Synthesis and DPPH radical scavenging activity of 5-arylidene-N, Ndimethylbarbiturates

Article abstract of DOI:10.2174/157340611795564231

Twenty-four derivatives of N,N-dimethylbarbituric acid 1-24 were screened for their DPPH radical scavenging activity. These compounds showed an excellent antioxidant activity. A structure-activity relationship has been discussed, while all the synthetic compounds were characterized by spectroscopic techniques and elemental analysis.

Full text of DOI:10.2174/157340611795564231

Medicinal Chemistry, 2011, 7, 231-236
231
Synthesis and DPPH Radical Scavenging Activity of 5-Arylidene-N,N-
Dimethylbarbiturates
Khalid Mohammed Khana,*, Momin Khana, Muhammad Alia, Muhammad Tahaa, Abdul Hameeda,
Sajjad Alia, Shahnaz Perveenb and M. Iqbal Choudharya
aH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
bPCSIR Laboratories Complex, Karachi Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan
Abstract: Twenty-four derivatives of N,N-dimethylbarbituric acid 1-24 were screened for their DPPH radical scavenging
activity. These compounds showed an excellent antioxidant activity. A structure-activity relationship has been discussed,
while all the synthetic compounds were characterized by spectroscopic techniques and elemental analysis.
Keywords: DPPH Radical scavengers, N,N-dimethylbarbiturates.
INTRODUCTION
DNA damages. Modes of action of antioxidants are attrib-
uted to their radical scavenging activity by contributing one
electron to the free radicals to convert them into harmless
molecules. Antioxidants thus protect cells from the oxidative
damage that leads to aging and diseases [6-8].
Barbituric acid and its derivatives have been reported as
antibacterials, hypotensive and tranquilizers. Furthermore,
arylidene barbituric acids are widely used as precursors for
the synthesis of bioactive molecules [1] while their deriva-
tives are important intermediates in organic synthesis [2].
Proteins, nucleic acids, lipids, and other classes of mole-
cules such as the extra cellular matrix glycosaminoglycans
(e.g. hyaluronic acid) are found to have strong affinity for
free radicals and cause different diseases. The polyunsatu-
rated fatty acids are more vulnerable to free radical damage,
causing cerebral ischemia and other CNS diseases [9].
Traditionally barbiturates are used as tranquilizing and
hypnotic agents, in schizophrenic patients, so called as
“sleep cures.” Thiobarbiturates are used as potential clinical
drugs in intravenous anesthesia [3]. Derivatives of barbituric
acids had been known for their potential use as clinical
drugs, however, biologically important constituents of barbi-
turic acid and its analogs attracted the interest of medicinal
chemists as potential drugs extensively.
Free radicals have also been found to contribute in the
pathology of arteriosclerosis, malaria and rheumatoid arthri-
tis, in neurodegenerative disease and aging [10, 11].
This discovery and development of effective antioxi-
dants, capable of supplementing body’s antioxidant system,
is an important area of research.
The interesting mechanism of action of barbital and phe-
nobarbital against epilepsy made them attractive targets for
medicinal chemists. They have also been investigated as
anticancer and anti-AIDS agents [4].
RESULTS AND DISCUSSION
We have recently reported 5-arylidene barbiturates as
novel class of DPPH radical scavengers [5]. Structural simi-
larity of N,N-dimethyl-5-arylidene barbiturates 1-24 with 5-
arylidene barbiturates, prompted us to test them for DPPH
radical scavenging activity. Interestingly, we found them
more active than our previous work, thereby proving that our
initial hypothesis as correct.
In recent past, we synthesized a number of lead mole-
cules of different classes of heterocycles [12-17]. In the pre-
sent study, 5-arylidene-N,N-dimethylbarbiturates 1-24 were
synthesized
from
commercially
available
N,N-
dimethylbarbituric acid by refluxing with different aromatic
aldehydes in water in very high yields (Scheme. 1). In a typi-
cal reaction, N,N-dimethylbarbituric acid (1.56 mmol) and
corresponding aldehyde (1.56 mmol, 1 eq.) were dissolved in
distilled water (10 mL) and the mixture was refluxed for 30
minutes. In all cases, solid product was formed which was
filtered, washed with cold water and ether followed by
drying under vacuum. The pure products were obtained as
fluffy solids. The structures of compounds 1-24 were
confirmed by using different spectroscopic techniques,
Antioxidants prevent injury to blood vessel membranes
thus ensure proper blood circulation and avoid cardiovascu-
lar diseases. They provide defense against cancer-causing
*Address correspondence to this author at the H. E. J. Research Institute of
Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi-75270, Pakistan; Tel: 00922134824910;
Fax: 00922134819018;
1
including H NMR and EI spectrometry. All compounds
E-mail: hassaan2@super.net.pk; khalid.khan@iccs.edu
gave a satisfactory CHN analysis.
1573-4064/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

232 Medicinal Chemistry, 2011, Vol. 7, No. 3
Khan et al.
R
N
O
O
O
O
H2O, 100 oC
30 min
O
N
N
N
R
H
Me
Me
Me
Me
O
O
Compd.
Compds.
No.
Compd.
No.
R
R
R
No.
1
1
1
2
3
6
OH
6
2
6
5
1
9
17
5
5
OMe
OEt
4
N
OMe
Me
Me
1
1
1
OH
2
3
6
5
6
2
3
6
2
3
4
5
6
7
8
10
11
12
13
14
15
16
18
19
20
21
22
23
24
5
5
OMe
4
Cl
Br
1
1
1
2
3
6
5
6
2
6
2
5
5
OH
Cl
4
OH
OH
1
1
1
NO2
2
6
6
2
6
5
5
3
Cl
MeO
OMe
4
Cl
OMe
1
1
1
OH
OEt
2
3
6
6
6
5
5
5
3
3
4
SMe
OH
1
1
1
2
3
OH
6
2
3
6
5
6
5
3
Me
4
NO2
OEt
1
1
1
OH
OH
6
2
3
6
5
6
5
2
5
NO2
4
4
OH
1
1
8
5
Cl
6
6
5
2
7
2
3
3
5
OEt
6
4
Cl
OH
Scheme 1. 5-Arylidene-N,N-dimethylbarbiturates 1-24.

Synthesis and DPPH Radical Scavenging Activity
Medicinal Chemistry, 2011, Vol. 7, No. 3 233
All the synthetic compounds 1-24 were subjected to in vi-
tro free radical scavenging activity, according to literature
protocol (Table. 1) [18].
(IC50 = 32.25 ± 1.56 μM) and 14 (IC50 = 34.29 ± 4.01 μM)
showed comparable free radical scavenging activities to
standard n-propyl gallate. However, compounds 13 (IC50
95.68 ± 1.48 μM), 17 (IC50 = 98.40 ± 3.64 μM), 3 (IC50
=
=
Table 1. In Vitro DPPH Radical Scavenging Activity of 5-
arylidene-N,N-dimethylbarbiturates 1-24
150.41 ± 1.74 μM) and 12 (IC50 = 185.8 ± 1.21 μM) were
found to be only moderately active. Compound 1 was found
to be completely inactive.
Compound No.
IC50 ± SEMa (ꢀM)
Compounds 11 and 7 were found to be the most active
among the series, with IC50 values of 16.32 ± 2.54 μM and
18.62 ± 2.81 μM, respectively. The free radical scavenging
potential of a compound is based on its ability to stabilize the
free radicals. Compound 11 possesses two vicinal hydroxyl
moieties, while compound 7 contains three hydroxyl groups
on the benzene ring which upon abstraction of hydrogen by
DPPH lead to the formation of stable phenoxide radical on
aromatic nucleus. Extended conjugation may help in their
stabilization. This ability of compounds to stabilize the free
radicals actually determines their free radical scavenging
strength.
1.
NAb
2.
26.00 ± 1.02
150.41 ± 1.74
32.25 ± 1.56
21.56 ± 2.08
24.19 ± 2.58
18.62 ± 2.81
29.50 ± 3.12
22.63 ± 2.98
27.62 ± 0.98
16.32 ± 2.54
185.8 ± 1.21
95.68 ± 1.48
34.29 ± 4.01
23.60 ± 2.00
21.85 ± 1.47
98.40 ± 3.64
19.30 ± 2.50
28.20 ± 3.09
31.25 ± 1.89
30.28 ± 1.79
25.96 ± 1.56
26.96 ± 1.25
29.65 ± 2.56
30. 27 ± 1.6
3.
4.
5.
6.
7.
4-Bromo- (18) and 4-methylthio- (5) analogs exhibited a
potent activity with IC50 values of 19.30 ± 2.50 and 21.56 ±
2.08 μM, respectively. It is predicted that a free radical is
formed at electron rich centers such as at bromine or sulfur
atoms.
8.
9.
10.
11.
Compounds 16, a 3-ethoxy-4-hydroxy- and 9, a 3-
ethoxy-2-hydroxy- analog of N,N-dimethyl-5-arylidene bar-
biturates also showed a good inhibitory effect with IC50 val-
ues 21.85 ± 1.47 and 22.63 ± 2.98 μM against the DPPH,
respectively. A small difference in these values might be due
to the position of hydroxyl group.
12.
13.
14.
15.
A general trend of increase in activity was observed in
compounds 22 (IC50 = 25.96 ± 1.56 μM), 10 (27.62 ± 0.98
μM), 24 (29.65 ± 2.56 μM), 21 (30.28 ± 1.79 μM), 20 (31.25
± 1.89 μM) and 14 (34.29 ± 4.01 μM) as all of them possess
electron donating groups.
16.
17.
18.
19.
The nitro-substituted arylidenes 15 (meta-derivative), 6
(para-substituted) and 12 (an ortho-analog) have the IC50
values of 23.60 ± 2.0 μM, 24.19 ± 2.58 and 185.8 ± 1.21 μM,
respectively. Nitro-group being an inductively and electron
withdrawing group mesomerrically offers more stabilization
to the free radicals when it resides at aromatic nucleus [5]. In
these cases, radicals are formed at benzylic carbon atoms.
The case of weak antioxidant potential of ortho-substituted
nitro analog 12 is somewhat unusual, as compared to meta-
and para-analogs 15 and 6. This noteworthy difference may
be attributed sterically more demanding ortho-nitro group.
20.
21.
22.
23.
24.
n-propyl gallatec
SEMa is the standard error of the mean, NAb Not active, n-propyl
gallate c standard inhibitor for DPPH radical scavenging activity
Para- and meta-chloro- substituted derivatives 2 (IC50
=
26.0 ± 1.02 μM) and 19 (IC50 = 28.2 ± 3.09 μM), were found
to have good DPPH radical scavenging activities. However,
dichloro substituted 5-arylidene barbiturates 8 (2,4-dichloro-
) with IC50 = 29.50 ± 3.12 μM and 4 (3,4-dichloro-) with
32.25 ± 1.56 μM exhibited a slight lower activity, as com-
pared to their mono chloro analogs 2 and 19. This demon-
strated that the addition of chloro group at aromatic ring re-
duces the antioxidant potential.
Most of the N,N-dimethyl barbituric acid derivatives
demonstrated an excellent free radical scavenging activity.
Out of twenty-four (24), fifteen compounds 11, 7, 18, 5, 16,
9, 15, 6, 22, 2, 23, 10, 19, 8, and 24 showed potent activities
with IC50 values 16.32 ± 2.54, 18.62 ± 2.81, 19.30 ± 2.50,
21.56 ± 2.08, 21.85 ± 1.47, 22.63 ± 2.98, 23.60 ± 2.00, 24.19
± 2.58, 25.96 ± 1.56, 26.00 ± 1.02, 26.96 ± 1.25, 27.62 ±
0.98, 28.20 ± 3.09, 29.50 ± 3.12 and 29.65 ± 2.56 μM, re-
spectively, when compared with standard n-propyl gallate
(IC50 = 30.27 ± 1.6 μM) as presented in Table 1. Compounds
21 (IC50 = 30.28 ± 1.79 μM), 20 (IC50 = 31.25 ± 1.89 μM), 4
CONCLUSION
In conclusion, it has been found that the newly synthe-
sized N,N-dimethyl-5-arylidene barbiturates 1-24 exhibited

234 Medicinal Chemistry, 2011, Vol. 7, No. 3
Khan et al.
far better antioxidant potential than previously reported 5-
arylidene barbiturates [5]. Among the new series fifteen
compounds demonstrated higher radical scavenging activity,
than the standard n-propyl gallate. These compounds, there-
fore, may serve as viable lead molecules in the existing
plethora of antioxidants.
5-(4-Chlorobenzylidene)-1,3-Dimethyl-2,4,6(1H,3H,5H)-
Pyrimidinetrione (2)
Yield: 0.235g (84%); 1H-NMR (DMSO-d6): 8.32 (s, 1H,
vin. H), 8.02 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4 Hz),
3.22 (s, 3H, N-CH3), 3.16 (s, 3H); MS: m/z (rel. abund. %),
278 (M+, 70), 277 (100), 136 (58), 101 (37); Anal. calcd. for
C13H11ClN2O3 (278.69): C, 56.03; H, 3.98; Cl, 12.72; N,
10.05; O, 17.22; Found: C, 56.05; H, 3.98; N, 10.02.
MATERIALS AND METHODS
Experimental
5-(4-Hydroxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (3)
EI Mass spectra were recorded with various MAT 711
(70 eV) spectrometers and data are tabulated as m/z. 1H-
NMR spectra were recorded in DMSO-d6 using Bruker
AC300 (300 MHz) spectrophotometers, respectively. Split-
ting patterns were as follows; s, singlet; d, doublet; dd, dou-
ble doublet; t, triplet; m, multiplet. Chemical shifts are re-
ported in ꢀ (ppm) and coupling constants are given in Hz.
The progress of all reactions was monitored by TLC which
was performed on 2.0 x 5.0 cm aluminum sheets pre-coated
with silica gel 60F254 to a thickness of 0.25 mm (Merck).
The chromatograms were visualized under ultraviolet light
(254-366 nm) or iodine vapors. The title compounds were
synthesized and characterized satisfactorily.
Yield: 0.23 g (88%); 1H-NMR (DMSO-d6): 10.79 (br. s,
1H), 8.30 (d, 2H, J = 8.7 Hz), 8.27 (s, 1H), 6.88 (d, 2H, J =
8.7 Hz), 3.21 (s, 6H); MS: m/z (rel. abund. %), 260 (M+,
100), 202 (34), 146 (62), 118 (51), 89 (37); Anal. calcd. for
C13H12N2O4 (260.25): C, 60.00; H, 4.65; N, 10.76; O, 24.59;
Found: C, 60.01; H, 4.64; N, 10.76.
5-(3,4-Dichlorobenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (4)
1
Yield: 0.26 g (83%); H-NMR (DMSO-d6): 8.28 (s, 1H),
8.27 (d, 1H, J = 2.1 Hz), 7.87 (dd, 1H, J= 2.1, 8.4 Hz), 7.30
(d, 1H, J = 8.4 Hz), 3.22 (s, 3H), 3.16 (s, 3H); MS: m/z (rel.
abund. %), 313 (M+, 77), 311(100), 198 (43), 170 (50), 135
(27); Anal. calcd. for C13H10Cl2N2O3 (313.14): C, 49.86; H,
3.22; Cl, 22.64; N, 8.95; O, 15.33; Found: C, 49.85; H, 3.23;
N, 8.93.
DPPH (1,1-Diphenyl-2-Picryl Hydrazyl) Free Radical
Scavenging Assay (In vitro)
The hydrogen donating activity of compounds was meas-
ured by 1,1-diphenyl-2-picrylhydrazil (DPPH) by using lit-
erature protocol [18]. Reaction mixture contains 5 μL of test
sample (1 mM in DMSO) and 95 μL of DPPH (Sigma, 300
μM) in ethanol. The reaction mixture was taken into a 96-
well microtiter plate and incubated at 37º C for 30 min. The
absorbance was measured at 515 nm on microtiter plate
reader (Molecular Devices, USA). Radical scavenging activ-
ity was determined by comparing with a DMSO containing
control (Table-1), all assays were conducted in triplicate and
in dark. IC50 values represent the concentration of com-
pounds to scavenge 50% of DPPH radicals. n-Propyl gallate
was used as a positive control. All the chemicals used were
of analytical grade (Sigma, USA).
1,3-Dimethyl-5-[4-(methylsulfanyl)benzylidene]-
2,4,6(1H,3H,5H)-pyrimidinetrione (5)
Yield: 0.25 g (86%); 1H-NMR (DMSO-d6): 8.29 (s, 1H),
8.14 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 3.22 (s,
3H), 3.19 (s, 3H), 2.55 (s, 3H); MS: m/z (rel. abund. %), 290
(M+, 100), 232(17), 176 (15), 133 (11); Anal. calcd. for
C14H14N2O3S (290.34): C, 57.92; H, 4.86; N, 9.65; O, 16.53;
S, 11.04; Found: C, 57.90; H, 4.87; N, 9.66.
1,3-Dimethyl-5-(4-Nitrobenzylidene)-2,4,6(1H,3H,5H)-
Pyrimidinetrione (6)
Yield: 0.24 g (83%); 1H-NMR (DMSO-d6): 8.41 (s, 1H),
8.25 (d, 2H, J = 9.0 Hz), 7.96 (d, 2H, J = 9.0 Hz), 3.35 (s,
6H); MS: m/z (rel. abund. %), 289 (M+, 100), 242 (64), 175
(42), 101 (56); Anal. calcd. for C13H11N3O5 (289.24): C,
53.98; H, 3.83; N, 14.53; O, 27.66; Found: C, 53.97; H, 3.82;
N, 14.52.
Synthesis and Characterization of New 5-Arylidene Bar-
biturates 1-24
N,N-Dimethyl barbituric acid derivatives (1.56 mmol)
and corresponding aldehyde (1.56 mmol, 1 eq.) were dis-
solved in 10 mL of distilled water and the mixture was re-
fluxed for 30 minutes. In all cases, solid product were
formed which were filtered off and washed with cold water
and ether followed by drying under vacuum. The pure com-
pounds 1-24 were obtained as fluffy solids having satisfac-
tory physical and spectroscopic data.
1,3-Dimethyl-5-(2,3,4-Trihydroxybenzylidene)-
2,4,6(1H,3H,5H)-Pyrimidinetrione (7)
Yield: 0.23 g (79%); 1H-NMR (DMSO-d6): 8.86 (s, 1H),
8.25 (d, 1H, J= 9.3 Hz), 6.40 (d, 1H, J = 9.3 Hz), 3.19 (s,
6H); MS: m/z (rel. abund. %), 292 (M+, 100), 275 (63), 205
(73), 150 (38); Anal. calcd. for C13H12N2O6 (292.24): C,
53.43; H, 4.14; N, 9.59; O, 32.85; Found: C, 53.45; H, 4.13;
N, 9.57.
5-[4-(Dimethylamino)Benzylidene]-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (1)
Yield: 0.25 g (87%); 1H-NMR (DMSO-d6): ꢀ 8.41 (2H, d,
J = 9.3 Hz), 8.22 (1H, s), 6.80 (2H, d, J= 9.3 Hz), 3.28 (6H,
s), 3.21 (6H,s); MS: m/z (rel. abund. %), 287 (M+, 100), 172
(14), 144 (26), 129 (10); Anal. calcd. for C15H17N3O3
(287.31): C, 62.71; H, 5.96; N, 14.63; O, 16.71; Found: C,
62.70; H, 5.98; N, 14.62.
5-(2,4-Dichlorobenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (8)
1
Yield: 0.26 g (83%); H-NMR (DMSO-d6): ꢀ 8.28 (s,
1H), 7.75 (d, 1H, J = 2.1 Hz), 7.69 (d, 1H, J = 8.7 Hz), 7.48
(dd, 1H, J = 2.1, 8.7 Hz), 3.22 (s, 3H), 3.11 (s, 3H,); MS: m/z
(rel. abund. %), 313 (M+, 10), 277 (100), 220 (73), 170 (15);

Synthesis and DPPH Radical Scavenging Activity
Medicinal Chemistry, 2011, Vol. 7, No. 3 235
Anal. calcd. for C13H10Cl2N2O3 (313.14): C, 49.86; H, 3.22;
Cl, 22.64; N, 8.95; O, 15.33; Found: C, 49.87; H, 3.21; N,
8.93.
61.31; H, 5.14; N, 10.21; O, 23.33; Found: C, 61.32; H, 5.13;
N, 10.20.
1,3-Dimethyl-5-(3-Nitrobenzylidene)-2,4,6(1H,3H,5H)-
Pyrimidinetrione (15)
5-(3-Ethoxy-2-Hydroxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (9)
Yield: 0.25 g (86%); 1H-NMR (DMSO-d6): 8.82 (s, 1H),
8.42 (s, 1H), 8.31 (dd, 1H, J =2.1, 8.1 Hz), 8.20 (d, 1H, J =
8.1 Hz), 6.31 (t, 1H, J = 8.1 Hz), 3.16 (s, 3H), 3.13 (s, 3H);
MS: m/z (rel. abund. %), 289 (M+, 100), 242 (59), 129 (27),
101 (35); Anal. calcd. for C13H11N3O5 (289.24): C, 53.98; H,
3.83; N, 14.53; O, 27.66; Found: C, 53.99; H, 3.82; N, 14.52.
Yield: 0.25 g (82%); 1H-NMR (DMSO-d6): 9.57 (s, 1H),
8.66 (s, 1H), 7.62 (d, 1H, J = 8.1 Hz), 7.11 (d, 1H, J = 8.1
Hz), 6.31 (t, 1H, J = 8.1 Hz), 4.07 (q, 2H, J = 6.9 Hz), 3.21
(s, 3H), 3.16 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz); MS: m/z (rel.
abund. %), 304 (M+, 100), 287 (94), 259 (76), 162 (48); A-
nal. calcd. for C15H16N2O5 (304.30): C, 59.21; H, 5.30; N,
9.21; O, 26.29; Found: C, 59.22; H, 5.31; N, 9.20.
5-(3-Ethoxy-4-Hydroxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (16)
5-(2-Hydroxy-3-Methoxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (10)
Yield: 0.27 g (89%); 1H-NMR (DMSO-d6): 10.47 (s, 1H),
8.34 (d, 1H, J = 1.8 Hz), 8.27 (s, 1H), 7.80 (dd, 1H, J = 1.8,
8.4 Hz), 6.90 (d, 1H, J = 8.4 Hz), 4.08 (s, 2H,), 3.21 (s, 6H),
1.37 (t, 3H, J = 6.9 Hz); MS: m/z (rel. abund. %), 304 (M+,
23), 166 (100), 137 (100), 109 (49); Anal. calcd. for
C15H16N2O5 (304.30): C, 59.21; H, 5.30; N, 9.21; O, 26.29;
Found: C, 59.20; H, 5.31; N, 9.22.
Yield: 0.23g (79%); 1H-NMR (DMSO-d6): 9.79 (s, 1H),
8.66 (s, 1H), 7.63 (d, 1H, J = 8.1 Hz), 7.11 (dd, 1H, J = 0.9,
8.1 Hz), 6.31 (t, 1H, J = 8.1 Hz), 3.83 (s, 3H), 3.22 (s, 3H),
3.15 (s, 3H); MS: m/z (rel. abund. %), 290 (M+, 100), 273
(97), 203 (45), 156 (22); Anal. calcd. for C14H14N2O5
(290.27): C, 57.93; H, 4.86; N, 9.65; O, 27.56; Found: C,
57.91; H, 4.87; N, 9.66.
5-(3,4-Dimethoxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (17)
5-(3,4-Dihydroxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (11)
Yield: 0.26 g (85%); 1H-NMR (DMSO-d6): 8.30 (s, 1H),
8.28 (d, 1H, J = 2.1 Hz), 7.91 (dd, 1H, J = 2.1, 8.7 Hz), 6.31
(d, 1H, J = 8.7 Hz), 3.87 (s, 3H), 3.81 (s, 3H), 3.22 (s, 3H),
3.21 (s, 3H); MS: m/z (rel. abund. %), 304 (M+, 100), 246
(21), 204 (13); Anal. calcd. for C15H16N2O5 (304.30): C,
59.21; H, 5.30; N, 9.21; O, 26.29; Found: C, 59.20; H, 5.31;
N, 9.21.
Yield: 0.22 g (79%); 1H-NMR (DMSO-d6): 8.18 (s, 1H),
8.17 (s, 1H), 7.87 (dd, 1H, J = 2.1, 8.4 Hz), 7.85 (d, 1H, J =
8.4 Hz), 3.21 (s, 6H); MS: m/z (rel. abund. %), 276 (M+,
100), 218 (23), 162 (22), 134 (11); Anal. calcd. for
C13H12N2O5 (276.24): C, 56.52; H, 4.38; N, 10.14; O, 28.96;
Found: C, 56.54; H, 4.35; N, 10.14.
1,3-Dimethyl-5-(2-Nitrobenzylidene)-2,4,6(1H,3H,5H)-
Pyrimidinetrione (12)
5-(4-Bromobenzylidene)-1,3-Dimethyl-2,4,6(1H,3H,5H)-
Pyrimidinetrione (18)
Yield: 0.23 g (80%); 1H-NMR (DMSO-d6): 8.69 (s, 1H),
8.24 (dd, 1H, J = 0.9, 8.4 Hz), 7.79 (dt, 1H, J = 0.9, 7.5 Hz),
6.31 (t, 1H, J = 7.5 Hz), 7.51 (d, 1H, J = 7.5 Hz), 3.30 (s,
3H), 3.24 (s, 3H); MS: m/z (rel. abund. %), 289 (M+, 00.0),
243 (100), 186 (82); Anal. calcd. for C13H11N3O5 (289.24):
C, 53.98; H, 3.83; N, 14.53; O, 27.66; Found: C, 53.97; H,
3.84; N, 14.53.
Yield: 0.29 g (90%); 1H-NMR (DMSO-d6): 8.28 (s, 1H),
7.93 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J = 8.4 Hz), 3.22 (s,
3H), 3.16 (s, 3H); MS: m/z (rel. abund. %), 323 (M+, 100),
264 (21), 243 (19), 101 (21); Anal. calcd. for C13H11BrN2O3
(323.14): C, 48.32; H, 3.43; Br, 24.73; N, 8.67; O, 14.85;
Found: C, 48.30; H, 3.44; N, 8.66.
5-(3-Chlorobenzylidene)-1,3-Dimethyl-2,4,6(1H,3H,5H)-
Pyrimidinetrione (19)
5-(2,4-Dihydroxybenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (13)
Yield: 0.23 g (82%); 1H-NMR (DMSO-d6): 8.30 (s, 1H),
8.01 (s, 1H), 7.82 (d, 1H, J = 7.5 Hz), 7.56 (d, 1H, J = 7.5
Hz), 7.48 (t, 1H, J = 7.8 Hz), 3.22 (s, 3H), 3.16 (s, 3H); MS:
m/z (rel. abund. %), 278 (M+, 89), 277 (100), 243 (14), 164
(37), 136 (52), 101 (33); Anal. calcd. for C13H11ClN2O3
(278.69): C, 56.03; H, 3.98; Cl, 12.72; N, 10.05; O, 17.22;
Found: C, 56.04; H, 3.99; N, 10.04.
Yield: 0.20 g (72%); 1H-NMR (DMSO-d6): 10.81 (br. s,
1H,), 10.74 (br. s, 1H), 8.81 (s, 1H), 8.64 (d, 1H, J = 9.0
Hz,), 6.88 (d, 1H, J = 2.4 Hz), 6.31 (dd, 1H, J = 2.4, 9.0 Hz),
3.18 (s, 6H); MS: m/z (rel. abund. %), 276 (M+, 100), 259
(100), 202 (48), 189 (66), 145 (27); Anal. calcd. for
C13H12N2O5 (276.24): C, 56.52; H, 4.38; N, 10.14; O, 28.96;
Found: C, 56.53; H, 4.36; N, 10.15.
5-(2-Hydroxy-5-Methylbenzylidene)-1,3-Dimethyl-
2,4,6(1H,3H,5H)-Pyrimidinetrione (14)
1,3-Dimethyl-5-(3,4,5-Trimethoxybenzylidene)-
2,4,6(1H,3H,5H)-Pyrimidinetrione (20)
Yield: 0.24 g (87%); 1H-NMR (DMSO-d6): 10.36 (s, 1H),
8.65 (s, 1H), 7.94 (s, 1H), 7.20 (dd, 1H, J = 2.1, 8.4 Hz), 6.83
(d, 1H, J = 8.4 Hz), 3.21 (s, 3H), 3.18 (s, 3H), 2.20 (s, 3H);
MS: m/z (rel. abund. %), 274 (M+, 81), 257 (100), 217 (59),
187 (82), 160 (57); Anal. calcd. for C14H14N2O4 (274.27): C,
Yield: 0.28 g (84%); 1H-NMR (DMSO-d6): 9.80 (s, 1H),
7.24 (s, 2H), 3.85 (s, 9H), 3.22 (s, 3H), 3.16 (s, 3H); : m/z
(rel. abund. %), 334 (M+, 97), 319 (34), 196 (100), 181 (53);
Anal. calcd. for C16H18N2O6 (334.32): C, 57.48; H, 5.43; N,
8.38; O, 28.71; Found: C, 57.50; H, 5.42; N, 8.38.

236 Medicinal Chemistry, 2011, Vol. 7, No. 3
Khan et al.
5-(2-Ethoxybenzylidene)-1,3-Dimethyl-2,4,6(1H,3H,5H)-
Pyrimidinetrione (21)
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7.1 (d, 1H, J = 8.4 Hz), 6.96 (t, 1H, J = 7.5 Hz), 4.13 (q, 2H,
J = 6.9 Hz), 3.21 (s, 3H), 3.15 (s, 3H), 1.34 (t, 3H, J = 6.9
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5-(4-Ethoxybenzylidene)-1,3-Dimethyl-2,4,6(1H,3H,5H)-
Pyrimidinetrione (22)
Yield: 0.23 g (80%); 1H-NMR (DMSO-d6):, 8.32 (d, 2H,
J = 8.4 Hz), 8.30 (s, 1H), 7.04 (d, 2H, J = 8.4 Hz), 4.15 (q,
2H, J = 7.2 Hz), 3.21 (s, 3H), 3.00 (s, 3H), 1.34 (t, 3H, J =
6.9 Hz); MS: m/z (rel. abund. %), 288 (M+, 100), 249 (78),
202 (15), 146 (16); Anal. calcd. for C15H16N2O4 (288.30): C,
62.49; H, 5.59; N, 9.72; O, 22.20; Found: C, 62.51; H, 5.58;
N, 9.73.
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5-Benzylidene-1,3-Dimethyl-2,4,6(1H,3H,5H)-
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Yield: 0.20 g (82%); 1H-NMR (DMSO-d6): 8.35 (s, 1H),
8.00 (d, 2H, J = 8.4 Hz), 7.50 (m, 3H), 3.22 (s, 3H), 3.17 (s,
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(38), 130 (33), 102 (56); Anal. calcd. for C13H12N2O3
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63.95; H, 4.94; N, 11.47.
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1,3-Dimethyl-5-(1-Naphthylmethylene)-2,4,6(1H,3H,5H)-
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8.01 (m, 2H), 7.81 (m, 2H), 7.56 (m, 3H), 3.27 (s, 3H), 3.08
(s, 3H); MS: m/z (rel. abund. %); 294 (M+, 100), 243 (80),
180 (81), 152 (100); Anal. calcd. for C17H14N2O3 (294.30):
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4.78; N, 9.51.
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ACKNOWLEDGEMENT
This work was financially supported by the Higher Edu-
cation Commission (HEC), Pakistan, under the National Re-
search Program for Universities.
Received: December 10, 2010
Revised: March 01, 2011
Accepted: March 05, 2011