Microwave supported synthesis of some novel 1,3-Diarylpyrazino[1,2-a] benzimidazole derivatives and investigation of their anticancer activities

Article abstract of DOI:10.1016/j.ejmech.2010.11.007

The syntheses of 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives and the investigation of their anticancer activities were studied. For this, 2-aryloylbenzimidazole derivatives were reacted with 2-bromoacetophenones in acetone to give 1-(2-aryl-2-oxoet

Full text of DOI:10.1016/j.ejmech.2010.11.007

European Journal of Medicinal Chemistry 46 (2011) 411e416
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Microwave supported synthesis of some novel 1,3-Diarylpyrazino[1,2-a]
benzimidazole derivatives and investigation of their anticancer activities
,
c
Seref Demirayak a, Ismail Kayagil b , Leyla Yurttas
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medipol University, 34083 Istanbul, Turkey
b Department of Chemistry, Faculty of Arts & Science, Mehmet Akif Ersoy University, 15030 Burdur, Turkey
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives and the investigation of their anti-
cancer activities were studied. For this, 2-aryloylbenzimidazole derivatives were reacted with 2-bro-
moacetophenones in acetone to give 1-(2-aryl-2-oxoethyl)-2-aryloylbenzimidazoles. The resulting
materials were reacted with ammonium acetate in acetic acid to obtain the aimed compound. In this
reaction, microwave irradiation method was applied as the reaction conditions. Anticancer activities of
the compounds obtained were investigated. It was observed that some of the compounds showed
remarkable anticancer activities.
Received 20 April 2010
Received in revised form
15 October 2010
Accepted 4 November 2010
Available online 12 November 2010
Keywords:
Ó 2010 Elsevier Masson SAS. All rights reserved.
2-Aryloylbenzimidazole
Pyrazino[1,2-a]benzimidazole
Anticancer activity
1. Introduction
2-bromoacetophenones to afford 1-(2-aryl-2-oxoethyl)-2-ary-
loylbenzimidazoles, 2aeo. To obtain 1,3-diarylpyrazino[1,2-a]
Cancer is the worldwide health problem and the most fright-
ening disease of human. In the present study we have concentrated
on identified numerous chemical substances, as we have done in
some our earlier publications [1e3], aiming to design the novel
antitumor reagents [4].
The importance of imidazo[1,2-a]pyrazines [5] stems especially
from their remarkable anticancer [6e10] and antimicrobial activi-
ties [11] along with antihypertensive [12,13], antibroncospastic
[14,15] and inotropic activities [16,17]on the cardiovascular system.
Motivated by the above observations and as an extension of our
previous works on imidazo[1,2-a]pyrazine [2] and pyrazino[1,2-a]
benzimidazole [3,18] which exhibited remarkable anticancer
activities especially on leukemia, we now report on the synthesis
and the anticancer activity testing of some 2,3,6,8-tetraarylimidazo
[1,2-a]pyrazine derivatives.
benzimidazole derivatives, 3aeo, the diketone derivatives 2aeo
were reacted with ammonium acetate in a minimum amount of
acetic acid by using microwave irradiation [2,19] as a facile
synthetic method. The synthesis pathway of compounds was out-
lined in Scheme 1. It was demonstrated that many organic reactions
can be conducted very rapidly under microwave irradiation. This
method was preferred due to high reaction rates, purer products
and operational simplicity. In this alternative reaction condition no
product could be obtained in the absence of solvent. Thus, a small
amount of acetic acid was used for solving the substrates and
microwave energy transfer.
In the IR spectra, carbonyl stretching bands, which are charac-
teristic for the compounds 2aep, were observed at about
1708e1685 cmꢀ1 and 1645e1632 cmꢀ1 regions. These two groups
of carbonyl stretching bands disappeared after cyclization to give
pyrazino[1,2-a]benzimidazole ring system.
In the NMR spectra, methylene protons resonated in aliphatic
area at 6.3 ppm for 2aeo. After cyclization, however, the corre-
sponding protons were shifted to the aromatic area in 3aeo and
observed at 9.6 ppm as singlets. Other characteristic peaks due to
the aromatic protons were observed as expected.
In the MS spectra, the electron spraying technique with positive
polarity mode was applied and M þ 1 peaks were detected as base
peak.
2. Chemistry
Some novel 1,3-diarylpyrazino[1,2-a]benzimidazole derivatives
were synthesized and their structures were elucidated by analytical
and spectroscopic methods. 2-Aryloylimidazole derivatives were
taken as starting materials. These compounds were reacted with
* Corresponding author. Tel.: þ90 248 212 27 80/1685; fax: þ90 248 212 27 81.
E-mail address: ikayagil@mehmetakif.edu.tr (I. Kayagil).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.11.007

412
S. Demirayak et al. / European Journal of Medicinal Chemistry 46 (2011) 411e416
R
R
R
1
N
N
i, ii
+
a
b
c
H
OCH3
Cl
Cl
N
H
O
N
O
1a-c
R
H
O
Br
iii
N
N
iv
1
+
O
O
R'
2a-o
R
R'
2, 3
R
R'
R
R'
2, 3
N
N
a
b
c
d
e
f
H
H
H
H
H
CH3
OCH3
F
Cl
H
OCH3
OCH3 Cl
F
i
j
N
3a-o
k
l
m
n
o
Cl
Cl
Cl
Cl
Cl
H
CH3
OCH3
F
Cl
H
OCH3
OCH3 CH3
OCH3 OCH3
g
h
R'
Scheme 1. Reagents and conditions; (i)(C2H5)3N, pyridine, stirring at RT; (ii) NaOH, H2O, reflux; (iii) K2CO3, CH3COCH3, stirring at RT; (iv) CH3COONH4, CH3COOH, MW irradiation,
2 min.
3. Results and discussion
tested at 10-fold dilutions of five concentrations (100, 10, 1, 0.1 and
0.01 M). The results were given as log10 GI50 (GI50: growth inhi-
m
In the first step, the compounds 2aee, 2hej, 2m, 2o, 3aef, 3j
and 3l were selected by NCI for the anticancer tests. The selected
compounds were tested in vitro against sixty human tumor cell
lines derived from nine neoplastic diseases and the test results
were determined as growth percent values for 10ꢀ5 M concen-
tration. The obtained growth percent values were depicted in
Table 1.
The remarkable low growth percent values were obtained for
the compounds 2c and 2h against leukaemia cell lines as ꢀ3.26 and
ꢀ2.92% respectively. With respect to mean values, the compound
2h exhibited the lowest growth percent value with 25.51%. The
compounds 2c, 2e and 2j also possessed remarkable growth values.
As the test method requires, the compounds having growth percent
lower than 75% were accepted for the further screening test. Thus,
2a, 2cee, 2h, 2j and 2m which are diketone compounds were taken
into the second stage. In this step, the selected compounds were
bition of 50%). The detailed test results are given in Table 2.
The test method states that the compounds having log10 GI50
values greater than ꢀ4 are considered as inactive. It can be seen
that for all compounds the log10 GI50 values are smaller than ꢀ4.
Therefore, we may conclude that all of our compounds under
investigation provide a notable activity level. melphalan and
cisplatin (cis-diaminodichloroplatinum) are two of the commonly
used chemotherapeutic agents and used as standard compounds.
When the mean graph midpoint (MG-MID) values of the
compounds melphalan and cisplatin, i.e. ꢀ5.09 and ꢀ6.20 respec-
tively, are considered, it is observed that our compounds provide
high activity levels. The MG-MID values of the compound 2cee, 2h
and 2j are lower than that of the control compound melphalan. In
this respect, 2c and 2h are remarkable compounds with the MG-
MID values, ꢀ5.54 and ꢀ5.46 respectively. The activity levels of the
compounds bearing methoxy or halogen are higher than that of the

S. Demirayak et al. / European Journal of Medicinal Chemistry 46 (2011) 411e416
413
Table 1
Anticancer activity of the compounds as % growth.
Compounds
L
NSCLC
CC
68.71
CNSC
M
OC
87.00
RC
86.38
PC
86.50
BC
58.75
80.51
23.32
48.89
9.00
18.28
81.51
28.82
59.95
103.27
85.14
85.71
85.34
88.78
75.67
88.87
103.72
98.47
Mean
2a
2b
2c
2d
2e
2h
2i
52.17
70.50
82.55
91.01
36.00
70.39
52.44
38.33
101.01
51.54
73.04
83.43
100.25
102.38
95.39
92.59
79.33
91.43
100.21
110.69
82.33
101.15
25.38
65.49
37.17
23.85
106.10
23.44
67.11
99.15
62.17
77.00
103.74
91.16
67.50
93.98
98.48
128.36
75.38
71.95
82.73
28.08
48.89
35.87
25.51
85.89
31.68
59.77
89.36
85.76
85.71
97.47
95.15
77.89
94.33
101.33
106.47
72.24
22.43
48.96
40.14
19.69
71.24
33.14
52.38
86.00
89.17
94.83
98.10
105.96
77.83
99.96
98.79
97.43
72.07
31.26
46.46
34.13
26.74
68.06
24.15
51.48
82.30
86.29
92.57
102.86
109.13
80.29
94.95
106.17
105.13
80.45
30.25
65.25
44.33
27.87
84.42
29.51
64.17
113.50
61.50
85.17
102.35
91.34
64.50
87.71
92.78
94.06
85.16
38.60
71.58
45.13
35.98
97.16
43.77
63.14
85.42
101.17
103.00
96.67
91.75
84.14
95.17
96.96
108.81
91.45
33.20
87.42
34.00
44.39
93.45
35.08
83.57
93.84
91.50
89.50
106.57
95.32
78.00
102.30
113.88
104.20
ꢀ3.26
29.98
21.67
ꢀ2.92
71.48
3.41
35.89
64.71
93.67
93.67
90.00
98.77
91.67
101.82
110.76
106.68
2j
2m
2o
3a
3b
3c
3d
3e
3f
3j
3l
first member of the series, i.e. 2a. It is interesting to see that the
more active compounds 2c and 2h bear methoxy group.
OCH3), 7.12 (2H, d, J: 8.8 Hz, AreH), 7.40e7.43 (1H, m, AreH),
7.47e7.5 (1H, m, AreH), 8.12 (2H, d, J: 8.78 Hz AreH), 11.40 (1H, bs,
NeH). Anal. Calcd. for C15H12N2O2 : C: 71.42, H: 4.79, N: 11.10.
Found: C: 71.35, H: 5.01, N: 10.95.
4. Experimental protocols
4.1. Chemistry
4.1.3. 2-(4-Chlorobenzoyl)benzimidazole (1c)
Yield: 62%. m.p. 224e226 ꢁC. IR(KBr)nmaks(cmꢀ1): 1648 (C]O),
Melting points were determined by using an Electrothermal 9100
Digital Melting Point Apparatus. Spectroscopic data were recorded
on the following instruments: IR, Shimadzu 8400 FTIR Spectropho-
tometer; 1H NMR; Bruker DPX 500 MHz NMR Spectrometer. Micro-
wave irradiated reactions were performed by using a Milestone
Microsynth Apparatus. Compound 1a, 2a,b,e, 3a,b,e were synthe-
sized in an our previous study [3]. 2-bromoacetophenone derivatives
[20] were prepared by using the reported literature methods.
1598e1490 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 7.41e7.44 (1H, m, AreH), 7.48e7.51 (1H, m, AreH), 7.69
(2H, J: 8.27 Hz, AreH), 8.32 (2H, d, J: 8.34 Hz, AreH), 11.45 (1H, bs,
NeH). Anal. Calcd. for C14H9ClN2O: C: 65.51, H: 3.53, N: 10.91.
Found: C: 65.27, H: 3.70, N: 11.02.
4.1.4. General procedure for 1-(2-aryl-2-oxoethyl)-2-
aryloylbenzimidazoles (2aeo)
A mixture of the suitable 2-aryloylbenzimidazole (5 mmol),
2-bromoacetophenone (5 mmol) and potassium carbonate
(5 mmol) in acetone (50 mL) was stirred at room temperature.
Stirring was continued at room temperature until the disappear-
ance of the starting material (4e6 h, TLC analyses). The solvent was
evaporated at low temperature. The residue was washed with
water and then ethanol. The raw product was recrystallized from
ethanol.
4.1.1. General procedure for 2-aryloylbenzimidazoles (1b,c)
Benzimidazole (100 mmol) was completely dissolved in pyri-
dine (30 mL) then added triethylamine (28.4 mL). A suitable ben-
zoylchloride (200 mmol) was gently and slowly dropped to the
reaction media during the solution was stirred in ice bath under
atmosphere with nitrogen gas. Then the mixture was stirred in
room temperature without nitrogen atmosphere during a day.
NaOH solution (7.5 N, 6 g NaOH and 20 mL water) was added to the
mixture and refluxed for an hour. The reaction media was poured
into ice-water and kept in a refrigerator for two days. The residue
was filtered and washed with water. The raw product was recrys-
tallized from ethanol.
4.1.5. 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-
benzoylbenzimidazole (2c)
Yield: 87%. m.p. 155e156 ꢁC. IR(KBr)nmaks(cmꢀ1) : 1685, 1652
(C]O), 1605e1500 (C]N and C]C), 1282, 1216 (CeOeAr), 1H NMR
(500 MHz)(DMSO-d6)
d (ppm): 3.90 (3H, s, OCH3), 6.26 (2H, s,
4.1.2. 2-(4-Methoxybenzoyl)benzimidazole (1b)
CH2CO), 7.16 (2H, d, J: 8.94 Hz, AreH), 7.42 (1H, t, J: 7.12 Hz and
7.20 Hz, AreH), 7.48 (1H, t, J: 7.23 Hz and 7.20 Hz, AreH), 7.60 (2H, t,
J: 7.57 Hz and 8.01 Hz, AreH), 7.72 (1H, t, J: 7.20 Hz and 7.24 Hz,
Yield: 55%. IR(KBr)nmaks(cmꢀ1): 1652 (C]O), 1605e1510 (C]N
and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 3.88 (3H, s,
Table 2
Log10 GI50 values of the selected compounds.
Compounds
L
NSCLC
CC
CNSC
M
OC
RC
PC
BC
MG_MID
2a
2c
2d
2e
2h
2j
2m
A
B
ꢀ4.28
ꢀ6.14
ꢀ5.85
ꢀ5.69
ꢀ6.13
ꢀ6.14
ꢀ5.59
ꢀ5.48
ꢀ6.39
ꢀ4.16
ꢀ5.03
ꢀ4.73
ꢀ4.74
ꢀ4.82
ꢀ4.84
ꢀ4.73
ꢀ5.17
ꢀ6.20
ꢀ4.2
ꢀ4.08
ꢀ5.40
ꢀ5.07
ꢀ5.88
ꢀ5.48
ꢀ5.47
ꢀ4.78
ꢀ5.12
ꢀ6.18
ꢀ4
ꢀ4
ꢀ4.06
ꢀ5.49
ꢀ5.56
ꢀ4.94
ꢀ5.41
ꢀ5.43
ꢀ4.85
ꢀ4.99
ꢀ6.17
ꢀ4.14
ꢀ5.49
ꢀ4.87
ꢀ5.37
ꢀ5.53
ꢀ5.52
ꢀ4.62
ꢀ4.49
ꢀ6.41
ꢀ5.03
ꢀ5.65
ꢀ5.40
ꢀ5.80
ꢀ5.62
ꢀ5.46
ꢀ5.21
ꢀ4.79
ꢀ6.05
ꢀ4.15
ꢀ5.54
ꢀ5.27
ꢀ5.25
ꢀ5.51
ꢀ5.46
ꢀ5.01
ꢀ5.09
ꢀ6.20
ꢀ5.82
ꢀ5.45
ꢀ5.33
ꢀ5.90
ꢀ5.60
ꢀ5.30
ꢀ5.11
ꢀ6.14
ꢀ5.53
ꢀ5.34
ꢀ5.43
ꢀ5.49
ꢀ5.61
ꢀ5.02
ꢀ5.08
ꢀ6.08
ꢀ5.44
ꢀ4.97
ꢀ5.05
ꢀ5.52
ꢀ5.28
ꢀ4.75
ꢀ5.18
ꢀ6.45
A: Melphalan, B: Cisplatin.

414
S. Demirayak et al. / European Journal of Medicinal Chemistry 46 (2011) 411e416
AreH), 7.85 (1H, d, J: 8.28 Hz, AreH), 7.93 (1H, d, J: 8.13 Hz), 8.12
(2H, d, J: 8.88 Hz, AreH), 8.28 (2H, d, J: 8.13 Hz, AreH). MS: (35 eV,
electron spray) m/z 371.1 (M þ 1, 100%), 372.0 (M þ 2, 35%). Anal.
Calcd. for C23H18N2O3$H2O: C: 71.12, H: 5.13, N: 7.21. Found: C:
71.02, H: 4.90, N: 6.96.
(500MHz)(DMSO-d6)d(ppm):3.89(3H, s,OCH3), 6.27(2H, s,CH2CO),
7.13 (2H, d, J: 9.03 Hz, AreH), 7.41 (1H, t, J: 7.28 Hz and 7.76 Hz, AreH),
7.47 (1H, t, J: 7.77 Hz and 7.68 Hz, AreH), 7.73 (2H, d, J: 8.63 Hz, AreH),
7.84(1H, d, J:8.25 Hz, AreH), 7.93(1H, d, J:8.08 Hz, AreH), 8.15 (2H, d,
J: 8.61 Hz AreH), 8.37 (2H, d, J: 8.98 Hz, AreH). MS: (35 eV, electron
spray) m/z 405.1 (M þ 1, 100%), 406.1 (M þ 2, 8%), 407 (M þ 3, 35%),
408(Mþ 4,10%). Anal.Calcd. forC23H17ClN2O3$H2O:C:65.33, H:4.53,
N: 6.62. Found: C: 65.45, H: 4.52, N: 6.55.
4.1.6. 1-(2-(4-Fluorophenyl)-2-oxoethyl)-2-benzoylbenzimidazole
(2d)
Yield: 76%. m.p. 177e179 ꢁC. IR(KBr)nmaks(cmꢀ1): 1700, 1638
(C]O), 1598e1480 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
4.1.12. 1-(2-Phenyl-2-oxoethyl)-2-(4-chlorobenzoyl)benzimidazole
(2k)
d
(ppm): 6.31 (2H, s, CH2CO), 7.42 (1H, t,), 7.47e7.51 (3H, m, AreH),
7.60 (2H, t, J: 7.47 Hz, AreH), 7.71e7.73 (1H, m, AreH), 7.86 (1H, d, J:
8.56 Hz, AreH), 7.94 (1H, d, J: 8.13 Hz), 8.24 (2H, dd, J: 8.89 Hz and
5.5 Hz, AreH), 8.28 (2H, d, J: 8.04 Hz, AreH). Anal. Calcd. for
C22H15FN2O2$H2O: C: 70.21, H: 4.55, N: 7.44. Found: C: 69.88, H:
4.32, N: 7.40.
Yield: 82%. m.p. 223e226 ꢁC. IR(KBr)nmaks(cmꢀ1): 1692, 1636
(C]O), 1603e1500 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 6.32 (2H, s, CH2CO), 7.42e7.62 (5H, m, AreH), 7.69 (2H, J:
8.27 Hz, AreH), 7.85 (1H, d, J: 8.68 Hz, AreH), 7.92 (1H, d, J: 8.53 Hz),
8.12 (2H,, J: 8.58 Hz, AreH), 8.32 (2H, d, J: 8.34 Hz, AreH). Anal.
Calcd. for C22H15ClN2O2$H2O: C: 67.26, H: 4.36, N: 7.13. Found: C:
67.11, H: 4.35, N: 7.00.
4.1.7. 1-(2-Phenyl-2-oxoethyl)-2-(4-methoxybenzoyl)
benzimidazole (2f)
Yield: 68%. m.p. 218e220 ꢁC. IR(KBr)nmaks(cmꢀ1): 1695, 1645
(C]O), 1590e1480 (C]N ve C]C), 1280, 1220 (CeOeAr), 1H NMR
4.1.13. 1-(2-(4-Methylphenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)
benzimidazole (2l)
(500 MHz)(DMSO-d6)
d
(ppm): 3.91 (3H, s, OCH3), 6.28 (2H, s,
Yield: 78%. m.p. 190e192 ꢁC. IR(KBr)nmaks(cmꢀ1): 1706, 1646
CH2CO), 7.42e7.62 (7H, m, AreH), 7.86 (1H, d, J: 8.56 Hz, AreH),
7.92 (1H, d, J: 8.13 Hz), 8.12 (2H, J: 8.58 Hz, AreH), 8.28 (2H, d, J:
8.25 Hz, AreH). Anal. Calcd. for C23H18N2O3$H2O: C: 71.12, H: 5.19,
N: 7.21. Found: C: 70.88, H: 5.10, N: 6.90.
(C]O), 1602e1598 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm) : 2.44 (3H, s, CH3), 6.32 (2H, s, CH2CO), 7.42 (1H, t, J: 7.62 Hz,
and 7.41 Hz, AreH), 7.46e7.52 (3H, m, AreH), 7.69 (2H, J: 8.05 Hz,
AreH), 7.87 (1H, d, J: 8.23 Hz, AreH), 7.93 (1H, d, J: 8.19 Hz, AreH),
8.03 (2H, d, J: 8.27 Hz, AreH), 8.36 (2H, d, J: 8.02 Hz, AreH). Anal.
Calcd. for C23H17ClN2O2$H2O: C: 67.90, H: 4.71, N: 6.89. Found: C:
68.10, H: 4.80, N: 6.90.
4.1.8. 1-(2-(4-Methylphenyl)-2-oxoethyl)-2-(4-methoxybenzoyl)
benzimidazole (2g)
Yield: 72%. m.p. 172e173 ꢁC. IR(KBr)nmaks(cmꢀ1): 1685, 1450
(C]O), 1602e1500 (C]N and C]C), 1288, 1218 (CeOeAr), 1H NMR
4.1.14. 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)
benzimidazole (2m)
(500 MHz)(DMSO-d6) d (ppm): 2.45 (3H, s, CH3), 3.89 (3H, s, OCH3),
6.25 (2H, s, CH2CO), 7.13 (2H, d, J: 8.94 Hz, AreH), 7.40 (1H, t, J: Hz,
7.76 Hz and 7.77 Hz, AreH), 7.44e7.48 (3H, m, AreH), 7.83 (1H, d, J:
8.21 Hz), 7.92 (1H, d, J: 8.08 Hz, AreH), 8.03 (2H, d, J: 8.18 Hz AreH),
8.36 (2H, d, J: 8.94 Hz, AreH). Anal. Calcd. for C24H20N2O3$H2O: C:
71.60, H: 5.51, N: 6.96. Found: C: 71.38, H: 5.50, N: 7.02.
Yield: 68%. m.p. 175e176 ꢁC. IR(KBr)nmaks(cmꢀ1): 1698, 1632
(C]O), 1595e1490 (C]N ve C]C), 1278, 1218 (CeOeAr), 1H NMR
(500 MHz)(DMSO-d6)
d (ppm): 3.90 (3H, s, OCH3), 6.25 (2H, s,
CH2CO), 7.17 (2H, d, 8.94 Hz, AreH), 7.42 (1H, t, J: 7.62 Hz, and
7.41 Hz, AreH), 7.49 (1H, t, J: 7.18 Hz and 7.22 Hz, AreH), 7.69 (2H,, J:
8.63 Hz, AreH), 7.86 (1H, d, J: 8.26 Hz, AreH), 7.93 (1H, d, J: 8.15 Hz,
AreH), 8.11 (2H, d, J: 8.88 Hz, AreH), 8.33 (2H, d, J: 8.67 Hz, AreH).
Anal. Calcd. for C23H17ClN2O3$H2O: C: 65.33, H: 4.53, N: 6.62.
Found: C: 65.20, H: 4.44, N: 6.57.
4.1.9. 1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-(4-methoxybenzoyl)
benzimidazole (2h)
Yield: 66%. m.p. 180e181 ꢁC. IR(KBr)nmaks(cmꢀ1): 1690, 1635
(C]O), 1597e1495 (C]N and C]C), 1290, 1232 (CeOeAr) 1H NMR
(500 MHz)(DMSO-d6)
d
(ppm): 3.89 (3H, s, OCH3), 3.90 (3H, s,
4.1.15. 1-(2-(4-Fluorophenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)
benzimidazole (2n)
OCH3), 6.23 (2H, s, CH2CO), 7.14 (4H, t, J: 9.1 Hz and 9.13 Hz, AreH),
7.40 (1H, t, J: 7.28 Hz, 7.76 Hz, AreH), 7.46 (1H, t, J: 7.81 Hz and
7.80 Hz, AreH), 7.82 (1H, d, J: 8.19 Hz), 7.92 (1H, d, J: 8.07 Hz, AreH),
8.11 (2H, d, J: 8.78 Hz AreH), 8.36 (2H, d, J: 8.78 Hz, AreH). Anal.
Calcd. for C24H20N2O4$2H2O: C: 66.04, H: 5.54, N: 6.42. Found: C:
65.88, H: 5.45, N: 6.77.
Yield: 82%. m.p. 207e208 ꢁC. IR(KBr)nmaks(cmꢀ1): 1688, 1634
(C]O), 1600e1496 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 3.90 (3H, s, OCH3), 6.25 (2H, s, CH2CO), 7.41 (1H, t, J:
7.62 Hz, and 7.46 Hz, AreH), 7.47e7.51 (3H, m, AreH), 7.69 (2H, J:
8.63 Hz, AreH), 7.86 (1H, d, J: 8.16 Hz, AreH), 7.93 (1H, d, J: 8.25 Hz,
AreH), 8.24 (2H, d, J: 8.76 Hz, AreH), 8.34 (2H, d, J: 8.75 Hz, AreH).
Anal. Calcd. for C22H14ClFN2O2$H2O: C: 64.32, H: 3.93, N: 7.13.
Found: C: 64.30, H: 4.21, N: 7.44.
4.1.10. 1-(2-(4-Fluorophenyl)-2-oxoethyl)-2-(4-methoxybenzoyl)
benzimidazole (2i)
Yield: 75%. m.p. 213e214 ꢁC. IR(KBr)nmaks(cmꢀ1): 1704, 1650
(C]O), 1612e1500 (C]N and C]C), 1282, 1220 (CeOeAr) 1H NMR
4.1.16. 1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)
benzimidazole (2o)
(500 MHz)(DMSO-d6)
d (ppm): 3.92 (3H, s, OCH3), 6.23 (2H, s,
CH2CO), 7.13 (2H, d, J: 8.76 Hz, AreH), 7.40 (1H, t, J: 7.28 Hz, 7.76 Hz,
AreH), 7.46e7.52 (3H, m, AreH), 7.83 (1H, d, J: 8.20 Hz, AreH), 7.94
(1H, d, J: 8.17 Hz, AreH), 8.24 (2H, d, J: 8.68 Hz AreH), 8.37 (2H, d, J:
8.68 Hz, AreH). Anal. Calcd. for C23H17FN2O3$H2O: C: 67.97, H: 4.71,
N: 6.89. Found: C: 67.85, H: 5.02, N: 6.90.
Yield: 85%. m.p. 186e188 ꢁC. IR(KBr)nmaks(cmꢀ1): 1702, 1647
(C]O), 1601e1500 (C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 6.30 (2H, s, CH2CO), 7.42 (1H, t, J: 7.62 Hz, and 7.41 Hz,
AreH), 7.50 (1H, J: 8.05 Hz and 7.21 Hz, AreH), 7.68 (2H, d, J:
8.14 Hz, AreH), 7.73 (2H, d, J: 8.03 Hz, AreH), 7.87 (1H, d, J: 8.13 Hz,
AreH), 7.94 (1H, d, J: 8.03 Hz, AreH), 8.16 (2H, d, J: 8.03 Hz, AreH),
8.34 (2H, d, J: 7.99 Hz, AreH). MS: (35 eV, electron spray) m/z 409
(M þ 1, 100%), 410 (M þ 2, 16%), 411 (M þ 3, 42%), 412 (M þ 4, 16%).
Anal. Calcd. for C22H14Cl2N2O2$2H2O: C: 61.62, H: 4.23, N: 6.53.
Found: C: 61.45, H: 4.20, N: 6.42.
4.1.11. 1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-(4-methoxybenzoyl)
benzimidazole (2J)
Yield: 77%. m.p. 184e186 ꢁC. IR(KBr)nmaks(cmꢀ1): 1700, 1638 (C]
O), 1599e1495 (C]N and C]C), 1288, 1223 (CeOeAr) 1H NMR

S. Demirayak et al. / European Journal of Medicinal Chemistry 46 (2011) 411e416
415
4.1.17. General procedure for 1,3-diarylpyrazino[1,2-a]
4.1.23. 1-(4-Methoxyphenyl)-3-(4-fluorophenyl)pyrazino[1,2-a]
benzimidazoles (3aeo)
benzimidazole (3i)
A mixture of suitable 2aeo (1 mmol) and ammonium acetate
(10 mmol) in 0.5 mL of acetic acid was irradiated at power 600 W in
a Microwave Organic Synthesis Apparatus for 2 min. The solution
was cooled, poured into ice-water and neutralized with sodium
carbonate. The precipitate formed was filtered and crystallized in
ethanol.
Yield: 65%. m.p. 211e213 ꢁC. IR(KBr)nmaks(cmꢀ1): 1615e1509
(C]N ve C]C), 1288, 1218 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6) d (ppm): 3.90 (3H, s, OCH3), 7.22 (2H, J: 9.91 Hz, AreH), 7.43 (2H,
t, J: 8.84 Hz, AreH), 7.56e7.59 (1H, m, AreH), 7.66e7.68 (1H, m,
AreH), 8.06 (1H, d, J: 9.00 Hz, AreH), 8.33e8.37 (2H, m, AreH), 8.57
(1H, d, J: 8.26 Hz), 9.07 (2H, d, J: 8.96 Hz, AreH), 9.68 (1H, s, AreH).
Anal. Calcd. for C23H16FN3O2: C: 74.78, H: 4.37, N: 11.38. Found: C:
74.34, H: 4.22, N: 11.05.
4.1.18. 1-Phenyl-3-(4-methoxyphenyl)pyrazino[1,2-a]
benzimidazole (3c)
Yield: 78%. m.p. 210e211 ꢁC. IR(KBr)nmaks(cmꢀ1): 1606e1500
4.1.24. 1-(4-Methoxyphenyl)-3-(4-chlorophenyl)pyrazino[1,2-a]
benzimidazole (3j)
(C]N ve C]C), 1280, 1226 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6)
d
(ppm): 3.86 (3H, s, OCH3), 7.15 (2H, J: 8.95 Hz, AreH),
Yield: 79%. m.p. 226e227 ꢁC. IR(KBr)nmaks(cmꢀ1): 1609e1490
7.56e7.59 (1H, m, AreH), 7.60e7.63 (1H, m, AreH), 7.65e7.68 (2H,
m, AreH), 8.06 (1H, J: 8.25 Hz, AreH), 8.28 (2H, d, J: 8.80 Hz, AreH),
8.60 (1H, d, J: 8.60 Hz, AreH), 9.03 (2H, d, J: 7.13 Hz, AreH), 9.67
(1H, s, AreH). MS: (35 eV, electron spray) m/z 351.1 (M þ 1, 100%),
352.1 (M þ 2, 25%), 353 (M þ 3, 12%). Anal. Calcd. for C23H17N3O: C:
78.61, H: 4.86, N: 11.96. Found: C: 78.56, H: 4.70, N: 11.78.
(C]N and C]C), 1278, 1222 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6) d (ppm) : 3.88 (3H, s, OCH3), 7.16 (2H, J: 8.90 Hz, AreH), 7.53 (1H, t,
J: 7.36 Hz and 7.80 Hz, AreH), 7.59 (2H, d, J: 8.55 Hz, AreH), 7.62 (1H,
t, J: 7.49 Hz and 6.63 Hz, AreH), 8.02 (1H, d, J: 8.24 Hz, AreH), 8.27
(2H, d, J: 8.55 Hz, AreH), 8.50 (1H, d, J: 8.23 Hz, AreH), 9.01 (2H, d, J:
8.88 Hz, AreH), 9.63 (1H, s, AreH). Anal. Calcd. for C23H16ClN3O: C:
71.60, H: 4.18, N: 10.89. Found: C: 71.65, H: 4.26, N: 11.00.
4.1.19. 1-Phenyl-3-(4-fluorophenyl)pyrazino[1,2-a]benzimidazole
(3d)
4.1.25. 1-(4-Chlorophenyl)-3-phenylpyrazino[1,2-a]benzimidazole
(3k)
Yield: 75%. m.p. 214e216 ꢁC. IR(KBr)nmaks(cmꢀ1): 1628e1508
(C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d
(ppm): 7.35 (2H, t,
Yield: 83%. m.p. 251e252 ꢁC. IR(KBr)nmaks(cmꢀ1): 1600e1498
J: 8.78 Hz, AreH), 7.50 (1H, t, J: 7.5 Hz, AreH), 7.55e7.59 (4H, m,
AreH), 8.00 (1H, d, J: 8.23 Hz, AreH), 8.27 (2H,, dd, J: 8.67 Hz and
5.52 Hz, AreH), 8.49 (1H, d, J: 8.25 Hz, AreH), 8.96 (2H, d, J: 8.19 Hz,
AreH), 9.60 (1H, s, AreH). Anal. Calcd. for C22H14FN3: C: 77.86, H:
4.16, N: 12.38. Found: C: 77.80, H: 4.20, N: 12.00.
(C]N and C]C), 1280, 1221 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6) d (ppm): 2.41 (3H, s, CH3), 7.33 (2H, J: 8.98 Hz, AreH), 7.54 (1H, t,
J: 7.25 Hz and 7.88 Hz, AreH), 7.63 (1H, t, J: 7.31 and 7.98 Hz, AreH),
7.68 (1H, d, J: 9.63 Hz, AreH), 8.02 (1H, d, J: 8.10 Hz, AreH), 8.14 (2H,
d, J: 8.54 Hz, AreH), 8.25 (1H, d, J: 8.54 Hz, AreH), 9.05 (2H, d, J:
8.64 Hz, AreH), 9.62 (1H, s, AreH). Anal. Calcd. for C22H14ClN3: C:
74.26, H: 3.97, N: 11.81. Found: C: 74.45, H: 4.20, N: 11.52.
4.1.20. 1-(4-Methoxyphenyl)-3-phenylpyrazino[1,2-a]
benzimidazole (3f)
Yield: 72%. m.p. 245e247 ꢁC. IR(KBr)nmaks(cmꢀ1): 1608e1505
4.1.26. 1-(4-Chlorophenyl)-3-(4-methylphenyl)pyrazino[1,2-a]
benzimidazole (3l)
(C]N and C]C), 1270, 1212 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6)
d
(ppm) : 3.87 (3H, s, OCH3), 7.17 (2H, d, J: 8.90 Hz, AreH), 7.43
Yield: 85%. m.p. 256e257 ꢁC. IR(KBr)nmaks(cmꢀ1): 1616e1500
(1H, t, J: 7.31 Hz and J: 7.27 Hz, AreH), 7.51e7.56 (3H, m, AreH), 7.62
(1H, t, J: 7.61 Hz and J: 7.54 Hz, AreH), 8.03 (1H, d, J: 8.23 Hz, AreH),
8.27 (2H, d, J: 7.52 Hz, AreH), 8.54 (1H, d, J: 8.23 Hz, AreH), 9.04(2H,
d, J: 8.88 Hz, AreH), 9.60 (1H, s, AreH). Anal. Calcd. for C23H17N3O:
C: 78.61, H: 4.86, N: 11.96. Found: C: 78.68, H: 4.57, N: 12.00.
(C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d (ppm): 2.41 (3H, s,
CH3), 7.29 (2H, J: 8.16 Hz, AreH), 7.57e6.60 (1H, m, AreH),
7.66e7.69 (1H, m, AreH), 7.74 (2H, d, J: 8.66 Hz, AreH), 8.07 (1H, d,
J: 8.26 Hz, AreH), 8.21 (2H, d, J: 8.16 Hz, AreH), 8.61 (1H, d, J:
8.28 Hz, AreH), 9.11 (2H, d, J: 8.67 Hz, AreH), 9.73 (1H, s, AreH).
Anal. Calcd. for C23H13ClN3: C: 74.69, H: 4.36, N: 11.36. Found: C:
74.73, H: 4.23, N: 11.20.
4.1.21. 1-(4-Methoxyphenyl)-3-(4-methylphenyl)pyrazino[1,2-a]
benzimidazole (3g)
Yield: 68%. m.p. 240e241 ꢁC. IR(KBr)nmaks(cmꢀ1): 1608e1500
4.1.27. 1-(4-Chlorophenyl)-3-(4-methoxyphenyl)pyrazino[1,2-a]
benzimidazole (3m)
(C]N and C]C), 1286, 1218 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6)
d
(ppm): 2.41 (3H, s, CH3), 3.91 (3H, s, OCH3), 7.22 (2H, J: 8.99 Hz,
Yield: 70%. m.p. 220e223 ꢁC. IR(KBr)nmaks(cmꢀ1): 1622e1510
AreH), 7.39 (2H, d, J: 8.13 Hz, AreH), 7.55e7.58 (1H, m, AreH),
7.64e7.67 (1H, m, AreH), 8.06 (1H,, J: 8.29 Hz, AreH), 8.22 (2H, d, J:
8.16 Hz, AreH), 8.59 (1H, d, J: 9.00 Hz), 9.08 (2H, d, J: 9.01 Hz,
AreH), 9.65 (1H, s, AreH). MS: (35 eV, electron spray) m/z 366.1
(M þ 1, 100%), 367.1 (M þ 2, 28%). Anal. Calcd. for C22H14Cl2N2O2: C:
61.62, H: 4.23, N: 6.53. Found: C: 61.45, H: 4.20, N: 6.42.
(C]N and C]C), 1285, 1220 (CeOeAr) 1H NMR(500 MHz)(DMSO-
d6) d (ppm) : 3.86 (3H, s, OCH3), 7.56e6.61 (1H, m, AreH), 7.66e7.69
(1H, m, AreH), 7.75 (2H,, d, J: 8.67 Hz, AreH), 8.07 (1H, d, J: 8.32 Hz,
AreH), 8.25 (2H, d, J: 8.79 Hz, AreH), 8.60 (1H, d, J: 8.26 Hz, AreH),
9.11 (2H, d, J: 8.68 Hz, AreH), 9.70 (1H, s, AreH). MS: (35 eV,
electron spray) m/z 386.1 (M þ 1, 100%), 387.1 (M þ 2, 25%), 388.0
(M þ 3, 36%). Anal. Calcd. for C23H16ClN3O: C: 71.60, H: 4.18, N:
10.89. Found: C: 72.00, H: 3.90, N: 10.50.
4.1.22. 1-(4-Methoxyphenyl)-3-(4-methoxyphenyl)pyrazino[1,2-a]
benzimidazole (3h)
Yield: 74%. m.p. 210e211 ꢁC. IR(KBr)nmaks(cmꢀ1): 1626e1505
4.1.28. 1-(4-Chlorophenyl)-3-(4-fluorophenyl)pyrazino[1,2-a]
benzimidazole (3n)
(C]N and C]C), 1280, 1216 (CeOeAr), 1H NMR(500 MHz)(DMSO-
d6)
d
(ppm): 3.83 (3H, s, OCH3), 3.88 (3H, s, OCH3), 7.09 (2H, J :
Yield: 83%. m.p. 255e257 ꢁC. IR(KBr)nmaks(cmꢀ1): 1612e1490
8.80 Hz, AreH), 7.16 (2H, d, J: 8.98 Hz, AreH), 7.51 (1H, t, J: 7.45 Hz
and 7.61 Hz, AreH), 7.61 (1H, d, J: 8.06 Hz and 7.23 Hz, AreH), 8.01
(1H, d, J: 8.24 Hz, AreH), 8.18 (2H, d, J: 8.76 Hz, AreH), 8.50 (1H, d, J:
8.99 Hz), 9.03 (2H, d, J: 8.15 Hz, AreH), 9.48 (1H, s, AreH). Anal.
Calcd. for C24H19N3O: C: 78.88, H: 5.24, N: 11.50. Found: C: 79.02, H:
5.28, N: 11.64.
(C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d (ppm): 7.32 (2H, t,
J: 7.95 Hz, AreH), 7.50 (1H, t, J: AreH), 7.58e7.62 (3H, m, AreH),
7.97 (1H, d, J: 8.22 Hz, AreH), 8.21 (2H,, dd, J: 8.67 Hz and 5.52 Hz,
AreH), 8.45 (1H, d, J: 8.22 Hz, AreH), 8.97 (2H, d, J: 8.65 Hz,), 9.57
(1H, s, AreH). Anal. Calcd. for C22H13ClFN3: C: 70.69, H: 3.51, N:
11.24. Found: C: 70.60, H: 3.68, N: 11.02.

416
S. Demirayak et al. / European Journal of Medicinal Chemistry 46 (2011) 411e416
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4.1.29. 1-(4-Chlorophenyl)-3-(4-chlorophenyl)pyrazino[1,2-a]
benzimidazole (3o)
Yield: 86%. m.p. 248e250 ꢁC. IR(KBr)nmaks(cmꢀ1): 1628e1510
(C]N and C]C), 1H NMR(500 MHz)(DMSO-d6)
d (ppm): 7.56e6.60
(1H, m, AreH), 7.63 (2H, d, J: 8.57 Hz, AreH), 7.65e7.70 (1H, m,
AreH), 7.72 (2H, d, J: 8.67 Hz, AreH), 8.06 (1H, d, J: 8.30 Hz, AreH),
8.31 (2H, d, J: 8.58 Hz, AreH), 8.56 (1H, d, J: 8.26 Hz, AreH), 9.07 (2H,
d, J: 8.66 Hz, AreH), 9.79 (1H, s, AreH). Anal. Calcd. for C22H13Cl2N3:
C: 67.71, H: 3.36, N: 10.77. Found: C: 68.00, H: 3.67, N: 10.55.
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cell lines derived from nine neoplastic diseases namely; Leukemia
(L, 4 or 6 cell lines), Non-Small Cell Lung Cancer (NSCLC, 9 cell lines),
ColonCancer(CC, 7 cell lines), Central Nervous System Cancer (CNSC,
6 cell lines), Melanoma (M, 8 or 9 cell lines), Ovarian Cancer (OC, 6 or
7 cell lines), Renal Cancer (RC, 8 cell lines), Prostate Cancer (PC, 2 cell
lines), Breast Cancer (BC, 6 or 8 cell lines). The evaluation of anti-
cancer activity was performed at the National Cancer Institute (NCI)
of Bethesda, USA, following the in vitro screening program, which is
based upon the use of multiple panels of 60 human tumour cell lines
against which our compounds were tested at 10-fold dilutions of five
concentrations ranging from 10ꢀ4 to 10ꢀ8 M. The percentage growth
was evaluated spectrophotometrically versus controls not treated
with test agents. A 48 h continuous drug exposure protocol was
followed and a sulforhodamine B (SRB) protein assay was used to
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Acknowledgement
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The authors present their thanks to NCI (USA) and Anadolu
University BIBAM (Türkiye) for anticancer test results and NMR
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