Synthesis, antitumor activity, and structure-activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h] quinoline derivatives

Article abstract of DOI:10.1007/s00044-012-0142-7

Several 4H-pyrano[3,2-h]quinoline (3a-d, 4a, 7a,b, 9a-c, 10a,b, 11a,b, and 13a-c) and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives (8a-c) were obtained by treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-methylquinoline (1b) with α-cyano-p

Full text of DOI:10.1007/s00044-012-0142-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0142-7
ORIGINAL RESEARCH
Synthesis, antitumor activity, and structure–activity relationship
of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[40,50:6,5]
pyrano[3,2-h]quinoline derivatives
•
Ahmed M. El-Agrody Hisham S. M. Abd-Rabboh
•
Abdullah M. Al-Ghamdi
Received: 23 February 2012 / Accepted: 1 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Several 4H-pyrano[3,2-h]quinoline (3a–d, 4a,
7a,b, 9a–c, 10a,b, 11a,b, and 13a–c) and 7H-pyrimi-
do[40,50:6,5]pyrano[3,2-h]quinoline derivatives (8a–c) were
obtained by treatment of 8-hydroxyquinoline (1a) and
8-hydroxy-2-methylquinoline (1b) with a-cyano-p-chloro/
bromocinnamonitrile (2a,b) or 4H-pyrano[3,2-h]quinoline
derivatives (3a,c,d) with different electrophilic reagents
followed by nucleophilic reagents. Structures of these
compounds were established on the basis of spectral data.
The antitumor activity of the synthesized compounds was
investigated in comparison with Vinblastine. Among them,
compounds 3c,d, 4a, 8b, 9b,c, 11a,b, and 13a,c inhibited
the growth of cancer cells compared to Vinblastine. The
structure–activity relationships were discussed.
natural products such as vitamins, hormones, antibiotics,
and alkaloid, as well as pharmaceuticals, herbicides, and
many other compounds. Nitrogen heterocyclic containing a
quinoline ring is often found in biologically active mole-
cules (Al-Ghamdi et al., 2012; Saugues et al., 2011; Guo
et al., 2011; Broch et al., 2010; Ramesh et al., 2009; Righi
et al., 2008; Musiol et al., 2007, 2006). 8-Hydroxyquino-
line moieties have also been shown to possess diverse
therapeutic activities such as antifungal (Thomas et al.,
2010), antibacterial (Chang et al., 2010; Harris and
Thorarensen, 2004; Musiol et al., 2008), antiprotozoic, as
well as antineoplastic (Badawey and Kappe, 1997) and
antiproliferative (Mrozek-Wilczkiewicz et al., 2010; Jam-
pilek et al., 2009) activities. In addition, the antiprolifera-
tive effects of styrylquinoline derivatives on tumor cell
lines have been observed and recently reported (El-Agrody
et al., 2012; Polanski, 2010; Thomas and Roy, 2008;
Andrew et al., 2007; Zouhiri et al., 2005; Pommier et al.,
2005). Other styrylquinoline derivatives have also gained
strong attention recently due to their extensive biological
activities (Larghi et al., 2009; Xin-Hua et al., 2009; Ganesh
et al., 2008; Narender et al., 2006).
Keywords 8-Hydroxyquinoline ꢀ
8-Hydroxy-2-methylquinoline ꢀ
4H-pyrano[3,2-h]quinoline ꢀ
7H-pyrimido[40,50:6,5]pyrano[3, 2-h]quinoline ꢀ
Antitumor ꢀ SAR
Introduction
As a result of remarkable pharmacological efficiency of
quinoline derivatives and in continuation of our program
on the chemistry of 4H-pyran derivatives (Al-Ghamdi et al.
2012; El-Agrody, 1994; El-Agrody et al., 1997a, b, 2000,
2001, 2002, 2011, 2012; El-Agrody and Al-Ghamdi, 2011;
Sabry et al., 2011; Abd-El-Aziz et al., 2004, 2007; Eid
et al., 2003; Khafagy et al., 2002; Bedair et al., 2000, 2001;
Sayed et al., 2000), we report herein the synthesis of new
4H-pyrano[3,2-h]quinoline and 7H-pyrimido[40,50:6,5]pyr-
ano[3,2-h]quinoline derivatives, and the evaluation of their
antitumor activities. The chemical structures of the studied
compounds and their structure–activity relationships (SAR)
are discussed in this work.
Heterocyclic compounds hold a special place among
pharmaceutically significant natural products and synthetic
compounds (Desai and Dodiya, 2011). Nitrogen heterocy-
clic are abundant in nature and are of great significance to
life; this is because their structural subunits exist in many
A. M. El-Agrody (&) ꢀ H. S. M. Abd-Rabboh ꢀ
A. M. Al-Ghamdi
Chemistry Department, Faculty of Science,
King Khalid University, Abha 9004, Saudi Arabia
e-mail: elagrody_am@yahoo.com
123

Med Chem Res
Scheme 1 Synthesis of
4H-pyrano[3,2-h]quinoline
derivatives (3a–d)
R
9
10
8
7
N
OH
1
10a
O
2 NH2
3 CN
R
N
CN
CN
pip.
EtOH /
reflux
6a
6
10b
4a
Ar-CH=C
+
4
Ar
5
1
2
3a-d
a, R = H
b, R = H
c, R = CH3 Ar = p-ClC6H4
d, R = CH3 Ar = p-BrC6H4
Ar = p-ClC6H4
a, Ar = p-ClC6H4
b, Ar = p-BrC6H4
a, R = H
b, R = CH3
Ar = p-BrC6H4
Chemistry
When 2-benzylideneamino-4-(4-chlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (4a) was treated with
hydrazine hydrate or phenyl hydrazine in ethanol at room
temperature or under reflux, the addition product 5 was
formed (R = H or Ph, respectively). From the intermediate
5, benzaldehyde hydrazone/phenylhydrazone were eliminated
to give b-enaminonitrile 3a (Khafagy et al., 2002) instead of
the pyrimidopyranoquinoline derivative 6 (Scheme 2). Struc-
ture 4a was established on the basis of spectral data.
Treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-
methylquinoline (1b) with a-cyano-p-chloro/bromocinna-
monitrile (2a,b) in ethanolic piperidine under reflux afforded
2-amino-4-(4-chloro/bromophenyl)-4H-pyrano[3,2-h]quin-
oline-3-carbonitrile (3a,b) and 2-amino-4-(4-chloro/-
bromophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-car-
bonitrile (3c,d) (Scheme 1).
Compounds 3a,c,d were subjected to electrophilic fol-
lowed by nucleophilic reactions to produce fused hetero-
tetracyclic systems incorporating pyrimidine nucleus in
addition to pyranoquinoline moiety. Thus, condensation of
3a with benzaldehyde in ethanol and piperidine under
reflux gave the 2-benzylideneamino-4-(4-chlorophenyl)-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (4a), while con-
densation of 3c,d with benzaldehyde was unsuccessful;
2-benzylideneamino derivatives 4b,c were not formed
(Scheme 2).
Treatment of 3c,d with acetic anhydride under reflux for
30 min afforded the N-acetylamino derivative 7a,b, while
heating of 3a,c,d with formamide under reflux provided the
aminopyrimidopyranoquinoline derivative 8a–c (Scheme 3).
Structures 7 and 8 were established on the basis of
spectral data and in conjunction with our previous work
(Abd-El-Aziz et al., 2004, 2007; Bedair et al., 2000, 2001;
Eid et al., 2003; El-Agrody, 1994; El-Agrody et al., 1997a,
b, 2000, 2001, 2002, 2011; Khafagy et al., 2002; Sayed
et al., 2000; Sabry et al., 2011).
CH3
N
O
N
Ph
N
O
N=CHPh
CN
N
NHR
R
N
6
NH
Ar
R = H or Ph
4b,c
Ar
3c,d
PhCHO
pip.
O
NH2
CN
-PhCH=NNHR
H
b, Ar = p-ClC6H4
c, Ar = p-BrC6H4
EtOH /
reflux
3a
N
N
NNHR
CHPh
H
N
3a,c,d Ar
O
N=CHPh
RNHNH2
CN
O
a, R = H
c, R = CH3 Ar = p-ClC6H4
d, R = CH3 Ar = p-BrC6H4
Ar = p-ClC6H4
CN
4a Ar
5
Ar
a, Ar = p-ClC6H4
R = H or Ph
Scheme 2 Preparation of compound (4a)
123

Med Chem Res
CH3
N
O
NHCOCH3
CN
R
a, Ar = p-ClC6H4
b, Ar = p-BrC6H4
N
7a,b
Ar
O
NH2
CN
2
reflux
R
HCONH
N
3a,c,d Ar
O
N
2
a, R = H
Ar = p-ClC6H4
a, R = H Ar = p-ClC6H4
c, R = CH3 Ar = p-ClC6H4
d, R = CH3 Ar = p-BrC6H4
b, R = CH3 Ar = p-ClC6H4
c, R = CH3 Ar = p-BrC6H4
N
NH2
8a-c
Ar
Scheme 3 Synthetic protocol of compounds (7a,b) and (8a–c)
Treatment of 3a,c,d with triethyl orthoformate in acetic
anhydride at reflux gave the corresponding imidate deriv-
atives 9a–c, while reaction of 3a,c with dimethylformaide-
dipentylacetal (DMF-DPA) in benzene under reflux
afforded the amidine derivatives 10a,b (Scheme 4).
Structures of 9 and 10 were established on the basis of IR,
instead of the cyclized compound, aminoimino derivative
12a (Scheme 5).
In a similar manner, reaction of 9a with methylamine
yielded the open form product 4-(4-chlorophenyl)-2-
methylaminomethyleneamino-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (11b), rather than the cyclized compound,
imino derivative 12b (Scheme 5). Attempts to cyclized
compounds 11a,b by reflux in ethanolic piperidine solution
were unsuccessful, the aminoimino and imino derivatives
12a,b, respectively, were not formed (Scheme 5).
The reaction of the imidate 9a with dimethylamine in
ethanol at room temperature yielded the amidine derivative
13
1H NMR, 13C NMR, C NMR-DEPT, and MS data.
Hydrazinolysis of 4-(4-chlorophenyl)-2-ethoxymethylen-
eamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile (9a) in
ethanol at room temperature under stirring afforded the
open form product 4-(4-chlorophenyl)-2-hydrazinomethy-
leneamino-4H-pyrano[3,2-h]quinoline-3-carbonitrile (11a)
Scheme 4 Synthetic protocol
of compounds (9a–c) and
(10a,b)
R
N
O
N=CHOEt
CN
R
2
9a-c
Ar
3
N
a, R = H
b, R = CH3 Ar = p-ClC6H4
c, R = CH3 Ar = p-BrC6H4
Ar = p-ClC6H4
O
NH2
CN
reflux
3
a
,
c
R
N
3a,c,d Ar
a, R = H
c, R = CH3 Ar = p-ClC6H4
d, R = CH3 Ar = p-BrC6H4
Ar = p-ClC6H4
O
N=CHN(Me)2
CN
10a,b
Ar
a, R = H
Ar = p-ClC6H4
b, R = CH3 Ar = p-ClC6H4
123

Med Chem Res
Scheme 5 Preparation of
compounds (10a) and (11a,b)
N
O
N=CHNHR
CN
N
11a,b Ar
O
N=CHOEt
a, R = NH2
b, R = CH3
a) NH2NH2.H2O
b) MeNH2
CN
9a
EtOH
Ar
3a
pip.
2
reflux
1
(Me)2NH
3
4
DMF-DPA
benzene
N
O
N
10
9
R
4a
a) NH2NH2.H2O/EtOH
5
N
10a
12a
7a
8
NH
7
Ar
6
b) NH2NH2.H2O/toluene
PTSA
12a,b
a, R = NH2
b, R = CH3
Ar = p-ClC6H4
10a (Scheme 5), which can also be obtained as described
before from the reaction of 3a with DMF-DPA (m.p. and
mixed m.p. are completely identical) (Scheme 4). The
structure of 11 was supported by spectral data.
7-(4-chlorophenyl)-7H-pyrimido[40,50:6,5]pyrano[3,2-h]
quinoline (8a) and 2-methyl derivatives 8b,c, together with
the open form product, 2-aminomethyleneamino-4H-pyr-
ano[3,2-h]quinoline-3-carbonitrile (13a) and 2-methyl
derivatives 13b,c. The open form product was separated
from the filtrate of the reaction mixture (Scheme 6).
The tetracyclic structure 8 was supported by its indepen-
dentsynthesisfrom3a,c,d andformamide(Bedairetal., 2000,
2001) as described before (Scheme 3) and also by cyclization
of 13a–c in ethanolic piperdine solution under reflux
(Khafagy et al., 2002) (m.p. and mixed m.p. are completely
identical) (Scheme 6). The structure of 13 was supported on
the basis of IR, 1H NMR, 13C NMR, and MS data.
Hydrazinolysis of the amidine 10a in ethanol at room
temperature under stirring or reflux was unsuccessful, the
aminoimino derivative 12a was not formed (Scheme 5).
Also, reaction of 10a with hydrazine hydrate in toluene in
the presence of p-toluenesulfonic acid under reflux failed
(Salaheldin et al., 2008), the aminoimino derivative 12a
was not formed (Scheme 5).
Treatment of the imidate 9a–c with NH3 gas bubbled in
methanol at room temperature for 1 h yielded the 8-amino-
R
R
N
N
O
N=CHOEt
NH3 gas
O
N=CHNH2
CN
CN
MeOH
9a-c
Ar
EtOH
pip.
13a-c Ar
a, R = H
b, R = CH3
c, R = CH3
Ar = p-ClC6H4
Ar = p-ClC6H4
Ar = p-BrC6H4
R
+
reflux
2
1
3
4
N
O
N
10
4a
5
a, R = H
Ar = p-ClC6H4
HCONH2
9
N
b, R = CH3 Ar = p-ClC6H4
3a,c,d
7a
c, R = CH3
8
7
Ar = p-BrC6H4
6
NH2
8a-c
Ar
Scheme 6 Synthetic protocol of compounds (8a–c) and (13a–c)
123

Med Chem Res
Scheme 7 Reaction of
compounds (9a,b) with
ammonia derivatives
CH3
N
CH3
N
H
N
CHOEt
NR
O
N=CHOEt
RNH2
O
CN
H
CN
9b,c
Ar
14 Ar
R = NH2 or CH3
- RN=CHOEt
CH3
b,
Ar = p-ClC6H4
c; Ar = p-BrC6H4
3c
(Me)2NH
9b
2
DMF-DPA
benzene
1
3c,d
3
4
N
O
N
a) NH2NH2.H2O/EtOH
10
9
R
4a
5
15a
10b
N
b) NH2NH2.H2O/toluene
PTSA
7a
8
NH
7
6
Ar
15a-d
a; R = NH2 Ar = p-ClC6H4
b; R = CH3 Ar = p-ClC6H4
c; R = NH2 Ar = p-BrC6H4
d; R = CH3 Ar = p-BrC6H4
When the imidate 9b,c was treated with hydrazine
hydrate or methylamine in ethanol at room temperature
under stirring, the addition product 14 was formed
(R = NH2 or CH3, respectively). From the intermediate 14,
ethyl N-methylformimidate or ethyl formohydrazonate was
eliminated to give b-enaminonitrile 3c,d (Khafagy et al.,
2002; Tacconi et al., 1980) instead of the aminoimino
derivatives 15a,c or imino derivatives 15b,d, respectively
(Scheme 7).
viabilities were determined as described in the literature
(Rahman et al., 2001). In vitro cytotoxicity evaluation using
viability assay was performed at the Regional Center for
Mycology & Biotechnology (RCMP), Al-Azhar University
using Vinblastine as standard drug. The inhibitory activity
of the synthetic compounds 3a–d, 4a, 7a,b, 8a,b, 9a–c,
10a,b 11a,b, and 13a–c against the three cell lines MCF-7,
HCT, and HepG-2 are given in Table 1 and Fig. 1.
Reaction of the imidate 9b with dimethylamine in ethanol
at room temperature under stirring afforded the amidine
derivative 10b (Scheme 7), which can be obtained as
described before from the reaction of 3c with DMF-DPA
(m.p. and mixed m.p. are completely identical) (Scheme 4).
Hydrazinolysis of the amidine 10b in ethanol at room tem-
perature under stirring or reflux was unsuccessful, the ami-
noimino derivative 15a was not formed (Scheme 7). Also,
reaction of 10b with hydrazine hydrate in toluene in the
presence of p-toluenesulfonic acid under reflux failed
(Salaheldin et al., 2008), the aminoimino derivative 15a was
not formed (Scheme 7).
Results and discussion
Quinoline derivatives were selected for this study as their
families are well-known to contain active compounds with a
wide range of biological and pharmacological activities (Al-
Ghamdi et al. 2012; El-Agrody et al., 2012; Saugues et al.,
2011; Guo et al., 2011; Desai et al., 2011; Broch et al., 2010;
Thomas et al., 2010; Chang et al., 2010; Mrozek-Wil-
czkiewicz et al., 2010; Jampilek et al., 2009; Ramesh et al.,
2009; Larghi et al., 2009; Xin-Hua et al., 2009; Ganesh et al.,
2008; Righi et al., 2008; Musiol et al., 2008, 2007, 2006;
Thomas and Roy, 2008; Andrew et al., 2007; Narender et al.,
2006; Zouhiri et al., 2005; Pommier et al., 2005; Harris and
Thorarensen, 2004; Badawey and Kappe, 1997). In the
present study, twenty compounds of 4H-pyrano[3,2-h]
quinoline and 7H-pyrimido[40,50:6,5]pyrano[3,2-h]quino-
line derivatives were prepared. Structures of the synthesized
Antitumor assays
Compounds 3a–d, 4a, 7a,b, 8a,b, 9a–c, 10a,b 11a,b, and
13a–c were evaluated for human tumor cell growth inhib-
itory activity against three cell lines: breast adenocarcinoma
(MCF-7), lung carcinoma (HCT), and hepatocellular car-
cinoma (HepG-2). The measurements of cell growth and the
compounds were elucidated on the basis of IR, 1H NMR, 13
NMR, 13C NMR-DEPT, 13C NMR-APT, and MS data.
C
123

Med Chem Res
Table 1 Effects of the treatment of MCF-7, HCT, and HepG-2 cells with various concentrations of the prepared compounds; cytotoxicity
(IC50) as measured by the MTT method
Compounds
Vinblastine
Conc.
(lg/ml)
MCF-7 cell
viability (%)
IC50
(lg/ml)
HCT cell
viability (%)
IC50
(lg/ml)
HepG-2 cell
viability (%)
IC50
(lg/ml)
50
07.82
15.18
29.60
48.75
60.35
76.24
100.00
26.79
49.82
72.86
82.50
91.61
100.00
100.00
39.11
58.93
70.00
75.71
83.93
94.82
100.00
28.00
58.20
71.40
78.20
87.00
100.00
100.00
41.25
62.32
71.79
75.18
82.32
93.93
100.00
26.50
33.33
37.17
40.83
48.33
55.00
100.00
6.1
16.27
21.68
28.20
38.06
47.54
53.42
100.00
27.40
48.20
67.40
76.80
92.60
100.00
100.00
42.40
78.40
91.20
97.80
100.00
100.00
100.00
27.60
35.80
55.60
66.80
79.00
94.00
100.00
36.60
48.80
58.20
66.60
88.00
100.00
100.00
09.13
11.59
14.76
19.41
30.22
38.46
100.00
2.6
14.38
16.13
24.25
45.13
55.00
72.13
100.00
52.78
57.22
63.52
68.15
68.52
79.63
100.00
91.80
96.27
98.35
100.00
100.00
100.00
100.00
23.15
33.70
35.56
37.59
42.96
51.85
100.00
21.97
29.34
39.61
44.87
63.95
77.50
100.00
18.62
31.40
37.86
42.50
48.92
56.14
100.00
4.6
25
12.5
6.25
3.125
1.56
0
3a
3b
3c
3d
4a
50
24.9
34.8
27.9
38.9
2.8
24
w
25
12.5
6.25
3.125
1.56
0
50
43.7
15.8
22.8
0.6
NA
1.8
5.5
2.8
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
123

Med Chem Res
Table 1 continued
Compounds
Conc.
(lg/ml)
MCF-7 cell
viability (%)
IC50
(lg/ml)
HCT cell
viability (%)
IC50
(lg/ml)
HepG-2 cell
viability (%)
IC50
(lg/ml)
7a
7b
8a
8b
9a
9b
50
46.17
54.00
68.67
76.83
86.50
96.33
100.00
23.38
32.13
51.25
65.75
79.88
94.75
100.00
45.40
68.80
75.80
81.20
94.50
100.00
100.00
70.24
81.68
89.23
94.46
97.28
100.00
100.00
42.96
67.07
74.18
81.37
92.96
98.31
100.00
37.54
48.62
63.44
76.56
87.38
96.12
100.00
38.6
13.5
44.6
w
21.98
42.54
53.33
77.46
85.16
96.43
100.00
22.54
44.52
71.75
86.83
95.08
99.84
100.00
26.43
42.00
62.14
74.57
78.57
83.14
100.00
41.63
51.12
78.88
90.51
98.78
100.00
100.00
23.85
51.42
67.08
73.26
81.71
93.44
100.00
15.21
18.40
25.96
35.32
54.89
75.53
100.00
14.6
21.3
19.2
26.4
25.7
3.6
23.78
35.85
60.22
78.56
89.70
100.00
100.00
32.56
51.20
68.58
81.60
90.66
98.78
100.00
64.26
67.59
73.33
83.33
90.37
94.44
100.00
28.33
37.00
43.67
50.83
60.17
68.33
100.00
39.44
57.12
72.28
86.63
91.04
97.56
100.00
45.21
68.96
79.38
85.13
96.38
100.00
100.00
17.8
26.5
w
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
50
6.3
25
12.5
6.25
3.125
1.56
0
50
45.4
31.1
25
12.5
6.25
3.125
1.56
0
50
23.8
44.5
25
12.5
6.25
3.125
1.56
0
123

Med Chem Res
Table 1 continued
Compounds
Conc.
(lg/ml)
MCF-7 cell
viability (%)
IC50
(lg/ml)
HCT cell
viability (%)
IC50
(lg/ml)
HepG-2 cell
viability (%)
IC50
(lg/ml)
9c
50
56.64
67.42
79.16
87.58
95.39
98.10
100.00
37.74
57.96
75.59
83.53
92.03
98.68
100.00
34.96
49.62
68.18
76.94
87.22
97.04
100.00
21.43
35.18
45.00
55.00
66.96
78.75
100.00
16.75
21.38
29.25
50.13
65.00
76.75
100.00
23.12
37.45
43.62
67.42
79.73
91.29
100.00
w
19.79
23.30
34.04
46.49
62.87
81.91
100.00
49.52
71.31
77.74
88.10
98.45
100.00
100.00
30.51
53.47
69.69
74.18
78.67
82.03
100.00
24.80
29.20
36.00
55.60
65.20
81.40
100.00
11.11
13.57
22.22
29.44
41.43
58.25
100.00
18.69
21.79
26.31
52.38
80.21
94.88
100.00
5.8
34.64
62.86
76.43
83.29
94.57
100.00
100.00
48.06
77.82
85.60
92.98
98.32
100.00
100.00
68.22
81.46
94.72
97.84
100.00
100.00
100.00
24.87
29.08
36.05
60.92
78.42
88.16
100.00
09.28
17.90
30.44
39.02
45.68
52.76
100.00
35.76
43.42
63.94
76.74
87.36
96.60
100.00
37.1
47.9
w
25
12.5
6.25
3.125
1.56
0
10a
10b
11a
11b
13a
50
29.3
24.4
8.4
49.4
28.2
7.4
25
12.5
6.25
3.125
1.56
0
50
25
12.5
6.25
3.125
1.56
0
50
8.7
25
12.5
6.25
3.125
1.56
0
50
6.3
2.3
1.9
25
12.5
6.25
3.125
1.56
0
50
10.5
6.8
23.6
25
12.5
6.25
3.125
1.56
0
123

Med Chem Res
Table 1 continued
Compounds
Conc.
(lg/ml)
MCF-7 cell
viability (%)
IC50
(lg/ml)
HCT cell
viability (%)
IC50
(lg/ml)
HepG-2 cell
viability (%)
IC50
(lg/ml)
13b
13c
a
50
63.60
74.22
81.54
89.32
96.51
98.38
100.00
56.24
69.62
81.18
89.76
97.32
100.00
100.00
w
35.92
44.18
65.20
70.71
82.24
91.63
100.00
24.80
34.08
42.86
49.80
65.00
86.94
100.00
21.7
41.17
53.83
57.67
68.00
76.67
80.50
100.00
52.33
60.67
65.50
81.17
89.33
98.83
100.00
32.9
25
12.5
6.25
3.125
1.56
0
50
w
6.2
w
25
12.5
6.25
3.125
1.56
0
IC50 values expressed in lg/ml as the mean values of triplicate wells from at least three experiments
NA not active
w weak activity (IC50 [ lg/ml)
Compounds 3a–d, 4a, 7a,b, 8a,b, 9a–c, 10a,b 11a,b,
and 13a–c were tested against three tumer cell lines: MCF-
7, HCT, and HepG-2. The cytotoxicity evaluation using
viability assays and inhibitory activities are given in
Table 1 and Fig. 1.
compounds 7a, 3c, 8a, 7b, 13b, 3d,a, 9a, 8b, and 10b
showed moderate activities, and compounds 3b and 10a
showed weak activities as compared with the standard drug
Vinblastine. Finally, compounds 3c, 11b, and 4a are the
most active compounds against HepG-2 and compounds
3d, 8b, and 11a exhibited very good activities, while
compounds 7a, 13a, and 7b showed moderate activities. In
addition, compounds 9a, 13b, 9c,b, 10a, 8a, 10b, 13c, and
3a showed weak activities, while compound 3b was inac-
tive as compared with the standard drug Vinblastine.
The results from Table 1 indicate that compound 4a was
the most active compound against MCF-7 and compounds
11b,a and 13a showed very good activity, while com-
pounds 7b, 9b,10b, 3a,c, 10a, 3b, 7a, and 3d showed
moderate activities. However, compounds 8a, 9a, 8b, 9c,
and 13b,c exhibited weak activities as compared with the
standard drug Vinblastine. Furthermore, compounds 4a and
11b are the most active compounds against HCT, com-
pounds 9b,c, 13c,a, and 11a had very good activities,
SAR studies
The SAR studies of 3a and its analogs revealed that
compound 4a has the highest potent antitumor activity
against MCF-7 compared to other compounds 11b,a, 13a,
3a, 10a, 3b, and 9a. These data indicate that the activity of
compound 4a was considerably attributed to the presence
of the electron-donating group (–N=CHPh-2) in 4H-pyrano-
[3,2-h]quinoline moiety, suggesting that blocking of the
(–NH2-2) group with a bulky electron-donating group
might be preferred at position C-2. The blocking of the
(–NH2-2) group with other electron-donating group such
as (–N=CHNHMe-2/–N=CHNHNH2-2/–N=CHNH2-2) in
compounds 11b,a, and 13a, resulted in slight reduction of
potency. In addition, the presence of other electron-
donating group such as (–NH2-2/–N=CHNMe2-2/–NH2-2/–N
=CHOEt-2) for compounds 3a, 10a, 3b, and 9a, in com-
bination with the electron-withdrawing groups (p-Cl/
Fig. 1 Antitumor activity of 4H-pyrano[3,2-h]quinoline and 7H-
pyrimido[40,50:6,5]pyrano-[3,2-h]quinoline derivatives
123

Med Chem Res
BrC6H4-4; –CN-3), resulted in more reduction of potency.
The introduction of an electron-donating group (–CH3-9) in
combination with the electron-withdrawing groups (p-Cl/
BrC6H4-4; –CN-3) and the electron-donating groups
(–NHCOMe-2/–N=CHOEt-2/–N=CHNMe2-2/–NH2-2/–N=C
HNHNH2-2) resulted in reduction of potency of compounds
7b, 9b, 10b, 3c, 7a, 3d, 13b,c, and 9c, less than its
hydrogen-substituted analog, suggesting that an electron-
donating group might not be preferred at position C-9.
Incorporating a pyrimidine nucleus with pyranoquinoline
moiety in the presence of electron-withdrawing group
(p-Cl/BrC6H4-7) and electron-donating group (–NH2-8) for
compound 8a resulted in reduction of potency. More
reduction of potency with the introduction of an electron-
donating group (–CH3-2) in compound 8b was observed.
In the case of HCT, investigation of (SAR) revealed that
compounds 4a and 11b had the most potent activity against
HCT compared to compound 3a and its analogs. This
potency could be attributed to the presence of the electron-
donating groups (–N=CHPh-2 or –N=CHNHMe-2) in
4H-pyrano[3,2-h]quinoline moiety, while the blocking of
the (–NH2-2) group with an electron-donating group such
as (–N=CHNH2-2/–N=CHNHNH2-2) in compounds 13a
and 11a resulted in slight reduction of potency. The pres-
ence of the electron-donating group (–NH2-2) resulted in
the reduction of potency for compound 3a, while blocking
(–NH2-2) group with other electron-donating group such as
(–N=CHOEt-2/N=CHNMe2-2) resulted in more reduction
of potency for compounds 9a, 3b, and 10a, suggesting that
there might be a size-limited pocket at position C-2. The
introduction of an electron-donating group (–CH3-9) in
4H-pyrano[3,2-h]quinoline nucleus, in combination with
the electron-withdrawing groups (p-Cl/BrC6H4-4; –CN-3)
and the electron-donating groups (–N=CHOEt-2/–N
=CHNHNH2-2), resulted in slight reduction of potency of
compounds 9b,c and 13c compared to its hydrogen-
substituted analog. The presence of other electron-donating
groups resulted in more reduction of potency of compounds
7a, 3c, 7b, 13b, 3d, and 10b. The presence of electron-
withdrawing group (p-ClC6H4-7) and the electron-donating
group (–NH2-8) in 7H-pyrimido[40,50:6,5]pyrano[3,2-h]
quinoline moiety for compound 8a resulted in reduction of
potency, while replacement of the hydrogen atom at posi-
tion C-2 with an electron-donating group (–CH3-2) resulted
in more reduction of potency for compound 8b.
compound 11a resulted in slight reduction of potency
and more reduction of potency with other electron-donat-
ing groups such as (–N=CHNH2-2/–N=CHOEt-2/–
N=CHNMe2-2/-NH2-2) in compounds 13a, 9a, 10a, and
3a,b. The introduction of an electron-donating group
(–CH3-9) in 4H-pyrano[3,2-h]quinoline nucleus, in com-
bination with the electron-withdrawing groups (p-Cl/
BrC6H4-4; –CN-3) and the electron-donating group
(–NH2-2) for compounds 3c,d, showed antitumor activity
against (HepG-2) higher than or closer to that of the
standard drug Vinblastine, suggesting that there might be a
size-limited pocket at position C-4. The presence of other
electron-donating groups such as (–NHCOMe-2/–N=CH
NH2-2/–N=CHOEt-2/–N=CHNMe2-2/–N=CHNH2-2) in
compounds 7a,b, 13b, 9c,b, 10b, and 13c, resulted in more
reduction of potency. In addition, the presence of an
electron-withdrawing group (p-ClC6H4-7) and the electron-
donating group (–NH2-8) in 7H-pyrimido[40,50:6,5]-pyrano
[3,2-h]quinoline moiety for compound 8a resulted in strong
reduction of potency, while replacement of the hydrogen
atom at position C-2 with the electron-donating group
(–CH3) resulted in strong improvement of potency for
compound 8b, suggesting that an electron-donating group
might be preferred at position C-2.
Conclusions
Our interest in the synthesis of quinoline derivatives is to
focus on their antitumor activities as a part of our recent
research line that aims at the development of new hetero-
cyclic compounds as strong potent antitumor agents
(Al-Ghamdi et al., 2012; El-Agrody et al., 2012). Thus, in
this paper we revealed the synthesis of some 4H-pyrano-
[3,2-h]quinoline and 7H-pyrimido[40,50:6,5]pyrano[3,2-h]
quinoline derivatives, followed by antitumor evaluation
for all of the novel compounds. Twenty compounds of
4H-pyrano[3,2-h]quinoline and 7H-pyrimido[40,50:6,5]-
pyrano[3,2-h]quinoline derivatives were prepared and their
structures were elucidated on the basis of IR, 1H NMR, 13
C
NMR, 13C NMR-DEPT, and MS data. Compounds 4a,
11b,a, and 13a had the most potent antitumor activities
against MCF-7 and compounds 4a, 11b, 9b,c, 11a, and
13a,c had the most potent activities against HCT, while
compounds 3c, 11b, 4a 3d, 8b, and 11a had the most
potent antitumor activities against HepG-2. A more
extensive study is also warranted to determine additional
antitumor parameters in order to give a deeper insight to its
structure–activity relationship and to optimize the effec-
tiveness of this series of molecules, which can then be used
in bigger scenarios such as drug design or development of
antitumor therapeutics.
Furthermore, compounds 11b and 4a showed higher
antitumor activities against HepG-2 than the standard drug
Vinblastine. This could be attributed to the presence
of the electron-donating groups (–N=CHNHMe-2) or
(–N=CHPh-2) in 4H-pyrano[3,2-h]quinoline moiety, sug-
gesting that there might be a size-limited pocket at position
C-2. Blocking the (–NH2-2) with (–N=CHNHNH2-2) in
123

Med Chem Res
Reaction of b-enaminonitrile (3c,d) with acetic
anhydride
Experimental
Melting points were determined with a Stuart Scientific Co.
Ltd apparatus. IR spectra were determined as KBr pellets
A solution of b-enaminonitrile 3c or 3d (0.01 mol) in Ac2O
(20 ml) was heated under reflux for 30 min. The solid
product was filtered, washed with cooled EtOH, dried and
recrystallized from proper solvent to give 7a,b. The phys-
ical and spectral data of compounds 7a,b are as follows:
1
on a Jasco FT/IR 460 plus spectrophotometer. H NMR
and 13C NMR spectra were recorded using a Bruker AV
500 MHz spectrometer. 13C NMR spectra were obtained
using distortionless enhancement by polarization transfer
(DEPT), where the signals of CH & CH3 carbon atoms
appear normal (up) and the signals of carbon atoms in CH2
environments appear negative (down). The MS were
measured on a Shimadzu GC/MS-QP5050A spectrometer.
Elemental analyses were performed on a Perkin-Elmer 240
microanalyser.
2-Acetylamino-4-(4-chlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7a)
Light brown crystals from ethanol; m.p. 225–226 °C;
83 %; IR (KBr) t (cm-1): 3383 (NH), 3060, 3023, 2940,
2820 (CH stretching), 2214 (CN), 1657 (CO); H NMR
1
(500 MHz) (CDCl3) d: 10.30 (bs, 1H, NH), 8.08-7.10
(m, 8H, aromatic), 5.07 (s, 1H, H-4), 2.84 (s, 3H, CH3), 2.27
(s, 3H, COCH3); 13C NMR (125 MHz) (CDCl3) d: 169.21
(CO), 160.57 (C-2), 151.40 (C-9), 143.02 (C-10b), 137.32
(C-10a), 136.71 (C-7), 129.42 (C-5), 128.82 (C-6a), 124.62
(C-8), 123.72 (C-4a), 120.42 (C-6), 116.41 (CN), 61.57
(C-3), 43.19 (C-4), 25.19 (CH3), 23.48 (CH3), 140.94,
133.95, 129.61, 125.70 (aromatic); MS m/z (%): 391
(M??2, 7), 389 (M?), (21), 278 (100), 236 (8), 209 (12),
111 (45), 75 (25); Anal. Calcd for C22H16ClN3O2: C, 67.78;
H, 4.14; N, 10.78. Found: C, 67.80; H, 4.17; N, 10.81 %.
Synthesis of 4H-pyrano[3,2-h]quinoline-3-carbonitrile
derivatives (3a-d)
Prepared as previously described (El-Agrody and
Al-Ghamdi, 2011).
2-Benzylideneamino-4-(4-chlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (4a)
A mixture of 3a (0.01 mol), benzaldehyde (0.01 mol),
ethanol (20 ml), and piperidine (0.5 ml) was refluxed for
2 h. The solid product was collected by filtration and
crystallized from ethanol giving 4a as yellow crystals; m.p.
185–186 °C; IR (KBr) t (cm-1): 3097, 3065, 3033, 2941,
2915 (CH), 2227 (CN); 1H NMR (500 MHz) (CDCl3)
d: 9.28 (s, 1H, N=CH), 8.10–7.05 (m, 14H, aromatic), 5.08
(s, 1H, H-4); 13C NMR (125 MHz) (CDCl3) d (ppm):
163.87 (C-2), 159.91 (=CH), 158.25 (C-10b), 152.10 (C-9),
134.63 (C-10a), 135.35 (C-7), 129.37 (C-5), 128.92 (C-6a),
122.29 (C-4a), 119.65 (CN), 113.43 (C-8), 112.33 (C-6),
83.42 (C-3), 43.70 (C-4), 141.18, 131.84, 130.73, 130.57,
130.10, 129.85, 129.56, 126.74; MS m/z (%): 423 (M??2,
8.02), 421 (M?, 23.35), 310 (100), 207 (3), 177 (14), 111
(26), 50 (21); Anal. Calcd for C26H16ClN3O: C, 74.02; H,
3.82; N, 9.96. Found: C, 74.08; H, 3.88; N, 10.02 %.
2-Acetylamino-4-(4-bromophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7b)
Light brown crystals from ethanol m.p. 249–250 °C; 80 %;
IR (KBr) t (cm-1): 3320 (NH), 3050, 2975, 2861 (CH),
1
2189 (CN), 1657 (CO); H NMR (500 MHz) (CDCl3) d:
8.60 (bs, 1H, NH), 7.93-7.04 (m, 8H, aromatic), 5.24 (s,
1H, H-4), 2.72 (s, 3H, CH3), 2.33 (s, 3H, COCH3); 13C
NMR (125 MHz) (CDCl3) d: 165.12 (CO), 162.48 (C-2),
160.00 (C-9), 158.28 (C-10b), 135.87 (C-10a), 131.52
(C-7), 126.55 (C-5), 126.06 (C-6a), 124.03 (C-8), 123.80
(C-4a), 121.82 (C-6), 120.95 (CN), 63.20 (C-3), 39.23
(C-4), 25.52 (CH3), 21.37 (CH3), 144.21, 138.18, 130.30,
123.02 (aromatic); MS m/z (%): 435 (M??2, 17), 433
(M?, 15), 278 (100), 209 (14), 184 (15), 149 (31), 79 (70);
Anal. Calcd for C22H16BrN3O2: C, 60.84; H, 3.71; N, 9.68.
Found: C, 60.85; H, 3.73; N, 9.70 %.
Reaction of 4a with hydrazine derivatives
Reaction of b-enaminonitrile (3a,c,d) with formamide
A mixture of 2-benzylideneamino-4-(4-chlorophenyl)-4H-
pyrano[3,2-h]quinoline-3-carbonitrile (4a) (0.01 mol) and
hydrazine hydrate or phenyl hydrazine (0.01 mol) in EtOH
(20 ml) was stirred at room temperature or refluxed for 2 h
to give 3a (m.p. and mixed m.p. are completely identical)
yielding (83 %).
A mixture of b-enaminonitrile 3a,c,d (0.01 mol) and
formamide (20 ml) was refluxed for 2 h. The solid product
was filtered, washed with cooled EtOH, dried and recrys-
tallized from proper solvent to give 8a–c. The physical and
spectral data of compounds 8a–c are as follows:
123

Med Chem Res
8-Amino-7-(4-chlorophenyl)-7H-pyrimido
[40,50:6,5]pyrano[3,2-h]quinoline (8a)
proper solvent to give 9a–c. The physical and spectral data
of the compounds 9a–c are as follows:
Colorless needles from benzene; m.p. 298–299 °C; 69 %;
4-(4-Chlorophenyl)-2-ethoxymethyleneamino-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (9a)
IR (cm-1) in KBr: 3433, 3290, 3195, (NH2), 3097, 2950,
1
2897,(CH), 1638 (C=N); H NMR (500 MHz) (CDCl3) d:
9.00 (s, 1H, H-10), 8.37–7.34 (m, 9H, aromatic), 6.85 (bs,
2H, NH2), 5.50 (s, 1H, H-4); 13C NMR (125 MHz)
(CDCl3) d: 162.70 (C-11a), 162.46 (C-8), 156.93 (C-10),
150.49 (C-1b), 144.14 (C-2), 138.09 (C-1a), 135.95 (C-4),
127.83 (C-6), 126.75 (C-4a), 123.76 (C-6a), 122.76 (C-3),
122.20 (C-5), 95.22 (C-7a), 37.86 (C-7), 143.01, 131.69,
129.47, 128.68 (aromatic); MS m/z (%): 362 (M??2, 8),
360 (M?, 26), 249 (100), 222 (25), 194 (12), 111 (8), 75
(12), Anal. Calcd for C20H13ClN4O: C, 66.58; H, 3.63; N,
15.53. Found: C, 66.03; H, 3.63; N, 15.21 %.
Colorless needles from benzene; m.p. 228–229 °C; 83 %;
IR (KBr) t (cm-1): 3044, 2987, 2936, 2903, 2864 (CH),
2205 (CN); H NMR (500 MHz) (CDCl3) d: 8.92 (s, 1H,
1
N=CH), 8.68–7.00 (m, 9H, aromatic), 4.98 (s, 1H, H-4),
4.40 (q, 2H, CH2, J = 7.5 Hz), 1.33 (t, 3H, CH3,
J = 7.5 Hz); 13C NMR (125 MHz) (CDCl3) d: 160.68
(N=CH), 157.94 (C-2), 150.77 (C-10b), 143.93 (C-9),
138.55 (C-10a), 135.93 (C-7), 129.58 (C-5), 128.46 (C-6a),
124.77 (C-4a), 122.22 (C-8), 119.96 (C-6), 117.89 (CN),
80.19 (C-3), 64.29 (CH2), 43.24 (C-4), 13.95 (CH3),
141.80, 133.75, 129.74, 126.74 (aromatic); MS m/z (%):
391 (M??2, 10), 389 (M?, 29), 278 (100), 222 (84), 140
(26), 75 (33); Anal. Calcd for C22H16ClN3O2: C, 67.78; H,
4.14; N, 10.78. Found: 68.61; H, 4.82; N, 11.46 %.
8-Amino-7-(4-chlorophenyl)-2-methyl-7H-
pyrimido[40,50:6,5]pyrano[3,2-h]quinoline (8b)
Colorless needles from benzene; m.p. 288–289 °C; 67 %;
IR (cm-1) in KBr: 3420, 3320, 3220, (NH2), 3091, 2945,
2897,(CH), 1654 (C=N); 1H NMR (500 MHz) (DMSO-d6)
d: 8.20 (s, 1H, H-10), 8.24–7.28 (m, 8H, aromatic), 6.94
(bs, 2H, NH2, cancelled by D2O), 5.46 (s, 1H, H-4), 2.74
(s, 3H, CH3); 13C NMR (125 MHz) (DMSO-d6) d: 162.67
(C-11a), 162.51 (C-8), 159.05 (C-10), 156.84 (C-2), 143.70
(C-1b), 137.57 (C-1a), 136.05 (C-4), 126.13 (C-6), 125.70
(C-4a), 123.51 (C-6a), 122.83 (C-3), 120.20 (C-5), 95.29
(C-7a), 37.85 (C-7), 24.97 (CH3), 143.13, 131.63, 129.41,
128.88 (aromatic); MS m/z (%): 376 (M??2, 8.25), 374
(M?, 20.30), 263 (100), 236 (33), 209 (18), 154 (6), 111
(46), 74 (55), 50 (28); Anal. Calcd for C21H15ClN4O: C,
67.29; H, 4.03; N, 14.95. Found: C, 67.48; H, 3.99; N,
14.98 %.
4-(4-Chlorophenyl)-2-ethoxymethyleneamino-9-methyl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (9b)
Colorless needles from benzene; m.p. 225–226 °C; 82 %;
IR (KBr) t (cm-1): 3049, 2985, 2935, 2867 (CH), 2207
(CN); 1H NMR (500 MHz) (CDCl3) d: 8.87 (s, 1H,
N=CH), 8.06–7.05 (m, 8H, aromatic), 5.03 (s, 1H, H-4),
4.51 (q, 2H, CH2, J = 7.5 Hz), 2.85 (s, 3H, CH3), 1.44
(t, 3H, CH3, J = 7.5 Hz); 13C NMR (125 MHz) (CDCl3)
d: 160.82 (N=CH), 159.99 (C-2), 157.80 (C-9), 143.30
(C-10b), 141.86 (C-10a), 136.28 (C-7), 129.23 (C-5),
126.71 (C-6a), 124.00 (C-8), 123.11 (C-6), 120.20 (C-4a),
117.92 (CN), 80.46 (C-3), 64.28 (CH2), 43.15 (C-4),
25.54 (CH3), 13.95 (CH3), 133.71, 129.66, 129.51, 125.87
13
(aromatic);
C NMR-DEPT spectrum at 135° CH, CH3
8-Amino-7-(4-bromophenyl)-2-methyl-7H-pyrimido
[40,50:6,5]pyrano[3,2-h]quinoline (8c)
[positive (up)], CH2 [negative (down)], revealed the fol-
lowing signals at d 160.82 (N=CH :), 136.28 (C-7 :),
129.51 (aromatic :) 129.23 (C-5 :), 125.87 (aromatic :)
124.00 (C-8 :), 123.11 (C-6 :), 64.28 (CH2 ;), 43.15 (C-4
:), 25.54 (CH3 :), 13.95 (CH3 :). In the DEPT spectrum
at 90° only CH signals are positive (up) and showed d
160.82 (N=CH :), 136.28 (C-7 :), 129.51 (aromatic :)
129.23 (C-5 :), 125.87 (aromatic :) 124.00 (C-8 :),
123.11 (C-6 :), 43.15 (C-4 :). In the DEPT spectrum at
45° (CH, CH2 and CH3 positive) revealed signals at d
160.82 (N=CH :), 136.28 (C-7 :), 129.51 (aromatic :)
129.23 (C-5 :), 125.87 (aromatic :) 124.00 (C-8 :),
123.11 (C-6 :), 64.28 (CH2 :), 43.15 (C-4 :), 25.54 (CH3 :),
13.95 (CH3 :); MS m/z (%): 405 (M??2, 11), 403 (M?,
28), 292 (100), 236 (80), 154 (11), 75 (14); Anal. Calcd
for C23H18ClN3O2: C, 68.40; H, 4.49; N, 10.40. Found: C,
69.33; H, 4.47; N, 10.65 %.
Colorless crystals from benzene; m.p. 292–293 °C; 71 %;
IR (cm-1) in KBr: 3095, 2947, 2899 (CH), 3391, 3318,
3193 (NH2), 1638 (C=N); MS m/z (%): 420 (M??2, 20.6),
418 (M?, 18.6), 263 (100), 263 (20.6), 126 (8.2), 77 (6.2);
Anal. Calcd for C21H15BrN4O: C, 60.16; H, 3.61; N, 13.36.
Found: C, 60.32; H, 3.72; N, 13.46 %.
Reaction of b-enaminonitrile (3a,c,d) with triethyl
orthoformate
A mixture of b-enaminonitrile 3a,c,d (0.01 mol), triethyl
orthoformate (0.01 mol), and acetic anhydride (30 ml) was
refluxed for 3 h. The solvent was removed under reduced
pressure and the resulting solid was recrystallized from
123

Med Chem Res
390 (M??2, 7), 388 (M?, 20), 277 (100), 222 (6), 178 (7),
75 (9); Anal. Calcd for C22H17ClN4O: C, 67.95; H, 4.41; N,
14.41. Found: C, 68.01; H, 4.22; N, 14.40 %.
4-(4-Bromophenyl)-2-ethoxymethyleneamino-9-methyl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (9c)
Colorless needles from benzene; m.p. 217–218 °C; 81 %; IR
(KBr) t (cm-1): 3035, 2933, 2931, 2864 (CH), 2208 (CN);
1H NMR (500 MHz) (CDCl3) d: 8.84 (s, 1H, N=CH),
8.05–7.03 (m, 8H, aromatic), 5.01 (s, 1H, H-4), 4.50 (q, 2H,
CH2, J = 7 Hz), 2.83 (s, 3H, CH3), 1.43 (t, 3H, CH3,
J = 7 Hz);13CNMR(125 MHz)(CDCl3)d: 160.76(N=CH),
159.98 (C-2), 157.80 (C-9), 143.42 (C-10b), 142.39 (C-10a),
136.18 (C-7), 126.71 (C-5), 125.80 (C-6a), 124.01 (C-8),
123.09 (C-6), 120.02 (C-4a), 117.97 (CN), 80.38 (C-3), 64.28
(CH2), 43.22 (C-4), 25.59 (CH3), 13.95 (CH3), 137.79,
132.18, 130.01, 121.83(aromatic);13CNMR-DEPTspectrum
at 135° CH, CH3 [positive (up)], CH2 [negative (down)],
revealed the following signals at d 160.76 (N=CH :), 136.18
(C-7 :), 132.18 (aromatic :) 130.01 (aromatic :), 126.71 (C-5
:), 124.01 (C-8 :), 123.09 (C-6 :), 64.28 (CH2 ;), 43.22 (C-4
:), 25.59 (CH3 :), 13.95 (CH3 :). In the DEPT spectrum at 90°
onlyCHsignalsarepositive(up)andshowedd160.76(N=CH
:), 136.18 (C-7 :), 132.18 (aromatic :) 130.01 (aromatic :),
126.71(C-5 :), 124.01 (C-8 :), 123.09 (C-6 :), 43.22 (C-4 :).
In the DEPT spectrum at 45° (CH, CH2 and CH3 positive)
revealed signals at d 160.76(N=CH :), 136.18(C-7 :), 132.18
(aromatic :) 130.01 (aromatic :), 126.71(C-5 :), 124.01 (C-8
:), 123.09 (C-6 :), 64.28 (CH2 :), 43.22 (C-4 :), 25.59 (CH3
:), 13.95 (CH3 :); MS m/z (%): 449 (M??2, 23), 447 (M?,
29), 292 (100), 264 (14), 236 (82), 157 (7), 66 (15); Anal.
Calcd for C23H18BrN3O2: C, 61.62; H, 4.05; N, 9.37. Found:
C, 61.44; H, 4.45; N, 9.77 %.
4-(4-Chlorophenyl)-2-dimethylaminomethyleneamino-9-
methyl-4H-pyrano-[3,2-h]quinoline-3-carbonitrile (10b)
Colorless needles from benzene; m.p. 260–261 °C; 81 %;
IR (KBr) t (cm-1): 3049, 2997, 2893, 2912, 2810 (CH),
1
2195 (CN); H NMR (500 MHz) (CDCl3) d: 8.56 (s, 1H,
N=CH), 7.93-6.95 (m, 8H, aromatic), 4.88 (s, 1H, H-4),
3.14, 3.08 (s, 6H, 2CH3), 2.73 (s, 3H, CH3); 13C NMR
(125 MHz) (CDCl3) d: 160.01 (N=CH), 159.48 (C-2),
154.64 (C-9), 144.27 (C-10b), 143.04 (C-10a), 138.17
(C-7), 129.56 (C-5), 126.57 (C-6a), 126.01 (C-8), 123.28
(C-4a), 122.72 (C-6), 120.22 (CN), 73.44 (C-3), 43.26 (CH3),
41.18 (CH3), 34.86 (C-4), 25.78 (CH3), 143.7; MS m/z (%):
404 (M??2, 8), 402 (M?, 26), 291 (100), 236 (5), 188 (6),
111 (91), 75 (65); Anal. Calcd for C23H19ClN4O: C, 68.57;
H, 4.75; N, 13.91. Found: C, 68.22; H, 4.43; N, 13.85 %.
Reaction of 9a with hydrazine hydrate and
methylamine
A mixture of imadate 9a (0.01 mol) and hydrazine hydrate
or methylamine (0.01 mol) in ethanol (30 ml) was stirred
at room temperature for 1 h. The solid product was col-
lected and recrystallized from proper solvent to give 11a,b.
The physical and spectra data of the compounds 11a,b are
as follows:
Preparation of compounds 10a,b
4-(4-Chlorophenyl)-2-(hydrazinomethyleneamino)-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (11a)
A mixture of b-enaminonitrile 3a or 3c (0.01 mol), DMF-
DPA (0.01 mol), and benzene (30 ml) was refluxed for 3 h.
The solvent was removed under reduced pressure and the
resulting solid was recrystallized from proper solvent to
give 10a,b. The physical and spectral data of the com-
pounds 10a,b are as follows:
Colorless needles from benzene; m.p. 203–204 °C; 81 %;
IR (KBr) t (cm-1): 3400, 3316, 3200 (NH & NH2), 3051,
2940, 2815 (CH), 2178 (CN); 1H NMR (500 MHz)
(CDCl3) d: 9.14 (s, 1H, N=CH), 8.91–7.01 (m, 9H, aro-
matic), 5.99 (bs, 2H, NH2), 5.00 (s, 1H, H-4), 4.87 (bs, 1H,
NH); 13C NMR (125 MHz) (CDCl3) d: 159.94 (N=CH),
158.18 (C-2), 156.94 (C-10b), 151.10 (C-9), 138.45
(C-10a), 136.13 (C-7), 129.44 (C-5), 128.28 (C-6a), 123.81
(C-4a), 122.19 (C-8), 121.24 (C-6), 120.04 (CN), 97.56
(C-3), 41.25(C-4), 143.57, 133.66, 129.77, 126.59(aromatic);
MS m/z (%): 375 (M?, 7), 268 (100), 232 (6), 175 (27), 101
(41), 75 (3); Anal. Calcd for C20H14ClN5O: C, 63.92; H, 3.75;
N, 18.64. Found: C, 63.51; H, 3.17; N, 18.41 %.
4-(4-Chlorophenyl)-2-dimethylaminomethyleneamino-4H-
pyrano[3,2-h]quinoline-3-carbonitrile (10a)
Colorless needles from benzene; m.p. 210–211 °C; 83 %;
IR (KBr) t (cm-1): 3015, 2921, 2850, 2808 (CH), 2196
(CN); 1H NMR (500 MHz) (CDCl3) d: 8.89 (s, 1H,
N=CH), 8.88–7.02 (m, 9H, aromatic), 4.91 (s, 1H, H-4),
3.14, 3.08 (s, 6H, 2CH3); 13C NMR (125 MHz) (CDCl3) d:
160.00 (N=CH), 154.54 (C-2), 150.99 (C-10b), 144.27
(C-9), 138.72 (C-10a), 136.16 (C-7), 129.16 (C-5), 128.34
(C-6a), 124.07 (C-4a), 122.18 (C-8), 121.87 (C-6), 120.11
(CN), 73.43 (C-3), 43.24 (CH3), 41.17 (CH3), 34.91 (C-4),
142.93, 133.24, 129.65, 127.00 (aromatic); MS m/z (%):
4-(4-Chlorophenyl)-2-(methylaminomethyleneamino)-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (11b)
Colorless needles from benzene; m.p. 201–202 °C; 81 %;
IR (KBr) t (cm-1): 3338 (NH), 3123, 3076, 2868 (CH),
123

Med Chem Res
1
2185 (CN); H NMR (500 MHz) (CDCl3) d: 9.15 (s, 1H,
3.84), 374 (M?, 10.05), 263 (56), 236 (21), 208 (7), 180
(6), 152 (6), 111 (100), 74 (89), 50 (16); Anal. Calcd for
C21H15ClN4O: C, 67.29; H, 4.03; N, 14.95. Found: C,
67.34; H, 3.91; N, 14.83 %.
N=CH), 8.95-7.03 (m, 9H, aromatic), 5.05 (s, 1H, NH),
4.85 (s, 1H, H-4), 3.36 (s, 3H, CH3); 13C NMR (125 MHz)
(CDCl3) d: 159.70 (N=CH), 157.50 (C-2), 150.95 (C-10b),
150.52 (C-9), 138.65 (C-10a), 136.12 (C-7), 128.34 (C-5),
127.04 (C-6a), 123.93 (C-4a), 122.15 (C-8), 121.20 (C-6),
119.80 (CN), 97.80 (C-3), 41.24 (C-4), 143.76, 133.59,
129.42, 126.86 (aromatic); MS m/z (%): 376 (M??2, 7),
374 (M?, 21), 268 (10), 222 (100), 184 (23), 139 (31), 75
(35); Anal. Calcd for C21H15ClN4O: C, 67.29; H, 4.03; N,
14.95. Found: C, 66.44; H, 3.57; N, 14.33 %.
2-(Aminomethyleneamino)-4-(4-bromophenyl)-9-methyl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (13c) Color-
less needles from ethanol; m.p. 252–253 °C; 40 %; IR
(KBr) t (cm-1): 3350, 3322, 3195 (NH2), 3050, 3010,
2974, 2879 (CH), 2189 (CN); 1H NMR (500 MHz)
(CDCl3) d: 8.21 (s, 1H, N=CH), 8.24–7.12 (m, 8H, aro-
matic), 7.17 (bs, 2H, NH2), 4.98 (s, 1H, H-4), 2.74 (s, 3H,
CH3); 13C NMR (125 MHz) (DMSO-d6) d: 162.51
(N=CH), 159.05 (C-2), 156.85 (C-10b), 143.55 (C-9),
136.12 (C-10a), 136.12 (C-7), 129.78 (C-5), 126.13 (C-6a),
125.77 (C-8), 123.51 (C-4a), 120.29 (C-6), 120.18 (CN),
95.22 (C-3), 40.08 (C-4), 137.57, 131.63, 131.85, 122.71
(aromatic); MS m/z (%): 420 (M??2, 9.21), 418 (M?,
10.31), 236 (84), 209 (23), 180 (10), 155 (38), 127 (4), 75
(100), 50 (16); Anal. Calcd for C21H15BrN4O: C, 60.16; H,
3.61; N, 13.36. Found: 60.21; H, 3.73; N, 13.42 %.
Reaction of 9a–c with ammonia
Method (a)
A mixture of imadate 9a–c (0.01 mol) and NH3 gas bub-
bled in methanol (30 ml) was stirred for 1 h and then the
mixture was left overnight. The solid product was collected
and recrystallized from proper solvent to give 8a–c.
Compounds 13a–c were separated from the reaction filtrate
and recrystallized from ethanol. The physical and spectral
data of compounds 13a–c are as follows:
Method (b)
2-(Aminomethyleneamino)-4-(4-chlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (13a) Colorless needles
from ethanol; m.p. 230–232 °C; 38 %; IR (KBr) t (cm-1):
3335, 3300, 3178 (NH2), 3046, 3009, 2876 (CH), 2194
(CN); 1H NMR (500 MHz) (CDCl3) d: 8.94 (s, 1H,
N=CH), 8.09–7.02 (m, 9H, aromatic), 5.04 (bs, 2H, NH2),
4.85 (s, 1H, H-4); 13C NMR (125 MHz) (CDCl3) d: 159.32
(N=CH), 150.67 (C-2), 144.95 (C-10b), 142.77 (C-9),
136.13 (C-10a), 135.12 (C-7), 129.17 (C-5), 128.37 (C-6a),
124.06 (C-4a), 122.14 (C-8), 121.15 (C-6), 119.34 (CN),
97.56 (C-3), 41.19 (C-4), 138.08, 133.49, 129.48, 127.00
(aromatic); MS m/z (%): 362 (M??2, 1), 360 (M?, 3), 344
(3), 342 (6), 249 (5), 222 (100), 195 (29), 117 (14), 75 (16);
Anal. Calcd for C20H13ClN4O: C, 66.58; H, 3.63; N, 15.53.
Found: C, 66.03; H, 3.63; N, 15.21 %.
A mixture of 3a,c,d (0.01 mol) and formamide (20 ml) was
stirred at reflux for 3 h. The solvent was removed under
vacuum. The solid obtained was recrystallized from ben-
zene to give 8a–c (m.p. and mixed m.p. are completely
identical) yield (71–67 %).
Method (c)
Compound 13a–c (0.01 mol) was heated under reflux in
ethanol (20 ml) and piperidine (0.5 ml) for 3 h to give
8a–c (m.p. and mixed m.p. are completely identical) yield
(58–60 %).
Reaction of the imadate (9a,b) with dimethylamine
Method (a)
2-(Aminomethyleneamino)-4-(4-chlorophenyl)-9-methyl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (13b) Color-
less needles from ethanol; m.p. 260–261 °C; 39 %; IR
(KBr) t (cm-1): 3463, 3340, 3200 (NH2), 3060, 3025, 2836
(CH), 2188 (CN); 1H NMR (500 MHz) (DMSO-d6) d: 8.24
(s, 1H, N=CH), 8.20–7.12 (m, 8H, aromatic), 7.18 (bs, 2H,
NH2, cancelled by D2O), 4.99 (s, 1H, H-4), 2.71 (s, 3H,
CH3); 13C NMR (125 MHz) (DMSO-d6) d: 162.51
(N=CH), 160.32 (C-2), 159.08 (C-9), 156.85 (C-10b),
137.56 (C-10a), 136.11 (C-7), 128.65 (C-5), 125.77 (C-6a),
123.51 (C-8), 122.79 (C-4a), 121.41 (C-6), 120.13 (CN),
95.28 (C-3), 40.42 (C-4), 24.97 (CH3), 142.60, 131.63,
129.52, 126.12 (aromatic); MS m/z (%): 376 (M??2,
A mixture of imadate 9a,b (0.01 mol) and dimethylamine
(0.01 mol) in ethanol (30 ml) was stirred at room temper-
ature for 1 h. The solid product was collected and recrys-
tallized from proper solvent to give 10a,b (m.p. and mixed
m.p. are completely identical) yield (88–87 %).
Method (b)
A mixture of b-enaminonitrile 3a,c (0.01 mol), DMF-DPA
(0.01 mol), and benzene (30 ml) was refluxed for 3 h. The
solvent was removed under reduced pressure and the
resulting solid was recrystallized from proper solvent to
123

Med Chem Res
give 10a,b (m.p. and mixed m.p. are completely identical)
yield (83–81 %).
DMSO present in the wells (maximal 0.1 %) was not found
to affect the experiment. After incubation of the cells for
24 h at 37 °C, various concentrations of sample were
added, and the incubation was continued for 48 h and
viable cells yield was determined by a colorimetric MTT
method.
Reaction of 10a,b with hydrazine hydrate
Method (a)
In brief, after the end of the incubation period, crystal
violet solution (1 %) was added to each well for 30 min.
The stain was removed and the plates were rinsed using tap
water until all excess stain was removed. Glacial acetic
acid was then added to all wells and mixed thoroughly, and
the plates were read on ELISA reader, using a test wave-
length of 490 nm. Treated samples were compared with the
control in the absence of the tested samples. All experi-
ments were carried out in triplicate. The cytotoxic effect of
each tested compound was calculated.
A mixture of imidine 10a,b (0.01 mol) and hydrazine
hydrate (0.01 mol) in ethanol (30 ml) was stirred at room
temperature or reflux for 1 h. The solid product was col-
lected and recrystallized from proper solvent to give 10a,b
(m.p. and mixed m.p. are completely identical) yield
(80–81 %).
Method (b)
A mixture of imidine 10a,b (0.01 mol), hydrazine hydrate
(0.01 mol), and p-toluenesulfonic acid (0.01 mol) in tolu-
ene (30 ml) was heated under reflux for 7 h. The solid
product was collected and recrystallized from proper sol-
vent to give 10a,b (m.p. and mixed m.p. are completely
identical) yield (78–80 %).
Acknowledgments This study was supported by King Abdulaziz
City for Science and Technology (KACST), No. A-S-11-0560. The
authors deeply thank the Regional Center for Mycology & Biotech-
nology (RCMP), Al-Azhar University for carrying out the antitumor
study and Mr. Ali Y. A. Alshahrani for making the 1H NMR and 13
NMR samples.
C
Antitumor screening
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