DOI 10.

1007/s11094-015-1305-x
Pharmaceutical Chemistry Journal, Vol. 49, No. 7, October, 2015 (Russian Original Vol. 49, No. 7, July, 2015)

ANTI-INFLAMMATORY ACTIVITY OF NEW SERIES

OF 1,4-DIHYDROPYRIDINE DERIVATIVES
A. Idhayadhulla,1 R. Surendra Kumar,1* A. Jamal Abdul Nasser,1
S. Kavimani,2 and S. Indhumathy2
Original article submitted May 15, 2014.
A series of 1,4-dihydropyridine derivatives (1a 1g) were prepared by multicomponent condensation reaction
of ethylchloroacetate, 4-substituted benzaldehyde, and ammonium hydroxide as starting materials. A new series of dihydrazine carbothioamides (2a 2g) were prepared by condensation of compounds 1a 1g with
thiosemicarbazide. The structures of synthesized compounds were confirmed by IR and 1H-NMR spectroscopy and elemental analysis. Compounds 1a g and 2a 2g were tested for anti-inflammatory activity on
Swiss albino rats.
Keywords: 1,4-dihydropyridine, thiosemicarzide, condensation, anti-inflammatory activity.

INTRODUCTION

RESULTS

1,4-Dihydropyridine derivatives are of interest because

of their potential biological activity such as vasodilators,
antihypertensive [1 4], anti-inflammatory [5], antihypoxic
and anti-ischemic agents [6], and calcium channel modulators of the nifedipine type [7]. Various methods were proposed for the preparation of 1,4-dihydropyridine derivatives
[8, 9]. The presence of ester groups at positions 3 and 5 of
the 1,4-dihydropyridine ring is of crucial importance for the
pharmacological effects of these compounds, and it has been
suggested that these groups are involved in hydrogen bonding with the receptor site [10]. Recently, some new 3,5-substituted 1,4-dihydropyridine derivatives have been synthesized, which exhibit pharmacological effects such as antihypertensive, bronchodilatory, and antitubercular [11 13].
Thiosemicarbazides also exhibit significant of biological activity including antitumor, fungicide, bactericide, anti-inflammatory, and antiviral properties [14 17]. Basically,
compounds containing the ester group interact with amine
group via amination [18, 19] and hydrazinolysis [20, 21] reactions. In view of these observations, we have synthesized a
new series of 1,4-dihydropyridine derivatives (2a 2f) and
carried out their screening for anti-inflammatory activity.

A series of diethyl 2,6-dimethyl-4-substituted phenyl1,4-dihydropyridine-3,5-dicarboxylates (1a 1g) were prepared by Hantzsch multicomponent condensation [22]. Then,
compounds 1a 1g were reacted with thiosemicarbazide by
hydrazinolysis method (Scheme 1) to give 2,2-{[4-(4-substitutedaromatic alcohols)-2,6-dimethyl-1,4-dihydropyridine3,5-diyl]dicarbonyl} dihydrazine carbothioamides (2a 2g).
Physicochemical data for the synthesized compounds are
presented in Table 1. The IR spectra of compounds 1a 1g
displayed absorption bands at 3332 3354 cm1 due to NH
stretching and another absorption band at 1741 1764 cm1
due to keto fragment containing ester group. The spectrum of
compound 1b showed absorption band due to Cl-C group at
837 cm1, the spectrum of compound 1c showed absorption
band of OH-C group at 1447 cm1, and the spectrum of compound 1d showed absorption band due to NO2C group at
1536) cm1. The 1H NMR spectra of compounds 1a 1g exhibited a singlet at d = 8.11 8.41 ppm attributable to NH
protons in 1,4-dihydropyridine ring. Another important peak
of 4-CH present in 1,4-dihydropyridine ring appeared as a
singlet at d = 4.67 4.79 ppm. The IR spectra of compounds
2a 2g showed an absorption band at 3320 3372 cm1 due
to NH group present in 1,4-dihydropyridine ring, and another
absorption band at 3118 3198 cm1 was due to NH-C=O
stretching. The absorption band of C=S group was observed
at 1245 1272 cm1. The 1H NMR spectra of 2a 2g
showed a singlet at d = 8.41 8.64 ppm attributable to NH
protons present in 1,4-dihydropyridine ring. The 4CH,

P. G. & Research Department of Chemistry, Jamal Mohamed College,

Tiruchirappalli, Tamil Nadu, 620020, India.
2
Department of Pharmacology, Mother Theresa Post-Graduate & Research
Institute of Health Science, Poduchary, 605006, India.
* e-mail: suren chem@yahoo.co.in

463
0091-150X/15/4907-0463 2015 Springer Science+Business Media New York

464

A. Idhayadhulla et al.
Scheme 1
R

O
EtO

O
OEt

DMSO

H2N NH

1a 1g

EXPERIMENTAL CHEMICAL PART

Melting points (M. P.) were recorded in open capillary
tubes and are uncorrected. The IR spectra (4000 400 cm1)
were recorded in KBr on FTIR Shimadzu 8201 PC spectrometer, and 1H NMR spectra were recorded on a Bruker
DRX-300 MHz instrument. Elemental analyses (C, H, N,
and S) were undertaken using a Vario EL III analyzer. Experimental analytical data correspond to the calculated values.
The purity of compounds was checked by thin layer chromatography (TLC) on silica gel plates.
Synthesis
Synthesis of diethyl 4-(furan-2-yl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate (1a). A mixture of ethyl
acetoacetate (2 mol), furfuraldehyde (1 mol) and ammonium
hydroxide (1 mol) in methanol (20 mL) was heated and

TABLE 1. Physicochemical Properties of Synthesized Compounds

1a 1g and 2a 22g
R

M.P., C

Yield, %

1a

- Furyl

1b

- Ph

253

66

1c,

4-ClC6H4

242

47

1d

4-OHC6H4

240

56

1e

4-NO2C6H4

197

72

1f

4-CH3OC6H4

229

69

1g,

4-(CH3)2N-C6H4

227

56

2a

- Furyl

125

59

2b

-Ph

192

53

2c

4-ClC6H4

194

68

2d

4-OHC6H4

201

74

2e

4-NO2C6H4

195

76

2f

4-CH3OC6H4

210

57

2g

4-(CH3)2N-C6H4

205

61

NH

O
NH

N
H

2a 2g

CONH, NHCS and NH2 protons resonated as singlets at

d = 5.10 5.21, 8.01 8.15, 2.02 2.12, and 9.14
9.82 ppm, respectively.

Compound

NH

NH2
S

N
H

H2N

HN

S
NH2

refluxed for 4 h. The obtained solid was filtered, washed

with water, and recrystallized from absolute ethanol. Analogous procedures were used for the synthesis of compounds
1b 1g.
Compound 1a: IR (KBr; n, cm1): 3349 (N-H str.),
3030(Ar-H), 2940 (C-H str. of CH3), 1745 (C=O, ester), 812
(Ar-H); 1H NMR (DMSO-d6; d, ppm): 8.20 (s, 1H, NH of
pyridine ring), 6.10 6.27 (d, 2H, furyl ring), 4.72 (s, 1H,
C4-H), 4.20 (q, 4H, C3-OCH2CH3 and C5-OCH2CH3), 2.31
(s, 6H, C2-CH3 and C6-CH3), 1.34 (t, 6H, C2-OCH2CH3 and
C6-OCH2CH3); C19H23NO4.
Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine3,5-dicarboxylate (1b): IR (KBr; n, cm1): 350 (N-H str.),
3034(Ar-H), 2953(C-H str. of CH3), 1755 (C=O, ester),
802(Ar-H) ; 1H NMR (DMSO-d6; d, ppm): 8.25 (s, 1H, NH
of pyridine ring), 7.33 7.27 (m, 5H, Ph ring), 4.70 (s, H,
C4-H), 4.22 (q, 4H, C3-OCH2CH3 and C5-OCH2CH3), 2.28
(s, 6H, C2-CH3 and C6-CH3), 1.32 (t, 6H, C2-OCH2CH3 and
C6-OCH2CH3 ); C19H23NO4.
Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1c): IR (KBr; n, cm1): 3332 (N-H
str.), 3074 (Ar-H), 2942 (C-H str. of CH3), 1741 (C=O, ester), 837 (C-Cl), 787(Ar-H); 1H-NMR (DMSO-d6; d, ppm):
8.31 (s, 1H, NH of pyridine ring), 7.36 7.19 (m, 4H, Ph
ring), 4.76 (s, 1H, C4-H), 4.18 (q, 4H, C3-OCH2CH3 and
C5-OCH2CH3), 2.21 (s, 6H, C2-CH3 and C6-CH3), 1.34 (t,
6H, C2-OCH2CH3 and C6-OCH2CH3; C19H22 ClNO4.
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1d): IR (KBr, n, cm1): 3342
(N-H str.), 3024 (Ar-H), 2922 (C-H str. of CH3), 1764 (C=O,
ester), 1447 (C-OH), 814(Ar-H); 1H NMR (DMSO-d6; d,
ppm): 9.47 (s, 1H, C-OH), 8.41 (s, 1H, NH of pyridine ring),
7.07 6.34 (m, 4H, Ph ring), 4.67 (s, 1H, C4-H), 4.28(q, 4H,
C3-OCH2CH3 and C5-OCH2CH3), 2.12 (s, 6H, C2-CH3 and
C6-CH3),1.28 (t, 6H, C2-OCH2CH3 and C6-OCH2CH3);
C19H23NO5.
Diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1e): IR (KBr; n, cm1): 3354
(N-H str.); 3037(Ar-H), 2973(C-H str. of CH3); 1762 (C=O,
ester); 1536 (C-NO2), 812 (Ar-H); 1H-NMR (DMSO-d6; d,
ppm) : 8.13 7.47 (m, 4H, Ph ring), 8.11 (s, 1H, NH of
pyridine ring), 4.79 (s, 1H, C4-H), 4.25 (q, 4H, C3-OCH2CH3
and C5-OCH2CH3), 2.31 (s, 6H, C2-CH3 and C6-CH3), 1.37
(t, 6H, C2-OCH2CH3 and C6-OCH2CH3); C19H22N2O6.

Anti-Inflammatory Activity of New Series

Diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1f): IR (KBr; n, cm1): 3352

(N-H str.), 3026 (Ar-H), 2961 (C-H str. of CH3), 1742 (C=O,
ester), 823(Ar-H); 1H NMR (DMSO-d6; d, ppm): 8.21 (s, 1H,
NH of pyridine ring), 6.86 7.17 (m, 4H, Ph ring), 4.69
(s,1H, C4-H), 4.23(q, 4H, C3-OCH2CH3 and C5-OCH2CH3),
3.84 (s, 3H, -OCH3), 2.23 (s, 6H, C2-CH3 and C6-CH3), 1.30
(t, 6H, C2-OCH2CH3 and C6-OCH2CH3); C20H25NO5.
Diethyl 4-(4-(dimethylamino)phenyl)-2,6-dimethyl1,4-dihydropyridine-3,5-dicarboxylate (1g): IR (KBr; n,
cm1): 3348 (N-H str.), 3027 (Ar-H), 2956 (C-H str of CH3);
1761 (C=O, ester), 808 (Ar-H); 1H-NMR (DMSO-d6; d,
ppm) : 8.37 (s, 1H, NH of pyridine ring), 7.28 7.21 (m, 4H,
Ph ring), 4.70 (s, 1H, C4-H), 4.22(q, 4H, C3-OCH2CH3 and
C5-OCH2CH3), 3.12 (s, 6H, -N(CH3)2, 2.28 (s, 6H, C2-CH3
and C6-CH3), 1.32 (t, 6H, C2-OCH2CH3 and C6-OCH2CH3);
C19H23NO4.
Synthesis of 2,2-{[4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl} dihydrazine carbothioamide (2a). A mixture of compound (1a) (0.1mol), thiosemicarbazide dissolved in ethanol (30 mL) and add few
drops DMSO, the reaction mixture was heated under reflux
for 10 h. The solid was obtained, after cooling and poured in
to crushed ice. The solid was collected by filtration, washed
with water, and recrystallized from ethanol. Analogous procedures were followed for the synthesis of compounds
2b 2g.
Compound 2a: IR (KBr; n, cm1): 3370 (NH), 3221
(NH2), 3192 (NH-C=O), 3037 (Ar-H), 1721 (C=O), 1263
(C=S), 1095 (N-C-N), 811 (Ar-H); 1H-NMR (DMSO-d6; d,
ppm) : 9.64 (s,2H, NH2), 8.46 (s,1H, NH of pyridine ring),
8.12 (d, 1H, C3 - CONH and C5- CONH), 7.22 (s, 5H, Ph
ring), 6.14 6.32 (d, 2H, furyl ring), 5.15 (s, 2H, C4-H), 2.33
(s, 6H, C2-CH3 and C6-CH3), 2.14 (d, 1H, -NHCS);
C17H21N7O2S2.
2,2-[(2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5diyl)dicarbonyl] dihydrazine carbothioamide (2b): IR
(KBr; n, cm1): 3372 (NH), 3218 (NH2), 3200 (NH-C=O),
3034 (Ar-H), 1718 (C=O), 1260 (C=S), 1091 (N-C-N); 808
(Ar-H); 1H-NMR (DMSO-d6; d, ppm): 9.62 (s,2H, NH2),
8.43 (s,1H, NH of pyridine ring), 8.09 (d,1H, C3-CONH and
C5-CONH), 7.39 7.22 (m, 5H, Ph ring), 5.17 (s, 2H, C4-H),
2.37 (s, 6H, C2-CH3 and C6-CH3), 2.12 (d, 1H, -NHC);
C17H21N7O2S2.
2,2-{[4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropy
ridine-3,5-diyl]dicarbonyl} dihydrazine carbothioamide
(2c): IR (KBr; n, cm1): 3325 (NH), 3231 (NH2), 3198
(NH-C=O), 3024(Ar-H), 1707 (C=O), 1265 (C=S), 1097
(N-C-N), 827(C-Cl); 1H-NMR (DMSO-d6; d, ppm): 9.41 (s,
2H, NH2), 8.41 (bs, 1H, NH of pyridine ring), 8.11 (d, 1H,
C3 - CONH and C5- CONH), 7.38 7.14 (dd, 4H, Ph ring),
5.10 (s, 1H, C4-H), 2.45 (s, 6H, C2-CH3 and C6-CH3), 2.08
(d, 1H, -NHC); C17H20ClN7O2S2.

465

2,2-{[4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydro
pyridine-3,5-diyl]dicarbonyl} dihydrazine carbothioamide (2d): IR (KBr; n, cm1): 3342 (NH), 3220 (NH2),
3192 (NH-C=O), 3028 (Ar-H), 1717 (C=O), 1472 (C-OH),
1242 (C=S), 1091 (N-C-N); 1H-NMR (DMSO-d6; d, ppm):
9.71 (s,2H, NH2), 9.41 (s, 1H, OH), 8.64 (bs, 1H, NH of
pyridine ring), 8.01 (d, 2H, C3-CONH and C5-CONH),
7.33 7.27 (dd, 4H, Ph ring), 5.11 (s, 1H, C4-H), 2.25 (s, 6H,
C2-CH3 and C6-CH3), 2.02 (d, 1H, -NHC); C17H21N7O2S2.
2,2-{[4-(4-nitrophenyl)-2,6-dimethyl-1,4-dihydropyri
dine-3, 5-diyl]dicarbonyl} dihydrazine carbothioamide
(2e): IR (KBr; n, cm1): 3310 (NH), 3241 (NH2), 3218
(NH-C=O), 3041 (Ar-H), 1710 (C=O), 1272 (C=S), 1530
(C-NO2), 1091(N-C-N); 1H-NMR (DMSO-d6; d, ppm) : 9.77
(s, 4H, 2,6-NH2), 8.60 (s, 1H, NH of pyridine ring), 8.15 (d,
2H, C3-CONH and C5-CONH), 7.42 7.18 (dd, 4H, Ph
ring), 5.17 (s, 1H, C4-H), 2.31 (s, 6H, C2-CH3 and C6-CH3),
2.08 (d, 1H, -NHC); C17H20N8O4S2.
2,2-{[4-(4-methoxyhenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]dicarbonyl} dihydrazine carbothioamide (2f): IR (KBr; n, cm1): 3323 (NH), 3251 (NH-C=O),
3231 (NH2), 3034 (Ar-H), 1717 (C=O), 1251 (C=S), 1091
(N-C-N), 808 (Ar-H); 1H-NMR (DMSO-d6; d, ppm): 9.82 (s,

TABLE 2. Anti-Inflammatory Activity (Carrageenan Induced Rat

Paw Edema Model) of Compounds 2a 2g
Dose,
mg/kg

Increase in paw
volume1
(3 h 0 h)

Control

0.56 0.01

2a

50

0.41 0.06*

26

100

0.24 0.04*

57

50

0.48 0.04*

14

100

0.32 0.05*

42

Compound

2b

2c

2d

2e

2f

2g

Standard
1

Percentage
activity (%)

50

0.41 0.04*

26

100

0.30 0.07*

46

50

0.48 0.05*

14

100

0.31 0.04*

47

50

0.44 0.04*

21

100

0.34 0.06*

39

50

0.52 0.09*

100

0.49 0.04*

12

50

0.47 0.06*

16

100

0.40 0.05*

28

20

0.20 0.01**

64

Significance levels: * p < 0.05 and ** p < 0.01 compared with

control; values represent the Mean S.E.M. of six rats for each
group; diclofenac sodium used as standard.

466

2H, 2,6-NH2), 8.57 (s, 1H, NH of pyridine ring), 8.05 (d, 1H,
C3-CONH and C5-CONH), 7.33 7.27 (dd, 4H, Ph ring),
5.21 (s, 1H, C4-H), 3.81(s, 3H, -OCH3), 2.25 (s, 6H, C2-CH3
and C6-CH3), 2.10 (d, 2H, 2,6-NHC); C18H23N7O3S2.
2,2-{[4-(4-dimethylnitrophenyl)-2,6-dimethyl-1,4-dih
ydropyridine-3,5-diyl]dicarbonyl} dihydrazine carbothioamide (2g): IR (KBr; n, cm1): 3321 (NH), 3211 (NH2),
3118 (NH-C=O), 3021 (Ar-H), 1712 (C=O), 1248 (C=S),
1091 (N-C-N), 808 (Ar-H); 1H-NMR (DMSO-d6; d, ppm):
9.66 (s, 2H, NH2), 8.52 (s, 1H, NH of pyridine ring), 8.03 (d,
2H, C3-CONH and C5- CONH), 6.62 7.07 (4H, Ph ring),
5.13 (s, 1H, C4-H), 2.07 (d, 2H, 2,6-NHC), 3.06 (s, 6H,
-(CH3)2), 2.19 (s, 6H, C2-CH3 and C6-CH3); C19H26N8O2S2.
EXPERIMENTAL BIOLOGICAL PART
The anti-inflammatory activity testing was performed by
the conventional method [23]. Albino rats of both sexes
weighing 150 g were divided into 4 groups, each consisting
of 5 animals. Inflammation was induced by subcutaneous injection of 0.1 mL of 1% carrageenan solution into the subplantar side of the left hind paw. One hour after the administration of the test compounds (100 mg/kg, p.o.), one group
was kept as control and received only 0.5% carboxymethyl
cellulose solution. The right hind paw volume was measured
before and after 3 h of carrageenan treatment by means of
plethysmometer. Percentage of anti-inflammatory activity
was estimated as (Vc Vt/Vc) 100%.
The anti-inflammatory activity of compounds 2a 2g
was compared to that of the standard drug diclofenac sodium
at the effective peroral dose. The standard dose (20 mg/kg)
has 64% activity in albino rats, whereas test compound 2a
showed 57% activity at 100 mg/kg after 4 h (Table 2). Compound 2a has higher activity than the other compounds. Data
obtained from animal experiments are represented by mean
standard error of the mean (Mean S.E.M.). Statistical differences between the treated and control groups were evaluated by the Students test. Values for compounds were considered significant at * p < 0.05 compared with control and
significant for standard at ** p < 0.01 compared with control.
Among the compounds containing thiosemicarbazone
(2a 2g), compound 2a has equipotent anti-inflammatory
activity comparable with that of diclofenac sodium (standard). This compound can be beneficial for further studies.
The synthesized compounds can be extended to various
pharmacological activities.

A. Idhayadhulla et al.

ACKNOWLEDGMENTS
We wish to thank the state Government of Tamil Nadu,
India, for providing state government fellowship for financial support. We wish to thank Mother Theresa Post Graduate & Research Institute of Health Science (Poduchary,
605006, India) for anti-inflammatory activity testing.
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