Synthesis and antimicrobial activity of a new series of 1,4-dihydropyridine derivatives

Article abstract of DOI:10.2298/JSC091127003K

A series of 1,4-dihydropyridine derivatives (1a-g) were prepared from Hantzsch syntheses. The compounds 1a-g were reacted with thiosemicarbazide to give the new series of compounds 2a-g. IR, ¹H-NMR, ¹³C-NMR, mass spectral and elemental analysis confirmed the synthesized compounds. The synthesized compounds were also screened for their antimicrobial activity.

Full text of DOI:10.2298/JSC091127003K

J. Serb. Chem. Soc. 76 (1) 1–11 (2011)
UDC 547.823+542.913:615.28–188
JSCS–4093
Original scientific paper
Synthesis and antimicrobial activity of a new series of
1,4-dihydropyridine derivatives
RADHAKRISHNAN SURENDRA KUMAR1, AKBAR IDHAYADHULLA1,
1
2
*
ABDUL JAMAL ABDUL NASSER and JOSEPH SELVIN
1P. G. & Research, Department of Chemistry, Jamal Mohamed College, Tiruchirappalli-620 020,
Tamil Nadu and 2Department of Microbiology, Bharathidasan University,
Tiruchirappalli-620024, Tamil Nadu, India
(Received 27 November 2009, revised 21 July 2010)
Abstract: A series of 1,4-dihydropyridine derivatives (1a–g) were prepared
from Hantzsch syntheses. The compounds 1a–g were reacted with thiosemi-
1
carbazide to give the new series of compounds 2a–g. IR, H-NMR, 13C-NMR,
mass spectral and elemental analysis confirmed the synthesized compounds.
The synthesized compounds were also screened for their antimicrobial activity.
Keywords: 1,4-dihydropyridine; thiosemicarbazide; condensation; antimicro-
bial activity.
INTRODUCTION
1,4-Dihydropyridine derivatives are of interest because of their biological
1–4
5
activity, such as vasodilators, antihypertensive,
anti-inflammatory, antihy-
6
poxic and anti-ischemic agents and calcium channel modulators of the nifedi-
pine type. Recently, it was reported that the amide group was involved in the
7
3,5-position of 1,4-dihydropyridine derivatives and it exhibited pharmacological
8,9
effects. Basically thiosemicarbazone containing heterocyclics have significant
biological activity, such as antitumour, fungicidal, bactericidal, anti-
10–13
inflammatory and antiviral activities.
In view of these observations, it was
decided to synthesize a new series of 1,4-dihydropyridine derivatives (2a–g) and
screen them for their level of antimicrobial activity.
RESULTS AND DISCUSSION
Chemistry
The series of diethyl 2,6-dimethyl-4-substituted phenyl-1,4-dihydropyridine-
14–19
-3,5-dicarboxylate (1a–f) are already published in literature
, but not their
*Corresponding author. E-mail: jamal_abdulchem@ymail.com
doi: 10.2298/JSC091127003K
1
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

2
SURENDRA KUMAR et al.
antimicrobial screening. On the other hand the syntheses and antimicrobial scre-
ening of compound 1g has not been published. The compounds 1a–g were re-
acted with thiosemicarbazide to give 4-aryl-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid, 3,5-bis[2-(aminothioxomethyl)hydrazide] (2a–g) by the
20,21
hydrazinolysis method
(Scheme 1).
O
R
O
O
O
EtO
OEt
CH3
EtOH
NH4OH
R -CHO
OEt
+
H3C
+
H3C
N
H
(1a-g)
O
R
O
O
R
O
H
N
H2N
H2N NH
EtO
OEt
DMSO
N
NH
H
NH2
+
S
HN
CH3
S
H3C
N
H
CH3
S
H3C
N
H
NH2
(2a-g)
(1a-g)
1a, 2a
1b, 2b
1c, 2c
1d, 2d
1e, 2e
1f, 2f
1g, 2g
: R = 2-Furyl
:
R = -Ph
:
R = 4-Cl-C6H4
R = 4-OH-C6H4
R = 4-NO2-C6H4
R = 4-CH3O-C6H4
R = 4-(CH3)2N-C6H4
:
:
:
:
Scheme 1. Synthesis of the compounds 2a–g.
Analytic and spectral data
Diethyl 4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(1a). Yield: 75 %; m.p.158 °C; Anal. Calcd. for C H NO : C, 63.94; H, 6.63;
17 21
5
–1
N, 4.39 %. Found: C, 63.98; H, 6.67; N, 4.35 %. IR (KBr, cm ): 3349 (N–H str),
3030 (Ar–H), 2940 (C–H str of CH ), 1745 (C=O, ester), 812 (Ar–H). H-NMR
1
3
(300 MHz, DMSO-d , δ / ppm ): 8.20 (1H, s, NH of pyridine ring), 7.27 (1H, s,
6
furyl ring), 6.10–6.27 (2H, d, furyl ring), 4.72 (1H, s, C4–H), 4.20 (4H, q, C3–
–CH CH and C5–OCH CH ), 2.31 (6H, s, C2–CH and C6–CH ), 1.34 (6H, t,
2
3
2
3
3
3
13
C2–OCH CH and C6–OCH CH ). C-NMR (300 MHz, DMSO-d , δ / ppm ):
2
3
2
3
6
142.1, 110.6, 106.7, 152.5 (furyl ring), 151.8 (C2,6), 33.2 (C4), 102.3 (3,5-
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1,4-DIHYDROPYRIDINE DERIVATIVES
3
-COOCH CH ), 61.1(3,5-COOCH CH ), 14.9 (3,5-COOCH CH ), 18.1 (2,6-
2
3
2
3
2
3
+
-CH ). MS (m/z (relative abundance, %)): 320.15 (M +1, 40.2), 275.29, 231.24,
3
203.23, 173.22, 161.20, 147.2, 134.12, 82.10.
Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1b).
Yield: 66 %; m.p. 253 °C; Anal. Calcd. for C H NO : C, 69.28; H, 7.04; N,
19 23
4
–1
4.25 %. Found: C, 69.24; H, 7.07; N, 4.28 %. IR (KBr, cm ): 3350 (N–H str),
3034 (Ar–H), 2953 (C–H str of CH ), 1755 (C=O, ester), 802 (Ar–H). H-NMR
1
3
(300 MHz, DMSO-d , δ / ppm ): 8.25 (1H, s, NH of pyridine ring), 7.33–7.27
6
(5H, m, Ph-ring), 4.70 (2H, s, C4–H), 4.22 (4H, q, C3–OCH CH and C5–
2
3
–OCH CH ), 2.28 (6H, s, C2–CH and C6-CH ), 1.32 (6H, t, C2–OCH CH
2
3
3
3
2
3
13
and C6–OCH CH ). C-NMR (300 MHz, DMSO-d , δ / ppm ): 125.1, 128.4,
2
3
6
127.1, 144.8 (phenyl ring), 150.7 (C2,6), 101.9 (3,5-COOCH CH ), 62.1 (3,5-
2
3
-COOCH CH ), 44.1 (C4), 19.1 (2,6-CH ), 15.4 (3,5-COOCH CH ). MS (m/z
2
3
3
2
3
+
(relative abundance, %)): 330.39 (M +1, 38.9), 285.33, 241.28, 185.26, 171.23,
157.21, 81.11, 68.11.
Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbo-
xylate (1c). Yield: 57 %; m.p. 240 °C. Anal. Calcd. for C H ClNO : C, 62.72;
19 22
4
–1
H, 6.09; N, 3.85 %. Found: C, 62.75; H, 6.07; N, 3.81 %. IR (KBr, cm ): 3332
(N–H str), 3074 (Ar–H), 2942 (C–H str of CH ), 1741 (C=O, ester), 812 (Ar–H),
3
1
610 (C–Cl), 787 (Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm ): 8.31 (1H, s,
6
NH of pyridine ring), 7.36–7.19 (5H, m, Ph-ring), 4.76 (1H, s, C4–H), 4.18 (4H,
q, 3C–OCH CH and C5–OCH CH ), 2.21 (6H, s, C2–CH and C6–CH ), 1.34
2
3
2
3
3
3
13
(6H, t, C2–OCH CH and C6–OCH CH ). C-NMR (300 MHz, DMSO-d , δ /
2
3
2
3
6
/ ppm): 131.4, 128.1, 130.8, 142.5 (Ph–Cl), 152.5 (C2,6), 34.6 (C4), 103.9 (3,5-
-COOCH CH ), 60.3 (3,5-COOCH CH ), 15.2 (3,5-COOCH CH ), 18.6 (2,6-
2
3
2
3
2
3
+
-CH ). MS (m/z (relative abundance, %)): 364.90 (M +1, 21.2), 275.57, 219.70,
3
185.26, 171.23, 157.21, 144.21
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbo-
xylate (1d). Yield: 56 %; m.p. 240 °C; Anal. Calcd. for C H NO : C, 69.07; H,
19 23
5
–1
6.71; N, 4.06 %. Found: C, 9.03; H, 6.75; N, 4.01 %. IR (KBr, cm ): 3342 (N–H
str), 3024 (Ar–H), 2922 (C–H str of CH ), 1764 (C=O, ester), 1447 (C–OH), 814
3
1
(Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm): 9.47 (1H, s, C–OH), 8.41
6
(1H, s, NH of pyridine ring), 6.34–7.07 (4H, m, Ph-ring), 4.67 (1H, s, C4–H), 4.28
(4H, q, C3–OCH CH and C5–OCH CH ), 2.12 (6H, s, C2–CH and C6–CH ),
2
3
2
3
3
3
13
1.28 (6H, t, C2–OCH CH and C6–OCH CH ). C-NMR (300 MHz, DMSO-
2
3
2
3
-d , δ / ppm ): 155.6, 116.2, 131.2, 138.2 (Ph-OH), 151.4 (C2,6), 44.9 (C4),
6
101.4 (3,5-COOCH CH ), 62.3 (3,5-COOCH CH ), 14.1(3,5-COOCH CH ),
2
3
2
3
2
3
+
18.4 (2,6-CH ). MS (m/z (relative abundance, %)): 346.81 (M +1, 12.3), 310.45,
3
257.81, 201.48, 187.22, 173.28, 157.21.
Diethyl
2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbo-
xylate (1e). Yield: 69 %; m.p.197 °C; Anal. Calcd. for C H N O : C, 60.95; H,
19 22
2 6
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

4
SURENDRA KUMAR et al.
–1
7.48; N, 7.48 %. Found: C, 60.91; H, 7.42; N, 7.41 %. IR (KBr, cm ): 3354 (N–H
str), 3037 (Ar–H), 2973 (C–H str of CH ), 1762 (C=O, ester), 1536 (C–NO ),
3
2
1
812 (Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm): 8.13–7.47 (4H, m, Ph-
6
-ring), 8.11 (1H, s, NH of pyridine ring), 4.79 (1H, s, C4–H), 4.25 (4H, q, C3–
–OCH CH and C5–OCH CH ), 2.31 (6H, s, C2–CH and C6–CH ), 1.37 (6H,
2
3
2
3
3
3
13
t, C2–OCH CH and C6–OCH CH ); C-NMR (300 MHz, DMSO-d , δ /
2
3
2
3
6
/ ppm): 144.8, 123.6, 126.9, 151.0 (Ph–NO ), 152.2 (C2,6), 43.9 (C4), 103.2
2
(3,5-COOCH CH ), 60.8 (3,5-COOCH CH ), 14.4 (3,5-COOCH CH ), 18.8
2
3
2
3
2
3
+
(2,6-CH ). MS (m/z (relative abundance, %)): 375.22 (M +1, 21.2), 286.26,
3
185.26, 171.23, 157.21.
Diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbo-
xylate (1f). Yield: 72 %; m.p. 197 °C; Anal. Calcd. for C H NO : C, 66.83; H,
20 25
5
–1
7.01; N, 3.90 %. Found: C, 66.87; H, 7.07; N, 3.97 %. IR (KBr, cm ); 3352 (N–H
str), 3026 (Ar–H), 2961 (C–H str of CH ), 1742 (C=O, ester), 823 (Ar–H). H-
1
3
-NMR (300 MHz, DMSO-d , δ / ppm): 8.21 (1H, s, NH of pyridine ring), 6.86–
6
–7.17 (5H, m, Ph-ring), 4.69 (1H, s, C4–H), 4.23 (4H, q, C3–OCH CH and C5–
2
3
–OCH CH ), 3.84 (3H, s, –OCH ), 2.23 (6H, s, C2–CH and C6–CH ), 1.30
2
3
3
3
3
13
(6H, t, C2–OCH CH and C6–OCH CH ). C-NMR (300 MHz, DMSO-d , δ /
2
3
2
3
6
/ ppm): 157.2, 114.6, 129.3, 135.9 (Ph), 158.3 (C2,6), 102.3 (3,5-COOCH CH ),
2
3
61.5 (3,5-COOCH CH ), 55.7 (Ph–OCH ), 43.6 (C4), 14.8 (3,5-COOCH CH ),
2
3
3
2
3
+
18.0 (2,6-CH ). MS (m/z (relative abundance, %)): 360.44 (M +1, 41.2), 331.81,
3
287.31, 243.25, 187.23, 157.21.
Diethyl 4-(4-(dimethylamino)phenyl)-2,6–dimethyl-1,4-dihydropyridine-3,5-
-dicarboxylate (1g). Yield: 56 %; m.p. 227 °C; Anal. Calcd. for C H N O : C,
21 28
2 4
–1
67.72; H,7.58; N, 7.52 %. Found: C, 67.77; H, 7.52; N, 7.58 %. IR (KBr, cm ):
3348 (N–H str), 3027 (Ar–H), 2956 (C–H str of CH ), 1761 (C=O, ester), 808
3
1
(Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm ): 8.37 (1H, s, NH of pyridine
6
ring), 7.28–7.21 (5H, m, Ph-ring), 4.70 (2H, s, C4–H), 4.22 (4H, q, C3–
–OCH CH and C5–OCH CH ), 3.12 (6H, s, –N(CH ) ), 2.28 (6H, s, C2–CH
2
3
2
3
3 2
3
13
and C6–CH ), 1.32 (6H, t, C2–OCH CH and C6–OCH CH ). C-NMR (300
3
2
3
2
3
MHz, DMSO-d , δ / ppm): 128.3, 112.9, 148.5, 133.9 (Ph), 151.8 (C2,6), 43.8
6
(C4), 102.8 (3,5-COOCH CH ), 60.5 (3,5-COOCH CH ), 40.8 (–N(CH ) ),
2
3
2
3
3 2
13.9 (3,5-COOCH CH ), 18.9 (2,6-CH ). MS (m/z (relative abundance, %)):
2
3
3
+
373.44 (M +1, 51.8), 284.35, 228.33, 185.26, 171.23, 157.21.
4-(Furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, 3,5-
-bis[2-(aminothioxomethyl)hydrazide] (2a). Yield: 63 %; m.p. 161 °C; Anal.
Calcd. for C H N O S : C, 44.00; H, 4.68; N, 23.94 ; S, 15.66 %. Found: C,
15 19
7 3 2
–1
44.06; H, 4.62; N, 23.97; S, 15.62 %. IR (KBr, cm ): 3372 (N–H), 3200 (NH–
1
–C=O), 3218 (NH ), 3021 (Ar–H), 1260 (C=S), 1091 (N–C–N), 828 (Ar–H). H-
2
-NMR (300 MHz, CDCl , δ / ppm): 9.62 (2H, s, NH ), 8.43 (1H, s, NH of pyri-
3
2
dine ring), 8.09 (1H, d, C3–CONH and C5–CONH), 7.51 (1H, d, 5’-H-furyl),
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1,4-DIHYDROPYRIDINE DERIVATIVES
5
6.24 (1H, d, 4’-H-furyl), 6.24 (1H, d, 3’-H-furyl); 5.17 (2H, s, C4–H), 2.28 (6H,
13
s, C2–CH and C6–CH ), 2.02 (1H, d, NHCS). C-NMR (300 MHz, CDCl , δ /
3
3
3
/ ppm): 111.8, 108.3, 143.2, 152.8 (C4 in furyl ring), 105.3 (C3,5 in pyridine ring),
166.2 (C=O), 182.1 (C=S), 148.9 (C2,6 in pyridine ring), 35.3 (C4 in pyridine
ring), 18.2 (C2,6–CH in pyridine ring); MS (m/z, (relative abundance, %)): 410
3
+
(M +1, 30.2), 291.30, 161.27, 175.22, 147.12, 81.11.
2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid, 3,5-bis[2-
-(aminothioxomethyl)hydrazide] (2b). Yield: 53 %; m.p. 192 °C; Anal. Calcd.
for C H N O S : C, 48.67; H, 5.50; N, 23.37; S, 15.29 %. Found: C, 48.64; H,
17 21
7 2 2
–1
5.57; N, 23.31; S, 15.34 %. IR (KBr, cm ): 3370 (N–H), 3175 (NH–C=O), 3218
1
(NH ), 3034 (Ar–H), 1718 (C=O), 1260 (C=S), 1091 (N–C–N), 808 (Ar–H). H-
2
-NMR (300 MHz, CDCl , δ / ppm): 9.60 (2H, s, NH ), 8.40 (1H, s, NH of pyri-
3
2
dine ring ), 8.11 (1H, d, C3–CONH and C5–CONH), 7.39–7.22 (5H, m, Ph-
-ring), 5.20 (2H, s, C4–H), 2.37 (6H, s, C2–CH and C6–CH ), 2.12 (1H, d,
3
3
13
–NHCS); C-NMR (300 MHz, CDCl , δ / ppm): 131.3, 128.5, 130.9, 141.8 (C4
3
in furyl ring), 106.8 (C3,5 in pyridine ring), 164.6 (C=O), 182.8 (C=S), 147.9
(C2,6 in pyridine ring), 34.6 (C4 in pyridine ring), 18.9 (2,6-CH in pyridine
3
+
ring); MS (m/z,(relative abundance, %)): 420.20 (M +1, 20.1), 301.34, 241.28,
185.2, 157.21, 81.11.
4-(4-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid,
3,5-bis[2-(aminothioxomethyl)hydrazide] (2c). Yield: 68 %; m.p. 194 °C; Anal.
Calcd. for C H ClN O S : C, 4.98; H, 4.40; N, 21.60; S, 14.14 %. Found: C,
17 20
7 2 2
–1
44.92; H, 4.46; N, 21.64; S, 14.18 %. IR (KBr, cm ): 3325 (N–H), 3231 (NH ),
2
3198 (NH–C=O), 3024 (Ar–H), 1265 (C=S), 1707(C=O), 1097 (N–C–N), 810
1
(Ar–H), 623 (C–Cl). H-NMR (300 MHz, CDCl δ / ppm): 9.41 (2H, s, NH ),
3,
2
8.41 (1H, s, NH of pyridine ring), 8.11 (1H, d, C3–CONH and C5–CONH ),
7.38–7.14 (5H, m, Ph-ring), 5.10 (2H, s, C4–H), 2.45 (6H, s, C2–CH and C6–
3
13
CH ), 2.08 (1H, d, –NHCS). C-NMR (300 MHz, CDCl , δ / ppm): 128.7,
3
3
108.3, 143.2, 152.8 (C4 in furyl ring), 105.3 (C3,5 in pyridine ring ), 166.2
(C=O), 182.1 (C=S), 148.9 (C2,6 in pyridine ring), 39.3 (C4 in pyridine ring),
18.2 (2,6–CH in pyridine ring); MS (m/z (relative abundance, %)): 454.12
3
+
(M +1, 12.3), 335.78, 275.73, 219.70, 157.21, 81.11.
4-(4-Hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid,
3,5-bis[2-(aminothioxomethyl)hydrazide] (2d). Yield: 74 %; m.p. 201 °C; Anal.
Calcd. for C H N O S : C, 46.88; H, 22.51; N, 4.86; S, 14.72 %. Found: C,
17 21
7 3 2
–1
46.81; H, 22.57; N, 4.81; S, 14.77 %. IR (KBr, cm ): 3342 (N–H), 3220 (NH ),
2
3192 (NH–C=O), 3028 (Ar–H), 1472 (C–OH), 1717 (C=O), 1242 (C=S), 1091 (N–
1
–C–N). H-NMR (CDCl δ / ppm ): 9.71 (2H, s, NH ), 9.41 (1H, s, OH), 8.64
3,
2
(1H, s, NH of pyridine ring ), 8.01 (1H, d, C3–CONH and C5–CONH ), 7.33–
–7.27 (5H, m, Ph-ring), 5.11 (2H, s, C4–H), 2.25 (6H, s, C2–CH and C6–CH ),
3
3
13
2.02 (1H, d, –NHCS). C-NMR (300 MHz, CDCl , δ / ppm): 155.8, 137.1,
3
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

6
SURENDRA KUMAR et al.
130.3, 114.2 (C4 in 4-OH-phenyl ring), 102.9 (3,5-C in pyridine ring), 164.9
(C=O), 184.6 (3,5 C=S), 148.1(C2,6 in pyridine ring), 43.8 (C4 in pyridine ring),
19.2 (2,6–CH in pyridine ring). MS (m/z (relative abundance, %)): 435.52
3
+
(M +1, 27.2), 257.28, 201.26, 173.21, 157.21, 81.11.
2,6-Dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid,
3,5-bis[2-(aminothioxomethyl)hydrazide] (2e). Yield: 76 %; m.p. 190 °C; Anal.
Calcd. for C H N O S : C, 43.96; H, 4.34; N, 24.12; S, 15.81 %. Found: C,
17 20
8 4 2
–1
43.91; H, 4.38; N, 24.17; S, 15.87 %. IR (KBr, cm ): 3310 (N–H), 3241 (NH ),
2
3218 (NH–C=O), 3041 (Ar–H), 1710 (C=O), 1530 (C–NO ), 1272 (C=S), 1094
2
1
(N–C–N). H-NMR (300 MHz, CDCl , δ / ppm): 9.77 (2H, s, NH ), 8.60 (1H, s,
3
2
NH of pyridine ring ), 8.15 (1H, d, C3–CONH and C5–CONH ), 7.42–7.18 (5H,
m, Ph-ring), 5.17 (2H, s, C4–H), 2.31 (6H, s, C2–CH and C6–CH ), 2.08 (1H, d,
3
3
13
–NHCS). C-NMR (300 MHz, CDCl , δ / ppm): 143.2, 123.7, 126.7 (C4 in 4-
3
-NO -phenyl ring), 102.9 (3,5-C in pyridine ring ), 164.9 (C=O), 181.9 (C=S),
2
149.9 (2,6-C in pyridine ring), 44.5 (4-C in pyridine ring), 19.7(2,6-C–CH in
3
+
pyridine ring). MS (m/z (relative abundance, %)): 465.52 (M +1, 12.78), 346.34,
286.20, 258.23, 230.21, 202.20, 81.11.
4-(4-Methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid,
3,5-bis[2-(aminothioxomethyl)hydrazide] (2f). Yield: 66 %; m.p. 210 °C; Anal.
Calcd. for C H N O S : C, 48.09; H, 5.16; N, 21.81; S, 14.27 %. Found: C,
18 23
7 3 2
–1
48.05; H, 5.19; N, 21.88; S,14.21 %. IR (KBr, cm ): 3323 (N–H), 3251 (NH–
C=O), 3231 (NH ), 3034 (Ar–H), 1717 (C=O), 1251 (C=S), 1091 (N-C-N), 808
2
1
(Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm): 9.82 (2H, s, NH ), 8.57 (1H,
6
2
s, N–H of pyridine ring), 8.05 (1H, d, C3–CONH and C5–CONH), 7.33–7.27
(5H, m, Ph-ring), 5.21 (2H, s, C4–H), 3.81 (3H, s, –OCH ), 2.25 (6H, s, C2–CH
3
3
13
and C6–CH ), 2.10 (1H, d, –NHCS). C-NMR (300 MHz, CDCl , δ / ppm):
3
3
111.8, 108.3, 143.2, 152.8 (C4 in 4-CH O-phenyl ring), 105.3 (3,5-C in pyridine
3
ring ), 166.2 (3,5-C=O), 181.7 (3,5-C=S), 147.7 (2,6-C in pyridine ring), 44.7
(C4 in pyridine ring), 18.8 (2,6-CH in pyridine ring), 55.9 (–OCH ); MS (m/z,
3
3
+
(relative abundance, %)): 450.21 (M +1, 29.12), 331.36, 271.31, 243.25, 215.29,
185.26, 157.21.
4-[4-(Dimethylaminophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbo-
xylic acid, 3,5-bis[2-(aminothioxomethyl)hydrazide] (2g). Yield: 61 %; m.p. 205
°C; Anal. Calcd. for C H N O S : C, 49.33; H, 5.67; N, 24.22; S, 13.86 %.
19 26
8 2 2
–1
Found: C, 49.37; H, 5.69; N, 24.27; S, 13.82 %. IR (KBr, cm ): 3320 (N–H),
3211 (NH ), 3118 (NH–C=O), 3021 (Ar–H), 1712 (C=O), 1248 (C=S), 1091 (N–
2
1
–C–N), 812 (Ar–H). H-NMR (300 MHz, DMSO-d , δ / ppm): 9.66 (2H, s,
6
NH ), 8.52 (1H, s, NH of pyridine ring), 8.03 (1H, d, C3–CONH and C5–
2
–CONH), 6.62–7.07 (4H, m, Ph-ring), 5.13 (2H, s, C4–H), 3.06 (1H, s, –N(CH ) ),
3 2
13
2.19 (6H, s, C2–CH and C6–CH ), 2.07 (1H, d, NHCS). C-NMR (300 MHz,
3
3
CDCl , δ / ppm) 112.8, 134.8, 128.3, 148.2, 152.8 (C4 in 4-(CH ) N-phenyl ring),
3
3 2
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1,4-DIHYDROPYRIDINE DERIVATIVES
7
106.3 (3,5-C in pyridine ring ), 165.2 (C=O), 181.1 (C=S), 147.9 (2,6-C in pyri-
dine ring), 39.3 (C4 in pyridine ring), 40.8 (N(CH ) ), 46.5 (C4 in pyridine ring),
3 2
18.2 (2,6-CH in pyridine ring). MS (m/z (relative abundance, %)): 463.22
3
+
(M +1, 16.24), 432.56, 344.41, 284.35, 256.29, 213.23, 199.24, 185.26.
Spectroscopy
The IR spectra of compounds 1a–g showed an absorption band at 3332 to
–1
–1
3354 cm due to N–H stretching, another absorption band at 1741–1764 cm
due to the keto group in the ester groups. Compound 1c showed an absorption
–1
band at 610 cm corresponding the to Cl–C bonds, compound 1d showed an ab-
–1
sorption band at 1447 cm corresponding to the HO–C bonds and compound 1e
–1
showed an absorption band at 1536 cm corresponding the O N–C groups. The
2
1
H-NMR spectra of compounds 1a–g showed a singlet at δ 8.11–8.41 ppm, at-
tributable to the NH protons present in the 1,4-dihydropyridine ring, and another
important singlet at δ 4.67–4.79 ppm, which was attributable to the C4–H proton
13
present in the 1,4-dihydropyridine ring. The C-NMR spectra of compounds 1a–g
showed peaks at δ 33.2–44.9 ppm, corresponding to C4 in the pyridine ring, δ
101.4–103.9 ppm, corresponding to the 3,5-position of C–COOEt, and δ 150.7–
–152.8 ppm, corresponding to the 2,6-position of C–CH in the pyridine ring.
3
The mass spectral analysis of compounds 1a–g showed molecular ion peaks,
which confirmed the molecular mass of these compounds. The IR spectra of
–1
compounds 2a–g showed an absorption band obtained at 3320–3372 cm cor-
responding to the NH group present in the 1,4-dihydropyridine ring and another
–1
absorption band at 3118–3200 cm which was due to NH–C=O stretching. An
–1
1
absorption band for the C=S group was observed at 1242–1272 cm . The H-
-NMR spectra of 2a–g showed as a singlet a band at δ 8.41–8.64 ppm, attribu-
table to the NH protons present in the 1,4-dihydropyridine ring. The C4–H, CONH,
NHCS and NH protons resonated as singlets at δ 5.10–5.21, 8.01–8.15, 2.02–
2
13
–2.12 and 9.14–9.82 ppm, respectively. The C-NMR spectra of compounds 2a–g
showed peaks at δ 163.1–166.2, 181.1–184.6, 34.6–46.5 and 18.2–19.7 ppm,
corresponding to the 3,5-position of CO-NH group in the pyridine ring, the 3,5-
-position of CS in the pyridine ring, the 4-position of carbon in the pyridine ring
and the 2,6-position of CH in the pyridine ring, respectively. Mass spectral ana-
3
lysis of compounds 2a–g showed molecular ion peaks, which confirmed the
molecular masses of these compounds.
Antibacterial screening
The bacterial zones of inhibition values (mm) are given in Table I. The anti-
microbial activities of compounds 1a–g and 2a–g were screened. The structure
activity relationship (SAR) analysis of the base compounds 1a–g was compared
with that of the thiosemicarbazone-containing compounds 2a–g. Ciprofloxacin
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

8
SURENDRA KUMAR et al.
–1
was used as a standard at 100 µg ml . Compounds 1a–g showed low activity
compared with compounds 2a–g towards all the tested organisms.
TABLE I. Antibacterial activity of the synthesized compounds 1a–g and 2a–g (disk diameter:
7 cm)
Compound
S. aureus
K. pneumoniae
E. coli
P. aeruginosa
1a
1b
–
6
–
7
10
5
14
6
1c
1d
10
–
–
8
8
–
10
–
1e
1f
1g
2a
2b
2c
2d
2e
5
–
5
9
17
25
15
13
11
10
22
5
6
–
–
18
15
16
12
18
7
6
5
12
15
6
30
18
10
–
20
22
16
32
10
16
12
13
25
16
15
18
27
2f
2g
Ciprofloxacin
19
Compounds 2a–g were screened for Staphylococcus aureus and compound
2c was found to be highly active compared with the standard ciprofloxacin be-
cause it contained an amide group in the 3,5-position with C=S and a 4-chloro-
phenyl group in the fourth position. On the other hand, compounds 2a, 2b and
2d–g had low activities compared with the standard ciprofloxacin.
Compounds 2a–g were screened for Klebsiella pneumoniae, whereby com-
pounds 2b and 2f showed equipotent activity with the standard ciprofloxacin. On
the other hand, compounds 2a, 2d–e and 2g had low activities compared with the
standard ciprofloxacin.
Compounds 2a–g were screened for Escherichia coli and the compound 2d
was found to have an equipotent activity compared with the standard ciproflo-
xacin. On the other hand, compounds 2a–c and 2e–g had low activities compared
with the standard ciprofloxacin.
Compounds 2a–g were screened for Pseudomonas aeruginosa, whereby the
compound 2a exhibited equipotent activity compared with the standard cipro-
floxacin, while the other compounds 2b–g had low activities compared with the
standard ciprofloxacin.
Antifungal screening
The fungacidal zones of inhibition, mm, values are given in Table II. Com-
pounds 2a–g were screened for Aspergillus niger; the compounds 2b–g were less
active compared with the standard clotrimazole, while compound 2a had no ac-
tivity.
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1,4-DIHYDROPYRIDINE DERIVATIVES
9
Compounds 2a–g were screened for Candida albicans. Compound 2d was
highly active compared with the standard clotrimazole because it contained an
amide group in the 3,5-position with C=S and 4-hydroxyphenyl in the fourth po-
sition, while the other compounds 2a–c and 2e–g had lower activities than the
standard clotrimazole.
TABLE II. Antifungal activity of the synthesized compounds 1a–g and 2a–g (disk diameter:
7 cm)
Compound
A. niger
C. albicans
M. audouinii
C. neoformans
1a
1b
1c
1d
–
9
10
14
8
8
10
8
–
12
–
–
9
8
–
–
10
16
–
1e
–
1f
1g
2a
12
5
–
15
16
8
11
12
6
9
–
7
2b
2c
2d
2e
2f
2g
10
15
16
8
16
14
22
–
–
6
20
26
11
10
17
24
14
18
15
18
16
26
13
15
15
24
–
Clotrimazole
25
Compounds 2a–g were screened for Microsporum audouinii. The com-
pounds 2a and 2c–g had lower activity than the standard clotrimazole, while
compound 2b was inactive.
Compounds 2a–g were screened for Cryptococcus neoformans, the com-
pound 2f had equipotent activity with the standard clotrimazole, while the other
compounds 2a–d and 2e had lower activities compared with the standard clotri-
mazole and compound 2g exhibited no activity.
EXPERIMENTAL
Chemistry
The melting points were recorded in open capillary tubes and are reported uncorrected.
The IR spectra were recorded in KBr on a Shimadzu 8201pc FTIR specrometer (4000–400
cm-1). The 1H-NMR and 13C-NMR spectra were recorded on a Bruker DRX-300 MHz instru-
ment. The mass spectra (EI) were obtained on a Jeol JMS D-300 spectrometer operating at 70
eV. Elemental analyses (C, H, N and S) were realized using an Element Analyzer, model Va-
rio EL III. The purity of the compounds was checked by thin layer chromatography (TLC).
Synthesis of diethyl 4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1a)
The reaction mixture consisting of ethyl acetoacetate (0.2 mol), furfural (0.1 mol) and
ammonium hydroxide (0.1 mol) in methanol (20 mL) was heated at reflux for 4 h. The ob-
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

10
SURENDRA KUMAR et al.
tained solid was filtered off, washed with water and recrystallized using absolute ethanol. The
above procedure was followed for the synthesis of compounds 1b–g.
Synthesis of 4-(furan-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid,
3,5-bis[2-(aminothioxomethyl)hydrazide] (2a)
The reaction mixture consisting of compound 1a (0.1 mol), thiosemicarbazide (0.2 mol)
dissolved in ethanol (30 mL) and a few drops DMSO was heated under reflux for 10 h. The
obtained solid was allowed to cool and then poured into crushed ice. The solid was collected
by filtration, washed with water and recrystallised using ethanol. The above procedure was
followed for the synthesis of compounds 2b–g.
In vitro antibacterial screening
The compounds 1a–g and 2a–g were evaluated for their in vitro antibacterial activity
against S. aureus (ATCC-25923), K. pneumoniae (recultured), E. coli (ATCC-25922) and P.
aeruginosa (ATCC-27853) by the agar diffusion method22,23 using Mueller–Hinton agar (Hi-
-Media) medium. Each compound was tested at a concentration of 100 μg mL-1 in DMSO. Ci-
profloxacin was used as the standard. The zone of inhibition (mm) was measured after 24 h
incubation at 37 ºC.
In vitro antifungal screening
The compounds 1a–g and 2a–g were evaluated for their in vitro antifungal activity against
A. niger, C. albicans, M. audouinii and C. neoformans (recultured) using an agar diffusion
method24,25 with Sabouraud’s dextrose agar (Hi-Media). Each compound was tested at a con-
centration of 100 μg mL-1 in DMSO. Clotrimazole was used as the standard. The zone of in-
hibition (mm) was measured after 24 h incubation at 37 °C.
CONCLUSIONS
A new series of 1,4-dihydropyriodine derivatives (2a–g) was synthesized.
The synthesized compounds were screened for their antibacterial activity, where-
by compound 2c was more active than ciprofloxacin against S. aureus organism.
When the synthesized compounds were screened for their antifungal activity, a
compound 2d showed higher activity than clotrimazole against C. albicans.
These findings could be of importance for further studies in this field.
Acknowledgments. We wish to thank for State Government of Tamil Nadu for providing
financial support through a state government fellowship. We wish to thank one of the authors
Dr. J. Selvin, Department of Microbiology for help in the antimicrobial studies. We sincerely
thank the management of Jamal Mohamed College for providing the Laboratory Facilities.
И З В О Д
СИНТЕЗА И АНТИМИКРОБНА АКТИВНОСТ НОВЕ СЕРИЈЕ ДЕРИВАТА
1,4-ДИХИДРОПИРИДИНА
R. SURENDRA KUMAR1, A. IDHAYADHULLA1, A. JAMAL ABDUL NASSER1 и J. SELVIN2
1P. G. & Research Department of Chemistry, Jamal Mohamed College, Tiruchirappalli-620 020, Tamil Nadu и
2Department of Microbiology, Bharathidasan University.Tiruchirappalli–620024, Tamil Nadu, India
Ханчовом синтезом добијена је нова серија деривата 1,4-дихидропиридина (1a–g). Једи-
њења 1а–g реаgовала су са тиосемикарбазидима и добијена је нова серија једињења 2а–g.
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1,4-DIHYDROPYRIDINE DERIVATIVES
11
Структура синтетисаних једињења је потврђена ИЦ, 1H-NMR, 13C-NMR и масеним спектрима
и елементалном анализом. Синтетисаним једињењима је одређена антибикробна активност.
(Примљено 27. новембра 2009, ревидирано 21. јула 2010)
REFERENCES
1. C. Gaudio, A. Korolkovas, Y. Takahata, J. Pharm. Sci. 83 (1994) 1110
2. K .J. Chleifer, J. Med .Chem. 42 (1999) 2204
3. S. Visentin, P. Amiel, R. Frittero, D. Boschi, C. Roussel, L. Giusta, E. Carbone, Gasco, J.
Med. Chem. 42 (1999) 1422
4. J.-L. Jiang, A.-H. Li, S.-Y. Jang, L. Chang, N. Melman, S. Moro, X.-D. Ji, E. B. Lobkov-
sky, J. C. Clardy, K. A. Jacobson, J. Med. Chem. 42 (1999) 3055
5. T. Godfraid, R. Miller, M. Wibo, Pharmocol. Rev. 38 (1986) 321
6. B. Khadilkar, S. Borkar, Synth. Commun. 28 (1998) 207
7. B. Schnell, W. Krenn, K. Faber, C. O. Kappe, J. Chem. Soc. Perkin Trans. 1 24 (2000)
4382
8. S. R. Pattan, V. B. Rasal, N. Venkatramana, A. B. Khade, S. R. Butle, S. G .Jadhav, B .G.
Desai, F. V. Manvi, Indian J. Chem. 46B (2007) 698
9. T .Suresh, S. K. Swamy, V. M. Reddy, Indian J. Chem. 46B (2007) 115
10. A. Bhavik, A. Dinesh Sureja, A. Yogesh Naliapara, A. Anamik Shaha, A. K. Saxenab,
Bioorg. Med. Chem. 91 (2001) 993
11. M. Amini, L. Navidpour, A. Shafiee, Daru 16 (2008) 9
12. K. Nandi, S .Chaudhri, S. K. Mazumdah, S. Ghosh, E. Ect, J. Chem. Soc. Perkin Trans 2
11 (1984) 1729
13. M. A. Ali, M. A. Chowdhary, M. Naziruddin, Polyhedron 3 (1984) 595
14. D. Suresh, D. Kumar, S. Jagir, S. Sandhu, Synth. Commun. 39 (2009) 1957
15. M.-S. Bai, Y.-Y. Chen, D.-L. Niu, L. Peng, Acta Crystallogr. E65 (2009) o799
16. P. P. Reddy, V. Vijayakumar, J. Suresh, T. Narasimhamurthyc, P. L. Nilantha Laksh-
mand, Acta Crystallogr. E66 (2010) o363
17. A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, Synlett 4 (2008) 509
18. V. Sivamurugan, R. Suresh Kumar, M. Palanichamy, V. Murugesan, J. Heterocycl.
Chem. 42 (2009) 969
19. J. S. Yadav, B. V. Subha-Reddy, P. T. Reddy, Synth. Commun. 31 (2000) 425
20. S. K. Srivastava, S. Srivastava, S. D. Srivastava, Indian J. Chem. 41B (2002)2357
21. S. Ojha, U. Ameta, N. Dhakar, G. L. Talesara, Indian J. Chem. 46B (2007) 860
22. W. Bauer, W. M. Kirby, J. C. S. Harris, J. C. Turck, Am. Clin. Pathol. 39 (1966) 493
23. R. G. Petersdorf, J. C. Sherris, Am. J. Med. 39 (1965) 766
24. S. H. Gillespie, Medical Microbiology-Illustrated, Butterworth Heinemann, London,
1994, p. 234
25. R. S. Varma, Antifungal Agents: Past, Present and Future prospects, National Academy
of Chemistry and Biology, Lucknow, 1998.
Available online at www.shd.org.rs/JSCS/
__________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

Copyright of Journal of the Serbian Chemical Society is the property of National Library of Serbia and its
content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.