Synthesis and biological evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipidemic and antioxidant agents

Article abstract of DOI:10.1016/j.ejmech.2009.10.036

N-aryl-1,4-dihydropyridines 2a-n were synthesized via iodine catalyzed three-component reaction of cinnamaldehydes, anilines and 2-keto esters in methanol. The synthesized compounds were screened for their antidyslipidemic and antioxidant activity in vivo

Full text of DOI:10.1016/j.ejmech.2009.10.036

European Journal of Medicinal Chemistry 45 (2010) 501–509
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological evaluation of N-aryl-1,4-dihydropyridines
as novel antidyslipidemic and antioxidant agents
,
a
a
a
b
Atul Kumar a , Ram Awatar Maurya , Siddharth Sharma , Mukesh Kumar , Gitika Bhatia
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, UP 226001, India
b Biochemistry Division, Central Drug Research Institute, Lucknow – 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
N-aryl-1,4-dihydropyridines 2a–n were synthesized via iodine catalyzed three-component reaction of
cinnamaldehydes, anilines and 2-keto esters in methanol. The synthesized compounds were screened for
their antidyslipidemic and antioxidant activity in vivo and in vitro. Compounds 2a, 2g, and 2l have
exhibited promising lipid and TG lowering activity, whereas compounds 2m and 2n have showed potent
antioxidant activity.
Received 26 May 2009
Received in revised form
16 August 2009
Accepted 22 October 2009
Available online 31 October 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
1,4-Dihydropyridines
Antidyslipidemic
Antioxidant
1. Introduction
lipoproteins present in the blood, which are responsible for the
initiation and progression of atherosclerosis [20]. Hyperlipidemia
Atherosclerosis and related diseases represent the prevalent
cause of morbidity and mortality in industrialized countries [1–4].
Elevated level of plasma concentration of cholesterol, especially
low density lipoprotein (LDL) and triglyceride along with free
radical oxidative stress are recognized as leading cause in the
development of atherosclerosis and coronary heart disease [5–10].
There is now an increasing amount of experimental and clinical
evidences which shows the involvement of oxidative modifications
of low density lipoproteins (LDL) in the pathogenesis of athero-
sclerosis. In most cases, oxidative damage takes place in the low
density lipoprotein (LDL) of plasma by the hydroxyl radicals
generated by the metal ions present in the serum due to the
alterations in their oxidation states [11,12]. The drugs, currently
being used in the treatment of dyslipidemia [13–19], act by
lowering cholesterol or by lowering triglyceride levels in plasma.
The commonly used antidyslipidemic statins have several side
effects like myositis, arthralgias, gastrointestinal upset and elevated
liver function tests. Therefore, there is need to discover potentially
better antidyslipidemic agents with minimum side effects.
may also induce other abnormalities like oxidation of free fatty
acids, leading to the formation of ketone bodies as well as masking
liver and muscles resistance to insulin which initiates the progress
of diabetes in patients [21]. Furthermore, in hyperglycemic
patients, several non-enzymatic glycosylation occurs accompanied
by glucose oxidation catalyzed by Cu2þ and Fe2þ resulting in the
formation of Oꢀ2 and ꢀOH radicals which further accelerates the risk
of cardiac diseases in dyslipidemic patients [22]. Therefore, besides
cholesterol lowering property, a hypolipidemic agent incorporating
antioxidant activity will be able to protect endothelial and
myocardial function and could serve as a better antiatherosclerotic
agent.
Hantzsch 1,4-dihydropyridines (1,4-DHPs) 1 are an important
class of biologically active heterocycles. The 1,4-DHPs 1 have been
shown to possess diverse range biological activities like anti-
hypertension [23], antitubercular, antioxidant [24,25], antiviral
[26], and anticancer activity [27]. Many members of this series (1,4-
DHPs) such as nifedipine, nicardipine, amlodipine, and felodipine
are clinically approved as drugs for the treatment of hypertension
and cardiovascular diseases. Cerivastatin (Fig. 1) was a synthetic
member of the class of statins, used to lower cholesterol and
prevent cardiovascular disease. It was withdrawn from the market
in 2001 because of the high rate of serious side effects [28].
Although Hantzsch 1,4-DHPs 1 have been extensively studied, the
corresponding N-aryl, 5 or 5,6-unsubstituted 1,4-DHPs 2 (Fig. 1) are
The involvement of hydroxyl free radicals has been shown to be
a
major contributing factor for the peroxidative damage to
* Corresponding author. Tel.: þ91 522 2612411; fax: þ91 522 2623405.
E-mail address: dratulsax@gmail.com (A. Kumar).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.10.036

502
A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
F
F
R2
R
O
R3
R4
R1
R
OH OH
O
OH OH
O
R1
O
OH
HO
OH
N
H
N
R2
2
N
N
1
Demethylated cerivastatin
NO2
Cerivastatin
Cl
Cl
NO2
COOMe MeOOC
O
CH2Ph
N
Cl
COOEt
MeOOC
NH2
MeOOC
COOEt MeOOC
O
O
N
H
N
H
N
N
H
H
Nicardipine
Felodipine
Nifedipine
Amlodipine
Fig. 1. Bioactive dihydropyridines and pyridines.
R
R
R1
O
R2
R6
NH2
O
R3
R4
R1
R2
I2
R6
N
+
+
R3
R4
Methanol
rt, 1 hr
O
CHO
R5
5
4
3
R5
2
Scheme 1. Synthesis of N–aryl–1, 4–dihydropyridine.
not well explored [29–31]. In our ongoing research towards the
exploration of biologically important heterocycles [32–34], recently
we also reported organocatalyzed N-aryl-1,4-dihydropyridines via
a simple multi-component reaction for the synthesis of same class
of compound [34]. we report here molecular iodine catalyzed
synthesis and antidyslipidemic as well as antioxidant activity of
1,4-DHPs of type 2.
Table 1
Synthesis of N-substituted 1,4-DHPs.a
R6
O
R5
N
R
R3
R4
R1 R2
2. Chemistry
2
1,4-DHPs 2 were synthesized via molecular iodine catalyzed
three-component reaction of substituted cinnamaldehydes,
anilines and 2-keto esters (Scheme 1). Although the reaction was
sluggish in dichloromethane, chloroform, THF, DMF, high yields of
products were obtained in methanol. Stirring a mixture of cinna-
maldehyde (1 mmol), aniline (1 mmol), 2-keto ester (1 mmol), and
molecular iodine (5 mol%) in methanol at room temperature was
found to be an optimized reaction condition for the synthesis of 1,4-
DHPs 2. Using optimized reaction protocol, we synthesized a series
of N-aryl-1,4-DHPs (Table 1).
Entry
R
R1
R2
R3
R4
R5
R6
Product Yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
CH3
F
Cl
Br
H
OC2H5 2a
OC2H5 2b
OC2H5 2c
OC2H5 2d
OC2H5 2e
OC2H5 2f
90
88
89
85
88
90
89
88
92
87
91
90
81
80
H
OCH3
2g
2h
2i
2j
2k
2l
OCH3 OCH3
9
H
H
H
H
H
Cl
OCH3
OCH3
OCH3
OCH3
OtBu
OtBu
10
11
12
13
14
CH3
3. Biological activity evaluation
CH3 CH3 CH3
H
H
H
H
H
H
2m
2n
3.1. Antidyslipidemic activity
H
H
a
Reaction conditions: cinnamaldehyde (1 mmol), aniline (1 mmol), 2-keto ester
(1 mmol), I2 (5 mol%), methanol, rt, 1 h.
Lipid lowering and post heparin lipolytic activity: The anti-
dyslipidemic activities of compounds 2a–n were evaluated in
b
Isolated yield.

A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
503
350
300
250
200
150
100
50
0
Test samples
Fig. 2. Total cholesterol lowering activity of compounds 2a–n and the standard drug gemfibrozil.
developed by administration of Triton WR-1339 (Sigma chemical
co., St. Louis, USA) at a dose of 400 mg/kg body wt. intraperito-
neally to animals of all groups except the control. Compounds
2a–n were macerated with gum acacia (0.2% w/v), suspended in
water and fed simultaneously with triton at a dose of 100 mg/kg
po to the animals of treated groups. Animals of the control and
triton group without treatment with test compounds were given
same amount of gum acacia suspension (vehicle). After 18 h of
treatment 1.0 mL blood was withdrawn from retro-orbital sinus
using glass capillary in EDTA coated eppendorf tube (3.0 mg/mL
blood). The blood was centrifuged (at 2500g) at 4 ꢂC for 10 min
and the plasma was separated. Plasma was diluted with normal
saline (ratio 1:3) and used for analysis of total cholesterol (TC),
phospholipids (PL), triglycerides (Tg) by standard enzymatic
procedures. Post heparin lipolytic activity (PHLA) was assayed
(Wing and Robinson, 1968) using spectrophotometer and Beck-
mann auto-analyzer and standard kits purchased from Beckmann
Coulter International, USA.
Table 2
Total cholesterol lowering activity of compounds 2a–n and the standard drug
gemfibrozil.
Entry
Compounds
Total cholesterol
lowering activity (%)
S.Da
1
2
3
4
5
6
7
8
Control
–
1.78
1.85
5.01
4.27
4.54
5.43
4.79
4.70
4.60
3.54
4.60
6.94
6.37
6.75
4.67
4.24
4.27
Triton only
Triton þ 2a
Triton þ 2b
Triton þ 2c
Triton þ 2d
Triton þ 2e
Triton þ 2f
Triton þ 2g
Triton þ 2h
Triton þ 2i
Triton þ 2j
Triton þ 2k
Triton þ 2l
Triton þ 2m
Triton þ 2n
Triton gemfibrozil
3.50
21.9
18.7
17.0
16.0
18.3
14.0
24.8
15.0
11.0
18.1
12.2
24.1
11.5
15.5
37.1
9
10
11
12
13
14
15
16
17
a
3.2. Antioxidant activity
Standard deviation.
Antioxidant activity (generation of free radicals): Superoxide
anions (Oꢀ2 ) were generated enzymatically by xanthine (160 mM),
a triton model [35]. Adult male Charles Foster rats (200 ꢁ 225 g)
bred in the animal house of the institute were used for the lipid
lowering activity. Rats were divided in control, triton induced,
triton plus compounds and gemfibrozil (100 mg/kg) treated
groups containing five rats in each. Hyperlipidemia was
xanthine oxidase (0.04 U), and nitroblue tetrazolium (320
mM) in
absence or presence of compounds 2a–n (100 g/mL) in 100 mM
m
phosphate buffer (pH 8.2). Fractions were sonicated well in
phosphate buffer before use. The reaction mixtures were
300
250
200
150
100
50
0
Test samples
Fig. 3. Phospholipid lowering activity of compounds 2a–n and the gemfibrozil.

504
A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
Table 3
Table 4
Phospholipid lowering activity of compounds 2a–n and the gemfibrozil.
Triglyceride lowering activity of compounds 2a–n and gemfibrozil.
Entry
Compounds
Phospholipid
lowering activity (%)
S.Da
2.40
Entry
Compounds
Triglyceride
lowering activity (%)
S.Da
1
Control
–
1
Control
–
2.81
6.70
4.96
4.28
5.16
4.78
3.56
5.04
4.00
4.49
3.49
5.35
6.00
4.35
6.30
2.58
5.55
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Triton only
Triton þ 2a
Triton þ 2b
Triton þ 2c
Triton þ 2d
Triton þ 2e
Triton þ 2f
Triton þ 2g
Triton þ 2h
Triton þ 2i
Triton þ 2j
Triton þ 2k
Triton þ 2l
Triton þ 2m
Triton þ 2n
Triton gemfibrozil
3.12
28.5
23.7
15.3
16.5
12.5
5.7
21.3
15.3
11.0
18.7
13.4
23.9
12.8
13.5
39.1
4.91
4.79
5.22
5.81
3.85
11.15
6.00
3.98
3.14
2.60
3.80
4.85
4.64
6.33
3.74
6.42
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Triton only
Triton þ 2a
Triton þ 2b
Triton þ 2c
Triton þ 2d
Triton þ 2e
Triton þ 2f
Triton þ 2g
Triton þ 2h
Triton þ 2i
Triton þ 2j
Triton þ 2k
Triton þ 2l
Triton þ 2m
Triton þ 2n
Triton gemfibrozil
3.14
25.3
21.2
13.6
9.8
12.1
10.5
18.7
20.7
8.1
18.7
8.9
25.7
11.0
11.5
36.1
a
a
Standard deviation.
Standard deviation.
incubated at 37 ꢂC and after 30 min the reaction was stopped by
adding 0.5 mL glacial acetic acid. The amount of formazone
formed was calculated spectrophotometrically. In another set of
experiment effect of compounds on the generation of hydroxyl
radical (OHꢀ) was studied by non-enzymatic reactants. Briefly,
OHꢀ were generated in a non-enzymatic system comprising deoxy
ribose (2.8 mM), FeSO4.7H2O (2 mM), sodium ascorbate (2.0 mM)
and H2O2 (2.8 mM) in 50 mM KH2PO4 buffer (pH 7.4) to a final
volume of 2.5 mL. The above reaction mixtures in the absence or
WR-1339 in rats induced marked hyperlipidemia as evidenced by
3.50 fold increase in the plasma levels of TC (320.60 ꢁ 8.64). The
standard drug gemfibrozil decreased the TC level by 37.1% as
compared to triton only group. The compounds 2a–n exhibited
their TC lowering activity in 11.0%–24.8% range. Three most active
compounds of the series were 2a (ꢀ21.9%), 2g (ꢀ24.8%) and 2l
(ꢀ24.1%). Treatment of rats with triton WR-1339 increased their
plasma phospholipids (PL) by 3.12 folds (Fig. 3, Table 3). The triton
only treated groups were compared with triton plus compound
treated groups. The compounds 2a–n showed their PL lowering
activities in 5.7%–28.5% range. In the series 2a (ꢀ28.5%) was found
to be the most active compound showing while gemfibrozil
exhibited 39.1% PL lowering activity.
Administration of triton in rats elevated their triglyceride (Tg)
levels by 3.14 fold (Fig. 4, Table 4). Treatment of hyperlipidemic rats
with compounds 2a–n reversed the plasma level of Tg with varying
extents. Compound 2a (ꢀ25.3%), 2g (ꢀ18.7%), 2h (ꢀ20.7%) and 2l
(ꢀ25.7%) showed potent Tg lowering activity, while other
compounds showed mild lipid lowering activity as compared to
triton. These data were compared with gemfibrozil, which showed
a decrease in Tg levels by 36.1%.
presence of test compounds (100
mg/mL and 200 mg/mL) were
incubated at 37 ꢂC for 90 min. The test compounds were also
studied for their inhibitory action against microsomal lipid per-
oxidation in vitro by non-enzymatic inducer. Reference tubes and
reagents blanks were also run simultaneously. Malondialdehyde
(MDA) contents in both experimental and reference tubes were
estimated spectrophotometrically by thiobarbituric acid as
mentioned above. Alloprinol, Mannitol and
a-tocopherol were
used as standard drugs for superoxide, hydroxylations and
microsomal lipid peroxidation.
4. Results and discussion
Triton induced rats caused inhibition of post heparin lipolytic
activity (PHLA) [36,37] (ꢀ32.6%) as compared to control. In PHLA,
the treatment with compound partially reactivated these lipolytic
The total cholesterol (TC) of control groups were estimated as
91.51 ꢁ 5.62 mg/dl (Fig. 2, Table 2). Administration of triton
300
250
200
150
100
50
0
Test samples
Fig. 4. Triglyceride lowering activity of compounds 2a–n and gemfibrozil.

A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
505
20
18
16
14
12
10
8
6
4
2
0
Test samples
Fig. 5. Post heparin lipolytic activity (PHLA) of compounds 2a–n and gemfibrozil.
Table 5
Post heparin lipolytic activity (PHLA) of compounds 2a–n and gemfibrozil.
extra hepatic tissues resulted an increase in the levels of circulatory
lipids [38,39]. The Structure activity relationship revealed that
compounds with methyl and ethyl esters are more active in
Entry
Compounds
Post heparin lipolytic
activity (%)
S.Da
t
comparison to butyl ester. Electron donating and electron with-
1
2
3
4
5
6
7
8
Control
–
0.51
0.09
0.12
0.09
0.26
0.12
0.12
0.11
0.10
0.17
0.24
0.09
0.25
0.17
0.38
0.17
0.27
drawing substitution on phenyl rings have not shown any signifi-
cant effect on activity.
Triton only
Triton þ 2a
Triton þ 2b
Triton þ 2c
Triton þ 2d
Triton þ 2e
Triton þ 2f
Triton þ 2g
Triton þ 2h
Triton þ 2i
Triton þ 2j
Triton þ 2k
Triton þ 2l
Triton þ 2m
Triton þ 2n
Triton gemfibrozil
32.6
16.3
24.9
8.1
The antioxidant activities of compounds 2a–n were evaluated
by generating free radicals [superoxide ions (Oꢀ2 ), hydroxyl radicals
(OHꢀ), microsomal lipid peroxidation] in vitro in the absence and
presence of these compounds. The scavenging potential of
compounds 2a–n and the standard drug alloprinol at 100 and
8.3
12.0
12.3
10.9
14.7
8.4
9
200 m
g/mL against formation of superoxide ions (Oꢀ2 ) are shown in
10
11
12
13
14
15
16
17
Fig. 6/Table 6. The compounds of the series 2a–n showed significant
antioxidant activity. The Structure activity relationship revealed
that compounds with tertiary butyl ester functionality (2m and 2n)
were most active compounds of the series.
Mannitol was taken as standard drug in order to compare the
Hydroxyl (OHꢀ) radical scavenging potential of compounds 2a–n.
Mannitol showed 31.1% and 44.5% hydroxyl radical scavenging
9.8
13.9
23.7
8.4
8.9
34.2
a
Standard deviation.
activity at 100 and 200
exhibited 10.9%–26.9% activity at 100
22.6%–37.1% activity at 200 g/mL concentrations. 2e, 2i, 2m and 2n
mg/mL respectively. The compounds 2a–n
mg/mL concentration and
activities in plasma of hyperlipidemic rats. However, gemfibrozil
causes the significant reversal of these enzymes level (Fig. 5, Table
5). Triton WR-1339 acts as surfactant, suppresses the action of
lipase and blocks the uptake of lipoproteins from the circulation of
m
were among the most active compounds of the series. The results of
this study are shown in Fig. 7/Table 7.
100 microgram/mL
200 microgram/mL
100
90
80
70
60
50
40
30
20
10
0
Compounds
Fig. 6. Superoxide ions (Oꢀ2 ) scavenging potential of compounds 2a–n and alloprinol.

506
A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
Table 6
Table 7
Superoxide ions (Oꢀ2 ) scavenging potential of compounds 2a–n and alloprinol.
Hydroxyl radical scavenging potential of compounds 2a–n and mannitol.
Test compound
Conc. of comp.
g/mL)
Generation of
superoxide
S.D
Activity
Test
compound
Generation of hydroxyl
SDa
SDb
Activityc
Activityd
(
m
radicals (OHꢀ
)
ions (Oꢀ2
)
Control
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Mannitol
72.98
60.92
57.84
65.00
57.83
62.15
64.60
53.35
62.85
62.70
59.62
64.23
58.57
56.05
58.95
50.24
3.78
2.95
3.06
2.52
1.24
2.68
1.25
1.47
2.02
2.27
2.51
2.09
5.07
1.38
2.53
4.3
Control
2a
90.06
70.71
59.45
69.46
57.85
66.9
3.04
2.47
4.29
2.61
2.33
2.46
2.44
3.68
2.92
4.11
2.54
2.94
3.50
2.95
2.01
2.47
3.54
1.77
2.20
2.95
2.28
1.94
2.15
2.78
2.50
2.07
3.97
2.12
1.86
1.88
0.75
–
51.62
49.08
54.35
50.29
46.91
53.35
56.16
56.51
48.18
52.77
56.22
51.58
45.89
47.76
40.52
2.50
3.16
1.80
1.47
3.59
1.47
1.70
1.68
1.67
1.84
1.30
1.45
2.59
1.75
0.96
ꢀ13.8%
ꢀ20.7%
ꢀ10.9%
ꢀ20.8%
ꢀ14.8%
ꢀ11.5%
ꢀ26.9%
ꢀ13.9%
ꢀ14.1%
ꢀ18.3%
ꢀ12.0%
ꢀ19.7%
ꢀ23.1%
ꢀ19.2%
ꢀ31.2%
ꢀ29.3%
ꢀ32.7%
ꢀ25.5%
ꢀ31.1%
ꢀ35.7%
ꢀ26.9%
ꢀ23.0%
ꢀ22.6%
ꢀ33.1%
ꢀ27.7%
ꢀ23.0%
ꢀ29.3%
ꢀ37.1%
ꢀ34.6%
ꢀ44.5%
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
ꢀ21.5%
ꢀ34.0%
ꢀ22.9%
ꢀ35.8%
ꢀ25.7%
ꢀ42.5%
ꢀ19.1%
ꢀ37.4%
ꢀ18.7%
ꢀ28.4%
ꢀ20.6%
ꢀ33.6%
ꢀ25.9%
ꢀ43.0%
ꢀ19.8%
ꢀ34.7%
ꢀ21.1%
ꢀ48.0%
ꢀ29.8%
ꢀ44.8%
ꢀ21.3%
ꢀ35.3%
ꢀ23.6%
ꢀ32.2%
ꢀ30.7%
ꢀ52.9%
ꢀ24.5%
ꢀ48.0%
ꢀ66.4%
ꢀ77.5%
2b
2c
51.76
72.82
56.41
73.21
64.45
71.48
59.76
66.70
51.34
72.21
58.85
71.03
46.84
63.20
49.74
70.84
58.29
68.84
61.04
62.45
42.42
65.30
46.80
30.24
20.29
2d
2e
2f
2g
2h
a
Standard deviation for 100
Standard deviation for 200
Dose of 100
Dose of 200
m
m
g/ml.
g/ml.
b
c
2i
m
m
g/ml.
g/ml.
d
2j
2k
cinnamaldehyde, anilines and 2-keto esters. All the synthesized
compounds were screened for their lipid lowering, and antioxidant
activities in vivo and in vitro. The compounds 2a, 2g, and 2l have
shown promising antidyslipidemic activity whereas compound 2m
and 2n have exhibited significant antioxidant activity. It is inter-
esting to observe that ester group is playing important role in
segregating antidyslipidemic and antioxidant activity. Compounds
having methyl/ethyl ester groups are exhibiting promising anti-
dyslipidemic activity whereas compounds with tertiary butyl ester
functionality are showing potent antioxidant activity.
2l
2m
2n
Alloprinol
The microsomal lipid peroxidation scavenging activities of N-
aryl-1,4-DHPs 2a–n was studied. -Tocopherol was taken as stan-
dard drug which showed 43.9% and 52.1% activity at 100 and
200 g/mL concentrations respectively. The synthesized
compounds 2a–n exhibited 14.7%–35.7% activity and 22.8%–38.4%
activity at 100 and 200 g/mL concentrations respectively. The
a
6. Experimental
m
6.1. Materials and general
m
results are shown in Fig. 8/Table 8.
Unless otherwise specified all the reagents and catalysts were
purchased from Sigma–Aldrich and were used without further any
purification. The common solvents were purchased from Ranbaxy.
Organic solutions were concentrated under reduced pressure on
a Bu¨chi rotary evaporator. Chromatographic purification of products
was accomplished using flash chromatography on 230–400 mesh
5. Conclusion
In conclusion, we have synthesized N-aryl-1,4-DHPs via
a
molecular iodine catalyzed three-component reaction of
100 microgram/mL
90
200 microgram/mL
80
70
60
50
40
30
20
10
0
Compounds
Fig. 7. Hydroxyl radical scavenging potential of compounds 2a–n and mannitol.

A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
100 microgram/mL 200 microgram/mL
507
100
90
80
70
60
50
40
30
20
10
0
Compounds
Fig. 8. Microsomal lipid peroxidation scavenging potential of compounds 2a–n and
a-tocopherol.
silica gel. Reactions were monitored by thin-layer chromatography
(TLC) on 0.25 mm silica gel plates visualized under UV light, iodine
or KMnO4 staining. 1H and 13C NMR spectra were recorded on
6.2.1. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-carboxylic
acid ethyl ester (2a)
Physical state: Oily. ESI MS (m/z) ¼ 320 (M þ H). IR (Neat, cmꢀ1):
a Brucker DRX -300 Spectrometer. Chemical shifts (
d) are given in
1691, 1568, 1221. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.19 (t, J ¼ 7.1 Hz,
ppm relative to TMS and coupling constants (J) in Hz. The purity of
all the synthesized compounds is >98%. IR spectra were recorded on
an FT IR spectrophotometer Shimadzu 8201 PC and are reported in
terms of frequency of absorption (cmꢀ1). Mass spectra (ESI MS)
were obtained by Micromass Quattro II instrument.
3H), 2.21 (s, 3H), 4.08 (q, J ¼ 7.1 Hz, 2H), 4.75 (d, 1H, J ¼ 5.5 Hz, CH),
5.07 (dd, J ¼ 5.5 & 7.6 Hz, 1H), 6.23 (d, J ¼ 7.6 Hz, 1H), 7.24–7.47 (m,
10H). 13C NMR (CDCl3, 50 MHz)
126.6, 127.8, 127.9, 128.0, 128.8, 129.9, 130.0, 144.1, 148.4, 148.9,
169.2. Elemental analysis calculated for C21H21NO2: C, 78.97; H,
6.63; N, 4.39. Found: C, 78.82; H, 6.50; N, 4.27.
d
¼ 14.7, 19.2, 40.6, 59.9, 102.1, 107.9,
6.2. General procedure for the synthesis of N-substituted-1,4-
dihydropyridines
6.2.2. 2-Methyl-4-phenyl-1-(4-methylphenyl)-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (2b)
Physical state: Oily. ESI MS (m/z) ¼ 334 (M þ H). IR (Neat, cmꢀ1):
Cinnamaldehyde (1 mmol), aniline (1 mmol), acetoacetate ester
(1 mmol) and molecular iodine (5 mol %) were taken in 25 ml round
bottom flask and stirred for 1 h. After completion the reaction
mixture was diluted with water and extracted with ethyl acetate.
The ethyl acetate layer was dried over anhydrous sodium sulphate
and concentrated to give crude, which was purified by silica gel
column chromatography.
1691,1568,1222.1H NMR (CDCl3, 200 MHz)
d
¼ 1.19 (t, J ¼ 7.1 Hz, 3H),
2.21 (s, 3H), 2.43 (s, 3H), 4.08 (q, J ¼ 7.1 Hz, 2H), 4.75 (d, J ¼ 5.4 Hz,1H),
5.05 (dd, J ¼ 5.4 & 7.6 Hz,1H), 6.19 (d, J ¼ 7.6 Hz,1H), 7.14 (d, J ¼ 8.2 Hz,
2H), 7.25–7.44 (m, 7H). 13C NMR (CDCl3, 50 MHz)
d
¼ 14.6, 19.1, 23.1,
40.7, 59.8, 101.7, 107.7, 126.6, 127.8, 128.0, 128.7, 130.0, 130.6, 137.7,
141.5,148.7,149.1,169.3. Elemental analysis calculated for C22H23NO2:
C, 79.25; H, 6.95; N, 4.20. Found: C, 79.12; H, 6.80; N, 4.27.
Table 8
6.2.3. 1-(4-Fluorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (2c)
Microsomal lipid peroxidation scavenging potential of compounds 2a–n and
tocopherol.
a-
Physical state: Oily. ESI MS (m/z) ¼ 338 (M þ H). IR (Neat, cmꢀ1):
Test compound
Microsomal
SDb
SDc
Activityd
(%)
Activitye
1693, 1569, 1216. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.19 (t, J ¼ 7.1 Hz,
lipid peroxidationa
(%)
3H), 2.20 (s, 3H), 4.09 (q, J ¼ 7.1 Hz, 2H), 4.75 (d, J ¼ 5.4 Hz, 1H), 5.06
(dd, J ¼ 5.4, 7.6 Hz, 1H), 6.14 (d, J ¼ 7.6 Hz, 1H), 7.11–7.20 (m, 5H),
Control
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
86.03
4.27
2.78
1.68
1.59
1.67
2.43
1.82
1.31
9.38
1.75
1.48
1.68
1.61
2.24
1.79
2.56
0.83
2.37
1.23
1.28
0.98
1.34
2.16
1.23
1.86
1.17
1.92
1.29
1.36
3.23
1.56
0.52
68.91
65.83
61.55
68.38
68.19
69.50
67.51
73.37
66.46
70.87
72.07
66.49
55.32
70.15
48.24
54.11
52.95
55.08
56.44
58.38
64.39
53.90
61.12
53.87
59.94
66.32
57.59
49.83
63.12
41.21
ꢀ19.9%
ꢀ23.5%
ꢀ28.5%
ꢀ25.5%
ꢀ20.7%
ꢀ19.2%
ꢀ21.5%
ꢀ14.7%
ꢀ22.7%
ꢀ17.6%
ꢀ16.2%
ꢀ22.7%
ꢀ35.7%
ꢀ18.5%
ꢀ43.9%
ꢀ37.1%
ꢀ38.4%
ꢀ35.8%
ꢀ34.4%
ꢀ32.1%
ꢀ25.1%
ꢀ37.3%
ꢀ28.9%
ꢀ37.4%
ꢀ30.3%
ꢀ22.8%
ꢀ33.1%
ꢀ42.1%
ꢀ26.6%
ꢀ52.1%
7.24–7.33 (m, 4H). 13C NMR (CDCl3, 50 MHz)
d
¼ 14.7, 19.0, 40.6,
59.9, 102.3, 108.0, 116.9 (d, J ¼ 22.6 Hz), 126.6, 128.0, 128.8, 129.8 (d,
J ¼ 8.2 Hz), 129.9, 140.1 (d, J ¼ 3.8 Hz), 148.2, 148.8, 161.9 (d,
J ¼ 247.2 Hz), 169.1. Elemental analysis calculated for C21H20FNO2:
C, 74.76; H, 5.97; N, 4.15. Found: C, 74.61; H, 5.82; N, 4.07.
6.2.4. 1-(4-Chlorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (2d)
Physical state: Oily. ESI MS (m/z) ¼ 355 (M þ H). IR (Neat, cmꢀ1):
1693, 1568, 1222. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.18 (t, J ¼ 7.1 Hz,
2m
2n
3H), 2.19 (s, 3H), 4.07 (q, J ¼ 7.1 Hz, 2H), 4.73 (d, J ¼ 5.4 Hz, 1H), 5.07
a
-Tocopherol
(dd, J ¼ 5.4, & 7.6 Hz, 1H), 6.16 (d, J ¼ 7.6 Hz, 1H), 7.16–7.44 (m, 9H).
a
b
c
13C NMR (CDCl3, 50 MHz)
126.7, 127.9, 128.8, 129.2, 129.5, 130.2, 133.4, 142.6, 147.7, 148.6,
169.1. Elemental analysis calculated for C21H20ClNO2: C, 71.28; H,
5.70; N, 3.96. Found: C, 71.11; H, 5.85; N, 3.87.
d
¼ 14.6, 19.1, 40.6, 59.9, 102.9, 108.2,
Microsomal lipid peroxidation (nmol MDA formed/h/mg protein).
Standard deviation for 100
Standard deviation for 200
Dose of 100
Dose of 200
m
m
g/ml.
g/ml.
d
e
m
m
g/ml.
g/ml.

508
A. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 501–509
6.2.5. 1-(4-Bromophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid ethyl ester (2e)
analysis calculated for C21H21NO3: C, 75.20; H, 6.31; N, 4.18.
Found: C, 75.02; H, 6.18; N, 4.11.
Physical state: Oily. ESI MS (m/z) ¼ 399 (M þ H). IR (Neat, cmꢀ1):
1691, 1565, 1221. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.18 (t, J ¼ 7.1 Hz,
6.2.11. 1-(3-Chloro-phenyl)-2,5-dimethyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid methyl ester (2k)
3H), 2.20 (s, 3H), 4.08 (q, J ¼ 7.1 Hz, 2H), 4.74 (d, J ¼ 5.5 Hz, 1H), 5.07
(dd, J ¼ 5.5 & 7.6 Hz, 1H), 6.17(d, J ¼ 7.6 Hz, 1H), 7.12 (d, J ¼ 8.1 Hz,
2H), 7.23–7.38 (m, 5H), 7.58 (d, J ¼ 8.1 Hz, 2H). 13C NMR (CDCl3,
Physical state: Oily. ESI MS (m/z) ¼ 354 (M þ H). IR (Neat, cmꢀ1):
2943, 1694, 1577, 1478, 1227. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.56 (s,
50 MHz)
d
¼ 4.7, 19.2, 40.6, 60.1, 103.0, 108.3, 121.3, 126.7, 128.0,
3H), 2.15 (s, 3H), 3.59 (s, 3H), 4.46 (s, 1H), 6.03 (d, J ¼ 1.3 Hz, 1H),
128.8, 29.5,129.6,135.2,143.1,147.6,148.6,169.0. Elemental analysis
calculated for C21H20BrNO2: C, 63.33; H, 5.06; N, 3.52. Found: C,
63.22; H, 5.05; N, 3.37.
7.08–7.37 (m, 9H). 13C NMR (CDCl3, 50 MHz)
d
¼ 18.7, 18.9, 45.9, 51.1,
102.3, 116.6, 125.4, 126.1, 126.7, 127.8, 128.1, 128.6, 130.8, 135.4,
145.3, 146.7, 147.1169.4. Elemental analysis calculated for
C21H20ClNO2: C, 71.28; H, 5.70; N, 3.96. Found: C, 71.12; H, 5.60; N,
3.87.
6.2.6. 2-Methyl-4-(2-nitrophenyl)-1-phenyl-1,4-dihydro-pyridine-
3-carboxylic acid ethyl ester (2f)
Physical state: Oily. ESI MS (m/z) ¼ 365 (M þ H). IR (Neat,
6.2.12. 1-(2,3-Dimethyl-phenyl)-2,5-dimethyl-4-phenyl-1,4-
dihydro-pyridine-3-carboxylic acid methyl ester (2l)
cmꢀ1): 1694, 1568, 1524, 1355, 1222. 1H NMR (CDCl3, 200 MHz)
d
¼ 0.95 (t, J ¼ 7.1 Hz, 3H), 2.24 (s, 3H), 3.90 (q, J ¼ 7.1 Hz, 2H), 5.21–
The compound was isolated as 1.13:1 rotamer mixture (2la
major rotamer, 2lb minor rotamer). Physical state: Oily. ESI MS (m/
z) ¼ 348 (M þ H). IR (Neat, cmꢀ1): 2938, 1690, 1566, 1385, 1231. 1H
5.25 (m, 2H), 6.14–6.16 (m, 1H), 7.22–7.50 (m, 6H), 7.62–7.65 (m,
1H), 7.75 (dd, J ¼ 8.1 & 1.5 Hz, 2H). 13C NMR (CDCl3, 50 MHz)
d
¼ 14.3, 19.0, 36.6, 59.9, 100.6, 106.6, 123.6, 127.1, 128.0, 128.1,
NMR (CDCl3, 300 MHz)
d
¼ 1.58 (s, 3H), 2.09 (s, 3H), 2.19 and 2.25
130.1, 130.4, 131.6, 133.6, 143.7, 143.8, 148.2, 150.3, 168.3. Elemental
analysis calculated for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69.
Found: C, 69.17; H, 5.40; N, 7.54.
(2s, 2la and 2lb, 3H, CH3), 2.36 (s, 3H), 3.60 and 3.61 (2s, 2la and
2lb, 3H, OCH3), 4.52 and 4.61 (2s, 2la and 2lb,1H, CH), 5.78 and 5.87
(2d, J ¼ 1.0 Hz, 2la and 2lb, 1H, CH), 7.00–7.57 (m, 8H). 13C NMR
(CDCl3, 75 MHz)
d
¼ 12.8, 12.9, 16.1, 16.3, 17.2, 17.3, 19.1, 19.2, 44.3,
6.2.7. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-carboxylic
acid methyl ester (2g)
44.5, 49.2, 97.3, 97.4, 98.7, 113.6, 114.2, 123.3, 123.9, 124.7, 124.8,
124.9, 125.1, 125.2, 125.3, 126.5, 126.7, 126.8, 127.4, 128.1, 128.2,
128.3, 133.8, 133.9, 134.0, 137.1, 137.5, 137.6, 141.1, 141.5, 145.6, 145.9,
146.9, 147.0, 148.5, 168.1, 168.2. Elemental analysis calculated
for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C, 79.42; H, 7.16;
N, 3.97.
Physical state: Oily. ESI MS (m/z) ¼ 306 (M þ H). IR (Neat, cmꢀ1):
3062, 2943, 1688, 1570, 1225. 1H NMR (CDCl3, 200 MHz)
d
¼ 2.07 (s,
3H), 3.50 (s, 3H), 4.58 (d, J ¼ 5.6 Hz,1H), 4.61 (dd, J ¼ 5.6 Hz & 7.6 Hz,
1H), 6.08 (d, J ¼ 7.8 Hz, 1H), 7.07–7.37 (m, 10H). 13C NMR (CDCl3,
50 MHz)
d
¼ 19.1, 40.4, 51.1, 101.8, 107.8, 126.5, 126.9, 127.4, 127.7,
127.9, 128.1, 128.2, 128.9, 129.0, 129.5, 129.9, 144.0, 148.6, 148.7,
169.6. Elemental analysis calculated for C20H19NO2: C, 78.66; H,
6.27; N, 4.59. Found: C, 78.60; H, 6.22; N, 4.48.
6.2.13. 2-Methyl-1,4-diphenyl-1,4-dihydro-pyridine-3-carboxylic
acid tert-butyl ester (2m)
Physical state: Oily. ESI MS (m/z) ¼ 348 (M þ H). IR (Neat,
cmꢀ1): 2956, 1690, 1571, 1235. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.34
6.2.8. 1-(4-Methoxy-phenyl)-2,5-dimethyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid methyl ester (2h)
(s, 9H), 2.16 (s, 3H), 4.71 (d, J ¼ 5.1 Hz, 1H), 5.00 (dd, J ¼ 5.1 &
7.7 Hz, 1H), 6.16 (d, J ¼ 7.7 Hz, 1H), 7.22–7.47 (m, 10H). 13C NMR
Physical state: Oily. ESI MS (m/z) ¼ 350 (M þ H). IR (Neat, cmꢀ1):
(CDCl3, 50 MHz,)
d
¼ 19.1, 28.6, 41.3, 79.6, 103.7, 107.6, 126.5, 127.6,
2947, 1690, 1567, 1508, 1439. 1H NMR (CDCl3, 300 MHz)
d
¼ 1.59 (s,
128.0, 128.7, 129.7, 129.9, 144.2, 147.2, 149.2, 168.0. Elemental
analysis calculated for C23H25NO2: C, 79.51; H, 7.25; N, 4.03.
Found: C, 79.40; H, 7.12; N, 3.90.
3H), 2.18 (s, 3H), 3.61 (s, 3H), 3.84 (s, 3H), 4.51 (s, 1H), 6.00 (d,
J ¼ 1.3 Hz,1H), 6.94–6.99 (m, 2H), 7.13–7.42 (m, 7H).13C NMR (CDCl3,
75 MHz)
d
¼ 12.8,12.9, 44.0, 48.8, 54.2, 98.6,113.4,114.1,124.4,124.5,
124.9,126.4,126.6,126.7,126.8,127.5,127.6,127.7,135.4,145.6,146.8,
157.3, 168.0. Elemental analysis calculated for C22H23NO3: C, 75.62;
H, 6.63; N, 4.01. Found: C, 76.54; H, 6.57; N, 3.98.
6.2.14. 1-(4-Chlorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid tert-butyl ester (2n)
Physical state: Oily. ESI MS (m/z) ¼ 382 & 384 (M þ H). IR (Neat,
cmꢀ1): 2966,1691, 1570,1236. 1H NMR (CDCl3, 200 MHz)
d
¼ 1.33 (s,
6.2.9. 2,5-Dimethyl-1,4-diphenyl-1,4-dihydro-pyridine-3-
carboxylicacid methyl ester (2i)
9H), 2.14 (s, 3H), 4.69 (d, J ¼ 5.1 Hz, 1H), 4.99 (dd, J ¼ 5.1 & 7.7 Hz,
1H), 6.10 (d, J ¼ 7.7 Hz, 1H), 7.14–7.41 (m, 9H). 13C NMR (CDCl3,
Physical state: Oily. ESI MS (m/z) ¼ 320 (M þ H). IR (Neat, cmꢀ1):
50 MHz)
d
¼ 19.1, 28.6, 41.3, 79.7, 104.5, 108.0, 126.6, 127.9, 128.8,
2945, 1690, 1567, 1493, 1382, 1226. 1H NMR (CDCl3, 300 MHz)
129.2, 129.3, 130.1, 133.2, 142.8, 146.5, 148.9, 168.6. Elemental
analysis calculated for C23H24ClNO2: C, 72.34; H, 6.33; N, 3.67.
Found: C, 72.41; H, 6.23; N, 3.51.
d
¼ 1.48 (s, 3H), 2.06 (s, 3H), 3.50 (s, 3H), 4.39 (s, 1H), 5.96 (d,
J ¼ 1.3 Hz, 1H), 7.09–7.37 (m, 10H). 13C NMR (CDCl3, 50 MHz)
d
¼ 17.3, 17.4, 44.5, 50.5, 99.7, 114.7, 124.4, 125.1, 126.1, 126.5, 126.7,
127.1, 128.5, 142.7, 145.6, 146.5, 168.2. Elemental analysis calculated
for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.82; H, 6.58; N,
4.31.
Acknowledgments
Acknowledgments: R. A. Maurya, S. Sharma and M. Kumar are
thankful to CSIR, New Delhi for financial support.
6.2.10. 4-(4-Methoxy-phenyl)-2-methyl-1-phenyl-1,4-dihydro-
pyridine-3-carboxylic acid methyl ester (2j)
References
Physical state: Oily. ESI MS (m/z) ¼ 336 (M þ H). IR (Neat,
cmꢀ1): 2946, 1692, 1595, 1236. 1H NMR (CDCl3, 200 MHz)
d
¼ 2.15
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