Synthesis of Novel 6-Mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinones

Article abstract of DOI:10.1002/jhet.2470

Novel 6-mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinone derivatives were synthesized through a user-friendly five-step reaction starting from isatoic anhydride. All products were characterized by IR,¹H-NMR,¹³C-NMR spectroscopy, and chemical analysis. All of them were evaluated for their in vitro cytotoxic activity against two cell lines namely MOLT-4 (human lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma).

Full text of DOI:10.1002/jhet.2470

Month 2015
Synthesis of Novel 6-Mercapto-12-phenethyl-quinazolino[3,4-a]
quinazolinones
a
a
b
b
*
Negar Mohammadhosseini, Shahram Moradi, Mehdi Khoobi and Abbas Shafiee
aFaculty of Chemistry, Tehran-North Branch, Islamic Azad University, Tehran, Iran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, Tehran, Iran
*
E-mail: ashafiee@ams.ac.ir
Received March 14, 2015
DOI 10.1002/jhet.2470
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Novel 6-mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinone derivatives were synthesized through a
user-friendly five-step reaction starting from isatoic anhydride. All products were characterized by IR,
1H-NMR, 13C-NMR spectroscopy, and chemical analysis. All of them were evaluated for their in vitro
cytotoxic activity against two cell lines namely MOLT-4 (human lymphoblastic leukemia) and MCF-7
(human breast adenocarcinoma).
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
preparation of quinazlinone derivatives is based on the
isatoic anhydride as a useful starting material [13,14]. At
this juncture, we have successfully developed efficient
procedures for the synthesis of a wide range of derivatives
of quinazolinone [15–18] and significant results
encouraged us to continue our research into the new
quinazolinones (Scheme 1). Herein, based on the antican-
cer activity of quinazolines and our experience in this field
[19–21], we synthesized novel 6-mercapto-12-phenethyl-
quinazolino[3,4-a]quinazolinone derivatives 9. Also, all
derivatives were evaluated in vitro against two cell lines
including MOLT-4 and MCF-7.
Quinazoline and its derivatives have occupied a signifi-
cant position in medicinal chemistry to explore novel
and efficient bioactive frameworks [1]. They have attracted
lots of attention owing to their versatile biological
properties such as antimicrobial [2], anticancer [3], anti-
cholinesterase [4], and antihypertensive [5] activities. In
this respect, quinazolinones have shown vital medicinal
properties and synthesis of novel derivatives has been im-
portant area of heterocyclic chemistry [6]. The efficiency
of quinazolines as anticancer agents goes back to the
discovery of raltitrexed (A) [7] and thymitaq (B) [8]
(Fig. 1). Among various quinazoline derivatives, mercapto-
substituted quinazolinones (C–E, Fig. 2) absorbed our
attention because of their important anticancer activity [9].
Important medicinal properties of fused quinazoiline de-
rivatives have attracted lots of attention, and in this regard,
there are various reports on the versatile procedure for
their synthesis. Some fused quinazolinone scaffolds were
synthesized through a palladium-catalyzed carbonylative
coupling followed by an intramolecular nucleophilic aro-
matic substitutions [10]. In a work described by Kamal
and Sattur, imidazo-fused quinazolinones were prepared
by the Baker’s yeast promoted cyclization reaction of
anthranilonitriles and ally1 isocyanatein [11]. Ibrahim et
al. prepared various fused quinazolines via the reaction of
quinazolin-4(3H)-ones with different and versatile nucleo-
philic reagents [12]. One of the versatile methods for the
RESULTS AND DISCUSSION
Chemistry. To prepare novel 6-mercapto-12-phenethyl-
quinazolino[3,4-a]quinazolinone 9, a five-step reaction
starting from isatoic anhydride was applied (Scheme 1).
At first, 2-amino-N-phenethylbenzamide 3 was easily
prepared from the reaction of isatoic anhydride 1 and 2-
phenylethan-1-amine 2 in water at room temperature [22].
Then, 2-(2-nitrophenyl)-3-phenethyl-2,3-dihydroquinazolin-4
(1H)-one 5 was synthesized through the reaction of
2-phenylethan-1-amine 2 and 2-nitrobenzaldehyde 4 in
refluxing EtOH in the presence of potassium carbonate.
The latter compound 5 tolerated reduction using Zn
and further reaction with carbon disulfide (CS2) to give
2-(2-aminophenyl)-3-phenethyl-2,3-dihydroquinazolin-
© 2015 HeteroCorporation

N. Mohammadhosseini, S. Moradi, M. Khoobi and A. Shafiee
Vol 000
signal at 6.78ppm was related to CH. As demonstrated in
Scheme 1, aromatic protons including H1, H2, H3, H4,
H8, H9, H10, H11, and phenyl protons were distinguished
in the range of 6.80–8.20ppm according to the expected
chemical shifts and coupling patterns that were detailed in
the experimental section. The most deshielded signal
belonged to the amide NH proton at 9.09ppm. 13C-NMR
spectrum showed expected 27 signals including 19
aromatic (between 110.4 and 167.9ppm) and 8 aliphatic
signals (between 24.5 and 69.7ppm).
Figure 1. The structure of raltitrexed (A) and thymitaq (B).
According to 13C-NMR data, it was found that
S-alkylation reaction was successfully achieved because
C = S carbon signal at 175.9ppm for compound 7 was
not observed for compounds 9 that confirmed S-alkylation
instead of N-alkylation.
Biological investigation. The in vitro cytotoxic activity of
all 6-mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinones
9 was evaluated against two cancer cell lines including
MOLT-4 and MCF-7 cells and compared with
doxorubicin as the reference drug. All results have been
summarized in Table 1. According to IC50 values, all
products except compounds 9p and 9r showed no
cytotoxicity. It seems that the presence of methoxy and
chlorine groups led to the elimination of cytotoxic
activity. Our results revealed that the presence of methyl
group especially at 4-position of aryl connected to
acetamide moiety (9p) increased cytotoxicity in both
cell line. Compound 9r having two methyl groups at
3,4-positions of aryl connected to acetamide moiety
showed better activity in MOLT4 cell line in
comparison with compound 9p. However, it exhibited
no activity against MCF-7 cell line.
Figure 2. The structure of mercapto-substituted quinazolinones C–E.
4(1H)-one 6 and 12-phenethyl-6-thioxo-11b,12-dihydro-6H-
quinazolino[3,4-a]quinazolin-13(7H)-one 7, respectively
[22]. Then, the reaction of compound 7 and 2-chloro-N-
substituted acetamides 8 was investigated under various
conditions to afford the title compounds 9. The solvent
and temperature screening confirmed that conducting the
reaction in the presence of potassium iodide in acetone at
room temperature led to the formation of the desired
products 9 in good yield (Table 1). It should be note that
2-chloro-N-substituted acetamides 8 were prepared by the
reaction of various amines and chloroacetyl chloride in
DMF at room temperature.
The structure of all products was confirmed by IR,
1H-NMR, 13C-NMR spectroscopy, and chemical analysis.
1
For example, in the H-NMR spectrum of N-cyclohexyl-
2-((13-oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)acetamide 9a, cyclohexyl pro-
tons were observed in the range of 0.79–1.88ppm (CH2)
as well as 3.56–3.64ppm (CH). Presence of three groups
of methylene protons (NCH2, PhCH2, and SCH2) were
confirmed by the signals at 2.27, 2.72, 3.10, 3.56–3.64,
and 3.78ppm that appeared as diastrophic protons. Singlet
CONCLUSIONS
In conclusion, we have developed a user-friendly and
effectual method for the synthesis of novel 6-mercapto-
12-phenethyl-quinazolino[3,4-a]quinazolinone derivatives.
Synthesis of the title compounds was achieved through a
five-step reaction starting from isatoic anhydride. In
Scheme 1. Synthesis of novel 6-mercapto-12-phenethyl-quinazolino[3,4-a]quinazolinones 9.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Quinazolino[3,4-a]quinazolinones
Table 1
Cytotoxic activity of newly synthesized compounds 9 assessed by the MTT reduction assay.
MOLT-4 cell line
MCF-7 cell line
Entry
Product 9
X
IC50 (μM)
IC50 (μM)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
Cyclohexyl
C6H5
>100
>100
>100
>100
>100
>100
>100
>100
>50
>100
>100
>100
>100
>100
>100
>100
>100
>50
2-OMe-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,5-diOMe-C6H3
3,4-diOMe-C6H3
3,4,5-triOMe-C6H2
2-Cl-C6H4
9
10
9j
3-Cl-C6H4
>100
>100
11
12
13
14
15
16
17
18
9k
9l
4-Cl-C6H4
>100
>100
>100
>100
>100
>100
>100
>100
2,5-diCl-C6H3
3,4-diCl-C6H3
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
9m
9n
9o
9p
9q
9r
>100
15.3 3.1
>100
14.2 2.3
0.023 0.002
>100
13.4 4.8
>100
>100
0.053 0.009
2,5-diMe-C6H3
3,4-diMe-C6H3
Doxorubicin
Values represent mean SEM of 3–4 independent experiments.
*The compound did not lower cell viability below 50%; therefore, IC50 was reported as more than the maximum
tested concentrations.
addition, all compounds were evaluated for their cytotoxic
activity against two cell lines, MOLT-4 and MCF-7 cells.
Although most of compounds showed no activity against
two cancer cell lines, compounds 9p and 9r were found to
be effective as cytotoxic agent.
precipitates were filtered off and used for the next step
without further purification.
Procedure for the synthesis of 2-(2-nitrophenyl)-3-phenethyl-2,
3-dihydroquinazolin-4(1H)-one (5). A mixture of 2-amino-
N-phenethylbenzamide 3 (2mmol), 2-nitrobenzaldehydes 4
(2mmol), and potassium carbonate (2mmol) was stirred in
refluxing EtOH (10mL) for 6h. After completion of the
reaction, potassium carbonate was filtered off from the hot
solution, and it was cooled down to room temperature to
give product 5 as yellow crystals.
EXPERIMENTAL
Melting points were taken on a Kofler hot stage
(England) apparatus and are uncorrected. 1H-NMR and
13C-NMR spectra were recorded on Bruker FT-500 and
FT-400 (Germany), using TMS as an internal standard.
The IR spectra were obtained on a Nicolet Magna FTIR
550 spectrometer (USA). The elemental analysis was
performed with an Elementar Analysensystem GmbH
VarioEL CHNS mode (Germany).
Procedure for the synthesis of 2-(2-aminophenyl)-3-
phenethyl-2,3-dihydroquinazolin-4(1H)-one (6). A methanol
solution (12 mL) containing 2-(2-nitrophenyl)-3-phenethyl-2,
3-dihydroquinazolin-4(1H)-one
5
(1mmol) and an
aqueous solution (2 mL) of NH4Cl (6mmol) were
combined, and zinc powder (20 mmol) was added to the
mixture in small portions at room temperature for 10min.
The reaction mixture was stirred for 2 h, and after
completion of the reaction, the solid was removed by
filtration through celite. Concentration of the filtrate gave
a white solid that was used without purification.
Procedure for the synthesis of 2-amino-N-phenethyl
benzamide (3).
A mixture of isatoic anhydride 1
(10 mmol) and 2-phenylethan-1-amine 2 (10 mmol) in
water (25 mL) was stirred for 3 h at room temperature.
Upon completion of the reaction, the obtained off-white
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Mohammadhosseini, S. Moradi, M. Khoobi and A. Shafiee
Vol 000
Procedure for the synthesis of 12-phenethyl-6-thioxo-6,
7,11b,12-tetrahydro-13H-quinazolino[3,4-a]quinazolin-13-
one (7). A mixture of 2-(2-aminophenyl)-3-phenethyl-
43.0, 48.2, 69.7, 116.4, 123.8, 124.7, 125.4, 126.3, 127.2,
128.3, 128.6, 128.8, 129.2, 131.3, 131.8, 135.6, 138.1,
139.2, 141.1, 156.8, 162.2, 167.9; Anal. Calcd. for
C31H32N4O2S: C, 70.96; H, 6.15; N, 10.68. Found: C,
71.14; H, 6.28; N, 10.51.
2,3-dihydroquinazolin-4(1H)-one 6 (2 mmol), carbon
disulfide (CS2) (5 mmol), and potassium hydroxide
(KOH) (2 mmol) in EtOH (10 mL) was heated at reflux
for 6 h. After completion of the reaction, the reaction
mixture was cooled down to room temperature, poured
in ice-cold water, and the white precipitates were
filtered off and recystilized from EtOH to give pure
produts 7.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-phenylacetamide (9b).
White
crystals; yield: 28%; mp 157–128°C; IR (KBr, cmÀ1) υ:
1
3450, 1695, 1662; H-NMR (500MHz, CDCl3) δ ppm:
2.14–2.18 (m, 1H, CH2), 2.41–2.57 (m, 1H, CH2),
2.92–3.01 (m, 1H, CH2), 3.46–3.56 (m, 1H, CH2), 4.02
(d, J=19.0Hz, 1H, SCH2), 4.09 (d, J=19.0Hz, 1H,
SCH2), 6.45 (s, 1H, CH), 6.70–6.74 (m, 2H, H2, H4),
6.27–7.03 (m, 1H, Ph), 7.08–7.30 (m, 6H, Ph- H9), 7.32
(t, J=6.8Hz, 1H, H10), 7.49 (d, J=6.8Hz, 1H, H8),
7.48–7.60 (m, 4H, ph), 7.64–7.74 (m, 1H, H11), 7.702
(t, 1H, H3), 8.03 (dd, J=1.2, 7.6Hz, 1H, H1), 10.30
(s, 1H, NH); 13C-NMR (125MHz, CDCl3) δ ppm: 35.1,
36.9, 42.7, 68.8, 116.0, 117.3, 119.6, 121.2, 123.8, 124.0,
125.5, 126.6, 127.2, 128.7, 128.1, 129.2, 129.7, 131.5,
132.6, 138.7, 139.3, 139.5, 155.9, 162.0, 166.3, 171.1;
Anal. Calcd. for C31H26N4O2S: C, 71.79; H, 5.05; N,
White crystals; yield: 75%; mp >250°C; IR (KBr, cmÀ1
)
υ: 3199, 3016, 2949, 1639, 1579; 1H-NMR (500MHz,
DMSO-d6) δ ppm: 2.24–2.28 (m, 1H, CH2), 3.01–3.05
(m, 1H, CH2), 3.49–3.51 (m, 2H, NCH2), 6.59 (s, 1H,
CH), 6.77–6.79 (m, 2H, H11, Ph), 7.14–7.18 (m, 2H, Ph),
7.28–7.30 (m, 2H, H8, H10), 7.48 (t, J=7.3Hz, 1H, H9),
7.56–7.61 (m, 4H, H2, H3, Ph), 7.71 (d, J=7.5Hz, 1H,
H4), 7.95 (d, J=7.5Hz, 1H, H1), 12.02 (s, 1H, NH);
13C-NMR (125MHz, DMSO-d6) δ ppm: 34.8, 42.7,
68.8, 113.6, 114.7, 123.8, 126.2, 126.3, 126.9, 127.1,
127.3, 128.3, 128.4, 130.8, 131.4, 134.8, 135.0, 138.1,
142.5, 162.5, 175.9; Anal. Calcd. for C23H19N3OS:
C, 71.66; H, 4.97; N, 10.90. Found: C, 71.45; H, 5.17;
N, 11.12.
10.80; Found: C, 71.54; H, 4.85; N, 10.94.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2-methoxyphenyl)acetamide
(9c).
White crystals; yield: 22%; mp 172–174°C; IR
Procedure for the synthesis of 6-mercapto-12-phenethyl-
(KBr, cmÀ1) υ: 3256, 1679, 1657; H-NMR (500MHz,
CDCl3) δ ppm: 2.04–2.15 (m, 1H, CH2), 2.30–2.38
(m, 1H, CH2), 2.92–3.01 (m, 1H, CH2), 3.42–3.51
(m, 1H, CH2), 3.60 (s, 3H, OCH3), 3.99 (d, J= 14.8 Hz,
1H, CH2), 4.11 (d, J= 14.8, 1H, CH2), 6.47 (s, 1H, CH),
6.63–6.68 (d, J = 6.4 Hz, 2H, H4,H3′), 6.77–6.87
(m, 2H, H2, H3), 6.95 (t, J=7.6Hz, 1H, H10), 7.08–7.17
(m, 3H, Ph), 7.34–7.42 (m, 2H, Ph), 7.52 (d, J=7.2Hz,
1H, H6), 7.55–7.66 (m, 3H, Ph), 7.69 (t, J=7.2Hz, 1H,
H3), 8.02 (t, J=9.5Hz, 2H, H1, H10), 9.56 (s, 1H,
NH);13C-NMR (125MHz, CDCl3) δ ppm: 34.9, 36.0,
42.7, 55.8, 68.9, 111.1, 113.4, 116.3, 117.4, 120.6,
120.7, 122.2, 124.3, 124.4, 125.5, 125.73, 126.1, 127.2,
127.5, 128.6, 128.8, 129.8, 131.4, 132.6, 138.6, 139.8,
141.5, 148.9, 156.1, 161.9, 166.8, 170.2; Anal. Calcd.
for C32H28N4O3S: C, 70.05; H, 5.14; N, 10.21. Found:
1
quinazolino[3,4-a]quinazolinone derivatives (9).
At first,
2-chloro-N-substituted acetamides 8 were prepared. A
mixture of the corresponding amine (1mmol) and
chloroacetyl chloride (1 mmol) in DMF (5 mL) was
stirred at room temperature for 24 h. Then water (5 mL)
was added to the reaction mixture, and the precipitates
were filtered off to give product 8. A solution of
compound 7 (1mmol), compound 8 (1 mmol), and
potassium iodide (1 mmol) in acetone (8 ml) was refluxed
for 24h. After completion of reaction, water (8 mL) was
added to the reaction mixture, the precipitates were
filtered off, and recrystallized from EtOH /H2O (90/10) to
give the corresponding product 9.
N-Cyclohexyl-2-((13-oxo-12-phenethyl-11b,12-dihydro-13H-
quinazolino[3,4-a]quinazolin-6-yl)thio)acetamide (9a).
White
crystals; yield: 32%; mp 196–197°C; IR (KBr, cmÀ1) υ:
3023, 1684, 1659; 1H-NMR (500 MHz, CDCl3) δ ppm:
0.79–0.91 (m, 1H, Cyclohexyl), 0.92–1.05 (m, 2H,
Cyclohexyl), 1.16–1.30 (m, 2H, Cyclohexyl), 1.37–1.56
(m, 3H, Cyclohexyl), 1.77–1.88 (m, 2H, Cyclohexyl),
2.27 (td, J = 6.0, 12.0 Hz, 1H, CH2), 2.72 (td, J = 6.0,
12.0 Hz, 1H, CH2), 3.10 (td, J = 6.0, 12.0 Hz, 1H,
NCH2), 3.56–3.64 (m, 3H, NCH, NCH2, SCH2), 3.78
(d, J = 14.4Hz, 1H, SCH2), 6.78 (s, 1H, CH), 6.79
(d, J=7.0Hz, 1H, H4), 7.10–7.20 (m, 3H, H8, H9, H10),
7.32 (t, J=7.0Hz, 1H, H2), 7.38 (d, J=7.8Hz, 1H, H11),
7.47–7.58 (m, 5H, Ph), 7.60 (t, J=7.0Hz, 1H, H3), 8.19
(d, J=7.0Hz, 1H, H1), 9.09 (s, 1H, NH); 13C-NMR
(125MHz, CDCl3) δ ppm: 24.5, 25.1, 32.7, 34.7, 35.4,
C, 70.25; H, 4.87; N, 9.97.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3-methoxyphenyl)acetamide
(9d). White crystals; yield: 26%; mp 122–124°C; IR
(KBr, cmÀ1) υ: 3533, 1696, 1667; H-NMR (500 MHz,
1
CDCl3) δ ppm: 2.06–2.16 (m, 1H, CH2), 2.40–2.53
(m, 1H, CH2), 2.88–2.31 (m, 1H, CH2), 3.46–3.56
(m, 1H, CH2), 3.65 (s, 3H, OCH3), 4.01 (d, J=18.5Hz,
1H, CH2), 4.08 (d, J = 8.5 Hz, 1H, CH2), 6.45 (s, 1H,
CH), 6.58 (dd, J = 2.0, 8.0 Hz, 1H, H4′), 6.69–6.75
(m, 2H, H2, H4), 7.05–7.09 (m, 1H, H8), 7.10–7.18
(m, 4H, Ph), 7.24–7.28 (m, 2H, H6′, H9), 7.32
(t, J = 9.0 Hz, 1H, H5′), 7.49 (d, J = 8.0 Hz, 1H, H11),
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Month 2015
Quinazolino[3,4-a]quinazolinones
7.53–7.61 (m, 2H, H10, ph), 7.65 (d, J = 8.0 Hz, 1H,
H2′), 7.66–7.74 (m, 1H, H3), 8.03 (s, 1H, H1), 10.29
(s, 1H, NH);13C-NMR (125MHz, CDCl3) δ ppm: 35.0,
36.9, 42.7, 55.3, 68.8, 105.3, 109.2, 111.7, 113.4, 116.1,
117.3, 122.1, 123.9, 125.5, 126.6, 127.2, 128.7, 128.7,
129.9, 131.5, 132.5, 138.7, 139.9, 140.5, 141.7, 155.9,
159.9, 162.0, 166.3, 171.4; Anal. Calcd. for
C32H28N4O3S: C, 70.05; H, 5.14; N, 10.21. Found: C,
69.71; H, 5.27; N, 10.55.
CDCl3) δ ppm: 2.24 (td, J =6.0, 12.0Hz, 1H, CH2), 2.60
(td, J= 6.0, 12.0Hz, 1H, CH2), 3.09 (td, J =6.0, 12.0Hz,
1H, CH2), 3.63–3.70 (m, 1H, CH2), 3.68 (s, 3H, OCH3),
3.69 (s, 3H, OCH3), 3.86–3.99 (m, 2H, CH2), 6.21
(s, 1H, CH), 6.67 (d, J= 7.9 Hz, 1H, H2), 6.70–6.75
(m, J= 7.4Hz, 2H, H8, H11), 7.18–7.26 (m, 4H, Phenyl),
7.32 (d, J= 2.2Hz, 1H, H2′), 7.38 (t, J = 7.5Hz, 1H, H10),
7.53–7.61 (m, 5H, Phenyl), 7.65 (t, J= 7.8Hz, 1H,
H3),8.20 (d, J =6.8Hz, 1H, H1), 10.21 (s, 1H,
NH);13C-NMR (125 MHz, CDCl3) δ ppm: 35.0, 35.3, 42.9,
55.7, 55.9, 69.8, 104.0, 111.0, 111.1, 113.3, 123.4, 124.5,
125.8, 126.2, 127.1, 128.3, 128.6, 129.0, 129.1, 131.5,
131.7, 131.9, 138.1, 139.0, 140.8, 145.4, 148.9, 157.8,
162.1, 166.6, 171.0; Anal. Calcd. for C33H30N4O4S: C,
68.49; H, 5.23; N, 9.68. Found: C, 68.75; H, 4.95; N, 9.81.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(4-methoxyphenyl)acetamide
(9e). White crystals; yield: 20%; mp 180–182°C; IR
1
(KBr, cmÀ1) υ: 3294, 1685, 1667; H-NMR (500 MHz,
CDCl3) δ ppm: 2.11 (t, J = 11.5 Hz, 1H, CH2),
2.38–2.56 (m, 1H, CH2), 2.95 (t, J=11.5Hz, 1H, CH2),
3.51 (t, J=11.5Hz, 1H, CH2), 3.51 (t, J=11.5Hz, 1H,
CH2), 3.66 (s, 3H, OCH3), 3.99 (d, J=18.5Hz, 1H,
CH2), 4.05 (d, J=18.5Hz, 1H, CH2), 6.45 (s, 1H, CH),
6.71 (d, J=7.2Hz, 2H, H2, H4), 6.77 (d, J=8.8Hz, 2H,
H3′,H5′), 7.08–7.20 (m, 3H, Ph), 7.29 (t, J=7.5Hz, 1H,
H10), 7.33 (t, J=7.2Hz, 1H, Ph), 7.43 (d, J=7.6Hz,
1H, H11), 7.49 (d, J = 7.2 Hz, 1H, Ph), 7.56
(d, J = 7.2 Hz, 2H, H2′, H6′), 7.65 (d, J = 7.6 Hz, 1H,
H8), 7.65(t, J=7.6Hz, 1H, H3), 8.03 (d, J=8.0Hz, 1H,
H1), 10.15 (s, 1H, NH);13C-NMR (125 MHz, CDCl3)
δ ppm: 35.0, 36.8, 42.7, 55.5, 68.8, 114.2, 117.3,
121.1, 124.0, 125.5, 126.6, 127.2, 127.3, 128.6,
128.7, 128.7, 129.7, 131.5, 132.4, 132.5, 138.7,
140.0, 141.7, 155.7, 155.9, 161.9, 165.7, 171.8; Anal.
Calcd. for C32H28N4O3S: C32H28N4O3S: C, 70.05; H,
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3,4,5-trimethoxyphenyl)acetamide
(9h). White crystals; yield: 21%; mp 134–136°C; IR (KBr,
cmÀ1) υ: 3449, 1697, 1662cmÀ1 1H-NMR (500MHz,
;
CDCl3) δ ppm: 2.30–2.38 (m, 1H, CH2), 2.64–2.69 (m, 1H,
CH2), 3.26–3.44 (m, 1H, CH2), 3.50–3.55 (m, 1H, CH2),
3.98–4.03 (m, 2H, CH2), 3.67 (s, 6H, OCH3), 3.72 (s, 3H,
OCH3), 6.22 (s, 1H, CH), 6.72–6.75 (m, 2H, H2′, H6′),
6.75–6.79 (m, 2H, H4, H11), 7.13–7.23 (m, 4H, Ph),
7.38 (t, J=7.4Hz, 1H, H10), 7.52–7.60 (m, 4H, Ph), 7.62
(t, J=7.6Hz, 1H, H3), 8.21(d, J=7.2Hz, 1H, H1), 10.17
(s, 1H, NH); 13C-NMR (125MHz, CDCl3) δ ppm: 35.1,
35.6, 43.1, 55.8, 60.8, 69.8, 96.9, 113.3, 116.4, 123.2,
124.5, 124.9, 125.9, 126.4, 127.1, 128.4, 128.5, 128.7,
129.1, 129.2, 131.4, 132.0, 134.1, 134.4, 138.1, 138.9,
140.7, 147.3, 153.2, 162.2, 166.7, 171.5; Anal. Calcd. for
C34H32N4O5S: C, 67.09; H, 5.30; N, 9.20. Found: C, 67.24;
5.14; N, 10.21. Found: C, 70.44; H, 4.79; N, 10.46.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2,5-dimethoxyphenyl)acetamide
H, 5.15; N, 9.34.
(9f).
White crystals; yield: 84%; mp 164–165°C; IR
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2-chlorophenyl)acetamide
(9i). White crystals; yield: 45%; mp 193–195°C; IR
1
(KBr, cmÀ1) υ: 3342, 1678, 1654; H-NMR (500MHz,
CDCl3) δ ppm: 2.28 (td, J= 4.4, 11.5Hz, 1H, CH2), 2.54
(td, J =4.4, 11.5Hz, 1H, CH2), 3.12 (td, J= 4.4, 11.5Hz,
1H, CH2), 3.40 (s, 3H, OCH3), 3.56 (td, J =4.4, 11.5Hz,
1H, CH2), 3.75 (s, 3H, OCH3), 3.96 (d, J= 14.2Hz, 2H,
CH2), 6.17 (s, 1H, CH), 6.45 (dd, J=2.9, 2.8Hz, 1H, H4′),
6.48–6.53 (m, 1H, H2, H4), 6.73 (dd, J=.6, 6.7Hz, 2H,
H11, H8), 7.10–7.20 (m, 4H, Ph), 7.34 (t, J=7.0Hz, 1H,
H10), 7.48–7.58 (m, 4H, Ph), 7.60 (t, J=7.4Hz, 1H, H3),
8.05 (d, J=2.8Hz, 1H, H6′), 8.19 (d, J=7.7Hz, 1H, H1),
9.53 (s, 1H, NH);13C-NMR(125MHz, CDCl3) δ ppm:
34.9, 35.6, 42.9, 55.6, 55.7, 69.8, 106.2, 108.7, 110.4,
116.6, 124.8, 125.3, 126.1, 127.1, 128.0, 128.2, 128.3,
128.5, 128.6, 129.0, 130.9, 131.8, 138.3, 139.2, 141.4,
142.3, 153.5, 156.1, 162.2, 167.0, 169.9; Anal. Calcd. for
C33H30N4O4S: C, 68.49; H, 5.23; N, 9.68. Found: C,
(KBr, cmÀ1) υ: 3505, 1659, 1545; 1H-NMR: 2.24
(td, J=4.6, 10.8Hz, 1H, CH2), 2.56 (td, J=4.6, 10.8Hz,
1H, CH2), 3.14 (td, J=4.6, 10.8Hz, 1H, CH2), 3.53
(td, J=4.6, 10.8Hz, 1H, CH2), 3.84 (d, J=14.3Hz, 1H,
CH2), 4.16 (d, J=14.3Hz, 1H, CH2), 6.16 (s, 1H, CH),
6.73 (d, J=5.9Hz, 2H, H2, H4′), 6.87 (t, J=7.4, 1H, H10),
7.05 (d, J=7.8Hz, 1H, H8), 7.10 (d, J=7.5Hz, 1H, H11),
7.12–7.20 (m, 5H, Ph), 7.31 (t, J=7.5Hz, 1H, H3),
7.48–7.61 (m, 5H, Ph), 8.21 (s, 1H, H1), 9.5 (s, 1H, NH);
13C-NMR (125MHz, CDCl3) δ ppm: 34.9, 35.4, 43.0,
69.9, 113.4, 116.6, 122.2, 123.2, 124.6, 124.7, 125.5,
126.1, 127.1, 127.3, 128.2, 128.5, 128.6, 128.9, 129.1,
131.1, 131.9, 134.6, 138.2, 139.2, 141.2, 156.2, 162.2,
167.3, 178.6; Anal. Calcd. for C31H25ClN4O2S: C, 67.32;
68.73; H, 4.98; N, 10.01.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide
H, 4.56; N, 10.13. Found: C, 67.20; H, 4.30; N, 9.96.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3-chlorophenyl)acetamide
(9j). White crystals; yield: 64%; mp 152–153°C; IR
(9g).
White crystals; yield: 65%; mp 180–182°C; IR
(KBr, cmÀ1) υ: 3325, 1702, 1641; H-NMR (500MHz,
(KBr, cmÀ1
)
υ: 3425, 1700, 1663; 1H-NMR
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Mohammadhosseini, S. Moradi, M. Khoobi and A. Shafiee
Vol 000
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3,4-dichlorophenyl)acetamide
(9m). White crystals; yield: 47%; mp 178–180°C; IR
(500 MHz, CDCl3) δ ppm: 2.30–2.50 (m, 1H, CH2),
2.52–2.54 (m, 1H, CH2), 3.10–3.30 (m, 1H, CH2),
3.53–3.55 (m, 1H, CH2), 3.60–3.70 (m, 2H, CH2),
6.20 (s, 1H, CH), 6.73 (d, J = 7.7 Hz, 2H, H2, H6′),
6.93–6.99 (m, 2H, H5′, H4′), 7.08–7.14 (m, 1H, H11), 7.18–
7.22 (m, 4H, Ph), 7.38 (t, J=7.6Hz, 1H, H10), 7.46–7.54
(d, J = 7.7 Hz, 2H, H4, H8), 7.56–7.60 (m, 2H, H9, Ph),
7.61–7.64 (m, 1H, H3), 7.67 (t, J = 7.6 Hz, 1H, H2′),
8.20 (d, J = 7.9 Hz, 1H, H1), 10.21 (s, 1H, NH);13C-
NMR (125 MHz, CDCl3) δ ppm: 35.3, 35.4, 43.0,
69.7, 116.5, 117.2, 119.4, 123.5, 123.9, 124.5,
125.8, 126.3, 127.1, 128.3, 128.5, 128.6, 129.0,
129.1, 129.7, 131.6, 131.9, 134.5, 138.0, 139.0,
139.1, 140.8, 157.7, 162.1, 167.1; Anal. Calcd. for
C31H25ClN4O2S: C, 67.32; H, 4.56; N, 10.13. Found: C,
1
(KBr, cmÀ1) υ: 3230, 1690, 1648; H-NMR (500 MHz,
CDCl3) δ ppm: 2.19 (td, J=4.6, 12.1Hz, 1H, CH2), 2.59
(td, J=4.6, 12.1Hz, 1H, CH2), 3.08 (td, J=4.6, 12.1Hz,
1H, CH2), 3.69 (td, J=4.6, 12.1Hz, 1H, CH2), 5.75 (d,
J=14.1Hz, 1H, CH2), 3.89 (d, J=14.1Hz, 1H, CH2),
6.70 (s, 1H, CH), 6.46 (m, 2H, H2, H6′), 6.99
(d, J = 8.7 Hz, 1H, H5′), 7.05 (dd, J = 2.5, 7.4 Hz, 1H,
H11), 7.15–7.20 (m, 3H, H4, H9, Ph), 7.21 (d, J=6.8Hz,
1H, H8), 7.40 (td, J = 9.0, 8.0 Hz, 1H, H10), 7.48
d, J = 7.6 Hz, 1H, ph), 7.51–7.61 (m, 3H, Ph), 7.68
(td, J=1.2, 7.7 Hz, 1H, H3), 7.71 (d, J=2.3Hz, 1H, H2′),
8.19 (dd, J=1.8, 5.6Hz, 1H, H1), 10.19 (s, 1H,
NH);13C-NMR (125 MHz, CDCl3) δ ppm: 35.3, 35.4,
42.9, 69.7, 116.5, 118.4, 120.9, 123.3, 124.4, 125.9,
126.3, 126.9, 127.2, 128.3, 128.5, 128.6, 129.1, 129.1,
131.7, 132.0, 132.6, 137.4, 137.9, 138.9, 140.8, 157.7,
162.1, 167.1, 171.1; Anal. Calcd. for C31H24Cl2N4O2S: C,
67.65; H, 4.28; N, 9.78.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(4-chlorophenyl)acetamide
(9k). White crystals; yield: 35%; mp 231–232°C; IR
(KBr, cmÀ1) υ: 3527 (NH), 1688, 1658; 1H-NMR
(500 MHz, CDCl3) δ ppm: 2.20 (td, J = 4.5, 11.9 Hz,
1H, CH2), 2.60 (td, J = 4.5, 11.9, 1H, CH2), 3.07
(td, J = 4.5, 11.9 Hz, 1H, CH2), 3.70 (td, J = 4.5,
11.9Hz, 1H, CH2), 3.81 (d, J = 14.5 Hz, 1H, CH2),
3.91 (d, J=14.5Hz, 1H, CH2), 6.21 (s, 1H, CH), 6.70
(dd, J=1.6, 6.7Hz, 2H, H2, H4), 7.00 (d, J=8.7Hz,
2H, H8, H11), 7.16–7.25 (m, 4H, Ph), 7.31 (d, J=8.8Hz,
2H, H3′, H5′), 7.39 (t, J = 7.2 Hz, 1H, H10), 7.49
(d, J = 7.8 Hz, 1H, Ph), 7.53–7.61 (m, 3H, Ph), 7.67
(t, J = 7.6 Hz, 1H, H2′), 8.19 (d, J = 7.8 Hz, 1H, H1),
10.16 (s, 1H, NH);13C-NMR (125 MHz, CDCl3) δ
ppm: 35.3, 35.4, 42.9, 69.8, 113.4, 116.6, 120.4,
123.5, 124.5, 125.9, 126.3, 127.2, 128.4, 128.6, 128.8,
129.1, 129.1, 131.6, 132.0, 136.5, 158.0, 139.0, 140.9,
157.8, 162.1, 167.0, 169.8; Anal. Calcd. for
C31H25ClN4O2S: C, 67.32; H, 4.56; N, 10.13. Found:
63.37; H, 4.12; N, 9.54. Found: C, 63.56; H, 4.28; N, 9.34.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2-methylphenyl)acetamide
(9n).
White crystals; yield: 57%; mp 199–200°C; IR
1
(KBr, cmÀ1) υ: 3253, 1691, 1669; H-NMR (500MHz,
CDCl3) δ ppm: 2.18 (s, 3H, CH3), 2.32 (td, J = 4.5,
12.4 Hz, 1H, CH2), 2.65 (td, J= 4.5, 12.4 Hz, 1H, CH2),
3.21 (td, J= 4.5, 12.4Hz, 1H, CH2), 3.46 (td, J= 4.5,
12.4 Hz, 1H, CH2), 3.89 (d, J = 14.3Hz, 1H, CH2), 4.03
(d, J= 14.3 Hz, 1H, CH2), 6.18 (s, 1H, CH), 6.77 (d,
J = 7.5 Hz, 2H, H, H11), 6.94–7.01 (m, 2H, H10), 7.10–
7.20 (m, 5H, Ph), 7.31 (t, J = 7.4 Hz, 1H, H3), 7.41 (d,
J = 7.8 Hz, 1H, H8), 7.53–7.64 (m, 4H, Ph), 7.74 (d,
J = 8.0 Hz, 1H, H4), 8.21 (d, J =9.3 Hz, 1H, H1),(s, 1H,
NH);13C-NMR (125 MHz, CDCl3) δ ppm: 17.9, 34.9, 35.3,
43.0, 69.9, 113.4, 116.2, 123.1, 124.2, 124.7, 125.0, 125.6,
126.2, 126.5, 127.2, 127.6, 128.3, 128.5, 128.6, 128.7,
129.0, 129.1, 130.2, 131.3, 131.9, 141.0, 157.0, 162.3,
167.3, 171.2; Anal. Calcd. for C32H28N4O2S: C, 72.16; H,
5.30; N, 10.52. Found: C, 72.34; H, 5.11; N, 10.88.
C, 67.15; H, 4.70; N, 9.81.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2,5-dichlorophenyl)acetamide
(9l).
White crystals; yield: 62%; mp 197–199°C; IR
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3-methylphenyl)acetamide
(9o). White crystals; yield: 23%; mp 186–188°C; IR
1
(KBr, cmÀ1) υ: 3474, 1691, 1673; H-NMR (500 MHz,
CDCl3) δ ppm: 2.21 (td, J=4.7, 11.7Hz, 1H, CH2), 2.55
(td, J=4.7, 11.7Hz, 1H, CH2), 3.12 (td, J=4.7, 11.7Hz,
1H, CH2), 2.53 (td, J=4.7, 11.7Hz, 1H, CH2), 3.77 (d,
J=14.3Hz, 1H, CH2), 4.21 (d, J=14.3Hz, 1H, CH2),
6.16 (s, 1H, CH), 6.58–6.63 (m, 3H, H2, H6′, H4), 6.80
(dd, J=2.3, 8.6Hz, 1H, H4′), 6.91 (d, J=8.6Hz, 1H,
H3′), 7.09–7.10 (m, 4H, Ph), 7.31 (t, J=7.2Hz, 1H, H10),
7.46–7.63 (m, 5H, Ph), 8.20 (d, J=7.4Hz, 1H, H1), 9.61
(s, 1H, NH); 13C-NMR (125MHz, CDCl3) δ ppm: 35.0,
25.4, 43.0, 69.8, 114.0, 116.7, 121.1, 121.9, 124.5, 124.6,
124.7, 125.6, 126.2, 127.3, 128.2, 128.5, 129.1, 129.5,
131.1, 131.9, 133.1, 135.5, 138.2, 139.1, 141.2, 156.3,
162.2, 167.4, 170.2; Anal. Calcd. for C31H24Cl2N4O2S: C,
63.37; H, 4.12; N, 9.54. Found: C, 63.66; H, 3.95; N, 9.30.
(KBr, cmÀ1
)
υ: 3273, 1699, 1662; 1H-NMR
(500 MHz, CDCl3) δ ppm: 2.13 (s, 3H, CH3), 2.25
(td, J = 4.6, 11.9 Hz, 1H, CH2), 2.64 (td, J = 4.6,
11.9 Hz, 1H, CH2), 3.10 (td, J = 4.6, 11.9 Hz, 1H,
CH2), 3.68 (td, J = 4.6, 11.9 Hz, 1H, CH2), 3.87 (d,
J = 14.2 Hz, 2H, CH2), 6.20 (s, 1H, CH), 6.43–6.60
(m, 3H, H2, H4′, H6′), 6.98 (t, J = 7.7 Hz, 1H, H5′),
7.73–7.80 (m, 5H, Ph), 7.47–7.58 (m, 1H, H4), 7.37
(t, J=6.8Hz, 1H, H10), 7.49–7.60 (m, 4H, Ph), 7.66
(t, J=6.7Hz, 1H, H3), 8.20 (d, J=7.7Hz, 1H, H1), 8.94
(s, 1H, NH); 13CNMR (125MHz, CDCl3) δ ppm: 21.2,
35.3, 35.6, 43.0, 69.8, 113.5, 116.4, 117.1, 120.0, 123.7,
124.6, 124.8, 125.7, 126.3, 127.2, 1287.3, 128.5, 128.6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Quinazolino[3,4-a]quinazolinones
129.0, 129.1, 131.5, 135.1, 131.9, 137.9, 138.2, 138.8,
139.1, 162.2, 167.0, 173.1; Anal. Calcd. for
C32H28N4O2S: C, 72.16; H, 5.30; N, 10.52. Found: C,
7.65 (t, J = 7.6 Hz, 1H, H3), 8.19 (d, J = 7.7 Hz, 1H, H1),
9.82 (s, 1H, NH); 13C-NMR (125 MHz, CDCl3) δ ppm:
19.0, 19.6, 35.4, 35.5, 43.0, 69.8, 116.5, 116.9, 120.7,
123.7, 124.6, 125.7, 126.2, 127.2, 128.3, 128.5, 128.6,
128.9, 129.1, 129.8, 131.5, 131.9, 132.2, 135.6, 137.1,
138.2, 139.2, 141.1, 157.5, 162.2, 166.8; Anal. Calcd.
for C33H30N4O2S: C, 72.50; H, 5.53; N, 10.25. Found:
C, 72.36; H, 5.39; N, 10.02.
72.37; H, 5.18; N, 10.68.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(4-methylphenyl)acetamide
(9p). White crystals; yield: 47%; mp 183–185°C; IR
(KBr, cmÀÀ1
)
υ: 3281, 1668, 1660; 1H-NMR
(500 MHz, CDCl3) δ ppm: 2.21 (s, 3H, CH3), 2.24
(td, J = 6.0, 12.1 Hz, 1H, CH2), 2.62 (td, J = 6.0,
12.1 Hz, 1H, CH2), 3.08 (td, J = 6.0, 12.1 Hz, 1H,
CH2), 6.88 (td, J = 6.0, 12.1 Hz, 1H, CH2), 3.86
(d, J = 14.7 Hz, 2H, CH2), 6.74 (d, J = 6.6 Hz, 2H, H2,
H4), 6.89 (d, J = 8.2 Hz, 2H, H3′, H5′), 7.13–7.22
(m, 5H, Ph), 7.27 (d, J = 7.1 Hz, 2H, H8, H11), 7.37
(t, J = 7.5 Hz, 1H, H10), 7.48–7.59 (m, 4H, Ph), 7.65
(t, J = 7.7 Hz, 1H, H3), 8.20 (d, J = 6.8 Hz, 1H, H1),
9.90 (s, 1H, NH); 13C-NMR (125 MHz, CDCl3) δ
ppm: 20.7, 35.3, 35.5, 42.9, 69.8, 116.5, 119.3,
123.6, 124.5, 125.7, 126.2, 127.1, 128.3, 128.4,
128.6, 129.0, 129.1, 129.3, 131.5, 131.9, 133.4,
135.4, 138.1, 139.1, 141.0, 157.5, 162.1, 166.8;
Anal. Calcd. for C32H28N4O2S: C, 72.16; H, 5.30; N,
10.52. Found: C, 71.95; H, 5.15; N, 10.67.
Biology Reagents and chemicals. Fetal bovine serum,
phosphate buffered saline, RPMI 1640 and trypsin
were purchased from Biosera (Ringmer, UK). 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) and penicillin/streptomycin were obtained from
Sigma-Aldrich (Saint Louis, MO, USA) and Invitrogen
(San Diego, CA, USA), respectively. Cisplatin and
doxorubicin were obtained from EBEWE Pharma
(Unterach, Austria) and dimethylsulfoxide was purchased
from Merck (Darmstadt, Germany).
Cell lines and cell culture. MOLT-4 (human lymphoblastic
leukemia), and MCF-7 (human breast adenocarcinoma)
cells were purchased from the National Cell Bank of Iran,
Pasteur Institute, Tehran, Iran. Cells were maintained at
37°C in humidified air containing 5% CO2 and were
grown in suspension (MOLT-4) or monolayer cultures
(MCF-7). Cells were maintained in RPMI 1640
supplemented with 10% fetal bovine serum, and 100
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(2,5-dimethylphenyl)acetamide
(9q). White crystals; yield: 33%; mp 171–173°C; IR
1
(KBr, cmÀ1) υ: 3266, 1691, 1664; H-NMR (500 MHz,
units/mL penicillin-G and 100 μg/mL streptomycin.
Cytotoxicity. The in vitro cytotoxic activity of all
CDCl3) δ ppm: 2.06 (s, 3H, CH3), 2.25 (s, 3H, CH3),
2.29–2.34 (m, 1H, CH2), 2.64 (td, J = 4.7, 11.3 Hz, 1H,
CH2), 3.19 (td, J = 4.7, 11.3 Hz, 1H, CH2), 3.47
(td, J = 4.7, 11.3 Hz, 1H, CH2), 3.90 (d, J = 14.6 Hz, 1H,
CH2), 4.03 (d, J = 14.6 Hz, 1H, CH2), 6.28 (s, 1H, CH),
6.74–6.80 (m, 2H, Ph), 6.85–6.93 (m, 1H, Ph),
6.98–7.07 (m, 2H, Ph), 7.10–7.19 (m, 3H, Ph), 7.31 (t,
J = 7.4 Hz, 1H, H10), 7.41 (t, J = 7.7 Hz, 1H, H3),
7.53–7.62 (m, 5H, Ph), 8.24 (d, J = 7.7 Hz, 1H, H1),
9.08 (s, 1H, NH); 13C-NMR (125 MHz, CDCl3) δ ppm:
17.5, 20.9, 34.9, 35.3, 43.0, 69.6, 116.5, 123.7, 124.0,
124.2, 124.7, 125.3, 125.6, 125.8, 126.2, 126.5, 126.9,
128.1, 128.3, 128.5, 128.6, 129.1, 129.4, 130.0, 131.1,
131.2, 132.2, 135.2, 136.2, 138.2, 139.0, 141.1, 156.3,
162.2, 167.3; Anal. Calcd. for C33H30N4O2S: C, 72.50;
synthesized compounds was determined against two
MOLT-4 and MCF-7 cell lines. The inhibitory effect of
synthesized compounds on cancer cells’ growth was
assessed by the MTT reduction assay [23], which is based
on the conversion of the yellow tetrazolium bromide to the
purple formazan by the action of mitochondrial enzyme
succinate dehydrogenase in viable cells. Synthesized
compounds were dissolved in dimethylsulfoxide and
diluted in growth medium at least 400 times. Cells were
seeded in 96-well plates (5000 cells/well) and incubated at
37°C for 24h. Different concentrations of test compounds
in the range of 10–100μM were added and after 72h of
further incubation at 37°C, 0.5 mg/ml MTT dissolved in
growth medium without phenol red was added to the
wells. After 4 h, formazan crystals were solubilized in
200 μL of dimethylsulfoxide, and the optical density was
measured at 570 nm, with background correction at
655 nm using a microplate reader. IC50 values, defined as
the concentration that caused 50% of maximum
inhibition of cell viability, was calculated with the
software CurveExpert version 1.34 for Windows (http://
curveexpert.software.informer.com/1.3/).
H, 5.53; N, 10.25. Found: C, 72.37; H, 5.36; N, 10.43.
2-((13-Oxo-12-phenethyl-11b,12-dihydro-13H-quinazolino
[3,4-a]quinazolin-6-yl)thio)-N-(3,4-dimethylphenyl)acetamide
(9r). White crystals; yield: 46%; 201–202°C; IR (KBr,
1
cmÀ1) υ: 3251, 1695, 1662; H-NMR (500 MHz, CDCl3)
δ ppm: 2.02 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.21
(td, J = 4.8, 2.2 Hz, 1H, CH2), 2.61 (td, J = 4.8, 2.2 Hz,
1H, CH2), 3.08 (td, J = 4.8, 2.2 Hz, 1H, CH2), 3.68
(td, J = 4.8, 2.2 Hz, 1H, CH2), 3.87 (d, J = 14.2 Hz, 2H,
CH2), 6.73 (s, 1H, CH), 6.40–6.52 (m, 2H, H2, H6′), 6.85
(d, J = 8.05 Hz, 1H, H5′), 7.11 (dd, J = 12.1 Hz, 1H, H4′),
7.14–7.16 (m, 3H, H2, H9, H11), 7.19 (d, J = 7.6 Hz, 1H,
H8), 7.37 (t, J = 7.3 Hz, 1H, H10), 7.48–7.60 (m, 5H, Ph),
Acknowledgments. This research was supported by Islamic Azad
University, Tehran-North Branch, Research Council of Tehran
University of Medical Sciences, and Iran National Science
Foundation (INSF).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Mohammadhosseini, S. Moradi, M. Khoobi and A. Shafiee
Vol 000
[13] Gopalsamy, A.; Yang, H. J Comb Chem 2000, 2, 378.
REFERENCES AND NOTES
[14] Yang, R.-Y.; Kaplan, A. Tetrahedron Lett 2000, 41, 7005.
[15] Asadi, M.; Ebrahimi, M.; Mahdavi, M.; Saeedi, M.;
Rashidi, P. R.; Yazdani, F.; Shafiee, A.; Foroumadi, A. Synth
Commun 2013, 43, 2385.
[16] Farzipour, S.; Saeedi, M.; Mahdavi, M.; Yavari, H.;
Mirzahekmati, M.; Ghaemi, N.; Foroumadi, A.; Shafiee, A. Synth
Commun 2014, 44, 481.
[1] Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur J Med Chem
2014, 76, 193.
[2] Kuyper, L. F.; Baccanari, D. P.; Jones, M. L.; Hunter, R. N.;
Tansik, R. L.; Joyner, S. S.; Boytos, C.; Rudolph, S. K.; Knick, V.;
Wilson, H. R.; Caddell, J. M.; Friedman, H. S.; Comley, J. C. W.; Stables,
J. N. J Med Chem 1996, 39, 892.
[3] Giardin, D.; Martarelli, D.; Sagratini, G.; Angeli, P.; Ballinari, D.;
Gulini, U.; Melchiorre, C.; Poggesi, E.; Pompei, P. J Med Chem 2009, 52,
4951.
[17] Asadi, M.; Masoomi, S.; Ebrahimi, S. M.; Mahdavi, M.;
Saeedi, M.; Shafiee, A.; Foroumadi, A. Monatsh Chem 2014,
145, 497.
[4] Decker, M. Eur J Med Chem 2005, 40, 305.
[18] Mahdavi, M.; Foroughi, N.; Saeedi, M.; Karimi, M.;
Alinezhad, H.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Synlett
2014, 25, 385.
[19] Rahmani-Nezhad, S.; Safavi, M.; Pordeli, M.; Ardestani, S. K.;
Khosravani, L.; Pourshojaei, Y.; Mahdavi, M.; Emami, S.; Foroumadi, A.;
Shafiee, A. Eur J Med Chem 2014, 86, 562.
[5] Jain, K. S.; Bariwal, J. B.; Kathiravan, M. K.; Phoujdar, M. S.;
Sahne, R. S.; Chauhan, B. S.; Shah, A. K.; Yadav, M. R. Bioorg Med
Chem 2008, 16, 4759.
[6] Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur J Med Chem
2015, 90, 124.
[20] Ramazani, A.; Khoobi, M.; Torkaman, A.; Nasrabadi, F. Z.;
Forootanfar, H.; Shakibaie, M.; Jafari, M.; Ameri, A.; Emami, S.;
Faramarzi, M. A.; Foroumadi, A.; Shafiee, A. Eur J Med Chem 2014,
78, 151.
[21] Esmati, N.; Foroughian, M.; Saeedi, M.; Mahdavi, M.;
Khoshneviszadeh, M.; Firuzi, O.; Tanideh, N.; Miri, R.; Edraki, N.;
Shafiee, A.; Foroumadi, A. J Heterocyclic Chem 2015, 52, 97.
[22] Shafii, B.; Saeedi, M.; Mahdavi, M.; Foroumadia, A.; Shafiee, A.
Synth Commun 2014, 44, 215.
[7] Widemann, B. C.; Balis, F. M. Godwin, K. S.; McCully, C.;
Adamson, P. C. Cancer Chemother Pharmacol 1999, 44, 439.
[8] Niculescu-Duvaz, I. Curr Opin Investig Drugs 2001, 2, 693.
[9] Alanazi, A. M.; Al-Suwaidan, I. A.; Abdel-Aziz, A. A.;
Mohamed, M. A.; Morsy, M. A.; El-Azab, A. S. Med Chem Res 2013,
22, 5566.
[10] Chen, J.; Natte, K.; Spannenberg, A.; Neumann, H.; Langer, P.;
Beller, M.; Wu, X.-F. Angew Chem Int Ed 2014, 53, 7579.
[11] Kamal, A.; Sattur, P. B. J Chem Soc, Chem Commun, 1989, 835.
[12] Ibrahim, S. S.; Abdel-Halim, A. M.; Gabr, Y.; El-Edfawy, S.;
Abdel-Rahman, R. M. J Chem Res 1997, 154.
[23] Shekari, F.; Sadeghpour, H.; Javidnia, K.; Saso, L.; Nazari, F.;
Firuzi, O.; Miri, R. Eur J Pharmacol 2015, 746, 233.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet