Synthesis of Dihydropyridine Derivatives under Eco-friendly Approach and Investigation of Cytotoxic Activity

Article abstract of DOI:10.1002/jhet.3561

In an effort for development of innovative biologically active agents, a sequence of 1,4-dihydropyridine analogues was synthesized through the green synthetic method. In addition, all compounds were evaluated for their cytotoxic activities against three h

Full text of DOI:10.1002/jhet.3561

Month 2019
Synthesis of Dihydropyridine Derivatives under Eco-friendly Approach
and Investigation of Cytotoxic Activity
a
a,b
c,d
Avula Krishna Kumari, Vemulapati Hanuman Reddy, *
Guda Mallikarjuna Reddy, *
b
e
Yellala Venkata Rami Reddy, and Suddala Leelavathi
a
Natural Product Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
b
Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
Chemical Engineering Institute, Ural Federal University, Yekaterinburg 620002, Russian Federation
c
d
Department of Chemistry, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil
e
Biology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
*
E-mail: vhrsvu@gmail.com; parameswara.eswari@gmail.com
Received September 27, 2018
DOI 10.1002/jhet.3561
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In an effort for development of innovative biologically active agents, a sequence of 1,4-dihydropyridine
analogues was synthesized through the green synthetic method. In addition, all compounds were evaluated
for their cytotoxic activities against three human cancer cell lines and mouse melanoma and figured out the
most active compounds. Besides, promoter reusability, easy handling of the chemical reagent, simple reac-
tion process, time minimization, ethanol–water solvent compatibility, and cost reduction reagent are key
tools for this fruitful path. Thus, these examinations recommended that dihydropyridine and their derivatives
are motivating moieties for the discovery of new anticancer drugs.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
efficiency, and pharmaceutical compatibility could all be
the foremost bounds in the eventual progress of capable
antioxidant and anticancer medicines. In this context,
calcium channel blockers 1,4-dihydropyridine (1,4-DHP)
and its derivatives have been taken up. 1,4-DHP
compounds are recognized to be energetic drugs to
control cardiovascular sicknesses like angina pectoris and
hypertension [4]. Moreover, DHP compound displayed
Diseases like tumor, arthritis, aging, autoimmune,
atherosclerosis, and cardiovascular illnesses and
neurodegenerative syndromes such as Parkinson’s and
Alzheimer’s sicknesses are caused by oxidative stress
1,2]. Thus, there is a need to develop antioxidants and
anticancer drug-related compounds. Because of tumor
illness, globally, 8 million people have died in the past
[
potential
antioxidant,
antituberculosis,
analgesic,
5
years; this is because of oxidative stress [3]. Animal
antimicrobial, and antitumor activity [5–7]. Recently,
Ahamed et al. reported dihydropyridine analogues, which
possess cytotoxic, antimicrobial, and anticoagulant
activities [8]. Biologically efficient 1,4-DHP and their
derivatives published by Mahinpour et al. group explained
that diethoxy-substituted dihydropyridine derivatives
displayed prominent antimicrobial activity [9]. German
researchers described that N-substituted dihydropyridine
derivatives showed as potential antituberculotic agents
skeleton has its own antioxidation system to control
damage from oxidative strain but not completely cure.
Consequently, the discovery of innovative antioxidants
and antitumor applicants is a dynamic arena of therapeutic
chemistry. The preparation of composites with antioxidant
property has improved in current centuries, and many of
structurally varied motifs have been reported. Besides,
nontoxic reaction paths, atom economy, synthetic
©
2019 Wiley Periodicals, Inc.

A. Krishna Kumari, V. Hanuman Reddy, G. Mallikarjuna Reddy, Y. V. Rami Reddy, and S. LeelavathiVol 000
with ABCB1-inhibiting properties [10]. Cytotoxic activity
contained 1,4-DHP derivatives, which were reported by
Radadiya et al. group [11]. In addition, these derivatives
were involved in oxidation–reduction reactions [12] and
act as an antitumor agent [13] and anti-inflammatory
drugs [14]. There are many synthetic methods that have
been reported for the synthesis of dihydropyridine
compounds using different catalysts and reagents like
ammonium carbonate [15], tetramethylsilyl iodide [16],
meglumine [17], grinding conditions [18], and other
methods [19–21]. Even though a diversity of tactics have
been familiar and are establishing to have individual
benefits, they experience from each other disadvantages,
for example, multistep, toxic reagents, higher temperature
conditions, heavy catalysts, and chemical exposure into
the environment.
Table 1
Yield of compounds 5(a–l).
0
Entry Compound
R
R
X
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
p-Br
p-Br
H
p-OCH
p-Br
CH
CH
CH
3
3
3
88
90
88
93
81
92
86
85
82
90
79
84
3
m-Br
p-OCH
p-Cl
p-I
CH3
3
p-OCH
P-F
3
CH
CH
CH
CH
3
3
3
3
p-Cl
m-CH
p-Cl
p-OCH
p-F
p-OCH3
3
3
C H
2
5
5
5
5
0
1
2
5j
5k
5l
H
p-NO
p-Br
2
C
2
C
2
C
2
H
H
H
o-OH
p-OCH
3
p-OCH
3
The earlier findings and our continued interest [22–24]
were kept in mind to develop biologically active
compounds. In the present work, 1,4-dihydropyridne
derivatives were synthesized by multicomponent reaction
condition using green catalyst and solvent media. All the
compounds were screened for their cytotoxic assay.
resulted with a yield of 90% each. All the compounds
were confirmed by analysis of the proton NMR, carbon
NMR, infrared (IR), and high-resolution mass
spectrometry (HRMS) spectral data. The advantage of
mentioned method was completion of one-pot four-
component path under natural solvent condition as well
as green catalyst situation. In this, the eco-friendly acid
K-10 catalyst acts in the most vital role to promote this
synthetic method. This may be justified to its acidic
nature to initiate the reaction and obtained the products
quantitatively (Scheme 2). Besides, promoter reusability,
easy handling of the chemical reagent, simple reaction
process, time minimization, ethanol–water solvent
compatibility, and cost reduction reagent are key tools for
this fruitful path.
Cytotoxic results. All dihydropyridine derivatives 5(a–l)
were evaluated to investigate their cytotoxic activities
against three human cancerous cell lines and mouse
melanoma. Most of the derivatives exhibited a moderate to
significant degree of cytotoxicity on U937, SKOV3, and
HepG2 cancerous cell lines (Table 2). In fact, all the
compounds showed no cytotoxicity against mouse
melanoma B16F10 at <200 μg/mL concentration. All the
RESULTS AND DISCUSSION
Chemistry. In the present study, new dihydropyridine
derivatives have been planned and prepared to test for
their biotic properties. The preparation of composites
5(a–l) followed the multicomponent reaction path drawn
in Scheme 1. A four-component reaction between
aromatic amine (3), arylaldehyde (1), malononitrile (2),
and alkyne (4) was carried out by using eco-friendly
montmorillonite K-10 acid catalyst and ethanol–water
solvent media (Scheme 1). Total products formed with
quantitative yields in a range between 79 and 93%
(Table 1). Among the products, compound 5d formed
with maximum output of 93% followed by motif 5f and
its yield value of 92%. In addition, moieties 5b and 5j
Scheme 1. Multicomponent synthesis of dihydropyridine derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Dihydropyridine Derivatives under Eco-friendly Approach and In-
vestigation of Cytotoxic Activity
Scheme 2. Plausible mechanism of product formation.
Table 2
In vitro cytotoxicity of dihydropyridine derivatives 5(a–l) against cancerous cell lines by MTT assay.
a
IC50 (μg/mL)
S. no.
Compound
U937
SKOV3
HepG2
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
75.28 ± 1.13
64.69 ± 2.29
74.59 ± 1.92
75.57 ± 2.59
81.04 ± 2.99
114.92 ± 4.45
156.86 ± 3.79
60.71 ± 2.89
75.22 ± 1.05
77.01 ± 1.33
61.58 ± 1.36
79.96 ± 9.66
7.69 ± 0.54
166.96 ± 2.52
98.55 ± 1.03
>200
134.67 ± 3.47
111.13 ± 2.11
>200
110.01 ± 2.15
117.74 ± 1.41
115.65 ± 2.22
121.46 ± 5.86
126.75 ± 5.46
>200
>200
>200
65.58 ± 0.96
109.98 ± 2.06
>200
142.16 ± 3.07
109.54 ± 2.13
4.32 ± 0.94
107.96 ± 6.92
121.31 ± 4.41
128.05 ± 1.28
170.49 ± 5.98
162.52 ± 4.72
2.62 ± 0.21
10
11
12
13
5j
5k
5l
b
Etoposide
Exponentially growing cells were treated with different concentrations of dihydropyridine derivatives for 24 h, and cell growth inhibition was analyzed
through MTT assay.
a
IC50 is defined as the concentration, which results in a 50% decrease in cell number as compared with that of the control cultures in the absence of an
inhibitor and were calculated using the respective regression analysis. The values represent the mean ± standard error of three individual observations.
b
Etoposide: a standard drug molecule, employed as positive control.
derivatives except 5f and 5g exhibited more cytotoxicity
<100 μg/mL) on U937 cells than the other two human
the commercially available drug molecule; nevertheless,
slight structural modification of these active derivatives
may yield as prospective anticancer drugs. Based on the
present results, it was warranted that these derivatives will
be further evaluated on other cancer cell lines.
(
cancerous cell lines. The order of cytotoxicity among the
cell lines was U937 > HepG2 > SKOV3. It is noteworthy
that the structure of the 5h seems to be an attractive and
promising molecule that showed activity against three cell
lines with less IC50 values. This may be due to its strong
interaction between the compound and the active part of
the U937 cell line. In addition, compound 5b showed next
higher cytotoxic activity. Its values were 64.69, 98.55, and
CONCLUSIONS
A certain library of 1,4-dihydropyridine derivatives were
synthesized and screened for their antitumor properties.
Total synthetic part was performed under greenery
conditions, and reagent K-10 played a prominent role in
obtaining quantitative yields. The victorious path is a
pedestal for further research developments in the field of
117.14 μg/mL against all the used cell lines. Furthermore,
compound 5k has only less IC50 value against U937 cell
line, and this value was lower than the value of compound
5b. It was concluded from the results that these
compounds have less IC50 values against the potent than
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Krishna Kumari, V. Hanuman Reddy, G. Mallikarjuna Reddy, Y. V. Rami Reddy, and S. LeelavathiVol 000
+
environmentally friendly reaction environment to develop
drugs. Among screened compounds, motif 5h seems to
be an attractive and auspicious molecule that showed
activity against three cell lines with less IC50 values.
52.0, 38.5; HRMS: m/z calcd for C H N O (M + H)
22 19 3 4
390.1448; found 390.1455.
Dimethyl-6-amino-4-(4-bromophenyl)-5-cyano-1-(4-
methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5b).
Light brown solid; mp 168–170°C; IR (KBr): 3466,
3
1
341, 3019, 2184, 1733, 1709, 1650, 1572, 1510, 1415,
355, 1300, 1215, 1115, 1071, 1045, 1010 cm ; H-
ꢀ
1
1
EXPERIMENTAL
NMR (500 MHz, CDCl ): δ 7.50–7.49 (d, J = 8.2 Hz,
3
2
4
H), 7.25–7.23 (m, 4H), 6.97–6.96 (d, J = 8.8 Hz, 2H),
General. Infrared spectra were recorded on Fourier
.64 (s, 1H), 4.12 (s, 2H), 3.85 (s, 3H), 3.59 (s, 3H), 3.49
transform infrared spectroscopy spectrometer (KBr) and
13
ꢀ
1
1
(s, 3H); C-NMR (125 MHz, CDCl
): δ 165.5, 163.4,
3
reported in reciprocal centimeters (cm ). For H-NMR,
tetramethylsilane was used as an internal standard
1
60.8, 150.0, 143.9, 142.4, 131.9, 128.7, 127.0, 121.4,
1
3
120.0, 115.0, 104.4, 62.1, 55.6, 52.7, 52.0, 38.1; HRMS:
m/z calcd for C H BrN O (M + H) 498.0659; found
(
δ = 0), and for C-NMR, CDCl3 (δ = 77.27) was
+
23
20
3 5
used as an internal standard. The proton values are
reported as chemical shift δ in parts per million,
integration, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, and br = broad),
and the coupling constants in Hertz. Carbon NMR
spectra were obtained with whole proton decoupling.
Low-resolution mass spectrometry and HRMS data
were obtained using electrospray ionization. Melting
points were measured on micro-melting point apparatus.
Reaction progress was monitored by analytic high-
performance liquid chromatography and by using
analytical thin-layer chromatography on pre-coated
silica gel GF254 plates, and the spots were detected
under UV light (254 nm).
4
98.0666.
Dimethyl-6-amino-1,4-bis(4-bromophenyl)-5-cyano-1,4-
dihydropyridine-2,3-dicarboxylate (5c). Yellow solid; mp
1
1
1
95–197°C; IR (KBr): 3480, 3382, 3018, 2186, 1743,
708, 1652, 1576, 1507, 1491, 1416, 1352, 1212,
157, 1116, 1093, 1016 cm
ꢀ1
1
;
H-NMR (500 MHz,
CDCl ): δ 7.57–7.55 (d, J = 8.5 Hz, 2H), 7.29–7.23
3
(m, 4H), 7.24–7.00 (dd, J = 9.6, 2.5 Hz, 2H), 4.86 (s,
13
1
H), 4.49 (s, 2H), 3.68 (s, 3H), 3.45 (s, 3H); C-NMR
(125 MHz, CDCl ): δ 165.4, 163.3, 160.9, 149.1,
3
1
1
41.3, 140.3, 136.9, 133.4, 131.5, 130.2, 128.6, 128.5,
20.0, 115.7, 115.5, 105.5, 63.3, 52.7, 52.1, 37.8;
+
HRMS: m/z calcd for C H Br N O (M + H)
4
2
2
17
2 3 4
44.1623; found 444.1661.
Dimethyl-6-amino-4-(3-bromophenyl)-5-cyano-1-(4-
Method for the preparation of dihydropyridine derivatives
5
(a–l).
Alkyne 4 (1 mmol) was injected out to a
combination of benzaldehyde 1a (1 mmol), malononitrile
2) (1 mmol), aniline 3a (1 mmol), and montmorillonite
iodophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5d).
Dark brown solid; mp 218–220°C; IR (KBr): 3476, 3378,
3019, 2927, 2854, 1734, 1646, 1568, 1436, 1216, 1108,
(
ꢀ
1 1
K-10 (1 mmol) in ethanol–water (1:2) solvent and was
rotated at 60°C until end of reaction (6–8 h) observed by
thin-layer chromatography. Then, ethyl acetate was
mixed to crude, filtered through a plug of cotton, and
concentrated under vacuum followed by recrystallization
to obtain product 5a. The cotton plug holding the reagent
was dipped into ethyl acetate solvent (5–7 mL) in a
beaker. When the K-10 stable down to the bottom of the
beaker, the cotton was removed, and the ethyl acetate
was decanted off. Catalyst was reprocessed up to multiple
cycles. The same procedure was used to prepare the
remaining compounds 5(b–l) with the use of their
corresponding starting compounds.
1
074, 1022 cm ; H-NMR (500 MHz, CDCl ): δ 8.03–
3
7.97 (d, J = 12.1 Hz, 1H), 7.91 (t, J = 1.8 Hz, 1H), 7.51–
7.48 (t, J = 1.5 Hz, 1H), 7.43 (dd, J = 6.5, 1.5 Hz, 2H),
7
.37 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.22 (dd, J = 7.2,
3.5 Hz, 2H), 4.71 (s, 1H), 4.03 (s, 2H), 3.63 (s, 3H), 3.46
(s, 3H); C-NMR (125 MHz, CDCl ): δ 165.9, 163.7,
1
3
3
1
49.9, 144.9, 142.0, 135.2, 130.7, 130.4, 130.1, 128.9,
127.3, 127.1, 120.7, 105.3, 62.7, 52.7, 52.2, 38.6;
HRMS: m/z calcd for C H BrIN O (M + H)
5
+
2
2
17
3 4
93.9519; found 593.9491.
Dimethyl-6-amino-5-cyano-1,4-bis(4-methoxyphenyl)-1,4-
dihydropyridine-2,3-dicarboxylate (5e). Pale yellow solid;
mp 164–166°C; IR (KBr): 3475, 3368, 3017, 2839, 2183,
1
740, 1704, 1649, 1609, 1572, 1509, 1463, 1413, 1300,
Dimethyl-6-amino-5-cyano-1,4-diphenyl-1,4-
dihydropyridine-2,3-dicarboxylate (5a). Light brown solid;
ꢀ
1
1
1215, 1174, 1108, 1031 cm
;
H-NMR (300 MHz,
mp 169–171°C; IR (KBr): 3472, 3370, 3017, 2952, 2184,
CDCl ): δ 7.30–7.28 (dd, J = 14.9, 6.0 Hz, 4H), 6.99–
3
1
1
743, 1707, 1649, 1573, 1491, 1452, 1413, 1354, 1326,
6.88 (dd, J = 17.1, 8.8 Hz, 4H), 4.61 (s, 1H), 4.06 (s,
ꢀ
1
1
215, 1116, 1075, 1029 cm
;
H-NMR (500 MHz,
2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.60 (s, 3H), 3.48 (s,
13
CDCl ): δ 7.50–7.48 (m, 3H), 7.37–7.35 (m, 6H), 7.29–
3H); C-NMR (75 MHz, CDCl ): δ 165.7, 163.5, 160.6,
3
3
7
.24 (t, J = 8.6 Hz, 1H), 4.67 (s, 1H), 4.12 (s, 2H), 3.58
158.5, 149.8, 141.8, 137.2, 131.3, 127.9, 127.1, 120.6,
1
3
(s, 3H), 3.42 (s, 3H); C-NMR (125 MHz, CDCl ): δ
114.8, 114.0, 105.1, 62.6, 55.5, 55.1, 52.4, 51.8, 37.6;
3
+
1
1
65.8, 163.6, 149.8, 144.8, 141.8, 135.1, 130.5, 130.2,
29.9, 128.8, 127.2, 127.0, 120.6, 105.2, 62.6, 52.6,
HRMS: m/z calcd for C H N O (M + H) 444.1623;
2
4 23 3 6
found 444.1661.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Dihydropyridine Derivatives under Eco-friendly Approach and In-
vestigation of Cytotoxic Activity
ꢀ
1 1
Dimethyl-6-amino-1-(4-chlorophenyl)-5-cyano-4-(4-
fluorophenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5f).
Yellow solid; mp 184–186°C; IR (KBr): 3466, 3342,
1216, 1108, 1015 cm ; H-NMR (500 MHz, CDCl ): δ
3
8
1
.38–8.36 (d, J = 7.7, Hz, 1H), 8.28–8.24 (d, J = 6.3 Hz,
H), 7.76–7.69 (dd, J = 12.3, 2.6 Hz, 2H), 7.41–7.30 (m,
5H), 4.70 (s, 1H), 4.07 (s, 2H), 4.02–3.88 (m, 4H), 1.11–
.08 (t, J = 14.3 Hz, 3H), 1.02–0.99 (t, J = 14.1 Hz, 3H);
C-NMR (125 MHz, CDCl ): δ 164.8, 162.8, 144.2,
140.6, 136.8, 136.6, 130.8, 130.1, 128.9, 128.4, 127.4,
27.2, 125.6, 125.3, 119.8, 106.9, 64.9, 62.4, 61.2, 38.7,
13.8, 13.5; HRMS: m/z calcd for C H N O (M + H)
463.1612; found 463.1610.
Diethyl-6-amino-1-(4-bromophenyl)-5-cyano-4-(2-
hydroxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5k).
Light brown solid; mp 204–206°C; IR (KBr): 3469,
3361, 3018, 2984, 2184, 1736, 1699, 1650, 1574,
485, 1455, 1417, 1394, 1371, 1325, 1215, 1109,
1013 cm ; H-NMR (500 MHz, CDCl ): δ 7.58–7.56
d, J = 8.6 Hz, 2H), 7.25–7.21 (dd, J = 15.2,
3
1
(
7
(
224, 2950, 2183, 1744, 1709, 1650, 1573, 1467, 1414,
ꢀ
1
1
352, 1329, 1218, 1115, 1070, 1022 cm
; H-NMR
1
13
500 MHz, CDCl ): δ 7.49–7.46 (d, J = 8.6 Hz 2H),
3
3
.33–7.27 (m, 4H), 7.08–7.04 (t, J = 17.2 Hz, 2H), 4.66
s, 1H), 4.08 (s, 2H), 3.60 (s, 3H), 3.50 (s, 3H); C-
13
1
+
NMR (125 MHz, CDCl ): δ 165.5, 163.3, 162.9, 161.0,
3
24 22 4 6
1
1
49.3, 141.4, 140.5, 136.9, 133.5, 131.6, 130.2, 128.6,
28.5, 120.2, 115.8, 115.6, 105.6, 63.1, 52.8, 52.1, 37.9;
+
HRMS: m/z calcd for C H ClFN O (M + H)
2
2
17
3 4
4
42.0964; found 442.0975.
Dimethyl-6-amino-4-(4-chlorophenyl)-5-cyano-1-(4-
methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5g).
Dark brown solid; mp 201–203°C; IR (KBr): 3476, 3351,
1
ꢀ
1
1
3
3
1
(
019, 2927, 2854, 1732, 1646, 1549, 1511, 1438, 1214,
(
ꢀ
1
1
033 cm ; H-NMR (500 MHz, CDCl ): δ 7.42–7.41
3
1.5 Hz, 3H), 7.12–7.10 (t, 1H), 6.94–6.91 (t, 1H),
6.82–6.81 (d, 1H), 4.88 (s, 1H), 4.24 (s, 2H), 4.11–
q, 2H), 7.39–7.28 (m, 2H), 7.20–7.17 (d, J = 8.0 Hz,
2
2
H), 6.98–6.96 (d, J = 8.6 Hz, 2H), 5.27 (s, 1H), 4.10 (s,
H), 3.86 (s, 3H), 3.55 (s, 3H), 3.49 (s, 3H); C-NMR
3
0
.80 (m, 4H), 1.13–1.10 (t, J = 14.1 Hz, 3H), 0.98–
1
3
13
.95 (t, J = 14.3 Hz, 3H);
C-NMR (125 MHz,
(125 MHz, CDCl ): δ 165.8, 16.7, 161.1, 150.3, 144.2,
CDCl ): δ 166.4, 162.9, 153.7, 150.6, 141.5, 134.3,
1
1
m/z calcd for C H BrN O (M + H) 444.1623;
found 444.1661.
3
3
1
1
42.7, 132.2, 131.7, 129.0, 127.3, 121.3, 120.7, 115.3,
33.1, 132.2, 130.9, 129.1, 128.6, 124.8, 120.9, 120.7,
04.7, 62.4, 55.9, 53.0, 52.3, 38.4; HRMS: m/z calcd for
17.4, 105.6, 62.1, 61.6, 61.5, 33.1, 13.8, 13.4; HRMS:
+
+
C H ClN O (M + H) 454.1164; found 454.1168.
Dimethyl-6-amino-5-cyano-1-(4-fluorophenyl)-4-m-tolyl-1,4-
dihydropyridine-2,3-dicarboxylate (5h). Yellow solid; mp
2
3
20
3 5
24
22
3 5
Diethyl-6-amino-5-cyano-1,4-bis(4-methoxyphenyl)-1,4-
1
1
1
7
4
2
75–177°C; IR (KBr): 3481, 3368, 3018, 2925, 2184,
dihydropyridine-2,3-dicarboxylate (5l). Light brown solid;
mp 156–158°C; IR (KBr): 3470, 3348, 3225, 3018, 2978,
2183, 1738, 1703, 1650, 1609, 1572, 1414, 1300, 1215,
1176, 1108, 1031 cm ; H-NMR (300 MHz, CDCl ): δ
7.30–7.27 (dd, J = 11.3, 2.6 Hz, 4H), 6.97–6.88 (dd,
J = 18.6, 9.0 Hz, 4H), 4.62 (s, 1H), 4.06 (s, 2H), 4.03–
3.82 (m, 4H), 3.84 (s, 3H), 3.81 (s, 3H), 1.14–1.11 (t,
J = 14.1 Hz, 3H), 1.02–0.97 (t, J = 14.3 Hz, 3H); C-
NMR (75 MHz, CDCl ): δ 165.3, 163.2, 160.7, 158.6,
743, 1708, 1651, 1575, 1507, 1413, 1353, 1215, 1153,
ꢀ
1 1
116, 1034 cm ; H-NMR (500 MHz, CDCl ): δ 7.86–
3
ꢀ
1 1
.84 (q, 1H), 7.48–7.47 (q, 1H), 7.36–7.34 (dd, J = 13.2,
.5 Hz, 2H), 7.20–7.07 (m, 4H), 4.63 (s, 1H), 4.01 (s,
H), 3.60 (d, 3H), 3.49 (s, 3H), 2.38 (s, 3H); C-NMR
3
1
3
(125 MHz, CDCl ): δ 21.6, 38.4, 52.1, 52.7, 63.0, 105.6,
3
13
1
1
16.9, 117.1, 120.5, 128.0, 128.7, 131.1, 132.3, 132.4,
38.3, 141.6, 144.5, 149.6, 162.2, 163.6, 164.2, 165.7;
3
+
HRMS: m/z calcd for C H FN O (M + H) 422.1510;
149.8, 141.7, 137.5, 131.6, 128.3, 127.4, 120.8, 114.8,
2
3
20
3 4
found 422.1508.
114.0, 105.4, 62.8, 61.9, 60.8, 55.6, 55.2, 37.8, 13.9,
Diethyl-6-amino-4-(4-chlorophenyl)-5-cyano-1-(4-
+
1
3.5; HRMS: m/z calcd for C H N O (M + H)
26 27 3 6
methoxyphenyl)-1,4-dihydropyridine-2,3-dicarboxylate (5i).
Light brown solid; mp 172–174°C; IR (KBr): 3482,
4
78.1972; found 478.1977.
3
1
350, 3278, 3018, 2930, 2184, 1737, 1704, 1651, 1571,
ꢀ
1
1
510, 1416, 1370, 1215, 1109, 1031 cm
;
H-NMR
Acknowledgments. The author Guda Mallikarjuna Reddy is
grateful to the Brazilian Higher Education Personnel Training
Coordination (CAPES: Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior) for the fellowship under the PNPD
program and also thankful to the Ural Federal University for
laboratory facilities.
(500 MHz, CDCl ): δ 7.48–7.12 (m, 6H), 6.98–6.90 (d,
3
J = 8.6 Hz, 2H), 5.30 (s, 1H), 4.09 (s, 2H), 3.99–3.89
1
3
(m, 4H), 3.85 (s, 3H), 1.06–1.00 (m, 6H); C-NMR
(125 MHz, CDCl ): δ 165.0, 163.0, 160.8, 150.2, 142.9,
3
1
1
1
42.5, 132.7, 131.8, 130.0, 129.8, 128.9, 128.2, 127.4,
27.1, 120.3, 114.9, 104.2, 62.0, 61.4, 60.8, 55.6, 35.8,
3.7, 13.5; HRMS: m/z calcd for C H ClN O
2
5
24
3
5
REFERENCES AND NOTES
+
(M + H) 482.1477; found 482.1472.
[
1] Yang, H.; Jin, X.; Lam, C. W. K.; Yan, S. K. Clin Chem Lab
Med 2011, 49, 1773.
2] Yoshikawa, T.; Naito, Y. Japan Med Assoc J 2002, 45, 271.
3] Plummer, M.; de Martel, C.; Vignat, J.; Ferlay, J.; Bray, F.;
Franceschi, S. Lancet Glob Health 2016, 4, 609.
Diethyl-6-amino-5-cyano-1-(4-nitrophenyl)-4-phenyl-1,4-
dihydropyridine-2,3-dicarboxylate (5j).
Yellow solid; mp
[
[
1
1
75–177°C; IR (KBr): 3473, 3384, 3019, 2988, 2179,
739, 1699, 1649, 1577, 1534, 1448, 1415, 1354, 1244,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Krishna Kumari, V. Hanuman Reddy, G. Mallikarjuna Reddy, Y. V. Rami Reddy, and S. LeelavathiVol 000
[
4] Zamponi, G. W.; Striessnig, J.; Koschak, A.; Dolphin, A. C.
Pharmacol Rev 2015, 67, 821.
5] Ioan, P.; Carosati, E.; Micucci, M.; Cruciani, G.; Broccatelli,
F.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr Med Chem 2001, 18,
901.
[16] Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett 2003, 44, 4129.
[17] Chen, H. S.; Guo, R. Y. Monatsh Chem 2015, 146, 1355.
[18] Kumar, A.; Sharma, S. Green Chem 2017, 2011, 13.
[19] Sun, J.; Shen, G.; Xie, Y.; Yan, C. Chin J Chem 2014, 32,
1143.
[
4
[
6] Carosati, E.; Ioan, P.; Micucci, M.; Broccatelli, F.; Cruciani,
G.; Zhorov, B. S.; Chiarini, A.; Budriesi, R. Curr Med Chem 2012, 19,
306.
[20] Pal, S.; Singh, V.; Das, P.; Choudhury, L. H. Bioorg Chem
2013, 48, 8.
4
[
7] Gadotti, V. M.; Bladen, C.; Zhang, F. X.; Chen, L.; Gündüz,
M. G.; Şimşek, R.; Şafak, C.; Zamponi, G. W. Arch Eur J Phys 2015,
67, 2485.
8] Ahamed, A.; Arif, I. A.; Mateen, M.; Kumar, R. S.;
Idhayadhulla, A. Saudi Biol Sci 2018 https://doi.org/10.1016/j.
sjbs.2018.03.001, 25, 1227.
9] Mahinpour, R.; Moradi, L.; Zahraei, Z.; Pahlevanzadeh, N. J
Saudi Chem Soc 2017 https://doi.org/10.1016/j.jscs.2017.11.001, 22, 876.
10] Lentz, F.; Hemmer, M.; Reiling, N.; Hilgeroth, A. Bioorg Med
Chem Lett 2016, 26, 5896.
11] Radadiya, A.; Khedkar, V.; Bavishi, A.; Vala, H.; Thakrar, S.;
Bhavsar, D.; Shah, A.; Coutinho, E. Eur J Med Chem 2014, 74, 375.
12] Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett 2002, 43, 3105.
[21] Azizi, K.; Azarnia, J.; Karimi, M.; Yazdani, E.; Heydari, A.
Synlett 2016, 27, 1810.
[22] Reddy, V. H.; Reddy, G. M.; Reddy, M. T.; Reddy, Y. V. R.
Res Chem Intermed 2015, 41, 9805.
[23] Reddy, G. M.; Garcia, J. R.; Reddy, V. H.; de Andrade, A. M.;
Camilo, A. Jr.; Ribeiro, R. A.; de Lazaro, S. R. Eur J Med Chem 2016,
123, 508.
4
[
J
[
[24] Reddy, G. M.; Garcia, J. R. J Heterocyclic Chem 2017, 54, 89.
[
[
SUPPORTING INFORMATION
[
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[
[
[
13] Boer, R.; Gekeler, V. Drugs Future 1995, 20, 499.
14] Bahekar, S.; Shinde, D. Acta Pharm A 2002, 52, 281.
15] Rekunge, D. S.; Khatri, C. K.; Chaturbhuj, G. U. Tetrahedron
Lett 2017, 58, 1240.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet