inhibitors of COX-2 isozyme active than the
reference drug celecoxib (IC50 =0.66 µM, SI=9.7). Traditional
NSAIDs possess the anti-inflammatory activity through non-
selective inhibition of both COX-1 and COX-2, such as aspirin,
19,20
indomethacin and ibuprofen.
Bleeding, gastrointestinal
irritation and ulceration side effects of the classical NSAIDs are
due to high COX-1 versus COX-2 selectivity. Therefore, the
development of efficient, new and selective COX-2 inhibitors is
2
1-23
essential in medicinal chemistry approaches.
1
10-120 °C. The reaction was monitored by TLC until the
Table 3. COX-1/COX-2 enzyme inhibition assay in vitro
a
reaction was over. Then the products was added sodium
chloride and extracted with acetic ether (30 mL×2), acetic
ether layer was washed with 10 ml 20 % HCl, then adjusted
pH 10 with 2 mol/L NaOH, the crude product was purified
using 95 % EtOH. Yield: 65 %, mp: 132.1-133.4 °C. IR
b
Compound
COX-1, IC50(µM)
COX-2, IC50(µM) COX-2, SI
2
2
a
5.42
0.47
1
1.5
cm-1
1
p
7.85
6.41
1.63
0.66
(
KBr)
MHz ): δ 2.92-2.97 (2H, t, -CH
.46 (1H, s, -CH), 6.56 (1H, s, -NH), 6.95-7.04 (4H, m, -
C H ), 7.06-7.25 (5H, m, -C H ), 7.30-7.36 (5H, m, -C H ).
: 3280, 1714, 1612, 1249. H-NMR (CDCl
3
, 300
4
.8
.7
2
), 3.75-3.78 (2H, t, -CH
2
),
Celecoxib
9
6
a
IC50 value is the compound concentration required to produce 50%
6
4
6
5
6
5
1
3
inhibition of COX-1 or COX-2 for means of three determinations and
deviation from the mean is <10% of the mean value.
C-NMR (CDCl , 75 MHz): δ 28.51, 40.47, 58.05, 120.03,
3
123.11, 126.53, 127.29, 127.52, 128.22, 128.45, 128.68,
128.86, 134.91, 136.23, 139.05, 142.50, 155.07. ESI-HRMS
b
SI: selectivity index (COX-1 IC50/COX-2 IC50 ).
+
+
20 2
calcd for C22H N O ([M+H] ): 328.4070; found: 328.4079.
A new series of (S)-N-substitued-1-phenyl-3,4-dihydro-
isoquinoline-2(1H)-carboxamide derivatives was synthesized for
evaluation as anti-inflammatory agents and analgesic agents in
vivo. All compounds showed good anti-inflammatory and
analgesic activities in vivo. Compounds 2a and 2n exhibited
better anti-inflammatory and analgesic activities than
indomethacin. In addition, compounds 2a and 2n are weak
inhibitors of COX-1 isozyme but exhibited moderate COX-2
isozyme inhibitory effects. Furthermore, compound 2a was more
inhibitors of COX-2 isozyme active than the reference drug
celecoxib.
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