Synthesis and antioxidant activity of a series of novel 3-chalcone-substituted 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1515/hc-2012-0070

New 3-chalcone-substituted 1,4-dihydropyridine (DHP) derivatives have been synthesized based on dimethyl or diethyl 2,6-dimethyl-4-phenyl-1,4-DHP-3,5- dicarboxylate. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR, and elemental analyses. The synthesized compounds were also screened for antioxidant properties.

Full text of DOI:10.1515/hc-2012-0070

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0070ꢀ ꢀHeterocycl. Commun. 2012; 18(5-6): 239–243
HSayo Snutn,hCehesngixsianagnShdanga, nLotnigofeixJiindanadnJiatn Zahcantgi*vity of a series of
novel 3-chalcone-substituted 1,4-dihydropyridine
derivatives
Abstract: New 3-chalcone-substituted 1,4-dihydropyri- substituents in the 3- and 5-positions. The structure-activity
dine (DHP) derivatives have been synthesized based on relationships of DHPs have indicated that the groups in the
dimethyl or diethyl 2,6-dimethyl-4-phenyl-1,4-DHP-3,5-di- 3- and 5-positions are very important for pharmacological
1
carboxylate. Their structures were confirmed by IR, H effects (Donkor et al., 1998; Foroumadi et al., 2002; Roh
NMR, 13C NMR, and elemental analyses. The synthesized et al., 2008). It has been reported that DHPs substituted by
compounds were also screened for antioxidant properties. flavone in the 4-position show a good bradycardic activity
(Budriesi et al., 2005), but the DHPs substituted by flavone
Keywords: antioxidant; chalcone; 1,4-dihydropyridine; in the 3- or 5-position have not been described.
synthesis.
In view of these observations, we decided to introduce
a chalcone moiety to the 3- or 5-position of the DHP ring,
in the hope of changing the biological activities of these
compounds. New 3-chalcone-substituted 1,4-DHP deriva-
tives were synthesized, and their radical-scavenging
effects investigated.
* Corresponding author: Jian Zhang, College of Chemistry and
Materials, South-Central University for Nationalities, Wuhan
430074, PR China, e-mail: jianzhangye@gmail.com
Hao Sun, Chengxiang Shang and Longfei Jin: College of Chemistry
and Materials, South-Central University for Nationalities, Wuhan
430074, PR China
Results and discussion
Introduction
Synthesis of compounds 4a–g
1,4-Dihydropyridine (DHP) and its derivatives have been The synthetic route to compounds 4a–g is outlined in
studied because of their biological activities (Fernandes Schemes 1–3. The DHPs 1a,b (Scheme 1) were prepared
et al., 2003; Matsubara et al., 2004; Ryabokon et al., 2005) using Hantzsch reaction (Hadizadeh et al., 2002). The
such as antitubercular (Fassihi et al., 2009), anti-inflamma- monoester derivatives 2a,b were prepared by partial
tory (Klegeris et al., 2002), and antitumor properties (Abbsa hydrolysis of 1a,b. The chalcones 3a–d (Schemes 2 and 3)
et al., 2010). Some of these compounds have been used for were synthesized in high yields by using a general proce-
the treatment of cardiovascular diseases (nifedipine and dure reported in literature (Luo et al., 2012).
amlodipine). Their antioxidant properties (Diaz-Araya et al.,
A subsequent condensation of 1,4-dihydropyri-
1998; Cominacini et al., 2003; Berkels et al., 2005; Borovic dine acids (DHPAs) 2a,b with chalcones 3a–d furnished
et al., 2006; Plotniece et al., 2009; Vijesh et al., 2011) have the desired 1,4-DHP derivatives 4a–g in 42–72% yields
received more attention in recent years. Studies on cardiac (Schemes 2 and 3).
and liver membranes point to an antioxidant protective
effect of these compounds that may contribute to their phar- three-compound condensation reaction of β-keto ester,
macological activity (Hassan et al., 2009). aromatic aldehyde, and ammonium hydroxide. At the
Most of 1,4-DHP derivatives were prepared using a
Chalcone and its derivatives have been reported to beginning, we wanted to introduce the chalcone moiety
possess various pharmacological activities, including anti- directly to the 1,4-DHP ring by one-step synthesis. A
inflammatory, anticancer, and antioxidant properties (Anto chalcone containing a β-diketone group was allowed to
et al., 1995; Liu et al., 2007). Both 1,4-DHP and chalcone react with aromatic aldehyde and ammonium hydroxide
have antioxidant properties. For a long time, we have instead of β-keto ester. This approach was not success-
been interested in the study of 1,4-DHPs bearing different ful. The target compounds 4a–g were synthesized via
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240ꢀ ꢀH. Sun et al.: Synthesis and antioxidant activity of 1,4-dihydropyridine derivatives
O
Ph
O
AcOH
R1O
OR1
2CH3COCH2COOR1
NH4OAc
PhCHO
Piperidine
N
H
1a-b
O
Ph
O
1a: R1 = Me
1b: R1 = Et
2a: R1 = Me
2b: R1 = Et
R1O
OH
N
H
2a-b
Scheme 1
O
HO
NaOH
HO
COCH3
ArCHO
Ar
3a-c
3a: Ar = 4-MeO-C6H4
3b: Ar = C6H4
O
Ar
3c: Ar = 2-thienyl
R1O
2a-b
4a: R1 = Me, Ar = 4-MeO-C6H4
4b: R1 = Me, Ar = C6H4
4c: R1 = Me, Ar = 2-thienyl
4d: R1 = Et, Ar = 4-MeO-C6H4
4e: R1 = Et, Ar = C6H4
4f: R1 = Et, Ar = 2-thienyl
O
O
DMAP EDC HCl
O
HN
4a-f
Scheme 2
4-dimethylamiopryidine (DMAP)/1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (EDC•HCl)-catalyzed
two-component condensation reaction of 1,4-DHP 2 and
hydroxy-substituted chalcone. At first, we attempted to
use dicyclohexylcarbodiimide (DCC) as a dehydrating
agent, but the workup proved to be difficult. The prepara-
tion of 4a–g was successful with EDC•HCl as the dehy-
drating agent. The structures of these products were fully
Data for the decolorization of DPPH solution by the test
samples are shown in Table 1, which express the free rad-
ical-scavenging capability. All compounds 4a–g exhibit
free radical-scavenging activities. Thienyl derivatives 4c
and 4f show better scavenging activities than the remain-
ing compounds 4. Compared with compound 1a and 1b,
compounds 4a–g showed downward trend of radical-
scavenging activity.
1
consistent with their IR, H NMR, and 13C NMR spectral
data. The elemental analysis results were also satisfactory.
Conclusions
Compounds 4 are good scavengers of radicals.
Antioxidant studies: DPPH radical-
scavenging assay
Experimental section
This assay is based on the measurement of the scaveng-
ing ability of compounds toward the stable radical DPPH.
1
IR spectra were taken in KBr pellets. H NMR and 13C NMR spectra
were recorded in CDCl3 on a Bruker 400 spectrometer at 400 and 100
MHz, respectively.
O
HO
NaOH
HO
CHO
PhCOCH3
Ph
3d
Compound
4a
4b
4c
4d
4e
IC50 (μm)
313 24
281 12
172 8
320 31
254 12
O
O
2a
4f
4g
1a
1b
O
O
O
DMAP EDC HCl
IC50 (μm)
184 10
621 43
132 7
156 11
HN
Ph
4g
Table 1ꢁDPPH radical-scavenging activity of compounds 1a,b and
4a–g.
Scheme 3
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H. Sun et al.: Synthesis and antioxidant activity of 1,4-dihydropyridine derivativesꢀ
ꢀ241
General procedure for the synthesis of
DHPs 1a,b
General procedure for the synthesis of
compounds 4a–g
A solution of benzaldehyde (2.5 mL, 0.025 mol), a keto ester (4.4 mL, A mixture of compound 2a,b (0.01 mol), compound 3a,d (0.01 mol),
0.05 mol), ammonium acetate (3.80 g, 0.05 mol), two drops of acetic 4-dimethylaminopyridine (0.20 g), and a solution of EDC•HCl
(1.00 g) in dichloromethane (50 mL) was stirred under a nitrogen at-
mosphere at room temperature for 24 h and then concentrated on a
rotary evaporator (water bath at 38°C). The yellow residue of 4a–g
was purified by silica gel column chromatography eluting with ethyl
acetate/petroleum ether (1:4).
acid, and two drops of piperidine in ethanol (50 mL) was stirred at
the reflux temperature. Afer the completion of the reaction, as moni-
tored by TLC, the solvent was removed under reduced pressure. The
yellow residue of 1a,b was crystallized from ethanol.
Dimethyl 2,6-dimethyl-4-phenyl-1,4-DHP-3,5-dicarboxylate (1a)
Yellow crystals; yield 82%; mp 158–160°C; IR: 3340, 3060, 1712, 1690,
1
1650, 1631, 1370, 1123, 1090, 1020, 768, 703, 679 cm-1; H NMR: δ 7.14–
4-[3-(E)-(4-Methoxyphenyl)acryloyl]phenyl-5-methyl-2,6-dime-
thyl-4-phenyl-1,4-DHP-3,5-dicarboxylate (4a)ꢀYellow crystals;
7.42 (m, 5H), 5.70 (s, 1H), 4.92 (s, 1H), 3.57 (s, 6H), 2.32 (s, 6H).
1
yield 72%; mp 101.1–102.3°C; IR: 3318, 3029, 2951, 1702, 1596 cm-1; H
NMR: δ 8.02 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 16.0 Hz, 1H), 7.61 (d, J = 8.2
Hz, 2H), 7.39 (d, J = 16.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.30–7.27 (m,
3H), 7.08 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 5.19
(s, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 1.28 (s, 6H); 13C NMR: δ 189.7, 168.1,
165.1, 161.8, 156.3, 154.7, 147.6, 145.0, 144.1, 135.5, 130.3, 129.9, 128.2,
127.9, 127.5, 126.5, 122.2, 119.6, 114.5, 104.7, 102.3, 55.4, 51.1, 39.7, 19.6,
19.2. Anal. Calcd for C32H29NO6: C, 73.41; H, 5.58; N, 2.68. Found: C,
73.27; H, 5.56; N, 2.64.
Diethyl 2,6-dimethyl-4-phenyl-1,4-DHP-3,5-dicarboxylate (1b)
Yellow crystals; yield 84%; mp 159–160°C; IR: 3290, 2996, 1711, 1674,
1332, 1209, 1123, 1090, 1020, 767, 691, 679 cm-1; 1H NMR: δ 7.12–7.31 (m,
5H), 5.55 (s, 1H), 4.11 (m, 4H), 4.02 (s, 1H), 2.37 (s, 6H), 1.25 (t, 6H).
General procedure for the synthesis of
compounds 2a,b
Methyl 4-[3-(E)-phenylacryloyl]phenyl-2,6-dimethyl-4-phenyl-1,
4-DHP-3,5-dicarboxylate (4b)ꢀYellow crystals; yield 62%; mp 92.3–
94.1°C; IR: 3338, 3032, 2952, 1700, 1604 cm-1; 1H NMR: δ 8.03 (d, J = 8.8
Hz, 2H), 7.82 (d, J = 16.0 Hz, 1H, -CH-), 7.66 (d, J = 6.6 Hz, 2H), 7.51 (d,
J = 16.0 Hz, 1H), 7.45–7.44 (m, 3H), 7.37 (d, J = 8.8 Hz, 2H), 7.31–7.27 (m,
3H), 7.09 (d, J = 8.0 Hz, 2H), 5.68 (s, 1H), 5.19 (s, 1H), 3.68 (s, 3H), 2.43
(s, 3H), 2.41 (s, 3H); 13C NMR: δ 189.7, 168.0, 165.8, 156.4, 154.9, 147.5,
145.1, 143.9, 135.2, 134.8, 130.6, 130.0, 129.3, 129.0, 128.5, 128.2, 127.9,
122.3, 122.0, 104.8, 102.3, 51.1, 39.7, 19.7, 19.3. Anal. Calcd for C31H27NO5:
C, 75.44; H, 5.51; N, 2.84. Found: C, 75.27; H, 5.44; N, 2.82.
DHP 1a,b (0.01 mol) was suspended in methanol (30 mL) and treated
with a solution of NaOH (1.60 g, 0.04 mol) in water at room tem-
perature with stirring. The mixture was stirred under reflux for 5 h,
cooled, quenched with water (200 mL), and filtered. The filtrate was
treated with activated carbon (0.20 g), and the mixture was stirred at
55°C for 30 min. Afer cooling, the carbon was filtered off, the filtrate
was acidified with 1 N HCl to pH 2.5, and the resultant precipitate of
2a,b was filtered and crystallized from methanol.
5-(Methoxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-DHP-3-carbox-
1
ylic acid (2a)ꢀWhite crystals; yield 72%; mp 202–204°C; H NMR:
δ 11.66 (s, 1H), 8.75 (s, 1H), 7.20–7.09 (m, 5H), 4.88 (s, 1H), 3.54 (s, 3H),
Methyl 4-[3-(E)-(2-thienyl)acryloyl]phenyl-2,6-dimethyl-4-phe-
nyl-1,4-DHP-3,5-dicarboxylate (4c)ꢀYellow crystals; yield 55%; mp
80.7–81.8°C; IR: 3336, 3026, 2946, 1698 cm-1; 1H NMR: δ 8.01 (d, J = 7. 2
Hz, 2H), 7.55 (d, J = 15.6 Hz, 1H), 7.44 (br s, 1H), 7.37 (m, 3H), 7.31 (d,
J = 15.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 6.8 Hz, 1H), 7.10 (m,
3H), 6.49 (s, 1H), 5.19 (s, 1H), 3.67 (s, 3H), 2.38, 2.36 (2s, 6H); 13C NMR:
δ 190.0, 168.0, 165.7, 154.8, 147.5, 143.9, 140.2, 137.3, 135.1, 132.1, 130.0,
129.9, 129.0, 128.6, 128.4, 128.2, 127.9, 126.5, 122.3, 104.8, 102.4, 51.1, 39.7,
19.7, 19.3. Anal. Calcd for C29H25NO5S: C, 69.72; H, 5.04; N, 2.80; S, 6.42.
Found: C, 69.58; H, 4.97; N, 2.75; S, 6.32.
2.25 (s, 6H).
5-(Ethoxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-DHP-3-carboxylic
acid (2b)ꢀWhite crystals; yield 75%; mp 191–192°C; 1H NMR: δ 11.64
(s, 1H), 8.72 (s, 1H), 7.20–7.10 (m, 5H), 4.88 (s, 1H), 3.99–3.55 (m, 2H),
2.26 (s, 6H), 1.19–1.15 (t, 3H).
General procedure for the synthesis of
chalcones 3a–d
A mixture of a solution of KOH (5.60 g) in 40 mL methanol,
4-hydroxyacetophenone (0.02 mol), or 4-hydroxybenzaldehyde
(0.02 mol) was stirred under nitrogen atmosphere for 24 h and then
acidified with 1 N HCl to pH 1. The resultant yellow solid of 3a–d
was filtered under reduced pressure and crystallized from metha-
nol. The structures of compounds 3a–d were confirmed by compari-
son of their melting points with those reported in the literature; 3a:
Ethylꢀ4-[3-(E)-(4-methoxyphenyl)acryloyl]phenyl 2,6-dimethyl-
4-phenyl-1,4-DHP-3,5-dicarboxylate (4d)ꢀYellow crystals; yield
68%; mp 98.8–100.4°C; IR: 3337, 3026, 2951, 1698, 1597 cm-1; 1H NMR:
δ 8.02 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 16.0 Hz, 1H), 7.61 (d, 2H, J = 8.0
Hz, 2H), 7.39 (d, J = 16.0 Hz, 1H), 7.37–7.28 (m, 3H), 7.21 (d, J = 6.8 Hz,
2H), 7.076 (d, J = 8.0 Hz, 2H), 6.96 (d, J 6.8 Hz, 2H), 6.12 (s, 1H), 5.18 (s,
1H), 4.33–3.68 (m, 2H), 3.87 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 1.47–1.00
mp 181.2–182.3°C, lit. mp 180–182°C (Dimmock et al., 1998); 3b: mp (m, 3H); 13C NMR: δ 189.7, 168.1, 165.9, 161.8, 156.4, 154.7, 147.6, 145.0,
172.4–173.2°C, lit. mp 172–173°C (Dimmock et al., 1998); 3c: mp 172.6– 144.2, 135.5, 130.4, 129.9, 128.2, 127.9, 127.5, 126.5, 122.2, 119.5, 114.5,
173.8°C, lit. mp 172°C (Gul et al., 2008); 3d: mp 180.6–181.7°C, lit. mp 104.6, 102.2, 55.4, 51.1, 39.6, 19.7, 19.3, 14.3. Anal. Calcd for C33H31NO6:
180–181°C (Dimmock et al., 1998).
C, 73.73; H, 5.81; N, 2.61. Found: C, 73.58; H, 5.73; N, 2.56.
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ꢀH. Sun et al.: Synthesis and antioxidant activity of 1,4-dihydropyridine derivatives
1
cm-1; H NMR: δ 8.03 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 16.0 Hz, 1H), 7.65
(d, J = 6.8 Hz, 2H), 7.51 (d, J = 16.0 Hz, 1H), 7.44 (br s, 3H), 7.37 (d, J =
8.4 Hz, 2H), 7.31–7.19 (m, 3H), 7.09 (d, J = 7.2 Hz, 2H), 5.91 (s, 1H), 5.19
(s, 1H), 3.68 (s, 3H), 2.43 (s, 3H), δ 2.40 (s, 3H); 13C NMR: δ 189.7, 168.2,
165.9, 154.9, 148.1, 147.7, 145.2, 144.3, 135.2, 134.7, 130.8, 130.1, 129.1,
128.6, 128.2, 127.9, 126.5, 122.4, 121.9, 104.6, 102.1, 51.2, 39.7, 19.6, 19.2.
Anal. Calcd for C31H27NO5: C, 75.44; H, 5.51; N, 2.84. Found: C, 74.34;
H, 5.42; N, 2.80.
Ethyl 4-[3-(E)-phenylacryloylphenyl-1,4-dihydro-2,6-dimethyl-
4-phenylpyridine-3,5-dicarboxylate (4e)ꢀYellow crystals; yield
67%; mp 87.2–88.5°C; IR: 3334, 3029, 2951, 1704, 1606 cm-1; 1H NMR: δ
8.05 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 15.6 Hz), 7.65 (d, J = 6.6 Hz, 2H), 7.54
(d, J = 15.6 Hz, 1H), 7.46–7.40 (m, 3H), 7.40 (d, J = 8.4 Hz), 7.32–7.26 (m,
3H), 7.11 (d, J = 8.0 Hz, 2H), δ 5.22, (s, 1H), δ 5.18 (s, 1H), δ 3.60–3.51 (m,
2H), δ 2.37 (s, 3H), 2.34 (s, 3H), δ 1.31–1.26 (m, 3H); 13C NMR: δ 189.7,
168.3, 166.0, 155.4, 155.0, 147.7, 145.2, 144.6, 135.2, 134.7, 130.8, 130.1,
129.1, 128.6, 128.4, 128.0, 126.6, 122.4, 121.9, 104.5, 101.9, 60.0, 39.7, 19.6,
19.1, 14.3. Anal. Calcd for C32H29NO5: C, 75.72; H, 5.76; N, 2.76. Found: C,
75.56; H, 5.69; N, 2.74.
Evaluation of the antioxidative activity
The free radical-scavenging activity of test samples 4a–g was
determined using DPPH. Briefly, a methanol solution (3 mL) of 100 μm
DPPH was mixed with 1 mL of different concentrations (from 10-5 to 103
mol) of compound (1 mL), and the mixture was incubated at 40°C. A
decrease in absorbance was measured at 517 nm (Hitachi 557 UV-VIS
spectrophotometer). The inhibition of colorization was expressed as
percentage and IC50 (obtained from the inhibition curve).
Ethyl 4-[3-(E)-(2-thienyl)acryloylphenyl-1,4-dihydro-2,6-dime-
thyl-4-phenylpyridine-3,5-dicarboxylate (4f)ꢀYellow crystals;
1
yield 42%; mp 78.2–79.6°C; IR: 3334, 3026, 2928, 1698, 1594 cm-1; H
NMR: δ 8.01 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 15.6 Hz, 1H), 7.38 (br s, 3H),
7.30 (d, J = 15.6, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.21 (br s, 2H), 7.11–7.07
(m, 3H), 5.97 (s, 1H), 5.18 (s, 1H), 3.68 (m, 2H), 2.42 (s, 3H), 2.40 (s,
1H), 1.28–1.23 (m, 3H); 13C NMR: δ 189.1, 168.3, 165.9, 155.0, 147.8, 144.6,
140.1, 137.3, 135.0, 132.4, 129.9, 129.3, 128.5, 128.2, 128.1, 127.9, 126.5,
122.4, 120.5, 104.4, 101.9, 60.0, 39.7, 19.5, 19.1, 14.32. Anal. Calcd for
C30H27NO5S: C, 70.16; H, 5.30; N, 2.73: Found: C, 69.95; H, 5.27; N, 2.68.
Acknowledgments: The authors express their thanks
to the South-Central University for Nationalities for the
financial support during this investigation.
Methyl 4-[3-oxo-3-phenylprop-1-(E)-enyl]phenyl-1,4-dihydro-2,6-
dimethyl-4-phenylpyridine-3,5-dicarboxylate (4g)ꢀYellow crys-
tals; yield 62%; mp 103.2–105.1°C; IR: 3339, 3026, 2948, 1698, 1603
Received May 15, 2012; accepted October 10, 2012
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