Synthesis and biological evaluation of new 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agents

Article abstract of DOI:10.1515/hc-2014-0081

Quinoxaline derivatives 4-11 were synthesized and evaluated for their in vitro growth inhibitory activities against liver carcinoma cell line (HEPG₂) using the sulforhodiamine B assay. The synthesis was achieved by reaction of 2,3-dichloroquino

Full text of DOI:10.1515/hc-2014-0081

Heterocycl. Commun. 2015; 21(1): 25–35
Mohamed G. Thabit*, Serry A.A. El Bialy and Magda N.A. Nasr
Synthesis and biological evaluation of new
3-(4-substituted phenyl)aminoquinoxaline
derivatives as anticancer agents
Abstract: Quinoxaline derivatives 4–11 were synthesized reactive radicals that produce cleavage of the double
and evaluated for their in vitro growth inhibitory activi- helix and cause a significant change in DNA conforma-
ties against liver carcinoma cell line (HEPG2) using the tion [11]. Intercalators bind to DNA by non-covalent inter-
sulforhodiamine B assay. The synthesis was achieved actions. The recognized forces that maintain the stability
by reaction of 2,3-dichloroquinoxalines 2a,b with 4-ami- of the DNA-intercalator complex are hydrogen bonding,
noacetophenone to give the corresponding compounds van der Waals interaction, polarization, and hydropho-
3a,b. Claisen-Schmidt condensation reaction of 3a,b with bic forces [11–14]. The compounds that bear heteroatoms
furfuraldehyde gave enones 4a,b, which were transformed such as nitrogen can increase the strength of the complex
into pyridines 6a,b, 8a,b, isoxazolines 9a,b, pyrazolines by forming hydrogen bonds with DNA [15, 16]. It has been
10a–d, and pyrimidines 11a,b via several synthetic routes. reported that the efficacy of the stacking interaction can
Virtual screening was carried out by molecular modeling be enhanced by the presence of fused polyaromatic nitro-
evaluation of the designed compounds. Biological evalu- gen heterocyclic chromophore substituted with a side
ation of the prepared compounds showed that most of the chain that penetrates into one of the two DNA grooves
synthesized compounds exhibit more than 50% growth [17].
inhibitory.
Many quinoxaline derivatives are antiviral [18], anti-
microbial [19], antidepressant [20], tuberculostatic [21],
Keywords: anticancer; isoxazolines; pyrazolines; pyri- anticonvulsant [22], and DNA cleaving agents [23]. There
dines; pyrimidines; quinoxaline.
are many quinoxaline derivatives with anticancer activ-
ity. For example, 2-[4-(7-chloroquinoxalin-2-yl)oxyphe-
noxy]propanoic acid (XK469) [24] is a topoisomerase II
DOI 10.1515/hc-2014-0081
Received May 8, 2014; accepted September 23, 2014; previously pub-
lished online January 23, 2015
inhibitor,
4-[3-(4-ethoxycarbonylphenyl)thioureido]-N-
(quinoxalin-2-yl)benzenesulfonamide (CTBS) shows very
potent anticancer activity against a human liver cancer
cell line (HEPG2) [25], and N-(quinoxalin-2-yl)acetamide
(Q22) [26] is a potent kinase (CDK) inhibitor (Figure 1).
These agents are structurally related to 5-(1,3-benzo-
dioxol-5-yl)-3-phenyl-4,5-dihydro-1H-pyrazole (I), which
shows anticancer activity against colon cancer cell line
(HCT116) [27], to 2-[4-(3-hydroxyphenyl)isoxazol-5-yl]-
4,5-dimethoxyphenol (II), which has antimetastatic
activity [28], and to 2,2′:6′,2″-terpyridine (III), which has
significant cytotoxicity against several human cancer cell
lines [29] (Figure 2).
Introduction
Cancer is a major health problem in developing and
undeveloped countries [1–9]. Accordingly, many diverse
strategies have been employed to synthesize new agents
or improve existing drugs [10]. Clinically important chem-
otherapeutics can be classified into three major groups.
Alkylating agents react covalently with DNA bases. DNA
strand breakers represent the second group. They are
In this work, the output compound of designed
feature (Figure 3) is the lead structure for synthesis of new
3-(4-substituted phenyl)aminoquinoxaline derivatives
with anticancer activity.
Accordingly, we synthesized a new series of quinoxa-
line hybrids with different aromatic and heterocyclic moi-
eties including pyridines, isoxazolines, pyrazolines, and
pyrimidines 5–11 (Schemes 1–3).
*Corresponding author: Mohamed G. Thabit, Faculty of Pharmacy,
Department of Pharmaceutical Organic Chemistry, Mansoura
University, Mansoura 35516, Egypt,
e-mail: medomedo1_medomedo1@yahoo.com
Serry A.A. El Bialy and Magda N.A. Nasr: Faculty of Pharmacy,
Department of Pharmaceutical Organic Chemistry, Mansoura
University, Mansoura 35516, Egypt
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ꢁꢁꢁꢂ
26ꢀ
ꢀM.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agents
H
O
S
O
H
Cl
N
N
O
N
N
N
N
N
N
Me
Me
CO2Et
S
O
O
COOH
N
N
H
H
XK469
CTBS
Q22
Figure 1ꢀQuinoxaline anticancer agents.
N
cyanoacetate in the presence of ammonium acetate gave
products 8a,b (Scheme 2). The structures 6a,d, 7a,b, and
8a,b were confirmed by elemental analyses and spectral
data.
NH2
S
O
HO
N
N
O
OH
O
NH2
Reaction of compounds 4a,b with hydroxylamine in
boiling ethanolic solution of potassium hydroxide gave
the corresponding oxazole derivatives 9a,b. Meanwhile,
enones 4a,b were condensed with hydrazine hydrate and
phenyl hydrazine to give the corresponding pyrazolines
10a–d. Also, dihydropyrimidines 11a,b were synthesized
by the reaction of 4a,b with urea in ethanolic HCl solution
(Scheme 3).
MeO
OMe
II
I
N
N
N
III
Figure 2ꢀPyrazole, isoxazole, and pyridine anticancer agents.
Molecular modeling
Results and discussion
It has been suggested that compound Q22 is an antican-
cer agent as CDK inhibitor using docking procedure with
the enzyme 1KE8 [26]. The enzyme 1KE8 (Figure 4) was
Chemistry
This study was initiated by the synthesis of downloaded from the Protein Data Bank (PDB) with the
2-(4-acetylphenylamino)-3-quinoxaline derivatives (3a,b)
through the reaction of 2,3-dichloroquioxaline deriva-
tives with an equimolar amount of 4-aminoacetophenone
according to the literature method [30].
H
N
N
O
R
N
H
O
The synthesis of enones 4a,b was achieved by con-
densation of the methyl ketones 3a,b with furfuraldehyde
in the presence of sodium hydroxide [31]. Meanwhile,
the hydrazones 5a,b were synthesized by the reaction
of methyl ketones 3a,b with salicylic acid hydrazide
(Scheme 1) [32].
Enones 4a,b are an important synthon for the con-
struction of variety of heterocycles [33–35]. In this work,
the Michael addition reaction of compounds 4a,b with
malononitrile in the presence of sodium alkoxide afforded
cyano alkoxypyridines 6a–d. A similar cyclocondensation
of 4a,b in the presence of ammonium acetate gave amino-
pyridines 7a,b. The treatment of enones 4a,b with ethyl
O
4a,b
B
C
H
N
N
N
Cl
Cl
N
A
Me
R
R
Cl
N
O
3a,b
a: R = H
b: R = Me
H
N
N
N
O
OH
N
H
N
Cl
N
R
N
N
H
Me
Spacer
noncyclic or
heterocycle
Lipophilic terminal
phenyl or
heterocyclic ring
5a,b
R
Scheme 1ꢀThe synthesis of 3a,b, 4a,b, and 5a,b: (A) 4-aminoace-
tophenone, EtOH; (B) ethanolic NaOH, furfuraldehyde; (C) salicylic
acid hydrazide, AcOH.
R = H, Me
Figure 3ꢀDesigned structural features of biological activity.
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M.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agentsꢀ
ꢀ27
H
N
N
A
O
R
R
N
H
O
N
N
CN
O
6a-d
R1
1
H
N
H
N
6a
: R = H; R = OMe
N
N
6b: R = Me ; R1 = OMe
6c : R = H; R1 = OEt
O
B
C
1
R
O
N
H
O
N
H
6d
7a 8a
7b 8b
: R = Me ; R = OEt
O
,
: R = H
7a,b
CN
O
4a,b
,
: R = Me
NH2
H
N
N
4a: R = H
4b: R = Me
R
N
H
O
HN
CN
8a,b
O
Scheme 2ꢀSynthesis of 6a–d, 7a,b, and 8a,b: (A) Na metal, CH2(CN)2, EtOH, or MeOH; (B) NH4OAc, CH2(CN)2, EtOH; (C) NH4OAc, NCCH2CO2Et,
EtOH.
H
N
N
A
O
O
R
N
H
O
N
O
N
9a,b
9a: R = H
9b: R = Me
10a: R = H; R1 = H
10b: R = Me; R1 = H
10c: R = H; R1 = Ph
10d: R = Me; R1 = Ph
11a: R = H
H
N
H
N
N
N
O
B
C
O
N
H
R
R
N
H
O
O
N
N
4a,b
10a-d
R1
11a: R = Me
H
N
N
O
4a: R = H
4b: R = Me
N
H
O
NH
11a,b
O
Scheme 3ꢀThe synthesis of 9a–11b: (A) NH2OH, NaOH; (B) NH2NH2 or PhNHNH2, EtOH; (C) urea, concentrated HCl, EtOH.
active ligand 4-{[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)
methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamide
[36] (Figure 5).
Docking studies have suggested that the most impor-
tant amino acids residues observed for the complex of
this active ligand with 1KE8 are asparagine 132, lysine
129, aspartate 127, glutaminate 12, and threonine 14. This
complex is shown in Figure 5. Our docking studies showed
that derivatives 4–11 can be docked in the same binding
site.
Figure 4ꢀStructure of the enzyme 1KE8.
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ꢀM.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agents
N
O
S
N
S
N
H
H
O
HN
O
Figure 5ꢀComplex of 1KE8 with the benzenesulfonamide active ligand.
O
H
N
N
O
Me
N
H
O
Figure 6ꢀComplex of 4b with the 1KE8 binding side.
O
HN
O
N
N
HN
NH
O
Figure 7ꢀDocking of 11a in 1KE8 binding side.
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M.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agentsꢀ
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Compound Q22 forms one hydrogen bond with ligand-enzyme binding energy is decreased to -130.79
leucine 83 amino acid in the enzyme 1KE8 active side. kJ/mol from -83.16 kJ/mol from the complex of Q22.
The enone 4b, which is a structural analogue of Q22,
Similar complexes were generated for other ligands
also forms one hydrogen bond with the same amino 6–9 (not shown). For example, compound 11a forms six
acid leucine 83, as shown in Figure 6. Importantly, the hydrogen bonds with the key amino acid residues in the
H
N
O
N
N
N
O
H
O
Figure 8ꢀDocking of 9b in 1KE8 binding side.
NH2
H
N
O
N
N
CN
N
H
O
Figure 9ꢀDocking of 7b in 1KE8 binding side.
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30ꢀ ꢀM.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agents
Table 1ꢀMolecular modeling results of the interaction of compounds 4–11 with amino acids of the enzyme 1KE8 and biological screening
results of these compounds against the HEPG2 human tumor cell line.
Compoundꢀ
no.ꢀ
Virtual screeningꢀ
Amino acids
Biological screening
% of growth inhibition
HB no.ꢀ
E of HBꢀ
E of interaction ligand-proteinꢀ
11aꢃ
6ꢃ
-7.88ꢃ
-145.07ꢃ
Asparagine 132ꢃ
78
ꢃ
ꢃ
ꢃ
ꢃ
Lysine 129
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Aspartate 14
Aspartate 86
Leucine 83
Lysine 129
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
9bꢃ
6ꢃ
-9.39ꢃ
-136.32ꢃ
77
77
ꢃ
ꢃ
ꢃ
ꢃ
Threonine 14
Isoleucine 10
Glycine 11
7bꢃ
5ꢃ
-6.05ꢃ
-139.42ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Valine 163
ꢃ
ꢃ
ꢃ
ꢃ
Threonine 14
ꢃ
ꢃ
ꢃ
ꢃ
Threonine 165 ꢃ
6dꢃ
4ꢃ
-9.11ꢃ
-163.02ꢃ
Lysine 129
Leucine 83
ꢃ
ꢃ
77
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Asparagine 132ꢃ
7aꢃ
ꢃ
ꢃ
4ꢃ
-7.79ꢃ
-152.22ꢃ
Aspartate 145
Leucine 83
ꢃ
ꢃ
76
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Asparagine 132ꢃ
ꢃ
ꢃ
ꢃ
Threonine 14
Histidine 84
Aspartate 86
Leucine 83
ꢃ
ꢃ
ꢃ
ꢃ
10aꢃ
4ꢃ
ꢃ
ꢃ
ꢃ
2ꢃ
ꢃ
3ꢃ
ꢃ
2ꢃ
ꢃ
2ꢃ
ꢃ
2ꢃ
1ꢃ
1ꢃ
1ꢃ
1ꢃ
1ꢃ
3ꢃ
ꢃ
1ꢃ
1ꢃ
1ꢃ
1ꢃ
-6.25ꢃ
-135.39ꢃ
76
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
Glutaminate 81 ꢃ
Asparagine 132ꢃ
10dꢃ
ꢃ
-3.51ꢃ
ꢃ
-145.62ꢃ
ꢃ
76
75
74
71
Leucine 83
ꢃ
ꢃ
11bꢃ
ꢃ
6bꢃ
ꢃ
10cꢃ
ꢃ
9aꢃ
5aꢃ
6cꢃ
10bꢃ
8bꢃ
4bꢃ
6aꢃ
ꢃ
5bꢃ
8aꢃ
4aꢃ
Q22ꢃ
-5.15ꢃ
ꢃ
-3.51ꢃ
ꢃ
-3.54ꢃ
ꢃ
-2.04ꢃ
-2.5ꢃ
-2.47ꢃ
-1.18ꢃ
-1.59ꢃ
-1.49ꢃ
-0.76ꢃ
ꢃ
-1.66ꢃ
-2.22ꢃ
-0.88ꢃ
-1.27ꢃ
-135.51ꢃ
ꢃ
-144.19ꢃ
ꢃ
-144.13ꢃ
ꢃ
-128.13ꢃ
-138.29ꢃ
-148.95ꢃ
-130.39ꢃ
-125.24ꢃ
-130.79ꢃ
-143.96ꢃ
ꢃ
-128.54ꢃ
-146.46ꢃ
-116.64ꢃ
-83.16ꢃ
Threonine 14
Threonine 165 ꢃ
Lysine 88
Histidine 84
Lysine 89
Leucine 83
Aspartate 145
Aspartate 145
Aspartate 86
Leucine 83
Glutaminate 12 ꢃ
Leucine 83
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
71
70
70
70
69.4
65
59
ꢃ
ꢃ
ꢃ
Threonine 14
Aspartate 145
Glutaminate 12 ꢃ
52
51
43
Histidine 84
Threonine 14
Leucine 83
ꢃ
ꢃ
ꢃ
HB, hydrogen bonds; E, energy (kJ/mol).
enzyme active side. One hydrogen bond is between the acid. The fourth interaction is formed between the
3-nitrogen atom of the dihydropyrimidine ring and the anilino nitrogen atom and the oxygen atom of aspartate
oxygen atom of the leucine 83 amino acid. The second 145 amino acid. The last two non-bonding interactions
bond connects the oxygen atom (2-oxo in the dihydro- are formed by the bifurcated hydrogen bonds between
pyrimidine ring) and the nitrogen atom of the leucine 83 the oxoquinoxaline oxygen atom and two nitrogen
amino acid. The third bond is between the furan oxygen atoms of asparagine 132 lysine 129 amino acids. In com-
atom and the nitrogen atom of the aspartate 86 amino parison to the complex of 4b, the ligand-enzyme binding
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acetone to give 3b: yield (2.43 g, 78%); mp 228–230°C; IR: 3311 (NH),
energy is decreased to -145.07 kJ/mol for 11a. The greater
binding affinity of 11a to the 1KE8-binding side (Figure
7) is nicely paralleled by the greater biological activity
of 11a in comparison to that of 4b. Thus, cyclization of
enone moiety in compound 4a to the dihydropyrimi-
dine ring of 11a results in an increased activity. Similar
results were obtained for the remaining compounds
(Figures 8, 9 and Table 1).
1
3026 (CH), 1678 cm-1 (CO); HNMR: δ 2.30 (s, 3H), 2.60 (s, 3H), 7.39–
8.01 (m, 7H), 9.00 (s, 1H); 13C NMR: δ 21.5, 28.2, 113.1, 127.5, 130.7, 132.7,
134.4, 137.2, 138.3, 139.9, 140.5, 142.1, 147.1, 165.1, 181.1. Anal. Calcd for
C17H14ClN3O (311.77): C, 65.43; H, 4.49; N, 13.47. Found: C, 65.47; H, 4.46;
N, 13.5.
General method for the synthesis of 3-({4[3-(furan-2-
yl)-1-oxo-prop-2-en-1-yl]phenyl}amino)-7-substituted
quinoxalin-2(1H)-one derivatives 4a,b
Biological activity
A mixture of 3a or 3b (0.01 mol) and furfuraldehyde (0.96 g, 0.01 mol)
in ethanolic sodium hydroxide solution (10%, 25 mL) was stirred at
room temperature for 10 h. The precipitated solid was collected by
filtration, dried, and crystallized from ethanol.
Many natural quinoxaline derivatives are antitumor antibiot-
ics [37–40]. All synthetic quinoxalines 4–11 were screened in
vitro, using single dose (500 μg/mL), against HEPG2 (human
liver carcinoma cell line), using the sulforhodamine-B (SRB)
assay [41] (Table 1). Based on the requirement set by NCI that
the growth percent of tumor cells (PG%) is 30% or less for
active agents lines, it may be concluded that most of these
compounds are active because their activities approach this
3-({4[3-(Furan-2-yl)-1-oxo-prop-2-en-1-yl]phenyl}amino)quinox-
alin-2(1H)-one (4a):ꢀYield (3 g, 84%); mp 160–162°C; IR: 3279 (NH),
3000 (CH), 1657 cm-1 (CO); 1H NMR: δ 6.70 (s, 1H), 7.10 (s, 1H), 7.39 (br
s, 3H), 7.62 (m, 4H), 7.94 (m, 3H), 8.13 (m, 3H); 13C NMR: δ 113.2, 114.9,
118.8, 121.6, 123.8, 123.9, 130.1, 130.9, 132.5, 137.9, 140.5, 143.5, 145.2,
149.3, 149.5, 154.8, 160.1, 166.2, 182.1; MS: m/z 357.59 (M+). Anal. Calcd
value. The exception is 4a, which shows a PG% of 43% in for C21H15N3O3 (357.36): C, 70.56; H, 4.23; N, 11.74. Found: C, 70.58; H,
HEPG2 cells at a concentration of 500 μg/mL.
4.46; N, 13.5.
3-({4[3-(Furan-2-yl)-1-oxo-prop-2-en-1-yl]phenyl}amino)-7-
methyl quinoxalin-2(1H)-one (4b):ꢀYield (3.12g, 84%); mp 164–
1
166°C; IR: 3383 (NH), 2900 (CH), 1648 cm-1 (CO); H NMR: δ 2.47 (s,
Conclusion
The results of molecular modeling and biological screen-
ing reveal that the structural modification of the lead
structure affects the activity in a predictable manner.
3H), 6.65 (s, 1H), 7.05 (s, 1H), 7.51–7.62 (m, 4H), 7.95–8.08 (m, 6H), 9.51
(s, 1H); 13C NMR: δ 22.1, 114.1, 115.1, 118.5, 122.4, 124.8, 128.4, 129.2,
131.2, 133.3, 138.7, 139.5, 142.1, 147.1, 148.1, 148.9, 153.1, 162.1, 165.1,
180.1. MS: m/z 371.42 (M+). Anal. Calcd for C22H17N3O3 (371.39): C, 71.08;
H, 4.57; N, 11.30. Found: C, 71.10; H, 4.59; N, 11.32.
General procedure for the synthesis of 1-({[4-(3-chloro-
6-substituted quinoxalin-2-yl)amino]phenyl}ethylidene)-
2-hydroxybenzohydrazide derivatives 5a,b
Experimental
Chemistry
A mixture of ketone 3a or 3b (0.001 mol) and salicylic acid hydrazide
(0.152 g, 0.001 mol) in acetic acid (5 mL) was heated under reflux for
10 h. Afer cooling, the resultant precipitate was collected by filtra-
tion, dried, and crystallized from glacial acetic acid.
Melting points were recorded using Fisher-Johns apparatus and are
uncorrected. Elemental analyses were performed at the Microanalyti-
cal Center, Cairo University, Egypt. IR spectra were recorded on Mat-
tason 500 FT-IR spectrometer in KBr pellets. The 1H NMR spectra (400
MHz) and 13C NMR spectra (100 MHz) were recorded in DMSO-d6 on
a Bruker 400 spectrometer at Georgia State University (Atlanta, GA,
USA). Mass spectra were obtained on a JOEL JMS-600H spectrometer
at Cairo University.
1-({[4-(3-Chloroquinoxalin-2-yl)amino]phenyl}ethylidene)-2-
hydroxy benzohydrazide (5a):ꢀYield (0.217 g, 50%); mp 172–174°C;
IR: 3481 (OH), 3324 (NH), 3160 (CH), 1680 cm-1 (CO); 1HNMR: δ 2.35 (s,
3H), 4.01 (s, 1H), 7.1–8.01 (m, 11H), 9.75 (s, 1H), 10.62 (s, 1H), 11.32 (s,
1H); 13C NMR: δ 20.1, 113.2, 118.1, 119.5, 122.9, 125.2, 129.1, 129.9, 130.1,
131.5, 134.7, 135.1, 135.9, 137.2, 138.1, 144.7, 145.1, 147.1, 159.1, 162.1, 165.5;
MS: m/z 434.00 (M+). Anal. Calcd for C23H18ClN5O2 (431.87): C, 63.90; H,
4.16; N, 16.21. Found: C, 63.92; H, 4.18; N, 16.24.
Synthesis of 1-{4-[3-chloroquinoxalin-2-yl)amino]
phenyl}ethan-1-one (3b)
1-({[4-(3-Chloro-6-methylquinoxalin-2-yl)amino]phenyl}
ethylidene)-2-hydroxybenzohydrazide (5b):ꢀYield (0.224 g,
50%); mp 178–180°C; IR: 3487 (OH), 3285 (NH), 3186 (CH), 1669 cm-
A mixture of 2,3-dichloro-6-methylquinoxaline (2b, 2.13 g, 0.01 mol)
and 4-aminoacetophenone (2.02 g, 0.015 mol) in absolute ethanol (10
mL) was heated under reflux for 6 h and then cooled. The resultant
precipitate was collected by filtration, dried, and crystallized from
1
1
(CO); HNMR: δ 2.41 (s, 3H), 2.65 (s, 3H), 3.92 (s, 1H), 7.1–8.01 (m,
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1
10H), 9.50 (s, 1H), 10.90 (s, 1H), 11.50 (s, 1H); 13C NMR: δ 21.1, 23.1, 160–162°C; IR: 3409 (NH), 2923 (CH), 2220 (CN), 1648 cm-1 (CO); H
112.1, 118.6, 118.9, 123.9, 126.7, 128.9, 129.1, 131.6, 132.6, 133.9, 134.4, NMR: δ 6.70 (s, 1H), 7.10 (s, 1H), 7.45 (m, 2H), 7.60 (m, 2H), 7.72 (m,
135.1, 136.3, 137.9, 144.9, 145.3, 147.9, 157.7, 162.8, 164.7; MS: m/z 448.00 2H), 7.95 (m, 2H), 8.00–8.25 (m, 5H), 9.65 (s, 1H); MS: m/z 420.00 (M+).
(M+). Anal. Calcd for C24H20ClN5O2 (445.90): C, 64.58; H, 4.48; N, 15.69. Anal. Calcd for C24H16N6O2 (420.42): C, 68.50; H, 3.80; N, 19.98. Found:
Found: C, 64.60; H, 4.50; N, 15.71.
C, 68.52; H, 3.82; N, 19.97.
2-Amino-4-(furan-2-yl)-6-{[4-(6-methyl-3-oxo-3,4-dihydroqui-
noxalin-2-yl) amino]pyridine-3-carbonitrile (7b):ꢀYield (0.312 g,
72%); mp 178–180°C; IR: 3374 (NH), 2915 (CH), 2203 (CN), 1589 cm-1
(CO); 1H NMR: δ 2.53 (s, 3H), 6.70 (s, 1H), 7.10 (s, 1H), 7.45 (m, 2H), 7.60
(m, 3H), 7.72 (m, 2H), 7.95 (m, 2H), 8.00–8.25 (m, 3H), 9.65 (s, 1H); MS:
m/z 434.53 (M+). Anal. Calcd for C25H18N6O2 (434.45): C, 69.05; H, 4.14;
N, 19.33. Found: C, 69.07; H, 4.12; N, 19.31.
General procedure for the synthesis of 2-alkoxy-4-(furan-
2-yl)-6-{[4-(3-oxo-6-substituted-3,4dihydroquinoxalin-2-yl)
amino]phenyl}-pyridine-3-carbonitrile derivatives 6a–d
A cooled freshly prepared solution of sodium alkoxide (0.001 mol)
[0.023 g sodium metal 0.001 mol in 50 mL absolute methanol for com-
pounds (6a,b) or absolute ethanol for compounds (6c,d)] was treated
with malononitrile (0.066 g, 0.001 mol) and then with compound 4a
or 4b (0.001 mol) at 60°C for 10 h. The precipitated solid was col-
lected by filtration, dried, and crystallized from ethanol.
General method for the synthesis of 4-(furan-2-yl)-2-oxo-
6-{4-[(3-oxo-6-substituted-3,4-dihydroquinoxalin-2-yl)
amino]phenyl}pyridine-3-carbonitrile derivatives 8a,b
4-(Furan-2-yl)-2-methoxy-6-{[2-oxo-(1,2dihydroquinoxalin-3-yl)
amino] phenyl}pyridine-3-carbonitrile (6a):ꢀYield (0.323 g, 72%);
mp 175–177°C; IR: 3384 (NH), 3278 (CH), 2216 (CN), 1648 cm-1 (CO);
1HNMR: δ 3.90 (s, 3H), 4.10 (s, 1H), 6.71–8.35 (m, 12H), 9.40 (s, 1H); MS:
m/z 435.00 (M+). Anal. Calcd for C25H17N5O3 (435.43): C, 68.89; H, 3.90;
N, 16.07. Found: C, 68.92; H, 3.88; N, 16.08.
A mixture of compound 4a or 4b (0.001 mol), ethyl cyanoacetate
(0.112 g, 0.001 mol), and ammonium acetate (0.616 g, 0.008 mol) in
absolute ethanol (25 mL) was heated under reflux for 8 h. The result-
ant solid was collected by filtration, dried, and crystallized from
ethanol.
4-(Furan-2-yl)-2-methoxy-6-{[4-(6-methyl-3-oxo-3,4dihydro-
quinoxalin-2-yl)amino]phenyl}pyridine-3-carbonitrile
(6b):ꢀYield (0.333 g, 72%); mp 185–187°C; IR: 3385 (NH), 2943 (CH),
4-(Furan-2-yl)-2-oxo-6-{4-[(2-oxo-1,2-dihydroquinoxalin-3-yl)
amino] phenyl}pyridine-3-carbonitrile (8a):ꢀYield (0.253 g,
60%); mp 180–182°C; IR: 3415 (NH), 2977 (CH), 2218 (CN), 1613 cm-1
(CO); 1H NMR: δ 6.70 (s, 1H), 7.10 (s, 1H), 7.45 (s, 1H), 7.60(m, 2H), 7.70
(m, 2H), 7.95 (s, 1H), 8.05 (m, 2H), 8.10 (m, 2H), 8.20 (m, 2H), 9.50 (s,
1H); MS: m/z 421.33 (M+). Anal. Calcd for C24H15N5O3 (421.41): C, 68.34;
H, 3.55; N, 16.61. Found: C, 68.32; H, 3.53; N, 16.63.
1
2216 (CN), 1614 cm-1 (CO); HNMR: δ 2.67 (s, 3H), 3.65 (s, 3H), 4.00 (s,
1H), 6.80–8.35 (m, 11H), 9.10 (s, 1H); MS: m/z 449.00 (M+). Anal. Calcd
for C26H19N5O3 (449.46): C, 69.41; H, 4.22; N, 15.57. Found: C, 69.43; H,
4.20; N, 15.60.
2-Ethoxy-4-(furan-2-yl)-6-{[4-(2-oxo-1,2-dihydroquinoxalin-3-yl)
amino] phenyl}pyridine-3-carbonitrile (6c):ꢀYield (0.313 g, 72%)
mp 195–197°C, IR: 3421 (NH), 2215 (CN), 1656 cm-1 (CO); 1HNMR: δ 1.50
(s, 3H), 4.50 (br s, 2H), 7.45 (m, 4H), 7.70 (m, 4H), 8.10 (m, 6H); MS:
m/z 449.00 (M+). Anal. Calcd for C26H19N5O3 (449.46): C, 69.41; H, 4.22;
N, 15.57. Found: C, 69.39; H, 4.21; N, 15.59.
4-(Furan-2-yl)-2-oxo-6-{4-[(6-methyl-3-oxo-3,4-dihydroquinoxa-
lin-2-yl) amino]pyridine-3-carbonitrile (8b):ꢀYield (0.261 g, 60%);
mp 188–190°C; IR: 3287 (NH), 3058 (CH), 2217 (CN), 1668 cm-1 (CO);
1HNMR: δ 2.55 (br s, 3H), 7.25 (s, 1H), 7.45 (s, 1H), 7.58 (s, 1H), 7.95(m,
4H), 8.15(m, 5H), 9.90 (br s, 2H); MS: m/z 435.33 (M+). Anal. Calcd for
C25H17N5O3 (435.43): C, 68.89; H, 3.90; N, 16.07. Found: C, 68.91; H, 3.88;
N, 16.09.
2-Ethoxy-4-(furan-2-yl)-6-{[4-(6-methyl-3-oxo-3,4-dihydroqui-
noxalin-2-yl)amino]phenyl} (6d):ꢀYield (0.323 g, 72%) mp 200–
202°C, IR: 3407 (NH), 2922 (CH), 2216 (CN), 1588 cm-1 (CO); 1HNMR: δ
1.50 (s, 3H), 2.50 (s, 3H), 4.50 (br s, 2H), 7.45 (m, 4H), 7.70 (m, 4H), 8.10
(m, 5H); MS: m/z 463.93 (M+). Anal. Calcd for C27H21N5O3 (463.49): C,
69.90; H, 4.53; N, 15.10. Found: C, 69.92; H, 3.51; N, 15.08.
General procedure for the synthesis of 3-({4-[5-(furan-
2-yl)-4,5-dihydroisox azol-3-yl]phenyl}amino)-7-substi-
tuted quinoxalin-2(1H)-one derivatives 9a,b
General procedure for the synthesis of 2-amino-4-(furan-
2-yl)-6-{[4-(3-oxo-6-substitutd-3,4-dihydroquinoxalin-
2-yl)amino]phenyl}pyridine-3-carbonitrile derivatives 7a,b
A mixture of compound 4a or 4b (0.001 mol), hydroxylamine hydro-
chloride (0.14 g, 0.002 mol), and sodium hydroxide solution (0.5 g in
2 mL water) in absolute ethanol (25 mL) was heated under reflux for
8 h. Afer addition of ice-cold water, the resultant solid was collected
by filtration, dried, and crystallized from ethanol.
A mixture of compound 4a or 4b (0.001 mol), malononitrile (0.066 g,
0.001 mol), and ammonium acetate (0.616 g, 0.008 mol) in absolute
ethanol (25 mL) was heated under reflux for 8 h. The resultant solid
was collected by filtration, dried, and crystallized from ethanol.
3-({4-[5-(Furan-2-yl)dihydroisoxazol-3-yl]phenyl}amino)quinox-
alin-2(1H)-one (9a):ꢀYield (0.287 g, 72%); mp 150–152°C; IR: 3400
1
(NH), 2923 (CH), 1644 cm-1 (CO); H NMR: δ 3.70 (s, 2H), 3.95 (s, 1H),
7.35(m, 2H), 7.57–7.62 (m, 2H), 7.78 (m, 2H), 7.96 (m, 3H), 8.27–8.29 (m,
2-Amino-4-(furan-2-yl)-6-{[4-(2-oxo-1,2-dihydroquinoxalin-3-yl)
amino]pyridine-3-carbonitrile (7a):ꢀYield (0.302 g, 72%); mp
4H); 13C NMR: δ 41.9, 72.4, 111.4, 111.9, 117.5, 119.1, 122.9, 125.1, 126.9,
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130.7, 132.2, 133.4, 143.1, 145.4, 146.9, 154.4, 158.1, 163.5, 167.2; MS: m/z
372.10 (M+). Anal. Calcd for C21H16N4O3 (372.38): C, 67.67; H, 4.29; N,
15.03. Found: C, 67.69; H, 4.27; N, 15.01.
General method for the synthesis of 3-({4-[6-(furan-
2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl]phenyl}amino)-
7-substituted quinoxalin-2(1H)-one derivatives 11a,b
3-({4-[5-(Furan-2-yl)dihydroisoxazol-3-yl]phenyl}amino)7-meth-
ylquinoxalin-2(1H)-one (9b):ꢀYield (0.297 g, 72%); mp 155–157°C;
IR: 3389 (NH), 2921 (CH), 1643 cm-1 (CO); 1H NMR: δ 3.10 (s, 3H), δ 3.70
(s, 2H), 3.95 (s, 1H), 6.50 (s, 1H), 7.10 (s, 1H) 7.20–7.29 (m, 5H), 7.70–7.80
(m, 5H); 13C NMR: δ 22.1, 41.1, 71.1, 112.6, 113.1, 119.9, 121.6, 123.9, 129.1,
131.5, 137.6, 139.1, 139.9, 142.1, 142.7, 144.9, 154.9, 155.3, 163.5, 167.2; MS:
m/z 386.40 (M+). Anal. Calcd for C22H18N4O3 (386.40): C, 68.32; H, 4.65;
N, 14.49. Found: C, 68.34; H, 4.63; N, 14.47.
A mixture of compound 4a or 4b (0.001 mol), urea (0.1 g, 0.001 mol),
and concentrated hydrochloric acid (2 mL) in ethanol (25 mL) was
heated under reflux for 8 h. Afer cooling, the precipitated solid was
collected by filtration, dried, and crystallized from ethanol.
3-({4-[6-(Furan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl]phenyl}
amino)quinoxalin-2(1H)-one (11a):ꢀYield (0.287 g, 72%); mp 153–
155°C; 1H NMR: δ 2.61 (s, 1H), 5.30 (br s, 2H), 6.71 (s, 1H), 7.10 (s, 1H),
7.45 (s, 1H), 7.70 (m, 4H), 7.90(s, 1H), 8.15 (m, 3H), 9.5 (s, 1H); 13C NMR: δ
40.7, 42.4, 110.1, 112.1, 117.8, 118.3, 122.5, 127.5, 131.6, 132.8, 132.9, 134.2,
142.4, 142.9, 143.5, 151.5, 161.9, 164.8, 165.6, 166.7; MS: m/z 397.10 (M+).
Anal. Calcd for C22H15N5O3 (397.39): C, 66.43; H, 3.77; N, 17.61. Found: C,
66.47; H, 3.80; N, 17.65.
General method for the synthesis of 3-({4-[5-(furan-
2-yl)-4,5-dihydro-1-substituted-pyrazol-3-yl]phenyl}
amino)-7-substituted quinoxalin-2(1H)-one derivatives
10a–d
3-({4-[6-(Furan-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl]phenyl}
amino)-7-methylquinoxalin-2(1H)-one (11b):ꢀYield (0.297 g, 72%);
A mixture of compound 4a or 4b (0.001 mol) and hydrazine hydrate
(98%) or phenyl hydrazine (0.001 mol) in ethanol or acetic acid,
respectively (5 mL), was heated under reflux for 8 h. The resultant
solid was collected by filtration, washed several times with hot
ethanol and dried.
1
mp 158–160°C; H NMR: δ 2.95 (s, 3H), 2.98 (s, 1H), 5.20 (s, 1H), 6.80
(s, 1H), 7.10 (s, 1H), 7.25 (s, 1H), 7.66 (m, 4H), 7.90–8.29 (m, 4H), 9.50
(s, 1H); 13C NMR: δ 21.1, 39.7, 40.4, 113.1, 118.1, 118.8, 128.3, 128.5, 130.5,
130.6, 130.8, 131.1, 134.2, 140.4, 140.9, 145.5, 145.5, 145.9, 159.8, 186.6,
186.7; MS: m/z 411.20 (M+). Anal. Calcd for C23H17N5O3 (411.41): C, 67.08;
H, 4.13; N, 17.01. Found: C, 67.11; H, 4.16; N, 17.04.
3-({4-[5-(Furan-2-yl)-4,5-dihydro-1H-pyrazol-3-yl]phenyl}amino)
quinoxalin-2(1H)-one (10a):ꢀYield (0.223 g, 60%) mp 163–165°C; IR:
3382 (NH), 2921 (CH), 1644 cm-1 (CO); 1H NMR: δ 3.45 (br s, 2H), 4.10 (br
s, 2H), 6.55–8.10 (m, 12H), 9.10 (s, 1H); 13C NMR: δ 41.75, 49.10, 111.4,
111.2, 117.5, 118.6, 124.5, 127.2, 128.1, 130.6, 131.1, 132.8, 142.5, 142.9, 144.1,
152.5, 155.1, 163.5, 167.2; MS: m/z 371.66 (M+). Anal. Calcd for C21H17N5O2
(371.14): C, 67.89; H, 4.58; N, 18.86. Found: C, 67.87; H, 4.56; N, 18.88.
Molecular modeling
The Molegro Virtual Docker (MVD) program was used to perform
docking. The protein-ligand interaction energies of the examined
compounds were calculated using the Pose Organizer option in the
MVD program [42] for five different orientations.
The structure of enzyme 1KE8 was downloaded from the PDB.
The docking results are shown in Table 1.
3-({4-[5-(Furan-2-yl)-4,5-dihydro-1H-pyrazol-3-yl]phenyl}
amino)-7-methyl quinoxalin-2(1H)-one (10b):ꢀYield (0.231 g,
1
60%); mp 166–168°C; IR: 3370 (NH), 2923 (CH), 1600 cm-1 (CO).); H
NMR: δ 2.45 (s, 3H), 3.69 (br s, 2H), 4.15 (br s, 2H), 6.65–8.00 (m, 11H),
9.50 (s, 1H); 13C NMR: δ 21.7, 43.7, 51.1, 112.7, 115.2, 116.5, 125.6, 128.6,
131.2, 133.3, 137.6, 139.9, 142.2, 144.4, 145.9, 147.1, 153.6, 155.1, 164.5,
166.3; MS: m/z 385.00 (M+). Anal. Calcd for C22H19N5O2 (385.42): C,
68.54; H, 4.93; N, 18.17. Found: C, 68.56; H, 4.95; N, 18.18.
Biological activity
SRB assay of cytotoxicity was used to analyze the effect of the syn-
thesized compounds on the HEPG2 human tumor cell line. The tumor
cells were obtained frozen in liquid nitrogen (-180°C) from the Ameri-
can type culture collection, RPMI-1640 medium (Sigma Chemicals,
St. Louis, MO, USA). Monolayer cells were incubated with the com-
pounds for 48 h before use; the medium was warmed at 37°C in a
water bath and supplemented with penicillin/streptomycin and FBS.
Cells were planted in 96-multiwell plates (5ꢀ× ꢀ104–105 cells/well) for
24 h before treatment with the compounds to allow attachment of
cells to the wall of the plate. Different concentrations of the com-
3-({4-[5-(Furan-2-yl)-1-phenyl-4,5-dihydropyrazol-3-yl]phenyl}
amino) quinoxalin-2(1H)-one (10c):ꢀYield (0.268 g, 60%); mp
1
140–142°C; IR: 3378 (NH), 2923 (CH), 1664 cm-1 (CO).); H NMR: 3.69
(br s, 2H), 4.00 (s, 1H), 5.00 (s, 1H), 6.65–8.00 (m, 16H), 9.50 (s, 1H);
13C NMR: δ 41.1, 55.2, 110.7, 111.2, 116.9, 118.6, 119.6, 121.2, 124.3, 127.6,
127.9, 132.2, 134.4, 135.9, 137.1, 143.6, 144.1, 145.5, 146.1, 153.9, 154.1,
163.6, 165.0: MS: m/z 447.19 (M+). Anal. Calcd for C27H21N5O2 (447.49):
C, 72.40; H, 4.69; N, 15.64. Found: C, 72.42; H, 4.67; N, 15.62.
3-({4-[5-(Furan-2-yl)-1-phenyl-4,5-dihydropyrazol-3-yl]phenyl} pounds tested (0, 5, 12.5, 25 and 50 μg/mL) were added to the cell
amino)-7-methylquinoxalin-2(1H)-one (10d):ꢀYield (0.277 g, monolayer at 37°C and in an atmosphere of 5% CO2. Control cells
1
60%); mp 148–150°C; IR: 3376 (NH), 3923 (CH), 1668 cm-1 (CO); H were treated with vehicle alone. Cultures were then fixed with trichlo-
NMR: 3.00 (s, 3H), 3.79 (br s, 2H), 4.20 (s, 1H), 5.50 (s, 1H), 6.65–8.00 roacetic acid and stained for 30 min with 0.4% (w/v) SRB dissolved
(m, 15H), 8.90 (s, 1H); 13C NMR: δ 21.9, 40.3, 54.2, 110.2, 111.9, 117.9, in 1% acetic acid. Unbound dye was removed by four washes with
118.1, 121.6, 123.2, 127.3, 129.9, 131.9, 132.8, 137.4, 138.9, 140.1, 143.6, 1% acetic acid, and protein-bound dye was extracted with 10 mm
144.1, 145.5, 146.1, 153.9, 154.1, 163.6, 167.1; MS: m/z 461.00 (M+). Anal. unbuffered Tris base [tris(hydroxymethyl)aminomethane] for deter-
Calcd for C28H23N5O2 (461.51): C, 72.85; H, 4.98; N, 15.17. Found: C, mination of optical density (OD). The OD of each well was measured
72.87; H, 5.00; N, 15.15.
spectrophotometrically at 564 nm with an ELIZA microplate reader.
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34ꢀ ꢀM.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agents
The mean background value of each drug concentration was calcu- [12] Waring, M. J.; Bailly, C. The purine 2-amino group as a critical
lated. The percentage of cell survival was calculated as follows: sur-
vival fractionꢀ= ꢀOD (treated cells)/OD (control cells).
recognition element for binding of small molecules to DNA.
Gene 1994, 149, 69–79.
[13] Rehn, C.; Pindur, U. Model building and molecular mechanics
calculations of mitoxantrone-deoxytetranucleotide complexes:
molecular foundations of DNA intercalation as cytostatic active
principle. Monatsh. Chem. 1996, 127, 631–644.
[14] Baginski, M.; Fogolari, F.; Briggs, J. M. Electrostatic and
non-electrostatic contributions to the binding free energies
of anthracycline antibiotics to DNA. J. Mol. Biol. 1997, 274,
253–267.
Acknowledgments: The authors gratefully acknowledge
Mansoura University for the financial support and the
National Cancer Institute of Cairo University for the bio-
logical evaluation of the synthesized compounds.
[15] Shui, X.; Peek, M. E.; Lipscomb, L. A.; Wilkinson, A. P.;
Williams, L. D.; Gao, M.; Ogata, C.; Roques, B. P.; Garbay-
Jaureuiberry, C. Effects of cationic charge on three-dimensional
structures of intercalative complexes: structure of a bis-
intercalated DNA complex solved by MAD phasing. Curr. Med.
Chem. 2000, 7, 59–71.
References
[1] Eckhardt, S. Recent progress in the development of anticancer
agents. Curr. Med. Chem. Anti-Cancer 2002, 2, 419–439.
[2] Medina, J. C.; Shan, B.; Beckmann, H.; Farrell, R. P.; Clark, D. L.; [16] Pindur, U.; Haber, M.; Sattler, K. Antitumor active drugs as
Learned, R. M.; Roche, D.; Li, A.; Baichwal, V.; Case, C.; et al.
Novel antineoplastic agents with efficacy against multidrug
resistant tumor cells. Bioorg. Med. Chem. 1998, 8, 2653–2656.
[3] Abdel-Aziz, A. A.-M. Novel and versatile methodology for syn-
thesis of cyclic imides and evaluation of their cytotoxic, DNA
binding, apoptotic inducing activities and molecular modeling
study. Eur. J. Med. Chem. 2007, 42, 614–626.
[4] Medina, J. C.; Roche, D.; Shan, B.; Learned, R. M.; Frankmoe-
lle, W. P.; Clark, D. L.; Rosen, T.; Jaen, J. C. Novel halogenated
sulfonamides inhibit the growth of multidrug resistant MCF-7/
ADR cancer cells. Bioorg. Med. Chem. 1999, 9, 1843–1846.
[5] Hwang, H. S.; Moon, E. Y.; Seong, S. K.; Choi, C. H.; Chung, C.
H.; Jung, S. H.; Yoon, S. J. Characterization of the anticancer
activity of DW2282, a new anticancer agent. Anticancer Res.
1999, 19, 5087–5093.
[6] Choo, H.-Y. P.; Kim, M.; Lee, S. K.; Kim, S. W.; Chung, S. W.
Solid-phase combinatorial synthesis and cytotoxicity of
3-aryl-2,4-quinazolindiones. Bioorg. Med. Chem. 2002, 10,
517–523.
[7] Al-Rashood, S. T.; Aboldahab, I. A.; Nagi, M. N.; Abou-zeid, L.
A.; Abdel-Aziz, A. A.-M.; Abdel-Hamide, S. G.; Youssef, K. M.;
Al-Obaid, A. M.; El-Subbagh, H. I. Synthesis, dihydrofolate
reductase inhibition, antitumor testing, and molecular mod-
eling study of some new 4-(3H)-quinazolinone analogs. Bioorg.
Med. Chem. 2006, 14, 8608–8621.
[8] Al-Obaid, A. M.; Abdel-Hamide, S. G.; El-Kashef, H. A.; Abdel-
Aziz, A. A.-M.; El-Azab, A. S.; Al-Khamees, H. A.; El-Subbagh, H.
I. Substituted quinazolines, part 3. Synthesis, in vitro antitu-
mor activity and molecular modeling study of certain 2-thieno-
4(3H)-quinazolinone analogs. Eur. J. Med. Chem. 2009, 44,
2379–2391.
[9] Al-Omary, F. A. M.; Abou-zeid, L. A.; Nagi, M. N.; Habib, E.
E.; Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Abdel-Hamide, S. G.;
Al-Omar, M. A.; Al-Obaid, A. M.; El-Subbagh, H. I. Nonclassi-
cal antifolates, part 2. Synthesis, biological evaluation and
molecular modeling study of some new 2,6-substituted-quina-
zolin-4-ones. Bioorg. Med. Chem. 2010, 18, 2849–2863.
[10] Avendao, C.; Menendez, J. C. Medicinal Chemistry of Antican-
cer Drugs; Elsevier: Amsterdam and Oxford, 2008.
intercalators of deoxyribonucleic acid: molecular models of
intercalation complexes. J. Chem. Educ. 1993, 70, 263–272.
[17] Geierstanger, B.; Wemmer, D. E. Complexes of the minor groove
of DNA. Annu. Rev. Biophys. Biomol. Struct. 1995, 24, 463–493.
[18] Fonsca, T.; Giganta, B.; Marques, M. M.; Gilchrist, T. L. Clercq,
E. D. Synthesis and antiviral evaluation of benzimidazoles,
quinoxalines and indoles from dehydroabietic acid. Bioorg.
Med. Chem. 2004, 12, 103.
[19] Habib, N. S.; EL-Hawash, S. A. Synthesis and antimicrobial test-
ing of thiazolinyl-(VI) and (VIII), thiazolidinonyl-quinoxalines
(X), and 1,2,4-triazolo(4,3-a)quinoxalines (IV). Pharmazie 1997,
57, 597.
[20] Sarger, R.; Howard, H. R.; Browne, R. G.; Lebel, L. A.; Seymour, P.
A.; Koe, B. K. 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel
class of potent adenosine receptor antagonists and potential
rapid-onset antidepressants. J. Med. Chem. 1990, 33, 2240–2254.
[21] Jaso, A.; Zarranz, B.; Aladana, I.; Monge, A. Synthesis of new
2-acetyl and 2-benzoylquinoxaline 1,4-di-N-oxide derivatives
as anti-Mycobacterium tuberculosis agents. Eur. J. Med. Chem.
2003, 38, 791–800.
[22] Bigge, C. F.; Malone, T. C.; Boxer, P. A.; Nelson, C. D.; Ortwine,
D. F.; Schelkun, R. M.; Retz, D. M.; Lescosky, L. G.; Borosky, S.
A.; Vartanian, M. G.; et al. Synthesis of 1,4,7,8,9,10-hexahydro-
9-methyl-6-nitropyrido[3,4-f]-quinoxaline-2,3-dione and
related quinoxalinediones: characterization of alpha-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (and N-methyl-
D-aspartate) receptor and anticonvulsant activity. J. Med.
Chem. 1995, 38, 3720–3740.
[23] Srinivas, Ch.; Sai-Pavan Kumar, Ch. N. S.; Jayathirtha-Rao, V.;
Palaniappan, S. Green approach for the synthesis of quinoxa-
line derivatives in water medium using reusable polyaniline-
sulfate salt catalyst and sodium laurylsulfate. Catal. Lett.
2008, 121, 291–296.
[24] Ding, Z.; Parchment, R. E.; LoRusso, P. M.; Zhou, J. Y.; Li, J.;
Lawrence, T. S.; Sun, Y.; Wu, G. S. The investigational new drug
XK469 induces G(2)-M cell cycle arrest by p53-dependent and
-independent pathways. Clin. Cancer Res. 2001, 7, 3336–3342.
[25] Ghorabi, M. M.; Ragab, F. A.; Heiba, H.; El-Gazzar, M. G.
Synthesis, in vitro anticancer screening and radiosensitiz-
ing evaluation of some new 4-[3-(substituted)thioureido]-
N-(quinoxalin-2-yl)-benzenesulfonamide derivatives. Acta
Pharm. 2011, 61, 415–425.
[11] Karikas, G. A.; Schulpis, K. H.; Reclos, G.; Kokotos, G. Meas-
urement of molecular interaction of aspartame and its metabo-
lites with DNA. Clin. Biochem. 1998, 31, 405–407.
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M.G. Thabit et al.: New 3-(4-substituted phenyl)aminoquinoxaline derivatives as anticancer agentsꢀ
ꢀ35
[26] Arun Kumar, V. A.; Keshav Mohan. Insights into binding of
potential antitumor quinoxaline analogues against cyclin
dependent kinase 2 using docking studies. J. Chem. Biol. Phys.
Sci. 2012, 4, 2419–2427.
[27] Mathew, A.; Sheeja, M. T. L.; Kumar, A. T.; Radha, K. Design,
synthesis and biological evaluation of pyrazole analogues of
natural piperine. Hygeia. J. D. Med. 2011, 3, 48–56.
[28] Lee, C. Synthetic Approaches to Biologically Active Sulfonates
and Sulfonamides; PhD thesis, Cairo University: Cairo, Egypt,
2010, pp 24–25.
[29] Jeong, B. S.; Choi, H.; Kwak, Y. S.; Lee, E. S. Synthesis of
2,4,6-tripyridyl pyridines, and evaluation of their antitumor
cytotoxicity, topoisomerase I and II inhibitory activity, and
structure-activity relationship. Bull. Korean Chem. Soc. 2011,
32, 3566–3570.
[30] Nasr, M. N.; Gnina, M. M.; Rashad, A. M. Synthesis and
anticonvulsant activity of novel 2- and 3-[4-(trisubstituted
pyridyl)-phenylamino]- and 2-[3- and 4-(trisubstituted pyridyl)-
phenoxy]-quinoxaline derivatives. Sci. Pharm. 2003,
71, 9–17.
[34] Shi, F.; Tu, S.; Fang, F.; Li, T. One-pot synthesis of 2-amino-3-
cyanopyridine derivatives under microwave irradiation without
solvent. Arkivoc 2005, 1, 137–142.
[35] Saleh, M. A.; Abdel-Megeed, M. F.; Abdo, M. A.; Shokr, A. M.
Synthesis of novel 3H-quinazolin-4-ones containing
pyrazolinone, pyrazole and pyrimidinone moieties. Molecules
2003, 8, 363–368.
[36] Bramson, H. N.; Corona, J.; Davis, S. T.; Dickerson, S. H.;
Edelstein, M.; Frye, S. V.; Gampe, R. T. Jr.; Harris, P. A.; Hassell,
A.; Holmes, W. D.; et al. Oxindole-based inhibitors of cyclin-
dependent kinase 2 (CDK2): design, synthesis, enzymatic
activities, and X-ray crystallographic analysis, J. Med. Chem.
2001, 44, 4339–4358.
[37] Waring, M. J.; Wakelin, L. P. G. Echinomycin: a bifunctional
intercalating antibiotic. Nature 1974, 252, 653–657.
[38] Basak, A.; Dugas, H. A synthetic bismethidium with a similar
topology does not bind to DNA as a bisintercalator. Tetrahe-
dron Lett. 1986, 27, 3–6.
[39] Dietrich, B.; Diederichsen, U. Synthesis of cyclopeptidic
analogues of triostin A with quinoxalines or nucleobases as
chromophores. Eur. J. Org. Chem. 2005, 2005, 147–153.
[40] Hunter, T.; Pines, J. Cyclins and cancer II: cyclin D and CDK
inhibitors come of age. Cell 1994, 79, 573–582.
[31] Wattanasin, S.; Murphy, W. S. Improved procedure for the
preparation of chalcones and related enones. Synthesis 1980,
8, 647–652.
[32] Bayoumi, W. A.; Elsayed, M. A. Synthesis of new phenylcar-
bamoylbenzoic acid derivatives and evaluation of their in vitro
antioxidant activity. Med. Chem. Res. 2012, 21, 1633–1640.
[33] Nasr, M. N. Synthesis and antibacterial activity of fused
[41] Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.;
Vistica, D.; Warren, J. T.; Bokesch, H.; Kenny, S.; Boyd, M. R.
New colorimetric cytotoxicity assay for anticancer-drug screen-
ing. J. Natl. Cancer Inst. 1990, 82, 1107–1112.
1,2,3-triazolo[4,3-a]quinoxaline and oxopyrimido[2,1:5,1]-1,2,4- [42] Kawamori, T.; Rao, C. V.; Seibert, K.; Reddy B. S. Chemopreven-
triazolo[4,3-a]quinoxaline derivatives. Arch. Pharm. Med.
Chem. 2002, 8, 389.
tive activity of celecoxib, a specific cyclooxygenase-2 inhibitor,
against colon carcinogenesis. Cancer Res. 1998, 58, 409–412.
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