Synthesis of some novel thiobarbituric acid derivatives and their related compounds from sulfa-drug as Antiinflammatory

Article abstract of DOI:10.14233/ajchem.2014.15516

In search for new antiinflammatory agents, some new substituted thiobarbituric acids (2) and their bis-fused or fused thiopyrimidinylpyrimidinone (7, 8) have been derived from sulfathiazole and dimethylmalonate with CS₂. structures of the synth

Full text of DOI:10.14233/ajchem.2014.15516

Asian Journal of Chemistry; Vol. 26, No. 3 (2014), 749-754
http://dx.doi.org/10.14233/ajchem.2014.15516
Synthesis of Some Novel Thiobarbituric Acid Derivatives and Their Related
Compounds from Sulfa-Drug as Antiinflammatory
MOHIE ALDIN M. ZAYED
Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
Corresponding author: Fax: +966 2 6952292; E-mail: mohiem@yahoo.com
Received: 21 March 2013;
Accepted: 26 April 2013;
Published online: 30 January 2014;
AJC-14628
In search for new antiinflammatory agents, some new substituted thiobarbituric acids (2) and their bis-fused or fused thiopyrimidinyl-
pyrimidinone (7, 8) have been derived from sulfathiazole and dimethylmalonate with CS2. structures of the synthesized compounds were
established by spectroscopic (FT-IR, 1H NMR, 13C NMR, Mass) and elemental analyses. The antiinflammatory activity of these compounds
was tested against carrageen-induced oedema with the reference of standard drug phenyl butazone. The results showed that compounds 2
and 3 are better antiinflammatory agents as compared to standard drug phenyl butazone.
Keywords: Synthetic, Thiobarbituric, Antiinflammatory.
INTRODUCTION
EXPERIMENTAL
Certain natural and synthetic 1,3-diketo-amine structural
analogues have attracted special interest by virture of their
varied and pharmaceutically useful biological actions as anti-
microbial, anticancer and anti HIV agents1-4. Also, several
cyclic derivatives containing diketo moiety and -NCSN- linkage
are well known for their demonstrable therapeutic efficacy5-8.
As well as, 1,3-diketoamine analogues forms easily a macro-
cyclic complexes with nickel(II) as catalytic and antimicrobial
aspects, in addition have a metalloenzyme reactions9. Abdel-
Rahman et al10 synthetic 1, 3-disubstituted thiobarbituric acids,
were showed anti HIV and anticancer activities especially
towards leukemia, non-small cell lung, colon cancer and mela-
noma and recorded a highly per cent of control towards
uninfected cells.
Melting points were determined with an electro thermal
bib by Stuart Scientific Melting Points SMPI (UK). The IR
spectra were recorded for KBr discs on Perkins lemer Spectrum
1
RXI FT-IR System 55529. H and 13C NMR spectra were
determined for solution in deuterated (DMSO) with a Brucker
NMR Advance DPX 400 MH using TMS as an internal
standard spectrometer. Electronic absorption spectra were
recorded on Shimadzu UV (DMF) and visible 3101 PC spectro-
photometer. Molecular weight determination and elemental
analysis were preformed by Microanalytical Center Cairo
University Egypt. MS were recorded on a gas chromatographic
GCMS qp 1000 ex Schimadzu instrument at 70 eV.
Preparation of 1,3-diketoamine compound (1): To pre-
heated dimethyl malonate (0.01 mol), sulfa thiazole (0.02 mol)
were added then warmed for 10-15 min, cooled. The obtained
solid was washed with ether then dried crystallized from THF
to give compound 1 m.p. 180 °C.
CH3
N
N
S
CH3
IR (KBr, νmax, cm–1): 3560 (OH), 3400 (NH), 1600, 1650
R
N
CH
CH
N
N
N
CH3
(2C=O) 2870, 1480 (str. & bending CH2), 1370, 1355
1
(SO2NH); H NMR (DMSO-d6): δ 8.55 (1H, NH-SO2-), 7.9
(s, 1H of NHa), 7.2 (s, 1H of NHb), 5.2 (s, 1H, OH of
O
O
R = COCH3, Ph
anti: HIV & anticancer [10]
O
4.2 (d, 2H, -CH2-), 8.2-7.3 (m, 12H, of
C
C
C
Thus, in continuation with our current interest in biocidal
heterocyclic systems11-15, the present work deals with synthetic
strategy of some new 1,3-diketoamine for building a type of
thiobarbituric acids and their fused and isolated bis-analogues
as biocidal agents.
HO
thiazole and aryl protons) ppm; UV (DMF), λmax 246 nm
(n-σ* & π-π*); MS: 508 (M- C3H2O2, 32.11 %), 92(C6H6N,
11.85 %), 84 (thiazole ions 100 %); Elemental analysis: Found:

750 Zayed
Asian J. Chem.
C, 43.16; H, 3.07; N, 14.38; S, 22.07 %. Calculated for
C21H18N6O6S4, C, 43.59; H, 3.11; N, 14.53; S, 22.14 %.
Synthesis of 1,3-diaryl-thiobarbituric acid (2):A mixture
of compound 1 (0.01 mol), CS2 (30 ml), DMF (50 mL) were
refluxed for 6 h, cooled then poured onto ice. The produced
solid was washed with cold ethanol and crystallized from
MeOH to give 2 m.p. 130 °C. IR (KBr, νmax, cm–1): 3100-2850
(b, aromatic & aliphatic CH), 1710, 1670 (2C=O) 1350
5H-pyrimidin-5yl)pyrimidine (8): Equimolar mixture of
compound 2 and ethyl 2-chloroacetoacetate or 3-chloroacetyl-
acetone and thiourea in sodium ethoxide (0.02 mol, 50 mL)
was refluxed for 4 h and cooled then pourd onto ice-HCl. The
obtained solid was filtered off and washed with cold water
and crystallized from EtOH to give 7 and 8, respectively 7
m.p. 221 °C; 8 m.p 265 °C.
IR (KBr, νmax, cm–1): 3120 (NH), 3000, 2980, 2870
(aromatic & aliphatic CH), 1700, 1680, 1660 & 1650 (4C=O),
1580 (C=N), 1350 (NCSN), 1480, 1440 (deformation Me),
1180 (C-S) cm-1. 1H NMR (DMSO-d6):7: δ 8.15 (s, 1H, NH),
7.9 (s, 1H, cyclic HC=C-), 7.7-7.2 (m, 12H, aromatic & thiazole
protons), 4.1 & 3.8 (each s, 2H, of Hα & Hβ of pyridine), 1.1
(s, 3H, CH3), 8: δ8.2 (s, 1H, NH), 7.8 (s, 1H, cyclic HC=C-),
7.6-7.15 (m, 12H, aromatic & thiazole protons), 4.1 (s, 1H, of
Hα of pyridine), 1.5 & 1.2 (s, two CH3) ppm. UV (DMF): 7
1
(SO2NH), 1180 (C-S) cm-1; H NMR (DMSO-d6): δ 8.8 (s,
1H, OH), 8.5 (s, 1H, cyclic -CH=), 8.2-7.3 (m, 12H, thiazole,
& aryl protons) ppm; 13C NMR (δ): 185.1 (C=S), 159.7 (C=\O),
27.5 (CH2-CO), 142 (C-N-C), 148.1 (C-S-12C), 156.8 (N-C-
S), 133.3 (C6-SO2), 131.36 (C1-N), 130.15, 129.3, 128.5, 127.2
(4C of aryl). UV (DMF), λmax 286 nm; MS: 620 (M+, 5.1), 576
(3.2), 520 (1.85), 293 (75.5), 155 (43.1), 84 (100 %). Found:
C, 42.19; H, 2.54; N, 13.17; S, 9.70 %. Calculated for
C22H16N6S5O6; C, 42.28; H, 2.58; N, 13.54; S, 9.92 %.
λ
max 286, 8 λmax 315 nm. Found (%) 7: C, 41.87; H, 2.57; N,
Synthesis of bis-fused Pyrido thiobarbituric acid (3):
A mixture of compound 2 (0.02 mol), 2-chloro-6-fluorobenzal-
dehyde (0.01 mol), ammonium acetate (0.01 mol) with few
drops of glacial acetic acid was fused under reflux for 4 h,
cooled then poured onto ice. The yielded solid was filtered off
and crystallized from DMF to give 3 m.p. 160°C. IR (KBr,
14.53; S, 24.93. Calcd. (%) for C27H20N8O7S6 C, 42.63; H,
2.63; N, 14.73; S, 25.26. Found (%) 8: C, 43.75; H, 2.84; N,
14.58; S, 24.84. Calcd. (%) for C28H22N8S6O6 C, 44.32; H,
2.90; N, 14.77; S, 25.32.
RESULTS AND DISCUSSION
ν
max, cm–1): 3140 (NH), 1710 (C=O), 1380 (NCSN), 1180
Heterocyclic ring plays an important role in biochemical
processes because the side groups of the most typical and
essential constituents of the living cells, DNA and RNA are based
on aromatic heterocycles16. Thus, a main aim of the present
work is to synthesize pyrimidinone as targets via warming of
preheated dimethyl malonate with sulfathiazole (1:2 by mole)
in dry conditions17 to produce 1,3-diketoamine 1. Heterocycli-
zation of compound 1 by refluxing with CS2 in DMF18
afforded 1,3-diarylthiobarbituric acid (2). Also, 6-aryl-1,4-
dihydro-2,4,8,10-tetraaryl-3,9-dithioxo-pyrido[2,3-d: 6,5-d]-
dipyrimidin-5,7-dione (3) was obtained from refluxing 2 with
2-chloro-6-fluorobenzaldehyde (2:1 by mole) in ammonium
acetate-glacial acetic acid (Scheme-I). Formation of 3 from 2
can be outlined in Scheme-II.
(C-S), 3010, 870 (aryl carbon), 450 (C-F) cm-1; H NMR
(DMSO-d6): δ 8.2, 6.8 (each s, NH, CH, of pyridine), 7.9-7.6
(m, 12H, thiazole & aryl protons), 7.5-7.2 (m, 3H of difluoro-
chlorophenyl) ppm; UV (DMF), λmax 320 nm. Found: C, 44.65; H,
2.30; N, 13.22; S, 23.22 %. Calculated for C51H32N13O10S10ClF;
C, 45.00; H, 2.85; N, 13.38; S, 23.52 %.
1
Trifluoroacetyl thiobarbituric acid derivative (4): A
mixture of compound 2 (2 g) and trifluoro acetic acid (5 mL)
in THF (50 mL) was refluxed for 2 h, cooled then poured onto
ice. The solid obtained filtered off and crystallized from EtOH
to give 4 m.p. 175°C.
IR (KBr, νmax, cm–1): 1710, 1680, 1650 (3C=O), 1200
(C-F), 1330 (NH-SO2-), 1180 (C-S), 3000 & 820 (str. & bending
aryl) cm-1; 1H NMR (DMSO-d6): δ 8.1, 7.2 (m, 12H, thiazole
& aryl protons), 8.2 (s, 1H, SO2NH), 3.8 (s, 1H, H-C5-CO)
ppm; Found, C, 39.82; H, 2.06; N, 11.57; S, 21.89 %. Calcu-
lated for C24H15N6O7S5F3; C, 40.22; H, 2.09; N, 11.73; S,
22.34 %.
Formation of 5-disubstituted methyl-N1,N3-diaryl-2-
thioxo-pyrimidin-4,6-diones (5 & 6):A mixture of compound
2 (0.01 mol) and 3-chloroacetyl acetone or ethyl 2-chloroaceto-
acetate (0.01 mol) in DMF (50 mL) was refluxed for 1 h, cooled
then poured onto ice. The produced solid was filtered off and
crystallized dioxane to give 5 and 6 from THF. 5 m.p. 202, 6
m.p. 285 °C.
IR (KBr, νmax, cm–1): 1720, 1710, (exocyclic 2C=O), 1680,
1660 (endocyclic 2 C=O) cm-1. Found (5): C, 44.47; H, 3.14;
N, 11.08; S, 21.11 %. Calculated for C28H24N6S5O9; C, 44.98;
H, 3.20; N, 11.22; S, 21.39 %. Found (6): C, 44.53; H, 3.02;
N, 11.35; S, 21.83 %. Calculated for C27H22N6S5O8; C, 45.12;
H, 3.06; N, 11.69; S, 22.28 %.
Presence of α-active proton of methylene group19 conta-
ining compound 2 was deduced from acylation using trifluoro-
acetic acid in boiling THF to give 5-trifluoroacetyl-1,3-diaryl-
2-thioxopyrimidin-4,6-(5H) dione (4) (Scheme-III).
It is interesting that a simple alkylation of α-active
proton of compound 2 via a nucleophilic attack to labile
chlorine atom containing α-halo alkylating agents20,21 such as
ethyl-2-chloroacetoacetate and/or 3-chloro acetyl acetone as
SN2 reactions in boiling DMF as basic-catalyzed to produce a
type of 5-alkyl derivatives 5 and 6 respectively (Scheme-III).
Finally, ring closure reactions of 1,3-bioxocompounds 5
and 6 by refluxing with thiourea in sodium ethoxide solution
afforded the thioxo pyrimidin-5-yl-pyrimidinone derivatives
7 and 8 respectively (Scheme-III). Formation of compound 8
from 2 may be takes place as shown in Scheme-IV.
Studies on static polarizabilities and hyper polarizabilities
have been performed extensively with increasing importance
of molecular orbitals calculation. Thus, a possible solubility
of the prepared compounds with sodium hydroxide solution
can be a good tool for obtaining some insight into molecular
property and as a result of tautomeric forms, in establishing
Synthesis of 2-thioxo-4-methyl-5,6-dihydro-5-(1,3-
diaryl-4,6-dioxo-5H-pyrimidin-5-yl)pyrimidin-6(1H)one
(7) and 4,6-dimethyl-2-thioxo-5-(1,3-diaryl-4,6-dioxo-

Vol. 26, No. 3 (2014)
Synthesis of Some Novel Thiobarbituric Acid Derivatives from Sulfa-Drug as Antiinflammatory 751
Base
Preheated
(2 min)
Base
Ammonium
acetate
Acetic acid
- H O
2
Scheme-I
the structure property relationship. In the present study, the
obtained systems 2-8 reported a free solubilities with sodium
hydroxide solution, which indicates that a higher polarization
of ketonic
enolic functional groups of these systems
and give additional physico-chemical property, as easily elec-
tronic mobilities over molecular centers.
CH COONH
3
4
H+
-2H O
2
Structures of obtained compounds 1-8 have been estab-
lished from their molecular weight determination and spectral
data.
Compound 1 showed characteristic IR absorption bands
in the region of 3560 (OH), 3400 (NH), 1700, 1650 (C=O,
Scheme-II
1,3-diketone, COCH=CH-OH
-COCH2CO-), 1370-
The structure of compound 3 assignment based on off 1H
NMR spectra which showed a resonance signals at δ 8.2 and
6.8 ppm (NH, CH of pyridine in addition at 7.2-7.5 ppm (3H
of dihalogen aryl protons). IR spectrum of 3 recorded n at
3140 (NH), 1710 (C=O), 1380 (NCSN), 1180 (C-S) and 1150
(C-F). UV absorption spectrum of 3 give a good indication
about a polyelectronic transition by showed λmax 320 nmin
compare with 2 at 286 nm.
1355 cm-1 (SO2NH). 1H NMR spectrum of 1 showed charac-
teristic resonance signals at δ 8.55 (SO2NH), δ 7.9 (NHb), 7.2
(NHa), 5.2 (OH), 4.2 (2H, CH2) in additional the thiazole and
aromatic protons at δ 7.2-8.2 ppm.
Compound 2 recorded the lacks of NH absorption bands
in IR spectrum. Also, exhibited resonance signals correspon-
ding to COCH2CO at δ 4.2 besides the thiazole and aromatic
protons at 8.2-7.3 ppm. UV absorption spectrum recorded λmax
286 nm while M/S spectroscopy recorded the molecular ion
peak at m/z 620 which under went further fragmentation
process gave the thiazole ion as base peak m/z 84 (100 %)
(Scheme-V).
1
On the other hand, structure of 4 deduced from its H
NMR spectrum which showed a resonated signals at δ 3.8
(1H of HC5-COCF3 of pyrimidindione), 8.2 (1H, SO2NH), in
addition of thiazole and aromatic protons at δ 8.1-7.2 ppm.

752 Zayed
Asian J. Chem.
S
C
Q
N
N
Q
O
C OEt
O
C Me
O
O
Cl CH
Cl CH
C Me
O
C Me
O
2
DMF
DMF
S
F C - COOH
3
T.H.F
C
S
Q
N
N
Q
C
H
Q
N
N Q
O
O
S
H
CH
C
O
O
C
O
Q
O
N
N Q
O
C
CH
H
OEt
C
Me
Me
Me
C
O
O
O
COCF3
6
H2N C NH2
S
NaOEt
4
H2N C NH2
S
NaOEt
S
S
C
C
Q N
O
N Q
Q N
N Q
H
H
O
O
O
N
Q =
Me
Me
O
Me
S
NH SO2
N
NH
N
NH
C
S
C
S
8
7
Scheme-III
S
S
The differential structures between compounds 7 and 8
was concerted in : Hα and Hβ of two pyrimidine rings at 3.8
and 4.1 ppm of compound 7 while that showed only Hα in the
compound 8. Also, compound 8 recorded two signals of two
methyl groups at 1.2 and 1.5 ppm while that of 7 exhibited
only one methyl group at 1.1 ppm. Both the compounds 7 and
8 recovered the resonated signals at 8.2 due to NH protons of
pyrimidindione. Finally, UV absorption spectra indicated that
λmax of compound 8 is more than that of 7, λmax of 8 at 315
while that of 7 at 280 nm.
C
C
Q
O
N
N
Q
Q
N
N
Q
Base
-HB
O
O
O
2
H
H
Cl
C
C
C
Me
Me
O
O
S
S
C
C
Q
N
N Q
Q
N
N
Q
IR spectra study of all obtained compounds in both the
solid states and their solution states (CHCl3 as solvent on cold
showed that lacks of OH, NH and or SH functional groups in
the solution states. These results confirm that these targets have
a higher possibilities to acidic character which enhanced their
biocidal efforts.
H
C
H
O
O
O
O
CH
Me
Me
Me
Me
C
C
C
O
C
O
O
OH
Pharmacology: In recent years, human pathogenic
microorganisms have developed resistance in response to the
indiscriminate use of commercial antimicrobial drugs commonly
employed in the treatment of infectious diseases. The discovery
of mefenamic acid and meclofenamate22 as useful agents for
clinical treatment of inflammatory disorders has led to the
exploration of anthranilic acid, with the aim to obtain better
antiinflammatory agents.
H N
2
C
S
NH
2
NaOEt
S
S
C
C
Q
N
N
Q
Q
N
N
N
Q
H
C
H
O
O
-H O
2
O
O
Base
Me
Me
Thus, the newly synthesized compounds were studied
for their antiinflammatory activity against carrageean-induced
oedema. All the compounds were tested with a dose of
50 mg/kg given orally following the reported technique22-24
(Table-1).
C
C
Me
Me
NH
N
OH
C
S
N
H
8
S
Scheme-IV: Formation of compound 8 from 2

Vol. 26, No. 3 (2014)
Synthesis of Some Novel Thiobarbituric Acid Derivatives from Sulfa-Drug as Antiinflammatory 753
were cut and weighed. The difference between weight of the
right kind paw and the left paw of each animal was taken as a
measure of edema. The % inhibition of inflammation was cal-
culated according to:
wt. of pawedema of control- wt. of paw edema filteraled
Inhibition(%) =
wt. of pawedemaof control
It is interesting to point out that all compounds showed
antiinflammatory activity within moderate to lethal activities.
Compounds 2 and 3 exhibited a high potency and dose-
dependent anti-inflammatory activity a maximum activity
69.62, 54.54 of 2 and of 3 at 45.45, 24.24 50 mg/kg, in compare
with the standard drug (phenyl butazone). QSAR showed that
methane group between two carbonyl led to a highly acidic
character of compound 2 as well as presence of fluorine and
chlorine atoms (highly electronegative) at positions 2 and the
phenyl ring caused the enhanced anti inflammatory activity25,26
.
Also, at lower sulfur (%) of the tested compounds exhibited a
higher inhibition (%)27.
Conclusions
This article presented the synthesis and characterization
of novel thiobarbituric acids and their bis-fused/isolated
analogues based on heterocyclization of 1,3-diketoamine with
α,β-bi-functional reagents. The evaluation of these compounds
as anti-inflammatory agents provides the following trends:
(i) Compounds 2 and 3 exhibited a highly effects in
compare with control phenyl butazone, while other tested
compounds recorded a lethal effects as antiinflammatory
activity.
(ii)At lower sulfur (%) of the tested compounds exhibited
a higher inhibition (%) as antiinflammatory agents.
(iii) A higher effects of compounds 2 and 3 is mainly due
to presence of fluorine and chloride atoms beside of a sulfa
moiety26-29
.
ACKNOWLEDGEMENTS
The authors are thankful to Prof. Dr. Z. El-Baza, Depart-
ment of Pharmaceutical Microbiology, National Center for
Radiation Research and Technology, Nasr City, Egypt for anti-
inflammatory evaluation.
Scheme-V: Mass fragmentation pattern of compound 2
TABLE-1
EFFECT OF NEW SYNTHESIZED COMPOUNDS ON
CARRAGEENAN-INDUCED PAW EDEMA IN RATS
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