Synthesis and reactions of some novel quinoxalines for anticancer evaluation

Article abstract of DOI:10.1080/10426500601142114

1,2-Dihydro-3-(2 '-naphthyl)quinoxaline-2-one (4) was prepared from the reaction of methyl(2 '-naphthyl)glyoxylate (3). Also, 2-chloro-and 2-hydrazinoquinoxaline derivatives 5 and 6 were prepared, which, upon reacting with different reagents, afforded the

Full text of DOI:10.1080/10426500601142114

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Synthesis and Reactions of
Some Novel Quinoxalines for
Anticancer Evaluation
E. R. Kotb a , M. A. Salama a , M. A. Anwar b & M. S.
Soliman b
a Photochemistry Department, National Research
Centre , National Research Centre , Dokki, Cairo,
Egypt
b Medicinal Chemistry Department, National
Research Centre , Dokki, Cairo, Egypt
Published online: 26 Apr 2007.
To cite this article: E. R. Kotb , M. A. Salama , M. A. Anwar & M. S. Soliman (2007)
Synthesis and Reactions of Some Novel Quinoxalines for Anticancer Evaluation,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:5, 1119-1130, DOI:
10.1080/10426500601142114
To link to this article: http://dx.doi.org/10.1080/10426500601142114
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Phosphorus, Sulfur, and Silicon, 182:1119–1130, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601142114
Synthesis and Reactions of Some Novel Quinoxalines
for Anticancer Evaluation
E. R. Kotb
Photochemistry Department, National Research Centre, Dokki,
Cairo, Egypt
M. A. Anwar
M. S. Soliman
Medicinal Chemistry Department, National Research Centre, Dokki,
Cairo, Egypt
M. A. Salama
Photochemistry Department, National Research Centre, Dokki,
Cairo, Egypt
1,2-Dihydro-3-(2 ꢀ-naphthyl)quinoxaline-2-one (4) was prepared from the reaction
of methyl(2 ꢀ-naphthyl)glyoxylate (3). Also, 2-chloro- and 2-hydrazinoquinoxaline
derivatives 5 and 6 were prepared, which, upon reacting with different reagents,
afforded the triazolo, tetrazolo, and amino quinoxaline derivatives. Compounds 5,
8b, 9, 10b, and 11b were evaluated for their anticancer activity.
Keywords Acetyl naphthalene; anticancer evaluation; hydrazinoquinoxaline; quinox-
alinone
INTRODUCTION
A literature survey revealed that attention has been increasingly paid
to the synthesis of heterocyclic quinoxaline derivatives, which exhibit
various biological activities including anticancer,1−6 antitubercular,7−11
antibacterial,12,13 anticonvulsant,14 and adenosine receptor antagonis-
tic properties.15,16 As an extension, our efforts are directed toward
the development of convenient synthetic approaches for the synthe-
sis of new heterocyclic compounds with an expected broad spectrum
of biological activity. In this article we report on the synthesis of new
quinoxaline derivatives starting with 2-bromoacetylnaphthalene (2).17
Received July 23, 2006; accepted October 17, 2006.
Address correspondence to M. A. Salama, Photochemistry Department, National Re-
search Centre, Dokki, Cairo, Egypt. E-mail: mowafsalam@yahoo.com
1119

1120
E. R. Kotb et al.
DISCUSSION
Synthesis of the new compounds was achieved by reaction of naphth-
alen-2-yl-oxo-acetic acid methyl ester (3)18 with O-Phenylenediamine
(OPDA) to afford 3-naphthalen-2-yl-1H-quinoxalin-2-one (4). The ele-
mental and spectroscopic data are consistent with assigned structures.
The IR spectral bands due to the C O and the NH groups in com-
pound 4 appeared in the region 1662 and 3447 cm−1, respectively. The
mass spectrum of compound 4 showed a molecular ion peak at m/z =
272, as a base peak, which is consistent with its molecular formula
C18H12N2O. The reaction of compound 4 with phosphorus oxychloride
afforded the corresponding 2-chloro-3-naphthalen-2-yl-quinoxaline (5),
which, upon treating with hydrazine hydrate, gave the corresponding 3-
(naphthalen-2-yl-quinoxalin-2-yl)hydrazine (6). The structures of com-
pounds 5 and 6 were confirmed with microanalyses and spectral data.
The IR spectrum of the chloro derivative 5 revealed the disappear-
ance of the carbonyl band at 1662 cm−1 and the presence of absorp-
tion bands at 1598 cm−1 (C N) and 1077 cm−1(strong, C-Cl-aryl). The
mass spectrum of compound 5 showed the two isotopic molecular ion
peaks (C18H11ClN2) at m/z = 290, which is the base peak, and M++2
at m/z = 292 (31.3%). The IR spectrum of compound 6 showed the ab-
1
sorption bands at 3420 cm−1 and 3290 cm−1 (NH-NH2). The H NMR
spectrum of compound 6 (DMSO-d6, δ) showed signals at 4.9 (s, 2H,
NH2, exchangeable with D2O), 6.9–8.2 (m, 11H, Ar H), and 9.8 (s, 1H,
NH, exchangeable with D2O). Compound 6 reacted with phenylisoth-
iocyanate in dry benzene to give 2-(aminophenylthioxohydrazidyl)-3-
(2 ꢀ-naphthyl)quinoxaline (7). The IR spectrum of the latter compound
showed the absorption bands at 3398, 3290, and 3057 cm−1(3 NH) and
an absorption band at 1260 cm−1 (C S).
Recently, it has been reported that hydrazino quinoxalines can
be considered as key starting materials for the synthesis of diverse
nitrogen bridgehead compounds. Thus, the hydrazino quinoxa-
line 6 reacted with formic or acetic acids to give the symmetrical
4-naphthalen-2-yl-[1,2,4]triazolo[4,3-a]quinoxaline (8a) and 1-methyl-
4-naphthalen-2-yl-[1,2,4]triazolo[4,3-a]quinoxaline (8b), respectively.
Moreover, when compound 6 was reacted with nitrous acid, it gave
4-naphthalen-2-yl-tetrazolo[4,5-a]quinoxaline (9). The elemental and
spectroscopic data of compounds 8 and 9 are consistent with the
assigned structures. Condensation of compound 6 with p-methoxy-
benzaldehyde and/or thiophene-2-carboxaldehyde took place by heating
under reflux in ethanol in the presence of a few drops of acetic acid.
The
N-(4-methoxy-benzylidene)-Nꢀ-(3-naphthalen-2-yl-quinoxalin-
2-yl) hydrazine (10a) and/or N-(3-naphthalen-2-yl-quinoxalin-
2-yl)-Nꢀ- thiophen-2-ylmethylene-hydrazine (10b) were produced.

Quinoxalines for Anticancer Evaluation
1121
Compound (10) underwent cyclocondensation with thioglycolic acid
in dry benzene19 to obtain 2-(4-methoxy-phenyl)-3-(3-naphthalen-
2-yl-quinoxalin-2-ylamino)thiazolidin-4-one (11a) and 3-(3-naph-
thalen-2-yl-quinoxalin-2-ylamino)-2-thiophen-2-yl-thiazoli-din-4-one
(11b). The IR spectra of compound 10 displayed absorption bands
near 3220 cm−1(NH) and 1615 cm−1 (C N), Spectra of 11a,b dis-
played absorption bands near 3447 cm−1(NH), 1613 cm−1 (C N) and
1
1720 cm−1(C O). The H NMR spectrum (DMSO-d6, δ) of 10a showed
signals at 3.70 (s, 3H, OCH3), 7.60-9.75 (m, 15H, Ar H + N=CH),
and 10.30 (s, 1H, NH, exchangeable with D2O). The1H NMR spectrum
(DMSO-d6, δ) of 11a, as an example, showed signals at δ 3.25 ppm (d,
2H, thiazolidine-H), 3.40 (s, 1H, CH-N), 3.75 (s, 3H, OCH3), 7.60–9.70
(m, 15H, Ar H), and 10.25 (s, 1H, NH, exchangeable with D2O).
On the other hand, the reaction of compound 5 with different amines,
namely morpholine, phenylhydrazine, and/or p-toluidine, afforded the
corresponding 2-morpholin-4-yl-3-naphthalen-2-yl-quinoxaline (12a),
N-(3-naphthalen-2-yl-quinoxalin-2-yl)-Nꢀ-phenyl-hydrazine
(12b),
and/or (3-naphthalen-2-yl-quinoxalin-2-yl)-p-tolylamine (12c) in high
yields. The elemental and spectroscopic data of compounds 12a–c are
consistent with the assigned structures (Scheme 1).
In conclusion, quinoxaline derivatives were synthesized for their an-
ticancer activity. Some of the new synthesized derivatives, 9 and 10b,
exhibited activities against liver carcinoma.
ANTICANCER EVALUATION
Five selected new compounds, 5, 8b, 9, 10b, and 11b, were tested for
cytotoxic activity against the HEPG2 (liver carcinoma cell line) and
H460 (lung carcinoma cell line).
MATERIALS AND METHODS
r
Tumor: human tumor cell
HEPG2 (liver carcinoma cell line)
H460 (lung carcinoma cell line)
All tested new compounds were dissolved in DMSO in different con-
centrations (1, 2.5, 5, and 10 µg/mL).
Preliminary experiments were made using the human tumor cell
r
r
r
r
line to identify the cytotoxicity of the selected compounds according
to Skehan and Storeng.20

1122
E. R. Kotb et al.
SCHEME 1

Quinoxalines for Anticancer Evaluation
1123
Measurement of Potential Cytotoxicity by Sulforhodamine B:
(SRB) Assay
Cells were plated in 96 multiwell plates (104 cells/well) for 24 h before
treatment with the compounds to allow attachment of cells to the
walls of the plate.
Different concentrations of the compounds (1, 2.5, 5, and 10 µg/mL)
were added to the cell monolayer.
r
r
r
Triplicate wells were prepared for each individual dose.
Monolayer cells were incubated with the compounds for 48 h at 37◦C
r
and in an atmosphere of 5% CO2.
After 48 h, cells were fixed, washed, and stained with Sul-
forhoolamine B (SRB) stain.
Excess stain was washed with acetic acid, and the attached stain was
recovered with tris ethyl enediamine tetraacetate (EDTA) buffer.
Color intensity was measured in an enzyme linked immuno sorbent
assay (ELISA) Reader.
The relation between surviving fraction and drug concentrations was
r
r
r
r
plotted to obtain the survival curve of each tumor cell line of the
specified compound.20
RESULTS
The tested compounds 9 and 10b showed cytotoxic activities against the
HEPG2 at the chosen drug concentrations 9.80 µg/ml and 9.97µg/ml,
respectively (chart I). However, the other compounds had no cytotoxic
activity against the HEPG2.
On the other hand, all tested compounds exhibited no cytotoxic ac-
tivity against the H460 at the chosen drug concentrations (chart II).
EXPERIMENTAL
All melting points are uncorrected and were measured using an Elec-
trothermal IA 9100 apparatus. Analytical data were performed by a
Vario El Mentar apparatus, organic microanalysis section, at the Na-
tional Research Centre, Cairo, Egypt. Their results were found to be in
agreement with the calculated values ( 0.5). The IR spectra (KBr) were
recorded on a Perkin-Elmer 1650 spectrophotometer. 1H NMR spectra
were determined on a Jeol 300 MHz in DMSO-d6, and chemical shifts
were expressed in δ value relative to TMS as the internal reference.
Mass spectra were run at 70 eV on EI + Q1 MSLMR UPLR.
Naphthalen-2-yl-oxo-Acetic Acid Methyl Ester (3)
To a solution of 2-bromoacetylnaphthalene (2, 12.5 gm, 50 mmol) in
absolute methanol was added SeO2 (5.5 g, 50 mmol). The solution was

1124
E. R. Kotb et al.
Chart I

Quinoxalines for Anticancer Evaluation
1125
Chart II

1126
E. R. Kotb et al.
refluxed with stirring for 48 h. Se was removed by filtration, and the
filtrate was evaporated leaving the oily glyoxylate 3 in a 90% yield; IR
spectrum (KBr, cm−1): 1740 (CO), 1683 (CO). MS, m/z (%): 214 (M+,
4.45), 155 (100).
3-Naphthalen-2-yl-1H-quinoxalin-2-one (4)
To a solution of OPDA (1.11 g, 10 mmol) in ethanol (20 mL) was added
compound 3 (2.11 g, 10 mmol), and the reaction mixture was refluxed
on a steam bath for 1 h. The formed precipitate was filtered off and
recrystallized from methanol to give compound 4 in an 80% yield; m.p.
230◦C. IR spectrum (KBr, cm−1): 3447 (NH), 1662 (CO), 1598 (C N).
MS, m/z (%): 272 (M+, 100). Analysis for C18H12N2O (272.31): required
C, 79.40; H, 4.44; N, 10.29; found C, 79.20; H, 4.32; N, 10.00.
2-Chloro-3-naphthalen-2-yl-quinoxaline (5)
A mixture of compound 4 (1.4 g, 5 mmol) in phosphorous oxychloride
(4 mL) was heated in a sand bath over 90–130◦C for 1 h. The solution
was cooled, cautiously poured onto ice water, and then was made slightly
basic with 30% NaOH solution. If salts separated at this point, they
were filtered off, and the desired compound was extracted with chlo-
roform. The dried magnesium sulfate extracts were concentrated, and
the brown residues were filtered off and recrystallized from methanol
to give the desired compound 5 in a 70% yield; m.p. 155◦C. IR spectrum
(KBr, cm−1): 1598 (C N), 1077 (C-Cl, aryl). MS, m/z (%):292 (M+, Cl37,
31.3), 290 (M+, Cl35, 100). Analysis for C18H11ClN2 (290.75): required
C, 74.35; H, 3.81; N, 9.63; found C, 74.05; H, 3.52; N, 9.41.
3-(Naphthalen-2-yl-quinoxalin-2-yl)hydrazine (6)
To a solution of compound5 (1.5 g, 5 mmol) in absolute ethanol (50 mL)
was added hydrazine hydrate (98%) in about a five-fold excess (1.3 g,
25 mmol), and the reaction mixture was refluxed for 3 h. Upon cooling, a
yellow precipitate formed, which was filtered off and recrystallized from
acetic acid to give compound 6 in a 75% yield; m.p. 198◦C. IR spectrum
1
(KBr, cm−1): 3420, 3290 (NH2, NH), 3096 (CH, Ar), 1598 (C N); H
NMR spectrum (DMSO-d6, δ): 4.9 (s, 2 H, NH2, D2O exchangeable),
6.9–8.2 (m, 11 H, Ar H), 9.8 (s, 1 H, NH, D2O exchangeable); MS, m/z
(%): 269 (M+ NH3, 100). Analysis for C18H14N4 (286.34): required C,
75.50; H, 4.93; N, 19.57; found C, 75.22; H, 4.69; N, 19.33.

Quinoxalines for Anticancer Evaluation
1127
2-(Aminophenylthioxohydrazidyl)-3-(2 ꢀ-naphthyl)quinoxaline
(7)
A mixture of 6 (2.8 g, 10 mmol), phenyl isothiocyanate (1.7 g, 13 mmol),
and triethylamine (3 drops) in dry benzene (50 mL) was refluxed for 6 h.
The solid that separated upon concentration and cooling was filtered off
and recrystallized from dioxane to give compound 7 in an 80% yield; m.p.
280◦C. IR spectrum (KBr, cm−1): 3398, 3290, 3057 (3 NH), 1260 (C S).
MS, m/z (%): 328 (M+ C6H7N, 100), 135 (50). Analysis for C25H19N5S
(421.53): required C, 71.24; H, 4.54; N, 16.61; S, 7.61; found C, 71.00;
H, 4.41; N, 16.46; S, 7.32.
Synthesis of 8a and 8b: General Procedure
A solution of compound 6 (2.8 g, 10 mmol) in formic acid or acetic acid
(25 mL) was allowed to stand at 25◦C for 24 h and then was refluxed
for 4 h. The reaction mixture was cooled and poured onto crushed ice.
The separated solids were filtered off, washed with cold water, and re-
crystallized from dioxane to give compounds 8a and 8b, respectively.
4-Naphthalen-2-yl-[1,2,4]triazolo[4,3-a]quinoxaline (8a)
Yield 70%; m.p. 230◦C. IR spectrum (KBr, cm−1): 3054 (CH, Ar), 1537
(C N); 1H NMR spectrum (DMSO-d6, δ): 7.5–9.5 (m, 12 H, Ar H); MS,
m/z (%): 296 (M+, 45), 269 (100). Analysis for C19H12N4 (296.33): re-
quired C, 77.01; H, 4.07; N, 18.90; found C, 77.00; H, 4.01; N, 18.62.
1-Methyl-4-naphthalen-2-yl-[1,2,4]triazolo[4,3-a]quinoxaline
(8b)
Yield 70%; m.p. 250◦C. IR spectrum (KBr, cm−1): 3049 (CH, Ar), 1599
(C N); 1H NMR spectrum (DMSO-d6, δ): 3.0 (s, 3H, CH3), 7.5–9.3 (m, 11
H, Ar H); MS, m/z (%): 310 (M+, 50), 269 (100). Analysis for C20H14N4
(310.36): required C, 77.40; H, 4.54; N, 18.05; found C, 77.23; H, 4.32;
N, 18.00.
4-Naphthalen-2-yl- tetrazolo[4,5-a]quinoxaline (9)
A solution of compound 6 (2.8 g, 10 mmol) in cold concentrated hy-
drochloric acid (30%, 5 mL) was treated gradually with a concentrated
solution of sodium nitrite (1 g in 15 mL of water) at 0–5◦C with stirring.
The reaction mixture was set aside at r.t. for 1 h. The precipitated prod-
uct was filtered, washed with cold water and recrystallized from dioxane

1128
E. R. Kotb et al.
to give compound 9 in 72% yield; m.p. 220◦C. IR spectrum (KBr, cm−1):
3056 (CH, Ar), 1533 (C N); MS, m/z (%): 297 (M+, 11), 269 (100). Anal-
ysis for C18H11N5 (297.32): required C, 72.71; H, 3.72; N, 23.55; found
C, 72.41; H, 3.42; N, 23.22.
Synthesis of 10a and 10b: General Procedure
A mixture of 6 (2.8 g, 10 mmol); the appropriate aldehyde, namelyp-
methoxy-benzaldehyde and/or thiophene-2-carboxaldehyde; and acetic
acid (3 drops) in absolute ethanol (25 mL) was refluxed for 10 h. The
solvent was evaporated, and the formed precipitate was filtered off and
recrystallized from the proper solvent to give compounds 10a and 10b.
N-(4-Methoxy-benzylidene)-N ꢀ-(3-naphthalen-2-yl-quinoxalin-
2-yl)hydrazine (10a)
From: ethanol, yield 75%; m.p. 220◦C. IR spectrum (KBr, cm−1): 3220
1
(NH), 3056 (CH, Ar), 1615 (C N); H NMR spectrum (DMSO-d6, δ):
3.7 (s, 3H, OCH3), 7.60–9.75 (m, 15 H, Ar H + N=CH), 10.3 (s, 1H,
NH, D2O exchangeable); MS, m/z (%): 296 (M+ C7H8O, 25), 272 (100).
Analysis for C26H20N4O (404.48): required C, 77.20; H, 4.98; N, 13.85;
found C, 77.00; H, 4.63; N, 13.51.
N-(3-Naphthalen-2-yl-quinoxalin-2-yl)-N ꢀ-thiophen-2-
ylmethylenehydrazine (10b)
From: dioxane, yield 65%; m.p. 240◦C. IR spectrum (KBr, cm−1): 3220
1
(NH), 3052 (CH, Ar), 1617 (C N); H NMR spectrum (DMSO-d6, δ):
7.30–10.35 (m, 14 H, Ar H + N=CH), 12.75 (s, 1H, NH, D2O ex-
changeable); MS, m/z (%): 296 (M+ C4H4S, 80), 269 (100). Analysis
for C23H16N4S (380.48): required C, 72.61; H, 4.23; N, 14.72; S, 8.42;
found C, 72.33; H, 4.00; N, 14.42; S, 8.00.
Synthesis of 11a and 11b: General Procedure
To a solution of compounds 10a,b (5 mmol) in dry benzene (30 mL)
was added thioglycolic acid (0.5 mL, 5 mmol) in dry benzene (5 mL),
and the reaction mixture was refluxed for 10 h. The residue obtained
after evaporation was recrystallized from the proper solvent to give the
desired compounds 11a and 11b.

Quinoxalines for Anticancer Evaluation
1129
2-(4-Methoxy-phenyl)-3-(3-naphthalen-2-yl-quinoxalin-2-
ylamino)thiazolidin-4-one (11a)
From: ethanol, yield 73%; m.p. 225◦C. IR spectrum (KBr, cm−1): 3447
(NH), 1720 (CO), 1613 (C N); 1H NMR spectrum (DMSO-d6, δ): 3.25 (d,
2H, thiazolidine protons), 3.40 (s, 1H, CH-N), 3.75 (s, 3H, OCH3), 7.60–
9.70 (m, 15 H, Ar H), 10.25 (s, 1H, NH, D2O exchangeable); MS, m/z
(%): 269 (M+ C10H11NO2S, 100). Analysis for C28H22N4O2S (478.58):
required C, 70.27; H, 4.63; N, 11.70; S, 6.70; found C, 70.00; H, 4.31; N,
11.50; S, 6.49.
3-(3-Naphthalen-2-yl-quinoxalin-2-ylamino)-2-thiophen-2-yl-
thiazolidin-4-one (11b)
From: dioxane, yield 70%; m.p. 245◦C. IR spectrum (KBr, cm−1): 3446
1
(NH), 1720 (CO), 1613 (C N); H NMR spectrum (DMSO-d6, δ): 3.30
(d, 2H, thiazolidine protons), 3.35(s, 1H, CH-N), 7.65–9.70 (m, 14
H, Ar H), 10.25 (s, 1H, NH, D2O exchangeable); MS, m/z (%): 269
(M+ C7H7NOS2, 100). Analysis for C25H18N4OS2 (454.58): required
C, 66.05; H, 3.99; N, 12.32; S, 14.10; found C, 66.00; H, 3.70; N, 11.99;
S, 13.99.
Synthesis of 12a–c: General Procedure
Compound5 (1.5 g, 5 mmol) was fused with different aromatic amines,
namely morpholine, phenyl hydrazine, and p-toluidine, at 150◦C for 3
h. The obtained solid was recrystallized from the proper solvent to give
desired compounds 12a–c.
2-Morpholin-4-yl-3-naphthalen-2-yl-quinoxaline (12a)
From: benzene/ethanol, yield 75%; m.p. 130◦C. IR spectrum (KBr, cm−1):
3056 (CH, aromatic), 1598 (C N); 1H NMR spectrum (DMSO-d6, δ): 3.30
(m, 4H, N(CH2)2), 3.60 (m, 4H, O(CH2)2), 7.30–9.10 (m, 11 H, Ar H);
MS, m/z (%): 341 (M+, 100). Analysis for C22H19N3O (341.41): required
C, 77.40; H, 5.60; N, 12.30; found C, 77.39; H, 5.42; N, 12.18.
N-(3-Naphthalen-2-yl-quinoxalin-2-yl)-N ꢀ-phenylhydrazine
(12b)
From: dioxane, yield 72%; m.p. 220◦C. IR spectrum (KBr, cm−1): 3422
1
(2NH), 1590 (C N); H NMR spectrum (DMSO-d6, δ): 7.10–9.30 (m,
16 H, Ar H), 8.9 (s, 1H, NH, D2O exchangeable), 9.7 (s, 1H, NH, D2O

1130
E. R. Kotb et al.
exchangeable); MS, m/z (%): 272 (M++H2 C6H6N, 100). Analysis for
C24H18N4 (362.43): required C, 79.52; H, 5.00; N, 15.45; found C, 79.32;
H, 4.88; N, 15.44.
(3-Naphthalen-2-yl-quinoxalin-2-yl)-p-tolylamine (12c)
From: benzene/methanol, yield 70%; m.p. 210◦C. IR spectrum (KBr,
cm−1): 3398(NH), 1590 (C N); 1H NMR spectrum (DMSO-d6, δ): 2.3 (s,
3H, CH3), 7. 0–8.5 (m, 15H, Ar H), 9.0 (s, 1H, NH, D2O exchangeable);
MS, m/z (%): 269 (M+ C7H8, 100). Analysis for C25H19N3 (361.45): re-
quired C, 83.08; H, 5.30; N, 11.62; found C, 83.06; H, 5.00; N, 11.33.
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