Synthesis, and pharmacological screening of novel sulfamoylphenylcarbamoylquinoxaline derivatives as anti-inflammatory, analgesic and antitumour agents

Article abstract of DOI:10.3184/174751911X12983997221326

Treatment of quinoxaline-2,3-dicarboxylic acid anhydride with some sulfonamides gave 3-sulfamoylphenylcarbamoylquinoxaline-2-carboxylic acid derivatives. While fusing the anhydride with the same sulfonamides produced the corresponding 3-sulfamoylphenylcarbamoylquinoxalines. On refluxing 3-sulfamoylphenylcarbamoyl derivatives with acetic anhydride gave the pyrrolo[3,4-d]quinoxaline derivatives. The imide linkage in the latter compound was opened via its reaction with amines under fusion conditions and quinoxalin-2,3-diamides were obtained. The pharmacological evaluation for some of the synthesised compounds revealed that in anti-inflammatory activity in chronic models, 3-{[4-(N-pyrimidin-2-ylsulfamoyl)phenyl]carbamoyl}quinoxaline-2- carboxylic acid was equipotent to the reference drug, indomethacin as well as having nonulcerogenic effect. All tested compounds showed moderate analgesic activity compared to the reference drug. The antitumour activity for the tested compounds showed that 3-{[4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl] carbamoyl}quinoxaline-2-carboxylic acid, 4-(1,3-dioxo-1H-pyrrolo[3,4-b] quinoxalin-2(3H)-yl)-N-(pyrimidin-2-yl)-benzenesulfonamide and N-carbamimidoyl-4-(1,3-dioxo-1H-pyrrolo[3,4-b]quinoxalin-2(3H)-yl) benzenesulfonamide were the most effective against the liver carcinoma cell line showing IC₅₀ values 0.5, 0.79 and 1.84 IC₅₀ μg mL^-1, respectively.

Full text of DOI:10.3184/174751911X12983997221326

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 163
MARCH, 163–166
Synthesis, and pharmacological screening of novel
sulfamoylphenylcarbamoylquinoxaline derivatives as anti-inflammatory,
analgesic and antitumour agents
Awatf Al-Said Farraga, Yousry Ahmed Ammarb*, Abd Allah Ghodran El-Sehemib,
Hamdy Khamees Thabetc, Nashwa Abd-Alim Hassana and Aziza Khalil Samya
aDepartment of Chemistry, Faculty of Science for Girls at Khorma, Taif University, Makka, Saudi Arabia
bDepartment of Chemistry, Faculty of Science, King Khaled University, Abha, Saudi Arabia
cDepartment of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Egypt
Treatment of quinoxaline-2,3-dicarboxylic acid anhydride with some sulfonamides gave 3-sulfamoylphenylcarbamo-
ylquinoxaline-2-carboxylic acid derivatives. While fusing the anhydride with the same sulfonamides produced the
corresponding 3-sulfamoylphenylcarbamoylquinoxalines. On refluxing 3-sulfamoylphenylcarbamoyl derivatives
with acetic anhydride gave the pyrrolo[3,4-d]quinoxaline derivatives. The imide linkage in the latter compound
was opened via its reaction with amines under fusion conditions and quinoxalin-2,3-diamides were obtained. The
pharmacological evaluation for some of the synthesised compounds revealed that in anti-inflammatory activity in
chronic models, 3-{[4-(N-pyrimidin-2-ylsulfamoyl)phenyl]carbamoyl}quinoxaline-2-carboxylic acid was equipotent to
the reference drug, indomethacin as well as having nonulcerogenic effect. All tested compounds showed moderate
analgesic activity compared to the reference drug. The antitumour activity for the tested compounds showed
that 3-{[4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl]carbamoyl}quinoxaline-2-carboxylic acid, 4-(1,3-dioxo-1H-pyr-
rolo[3,4-b]quinoxalin-2(3H)-yl)-N-(pyrimidin-2-yl)-benzenesulfonamide and N-carbamimidoyl-4-(1,3-dioxo-1H-pyr-
rolo[3,4-b]quinoxalin-2(3H)-yl)benzenesulfonamide were the most effective against the liver carcinoma cell line
showing IC50 values 0.5, 0.79 and 1.84 IC50 µg mL−1, respectively.
Keywords: quinoxaline-2-carboxamides, pyrrolo[3,4-d]quinoxalines analgesic, anti-inflammatory, antitumour activities
Among the wide range of heterocycles studied to develop
pharmaceutically important molecules, quinoxaline has played
an important role in medicinal chemistry. A survey of the lit-
erature has shown that compounds having a quinoxaline
nucleus possess a broad range of biological activities such as,
antitumour,1–3 anti-inflammatory,4,5 anti-diabetic,6 analgesic7,8
and antiulcer activities.9 On the other hand, compounds com-
prising a sulfone backbone have a wide range of biological
activities as antibacterial,10 anti-inflammatory,11 hypoglycae-
mic12 and antitumour13 activities. Among the quinoxaline
and sulfonamide derivatives, some have found their way into
clinical applications. For example, the two known antine-
oplastic quinoxaline tropoisomerase II inhibitors, 2-[4-(7-
chlorophenylquinoxaline-2-yl)-phenoxypropionic acid (I)14
and chloroquinoxaline sulfonamide (II).15 Furthermore,
actazolamide (III) has been reported as a strong inhibitor
of several CA isozymes,16 it acts as a potential modulator of
anticancer therapies.
synthesised by the reaction of 1,2-phenylenediamine with
disodium dihydroxytartarate to yield quinoxaline-2,3-dicar-
boxylic acid 1 followed by treatment with acetic anhydride.
The reactivity of compound 2 towards some sulfonamides
as nitrogen nucleophiles was investigated under different
conditions22,23 in the hope of obtaining derivatives of quinoxa-
linecarboxamides. When, compound 2 was treated with some
sulfa derivatives in refluxing ethanol, it led to the opening
of the lactone ring and the obtained product was identified as
3-sulfamoylphenylcarbamoylquinoxaline-2-carboxylic acids
3a–e on the basis of elemental analysis and spectral data.
While, heating the anhydride derivative 2 under fusion condi-
tions with the same sulfa derivatives afforded quinoxaline-
2-carboxamide derivatives 4a–e. These compounds were also
prepared through another route, by fusion of compounds 3a–e
in quinoline containing copper powder. This means that, the
reaction of the anhydride 2 with sulfonamides under fusion
condition take place to give 3 which is then decarboxylated
to yield 4 (Scheme 1). The analytical and spectroscopic data of
4 are consistent with its proposed structure.
Results and discussion
Pyrroloquinoxaline derivatives 5a–e were obtained by
refluxing compounds 3a–e in acetic anhydride which caused
cyclisation through loss of 1 mole of water. The products were
verified by their micro-analytical and spectral data. Fusion of
5a with piperidine, morpholine or p-anisidine caused opening
of the imide ring and the corresponding quinoxaline-diamide
derivatives 6a–c were obtained (Scheme 2).
As an extension of our efforts directed towards the develop-
ment of convenient synthetic approaches for the synthesis of
many quinoxaline derivatives with an expected broad spectrum
of biological activities,17–20 we introduced sulfonamide moiety
into quinoxaline structure with the aim of obtaining more
potent pharmacological active compounds. Quinoxaline-2,3-
dicarboxylic anhydride 221 was used as a starting material and
* Correspondent: E-mail: yossry@yahoo.com

164 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1 Synthesis of compounds 2–4.
Scheme 2 Synthesis of compounds 5a–e, 6a–e.
Anti-inflammatory, ulcerogenic and analgesic activities
other hand, compounds 3b, 3c, 3e, 4a, 4b, 4d and 4b exhibited
strong anti-inflammatory activities, ranged from 0.8 to 0.9%
potencies comparable to the reference drug. Compounds 3a
and 4e showed moderate activities, while mild effects were
exerted by compounds 4c and 5a. In addition, the ulcerogenic
activity results revealed that most of the tested compounds
The screening of the anti-inflammatory activity (chronic
model) of the tested quinoxaline compounds revealed that, the
2-(4-(N-pyrimidin-3-yl)sulfamoylphenyl)carbamoyl)quinoxal
ine-3-carboxylic acid 3d was equipotent to the reference drug,
Indomethacin as well as having non-ulcerogenic effect. On the

JOURNAL OF CHEMICAL RESEARCH 2011 165
10.96, 11.65 (3s, 3H, 2NH + OH). MS: m/z 414 (M+; 12), 397, 370,
353, 130, 102, 76. Anal. Calcd for C17H14N6O5S: C, 49.27; H, 3.41;
N, 20.28. Found: C, 49.15; H, 3.15; N, 20.10%.
were considered safe, as they displayed reduced ulcerogenic
effect (P = 0.1–0.3) compared indomethacin (10 mg kg−1).
Analgesic activity was measured for the tested compounds and
the reference novalgin. All compounds showed moderate
analgesic activity compared to that of novalgin.
3-{[4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl]carbamoyl}qui-
noxaline-2-carboxylic acid (3c): Yield: 72%. M.p. 253–254 °C (acetic
acid); IR (KBr) ν = 3350 (OH), 3250, 3140 (2NH), 1710 (C=O; car-
boxylic), 1654 (C=O; amide), 1598 (C=N quinoxaline) and 1400,
1
Antitumour results
1315 (SO2). H NMR (DMSO-d6, 300 MHz, δ ppm): 2.31 (s, 3H,
CH3), 6.06 (s, 1H, H-isoxazole), 7.81–8.30 (m, 9H, ArH + NH), 11.10,
11.20 (2s, 2H, NH + COOH). 13C NMR (DMSO-d6, 300 MHz,
δ ppm): 11.85 (CH3), 95.30 (CH-oxazole), 120.55–144.15 (12 Ar-C),
143.25 (C=N, quinoxaline), 146.57 (C=N, iso-oxazole), 157.6 (C=N,
quinoxaline), 162.67 (C=O, CONH), 166.31 (C=O, COOH), 170.41
(C–O, iso-oxazole). Anal. Calcd for C20H15N5O6S: C, 52.98; H, 3.33;
N, 15.45. Found: C, 52.75; H, 3.40; N, 15.26%.
The response parameter calculated for each cell line was the
IC50, a value which corresponds to the compounds concentra-
tion causing 50% mortality in the net cells. The results showed
that compounds 3c, 5d and 5b were the most effective against
the liver carcinoma cell line showing IC50 values 0.5, 0.79 and
1.84 IC50 µg mL−1, respectively. Activity order of the other
compounds was 4d > 3a > 6c > 4c > 5e > 4b > 3d > 3b > 4a
showing IC50 values of 2.94, 3.61, 4.65, 4.75, 4.82, 4.95, 5.89,
6.00 and 6.79 µg mL−1 respectively, whereas, compounds 3e,
4a, 4e, 5c, 6a and 6b were nontoxic against the liver carcinoma
cell line. The activity of the tested compounds could be corre-
lated to structure variations and modifications. The 2-(4-N-
(5-methylisoxazol-3-ylsulfamoylphenyl)carbamoylquinoxaline-
3-carbxylic acid (3c) was the most effective derivative
of all the tested compounds showing IC50 0.5 µg mL−1, its along
3b and 3d were also active against the liver carcinoma cell
line, IC50 6.00 and 5.89 µg mL−1 showing that the presence of
the carboxylic group is important for the activity. The presence
of pyrimidine moiety in quinoxaline as compound 4d seems
to enhance the antitumour activity as it showed IC50 0.79 µg
mL−1 whereas, the presence of iso-oxazole ring in structure
5e resulted in a decrease in the activity to the moderate range.
The resulted obtained from this study showed that the N-
carbami-midoyl-4-(1,3-dioxo-1H-pyrrolo[3,4-b]-quinoxaline-
2-(3H)-yl)-benzene-sulfonamide 5b showed cytotoxicity
approximately three-fold that of the 4-(1,3-dioxo-1H-pyr-
rolo[3,4-b]quinoxaline-2(3H)-yl)benzenesulfonamidecarboxa
mide 5a, IC50 1.84 and 6.79 µg mL−1 respectively, suggesting
that in this series of compounds the presence of guanidinyl
moiety in the structure of compound 5b imparts higher
cytotoxic effect than compound 5a.
3-{[4-(N-pyrimidin-2-ylsulfamoyl)phenyl]carbamoyl}quinoxaline-
2-carboxylic acid (3d): Yield: 71%. M.p. 262–263 °C (acetic acid);
IR (KBr) ν = 3340 (OH), 3290, 3150 (NH), 1705 (C=O; carboxylic),
1
1668 (C=O; amide), 1605 (C=N quinoxaline), 1400, 1320 (SO2). H
NMR (DMSO-d6, 300 MHz, δ ppm): 7.15 (s, 2H, pyrimidine H-4,
H-6), 7.93–8.64 (m, 9H, ArH + pyrimidine H-5), 9.22, 11.18, 11.30
(3s, 3H, 2NH + OH). MS: m/z 450 (M+; 6), 406, 276, 130, 76. Anal.
Anal. Calcd for C20H14N6O5S: C, 53.33; H, 3.13; N, 18.66. Found:
C, 53.12; H, 3.23; N, 18.52%.
3-{[4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl]carbamoy
l}quinoxa-line-2-carboxylic acid (3e): Yield: 77%. M.p. 243–244 °C
(ethanol/dimethylformamide); IR (KBr) ν = 3350 (OH), 3295, 3140
(NH), 1710 (C=O; carboxylic), 1660 (C=O; amide), 1598 (C=N qui-
noxaline), 1400, 1330 (SO2). 1H NMR (DMSO-d6, 300 MHz, δ ppm):
2.30 (s, 6H, 2CH3), 6.61 (s, 1H, pyrimidine H-5), 7.91–8.40 (m, 9H,
ArH + NH), 10.33, 11.12 (2s, 2H, NH + OH). MS: m/z 478 (M+; 13),
434, 304, 276, 174, 130, 76. Anal. Calcd for C22H18N6O5S: C, 55.22;
H, 3.79; N, 17.56. Found: C, 55.12; H, 3.55; N, 17.45%.
Synthesis of quinoxaline-2-carboxamides 4a–e
Method A: A mixture of compound 2 (100 mmol) and the appropriate
sulfonamides (100 mmol) was fused for 15 minutes at 160 °C, then
allowed to cool. The solid product was collected and recrystallised
from the proper solvent to give (4a–e).
Method B: A mixture of 3 (100 mmol) and copper powder (1g) in
quinoline (10 mL) was refluxed for 0.5 h. The copper powder was
filtered off when hot, and the mother liquor was left to cool and treated
as above to give 4a–e.
N-(4-Sulfamoylphenyl)quinoxaline-2-carboxamide (4a): Yield:
72%. M.p. 253–254 °C (acetic acid); IR (KBr) ν = 3350, 3262 (NH2,
NH), 1668 (C=O), 1592 (C=N quinoxaline) and 1400, 1310 (SO2). 1H
NMR (DMSO-d6, 300 MHz, δ ppm): 7.88–8.32 (m, 8H, ArH), 9.57 (s,
1H, quinoxaline-3), 6.90 (s, 2H, NH2), 11.18 (s, 1H, NH). Anal. Calcd
for C15H12N4O3S: C, 54.87; H, 3.68; N, 17.06. Found: C, 54.68;
H, 3.72; N, 17.15%.
Experimental
All melting points are uncorrected and were determined on a digital
Gallenkamp MFB-595 instrument. IR spectra (KBr) were recorded on
a Shimadzu 440 spectrometer. H NMR and 13C NMR spectra were
1
determined on a Varian Mercury (300 MHz) spectrometer (Varian,
UK) Faculty of Science, Cairo University, Egypt. The chemical shifts
are expressed in ppm relative to TMS as internal reference. Mass
spectra were measured on GCMS-QP 1000 EX mass spectrometer at
70 eV. Elemental analyses were carried out at the Microanalytical
Center of Cairo University.
N-{4-[N-Carbamimidoylsulfamoyl]phenyl}quinoxaline-2-carbox-
amide (4b): Yield: 68%. M.p. 168–169 °C (dimethylformamide); IR
(KBr) ν = 3436, 3360, 3180 (NH2, NH), 1686 (C=O), 1628 (C=N qui-
noxaline), 1398, 1315 (SO2). 1H NMR (DMSO-d6, 300 MHz, δ ppm):
6.74 (s, 2H, NH2), 7.81–8.29 (m, 8H, ArH), 8.20 (s, 1H, NH), 9.58
(s, 1H, quinoxaline H-3), 9.81, 11.11 (2s, 2H, 2NH). MS: m/z 353
(M-NH3), 130, 129, 102, 76. Anal. Calcd for C16H14N6O3S: C, 51.88;
H, 3.81; N, 22.69. Found: C, 51.75; H, 3.55; N, 22.52%.
Synthesis of 2-sulfamoylphenylcarbamoylquinoxaline-3-carboxylic
acids (3a–e)
A suspension of compound 2 (100 mmol) and the requisite sulfon-
amides (100 mmol) in dimethylformamide/ethanol (10 mL : 10 mL)
was refluxed for 1 h, the solid that was obtained after cooling was
collected and recrystallised from the proper solvent to give 3a–e.
N-{4-[N-(5-methylisoxazol-3-yl)sulfamoyl]phenyl}quinoxaline-2-
carboxamide (4c): Yield: 71%. M.p. 190–192 °C (dimethylfor-
mamide); IR (KBr) ν = 3336, 3280 (NH), 2980 (CH-aliph.), 1690
3-(4-Sulfamoylphenylcarbamoyl)quinoxaline-2-carboxylic
acid
(3a): Yield: 75%. M.p. 248–249 °C (acetic acid); IR (KBr) ν = 3500
(OH), 3354, 3256 (NH2, NH), 1730 (C=O; carboxylic), 1682 (C=O;
amide), 1596 (C=N quinoxaline), 1410, 1322 (SO2). 1H NMR (DMSO-
d6, 300 MHz, δ ppm): 7.37 (s, 2H, NH2), 7.89–8.07 (m, 8H, ArH),
8.18, 11.31 (2s, 2H, NH, COOH). MS: m/z 372 (M+), 328, 130, 129,
102, 76. Anal. Calcd for C16H12N4O5S: C, 51.61; H, 3.25; N, 15.05.
Found: C, 51.47; H, 3.32; N, 14.93%.
1
(C=O), 1618 (C=N quinoxaline) and 1402, 1340 (SO2). H NMR
(DMSO-d6, 300 MHz, δ ppm): 2.12 (s, 3H, CH3), 6.61 (s, 1H,
H-isoxazole), 7.70–8.34 (m, 9H, ArH + NH), 9.61 (s, 1H, quinoxaline
H-3), 11.10 (s, 1H, NH). MS: m/z 409 (M+), 312, 248, 130, 129, 102,
76. Anal. Calcd for C19H15N5O4S: C, 55.74; H, 3.69; N, 17.11. Found:
C, 55.50; H, 3.45; N, 17.20%.
N-{4-[N-Pyrimidin-2-ylsulfamoyl]phenyl}quinoxaline-2-carbox-
amide (4d): Yield: 73%. M.p. 182–183 °C (acetic acid); IR (KBr)
ν = 3352, 3300 (NH), 1686 (C=O), 1584 (C=N quinoxaline) and
3-{[4-(N-carbamimidoylsulfamoyl)phenyl]carbamoyl}quinoxaline-
2-carboxylic acid (3b): Yield: 78%. M.p. 232–233 °C (ethanol/
dimethylformamide); IR (KBr) ν = 3460 (OH), 3350, 3250 (NH2,
NH), 1700 (C=O; carboxylic), 1678 (C=O; amide), 1598 (C=N qui-
noxaline), 1402, 1320 (SO2). 1H NMR (DMSO-d6, 300 MHz, δ ppm):
7.62–8.14 (m, 8H, ArH), 8.42 (s, 1H, NH), 6.55 (s, 2H, NH2), 9.76,
1
1406, 1336 (SO2). H NMR (DMSO-d6, 300 MHz, δ ppm): 7.04
(s, 2H, pyrimidine H-4, H-6), 8.09–8.49 (m, 9H, ArH + pyrimidine
H-5), 9.56 (s, 1H, quinoxaline H-3), 11.18, 11.30 (2s, 2H, 2NH). Anal.

166 JOURNAL OF CHEMICAL RESEARCH 2011
1
Calcd for C19H14N6O3S: C, 56.15; H, 3.47; N, 20.68. Found: C, 56.20;
H, 3.20; N, 20.44%.
(C=O), 1606 (C=N quinoxaline), and 1395, 1328 (SO2). H NMR
(DMSO-d6, 300 MHz, δ ppm): 3.10–3.36 (m, 4H, 2 NCH2), 3.63–3.74
(m, 4H, 2 OCH2), 7.89–8.34 (m, 8H, ArH), 7.48 (s, 2H, NH2), 11.30
(s, 1H, NH). Anal. Calcd for C20H19N5O5S: C, 54.41; H, 4.34;
N, 15.86. Found: C, 54.30; H, 4.18; N, 15.71%.
N-{4-[N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl]phenyl}quinoxali
ne-2-carboxamide (4e): Yield: 68%. M.p. 213–214 °C (dimethylfor-
mamide); IR (KBr) ν = 3352, 3130 (NH), 2920 (CH-aliph.), 1692
(C=O), 1598 (C=N quinoxaline), 1400, 1320 (SO2). 1H NMR (DMSO-
d6, 300 MHz, δ ppm): 2.26 (s, 6H, 2CH3), 6.76 (s, 1H, pyrimidine
H-5), 8.02–8.30 (m, 9H, ArH + NH), 9.55 (s, 1H, quinoxaline H-3),
11.12 (s, 1H, NH). Anal. Calcd for C21H18N6O3S: C, 58.05; H, 4.18;
N, 19.34. Found: C, 58.20; H, 4.05; N, 19.20%.
N2-(4-Methoxyphenyl)-N3-(4-sulfamoylphenyl)quinoxaline-2,3-
dicarboxamide (6c): Yield: 79%. M.p. 268–269 °C (dimethylfor-
mamide); IR (KBr) ν = 3340, 3272 (NH2, NH), 2948, 2840 (CH-
1
aliph.), 1688 (C=O), 1606 (C=N quinoxaline), 1390, 1328 (SO2). H
NMR (DMSO-d6, 300 MHz, δ ppm): 3.76 (s, 3H, OCH3), 6.94–8.33
(m, 12H, ArH), 7.30 (s, 2H, NH2), 10.80, 11.13 (2s, 2H, 2NH). MS:
m/z 477 (M+, 2.5), 305, 290, 274, 157, 128, 102, 76, 52. Anal. Calcd
for C23H19N5O5S: C, 57.85; H, 4.01; N, 14.67. Found: C, 57.71;
H, 4.05; N, 14.44%.
Synthesis of 1,3-dioxo-1H-pyrrolo[3,4-b]-quinoxalines 5a–e
A solution of 3 (100 mmol) in acetic anhydride (10 mL) was refluxed
for 30 minutes, the crystals which formed on cooling were separated
off, washed with 5 ml petroleum ether, dried, and recrystallised from
the proper solvent to give (5a–e).
4-{1,3-Dioxo-1H-pyrrolo[3,4-b]quinoxalin-2(3H)-yl}benzenesul-
fonamide (5a): Yield: 84%. M.p. >300 °C (dimethylformamide); IR
(KBr) ν = 3380, 3140 (NH2, NH), 1690 (C=O), 1590 (C=N quinoxa-
line), 1405, 1310 (SO2). 1H NMR (DMSO-d6, 300 MHz, δ ppm): 6.83
(s, 2H, NH2), 7.77–8.23 (m, 8H, ArH). MS: m/z 354 (M+), 198, 156,
130, 129, 102, 76, 41. Anal. Calcd for C16H10N4O4S: C, 54.23; H, 2.84;
N, 15.81. Found: C, 54.35; H, 2.67; N, 15.63%.
The authors gratefully acknowledge the financial support by
Taif University (Project No.1/430/463).
Received 7 December 2010; accepted 7 February 2011
Paper 1000468 doi: 10.3184/174751911X12983997221326
Published online: 23 March 2011
N-Carbamimidoyl-4-(1,3-dioxo-1H-pyrrolo[3,4-b]quinoxalin-2
(3H)-yl)benzene-sulfonamide (5b): Yield: 80%. M.p. >300 °C
(dimethyl-formamide); IR (KBr) ν = 3410, 3240 (NH2, NH), 1688
References
1
2
3
M.J. Waring, T. Bin-Hadda, A. T. Kotchevar, A. Ramdani, R. Touzani, S.
Elkadiri, A. Hakkou, M. Bouakka and T. Ellis, Molecules, 2002, 7, 641.
K.M. Amin, M.M.F. Ismail, E. Noaman, D.H. Soliman and Y.A. Ammar,
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E.R. Kotb, M.A. Anwar, M.S. Soliman and M.A. Salama, Phosphorus,
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1
(C=O), 1602 (C=N quinoxaline) and 1404, 1340 (SO2). H NMR
(DMSO-d6, 300 MHz, δ ppm): 6.43 (s, 2H, NH2), 7.55–8.06 (m, 8H,
ArH), 9.76, 10.41 (2s, 2H, 2NH). MS: m/z 396 (M+, 16) 379, 353,
240, 198, 156, 130, 129, 102, 76. Anal. Calcd for C17H12N6O4S:
C, 51.51; H, 3.05; N, 21.20. Found: C, 51.38; H, 2.83; N, 21.33%.
4-(1,3-Dioxo-1H-pyrrolo[3,4-b]quinoxalin-2(3H)-yl)-N-(5-methy-
lisoxazol-3-yl)-benzenesulfonamide (5c): Yield: 81%. M.p. >300 °C
(dimethyl-formamide); IR (KBr) ν = 3220 (NH), 1710 (C=O), 1592
(C=N quinoxaline), 1380, 1310 (SO2). 1H NMR (DMSO-d6, 300 MHz,
δ ppm): 1.91 (s, 3H, CH3), 6.74 (s, 1H, iso-oxazole H-4), 7.87–8.42
(m, 8H, ArH), 11.40 (s, 1H, NH). Anal. Calcd for C20H13N5O5S:
C, 55.17; H, 3.01; N, 16.08. Found: C, 55.06; H, 2.74; N, 15.87%.
4-(1,3-Dioxo-1H-pyrrolo[3,4-b]quinoxalin-2(3H)-yl)-N-(pyrimidin-
2-yl)-benzenesulfonamide (5d): Yield: 78%. M.p. >300 °C (dimeth-
ylformamide); IR (KBr) ν = 3226 (NH), 1715 (C=O), 1584 (C=N
quinoxaline), 1402, 1330 (SO2). 1H NMR (DMSO-d6, 300 MHz,
δ ppm): 7.06 (s, 2H, pyrimidine H-4, H-6), 8.02–8.50 (m, 9H, ArH +
pyrimidine H-5), 11.32 (s, 1H, NH). Anal. Calcd for C20H12N6O4S:
C, 55.55; H, 2.80; N, 19.44. Found: C, 55.37; H, 2.52; N, 19.23%.
N-(4,6-dimethylpyrimidin-2-yl)-4-(1,3-dioxo-1H-pyrrolo[3,4-b]
quinoxalin-2(3H)-yl)benzenesulfonamide (5e): Yield: 82%. M.p.
>300 °C (dimethylformamide); IR (KBr) ν = 3280 (NH), 1700 (C=O),
1600 (C=N quinoxaline) and 1400, 1315 (SO2). 1H NMR (DMSO-d6,
300 MHz, δ ppm): 2.33 (s, 6H, 2CH3), 6.75 (s, 1H, pyrimidine H-5),
7.95–8.30 (s, 8H, ArH), 11.25 (s, 1H, NH). 13C NMR (DMSO-d6,
300 MHz, δ ppm): 22.84, 113.44, 119.08, 129.40, 132.20, 135.70,
140.64, 141.84, 145.85, 163.48, 166.07, 167.33. MS: m/z 461 (M+ +1,
12), 460 (M+, 80.30), 432, 304, 262, 198, 156, 130, 129, 102, 76. Anal.
Calcd for C22H16N6O4S: C, 57.38; H, 3.50; N, 18.25. Found: C, 57.22;
H, 3.52; N, 18.10%.
4
5
H. Yamamoto, Jap Pat 6917136 1969; Chem. Abstr. 1990, 71, 124505d.
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8
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K. Karabelas, H. Lonn, P. Sjo, PCT Int. Appl WO 99 46, 260 (Cl. CO7D
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11 A. Balsamo, F. Muncini, C. Milanese, E. Oralandini, G. Ortore, M. Pinza,
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13 E. Pomarmacka and I.K. Kedra, Farmaco, 2003, 58, 423.
14 Z. Ding, R.E. Parachment, P.M. Lorusso, J.Y. Zhou., Clin. Cancer Res.,
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15 J.R. Rigas, W.P. Tang, M.G. Kris and J.P. Orazem, Anticancer Res. 1992,
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16 B.A. Teicher, S.D. Liu, J.T. Liu, Anticancer Res., 1993, 13, 1549.
17 M.M.E. Ismail, Y.A. Ammar, M.K. Ibrahim and H.S.A. El-Zahaby,
Arzneim-Forsch/Drug Res., 2006, 55(12), 738.
18 Y.A. Ammar, M.M.F. Ismail, M.K. Ibrahim and H.S.A. El-Zahaby,
Afinidad, 2005, 62, 151.
19 M.M.F. Ismail, K.A. Amin, E. Noaman, D.H. Soliman and Y. A. Ammar,
Eur. J. Med. Chem., 2010, 45, 2733.
20 Y.A. Ammar, A.M. Sh. El-Sharief, M.M. Ali, Y.A. Mohamed and Sh. I.
Mohamed, Phosphorus, Sulfur Silicon, 2000, 166, 173.
21 Y.A. Ammar, J. Serb. Chem., 1990, 55, 515.
Synthesis of quinoxalin-2,3-dicarboxamides 6a–c
A mixture of 5 (100 mmol) and the requisite amine (100 mmol) was
fused at 160 °C for 15 minutes, then allowed to cool. The solid
product was collected and recrystallised from the proper solvent to
give (6a–c).
22 Y.A. Ammar, Y.A. Mohamed, A.M. Sh. Al-Sharief and M.A. Zahran,
Egypt. J. Chem., 1991, 34, 361.
23 Y.A. Mohamed, Y.A. Ammar, A.M. Sh. Al-Sharief and M.A. Zahran,
Affinidad, 1993, 444, 123.
3-(Piperidin-1-carbamoyl)-N-(4-sulfamoylphenyl)quinoxaline-2-
carboxamide (6a): Yield: 73%. M.p. 228–229 °C (acetic acid);
IR (KBr) ν = 3200, 3150 (NH2, NH), 2940, 2850 (CH-aliph.), 1686
(C=O), 1624 (C=N quinoxaline) and 1404, 1328 (SO2).1H NMR
(DMSO-d6, 300 MHz, δ ppm): 1.45–1.65 (m, 6H, 3 CH2), 3.43–3.66
(m, 4H, 2NCH2), 7.89–8.32 (m, 8H, ArH), 7.89 (s, 2H, NH2), 11.64
(s, 1H, NH). MS: m/z 439 (M+), 355, 128, 102, 76, 52. Anal. Calcd
for C21H21N5O4S: C, 57.39; H, 4.82; N, 15.94. Found: C, 57.45;
H, 4.59; N, 15.73%.
24 G. Paget and E. Berner, Toxicity tests in evaluation of drugs activity cited
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45, 232.
28 R. Charlier, M. Prost, F. Binon and G. Deltour, Arch. Intern. Pharmacodyn.,
1961, 134, 306.
3-(Morpholin-1-carbamoyl)-N-(4-sulfamoylphenyl)quinoxaline-2-
carboxamide (6b): Yield: 74%. M.p. 236–238 °C (acetic acid); IR
(KBr) ν = 3335, 3270 (NH, NH2), 2948, 2835 (CH-aliph.), 1688
29 P. Skehan, R. Storeng, D. Seudiero, A. Monks, J. McMahon, D. Vistica,
J.T. Warren, J. Bokesch, S. Kenny and M.R. Boyd, J. Nat. Cancer Inst.,
1990, 82, 1107.

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