Halogenated 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitriles as antitumor agents and structure–activity relationships of the 4-, 6-, and 9-positions

Article abstract of DOI:10.1007/s00044-016-1747-z

A series of halogenated 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives were prepared via interaction of 8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, and 8-hydroxy-2-methylquinoline with various α-cyanocinnamonitriles. The assignme

Full text of DOI:10.1007/s00044-016-1747-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1747-z
ORIGINAL RESEARCH
Halogenated 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitriles
as antitumor agents and structure–activity relationships of the
4-, 6-, and 9-positions
Ahmed M. Fouda1
Received: 27 October 2015 / Accepted: 9 November 2016
© Springer Science+Business Media New York 2016
Abstract A series of halogenated 2-amino-4-aryl-4H-pyr-
ano[3,2-h]quinoline-3-carbonitrile derivatives were pre-
pared via interaction of 8-hydroxyquinoline, 5-chloro-8-
hydroxyquinoline, and 8-hydroxy-2-methylquinoline with
various α-cyanocinnamonitriles. The assignments of the
structure of all synthesized compounds were based on
spectral data. The cytotoxic activities of the synthesized
compounds against four human tumor cell lines MCF-7,
HCT-116, HepG-2, and A549 in comparison with the
reference drugs Vinblastine and Colchicine were deter-
mined by microculture tetrazolium assay. Several com-
pounds showed significant cytotoxic activity. The
structure–activity relationship studies reported that the
substitution at 4-, 6-, and 9-positions in several 2-amino-
4H-pyrano[3,2-h]quinoline nucleus with the specific halo-
gen atom and lipophilicity increases the ability of the
molecule against the different cell lines.
many classes of biologically active compounds (El-Agrody
et al. 2013; Thomas et al. 2010; Chang et al. 2010; Larghi
et al. 2009; Liu et al. 2009; Ramesh et al. 2009; Righi et al.
2008; Ganesh et al. 2008; Musiol et al. 2007). Many
compounds that synthesized from 8-hydroxyquinoline and
its derivatives have been also shown to have diverse ther-
apeutic activities such as antiprotozoic drugs as well as
antineoplastics (Jampilek et al. 2009) and antiproliferative
(Musiol et al. 2008; Badawey and Kappe 1997) activities. In
addition styrylquinoline derivatives have been explored as
perspective HIV integrase inhibitors (Mrozek-Wilczkiewicz
et al. 2010; Leonard and Roy 2008; Zouhiri et al. 2005) and
biologically active compounds (Chang et al. 2010; Larghi
et al. 2009, Ma et al. 2004; Jiang et al. 1990). They also
exhibit antimalarial (Kaur et al. 2009), antitumor (Behforouz
et al. 2007), antioxidant (Mallesha et al. 2013), antil-
eishmanial (Rocha et al. 2005), and antiplatelet activities
(Kuo et al. 2001). In addition several 4H-pyrano[3,2-h]
quinoline
derivatives
has
antitumor
activity
●
Keywords 8-Hydroxyquinoline derivatives 4H-Pyrano
(El-Agrody et al. 2012; Al-Ghamdi et al. 2012) against
different human tumor cell lines. Furthermore, they function
as pharmacologically active synthetic compounds (Watson
et al. 2001) such as DNA binding capabilities (Atwell et al.
1989) and DNA-intercalating carrier (Chen et al. 2000). In
view of the above-mentioned findings, I report herein
the synthesis of a series of halogenated 2-amino-4-aryl-4H-
pyrano[3,2-h]quinoline-3-carbonitrile derivatives and their
evaluation as antitumor, hoping to add some synergistic
biological significance to the target molecules. The
structural–activity relationship (SAR) of 4-, 6-, and
9-positions for the prepared compounds and lipophilicity
was also discussed.
●
●
●
[3,2-h]quinoline Antitumor Lipophilicity SAR
Introduction
The chemistry of quinoline derivatives has attracted many
researchers due to their applications as biological activities
and pharmacological agents. Quinoline moiety is present in
* Ahmed M. Fouda
amfouda@hotmail.com
1
Chemistry Department, Faculty of Science, King Khalid
University, P.O. Box Abha 9004, 61413 Abha, Saudi Arabia

Med Chem Res
9
Scheme 1 Synthesis of 2-
amino-4-aryl-4H-pyrano[3,2-h]
quinoline-3-carbonitrile
derivatives (3a–j)
a; Ar = 2-ClC6H4
10
8
7
b
N
a
b; Ar = 3-ClC6H4
OH
1
c
10a
d
10b O
NH2
CN
2
3
c; Ar = 4-ClC6H4
N
1
2
CN
=C
CN
6a
e
h
ip.
d; Ar = 2,3-Cl2C6H3
e; Ar = 2,4-Cl2C6H3
f; Ar = 2,5-Cl2C6H3
g; Ar = 2,6-Cl2C6H3
h; Ar = 3,4-Cl2C6H3
i; Ar = 4-BrC6H4
tOH / p
E
Ar-CH
2a-j
3
f
g
+
6
4a
ref lux
4
5
Ar
3a-j
1
j; Ar = 2,3,5-MeOBr2C6H2
9
Scheme 2 Synthesis of 2-
amino-4-aryl-6-chloro-4H-
pyrano[3,2-h]quinoline-3-
carbonitrile derivatives (5a–j)
a; Ar = 2-ClC6H4
10
8
7
b
a
N
b; Ar = 3-ClC6H4
OH
Cl
1
c
10a
d
O
NH2
2
3
c; Ar = 4-ClC6H4
10b
N
1
CN
6a
2
3
e
h
g
pip.
d; Ar = 2,3-Cl2C6H3
e; Ar = 2,4-Cl2C6H3
f; Ar = 2,5-Cl2C6H3
g; Ar = 2,6-Cl2C6H3
h; Ar = 3,4-Cl2C6H3
i; Ar = 4-BrC6H4
EtOH /
reflux
Ar-CH=
C
f
+
6
Cl
CN
4a
CN
4
5
Ar
2a-j
4
5a-j
j; Ar = 2,3,5-MeOBr2C6H2
Me
Scheme 3 Synthesis of 2-
amino-4-aryl-9-methyl-4H-
pyrano[3,2-h]quinoline-3-
carbonitrile derivatives (7a–j)
9
a; Ar = 2-ClC6H4
10
8
7
b
a
N
b; Ar = 3-ClC6H4
OH
1
O
1
c
10a
10b
d
NH2
2
c; Ar = 4-ClC6H4
Me
N
CN
6a
2
3
e
h
g
ip.
tOH / p
d; Ar = 2,3-Cl2C6H3
e; Ar = 2,4-Cl2C6H3
f; Ar = 2,5-Cl2C6H3
g; Ar = 2,6-Cl2C6H3
h; Ar = 3,4-Cl2C6H3
i; Ar = 4-BrC6H4
E
Ar-CH
2a-j
=C
f
+
6
3
CN
4a
CN
reflux
4
5
Ar
7a-j
6
j; Ar = 2,3,5-MeOBr2C6H2
Results and discussion
Chemistry
trisubstituted cinnamonitriles 2a–j in ethanolic piperidine
under reflux for 1 h gave 2-amino-4-aryl-6-chloro-4H-pyr-
ano[3,2-h]quinoline-3-carbonitrile derivatives (5a–j) as
shown in Scheme 2. The 4-position of compounds 5a–j is a
chiral center and all the reaction progress was observed by
TLC.
The assignment of structure 5 was established on the
basis of spectral data. The IR spectra of 5 showed the
appearance of a NH2 stretch at υ 3479–3432, 3349–3321,
3205–3182 cm−1 and a CN stretch at υ 2201–2192 cm−1.
The 1H and 13C NMR spectra of 5 revealed the presence of
4H signals at δ 6.03–5.00 (s, 1H, H-4) and 40.50–36.78 ppm
(C-4), respectively. The 13C NMR-APT spectra of com-
pound 5 provided additional evidence in support of the
proposed structure. In addition, the mass spectra of com-
pound 5 gave also additional evidences for the proposed
structures.
Similarly, reaction of 2-methyl-8-hydroxyquinoline (6)
with α-cyanomono, di- or trisubstituted cinnamonitriles
2a–j in ethanolic piperidine under reflux for 1 h gave 2-
amino-4-aryl-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbo-
nitrile derivatives (7a–j) as shown in Scheme 3. The
4-position of compounds 7a–j is chiral center and all the
reaction progress was observed by TLC.
Interaction of 8-hydroxyquinoline (1) with α-cyanomono, di
or trisubstituted cinnamonitriles (2a–j) in ethanolic piper-
idine under reflux for 1 h afforded the corresponding 2-
amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile
derivatives (3a–j) as depicted in Scheme 1. The 4-position
of compounds 3a–j is a chiral center and all the reaction
progress was observed by TLC.
The assignment of structure 3 was established on the
basis of spectral data. The infrared (IR) spectra of 3 showed
the appearance of a NH2 stretch at υ 3478–3407,
3371–3322, 3210–3188 cm−1 and a CN stretch at υ
2198–2186 cm−1. The 1H and 13C NMR spectra of 3
revealed the presence of 4H signals at δ 5.56–4.89 (s, 1H,
H-4) and 40.80–38.12 ppm (C-4), respectively. The 13C
NMR-attached proton test (APT) spectra of compound 3
provided additional evidence in support of the proposed
structure. In addition, the mass spectra of compound 3 gave
also additional evidences for the proposed structures.
In
a
similar manner, reaction of 5-chloro-8-
hydroxyquinoline (4) with α-cyanomono, di or

Med Chem Res
The assignment of structure 7 was established on the
basis of spectral data. The IR spectra of 7 showed the
appearance of a NH2 stretch at υ 3471–3431, 3366–3323,
3205–3182 cm−1 and a CN stretch at υ 2195–2188 cm−1.
The 1H and 13C NMR spectra of 7 revealed the presence of
4H signals at δ 6.01–4.97 (s, 1H, H-4) and 40.54–36.68 ppm
(C-4), respectively. The 13C NMR-APT spectra of com-
pound 7 provided additional evidence in support of the
proposed structure. In addition, the mass spectra of com-
pound 7 gave also additional evidences for the proposed
structures.
MCF-7 as compared to Vinblastine and Colchicine, sug-
gesting that the dichloro atoms at 2,3-position or 3,4-posi-
tion and the monochloro atom at 3-position or 2-position at
the phenyl ring (hydrophobic group) at 4-position of the
4H-pyrano[3,2-h]quinoline moiety is preferred over the other
substituted groups with decreasing of partition coefficient as
shown in Table 1. Replacement of the 6-H for compound 3
with 6-Cl improved of the antitumor activities of compound
5. Compounds 5b, i, e, d (IC50 = 0.9–2.47 µg/ml) have the
higher potent antitumor activities
against the
MCF-7 as compared to Vinblastine (IC50 = 6.1 μg/ml) and
the other compounds 5f, h, j, a, c, g (IC50 = 7.76–10.2 and
>50 μg/ml), while compounds 5b, i, e, d, f, h, j, a, c dis-
played good activity (IC50 = 0.9–10.2 µg/ml) against the
MCF-7 as compared to Colchicine (IC50 = 17.7 μg/ml) and
compound 5g inactive (IC50 = >50 μg/ml). This potency
could be attributed to the presence of the monochloro/
bromo atom at 3-position or 4-position, the dichloro atoms
at 2,4-position or 2,3-position of the phenyl ring (hydro-
phobic group) at 4-position of the 4H-pyrano[3,2-h]quino-
line moiety with chloro atom at 6-position, suggesting that
this positions at the phenyl ring at 4-position was superior in
inhibiting the growth of MCF-7 than the other positions
with increasing of partition coefficient as shown in Table 1.
In addition, replacement of the 9-H for compound 3 with 9-
Me improved of the antitumor activities of compound 7.
Compounds 7h, d, a, j, b, f (IC50 = 1.24–5.92 µg/ml)
exhibited very good activities against the MCF-7 as com-
pared to Vinblastine (IC50 = 6.1 μg/ml) and Colchicine
(IC50 = 17.7 μg/ml) and the other compounds 7c, e, i, g
(IC50 = 27.9–38.9 and >50 μg/ml). These data indicate that
the activity of compounds 7h, d, a, j, b, f was considerably
attributed to the presence of the dichloro atoms at 3,4-
position, 2,3-position, 2,5-position, monochloroatom at 2-
position, 3-position and trisubstituted of the phenyl ring
(hydrophobic group) at 4-position of the 4H-pyrano[3,2-h]
quinoline moiety, suggesting that these positions were
superior in inhibiting the growth of MCF-7 with 9-Me and
with decreasing of partition coefficient as shown in Table 1.
In the case of human colon carcinoma (HCT-116),
investigation of SAR revealed that the 2,3-dichlorosub-
stituted and the 3-chlorosubstituted phenyl 3d, b exhibited
good activity (IC50 = 1.3 and 1.35 μg/ml) as compared to
Vinblastine (IC50 = 2.6 μg/ml) and the other compounds 3h,
a, j, f, c, e, g, i (IC50 = 3.9–43.7 μg/ml), while compounds
3d, b, h, a, j, f, c, e, g has the higher potent antitumor
activity (IC50 = 1.3–31.2 μg/ml) against HCT-116 as com-
pared to Colchicine (IC50 = 42.8 μg/ml) and the compound
3i (IC50 = 43.7 μg/ml). This indicated that the dichloro
atoms at 2,3-position and the monochloro atom at 3-
position have a variable influence on the cytotoxic activity
against HCT-116 with decreasing of partition coefficient as
shown in Table 1. Replacement of the 6-H for compound 3
Antitumor activity
All the synthesized compounds 3a–j, 5a–j, and 7a–j were
screened for their in vitro antitumor activity against four
human cancer cell lines: breast adenocarcinoma (MCF-7),
human colon carcinoma (HCT-116), hepatocellular carci-
noma (HepG-2), and lung carcinoma (A549) at various
concentrations ranging from 0 to 50 μg/ml and the cell
viability was measured by the microculture tetrazolium
(MTT) assay as described in the literature (Rahman et al.
2001). In vitro cytotoxic evaluation using cell viability
assay was performed at the Regional Center for Mycology
& Biotechnology (RCMP), Al-Azhar University, Cairo,
Egypt using Vinblastine and Colchicine as reference drugs.
The inhibitory concentration (IC50, in µg/ml) of target
compounds 3a–j, 5a–j, and 7a–j against the four human
cancer cell lines MCF-7, HCT-116, HepG-2, and A549
were given in Table 1.
SAR studies
The partition coefficient (Log P), which is well known as an
index of lipophilicity, is an important physicochemical
parameter was measured by ACD/Labs Log P calculated,
ver.14.02 and was cited in Table 1. The SAR studies at the
4-, 6-, and 9-positions and the relationship between lipo-
philicity and antitumor activity were explored. The SAR
studies of compounds 3a–j revealed that compounds 3d, b,
h, a has the highest potent antitumor activity (IC50
1.17–5.33 μg/ml) against breast adenocarcinoma (MCF-7)
as compared to the other compounds 3j, f, e, c, i, g (IC50
=
=
10.8–38.2 μg/ml) and the reference drug Vinblastine
(IC50 = 6.1 μg/ml), while compounds 3d, b, h, a, j, f has the
higher potent antitumor activity (IC50 = 1.17–11 μg/ml)
against MCF-7 as compared to the compounds 3e, c, i, g
(IC50 = 23.8–38.2 μg/ml), and the reference drug Colchicine
(IC50 = 17.7 μg/ml). The comparison of IC50 values of the
halosubstituted compounds 3a–j at the phenyl ring at 4-
position demonstrated that the dichloro atoms at 2,3-posi-
tion or 3,4-position and the monochloro atom at 3-position
or 2-position increased the antitumor activity profile against

Med Chem Res
Table 1 SAR of the 4-aryl group and the IC (IC50, in µg/ml) of target compounds against the four human cancer cell lines in comparison with
Vinblastine and Colchicine as measured with the MTT method
Compounds
Ar
MCF-7
HCT-116
HepG-2
A549
Log P
3a
3b
3c
3d
3e
3f
2-ClC6H4
5.33 0.2
1.42 0.3
24.9 0.05a
1.17 0.11
23.8 0.3
11 0.22
4.64 0.1
1.35 0.2
24 0.05a
1.3 0.12
24.3 0.11
12.8 0.2
31.2 0.04
3.9 0.15
43.7 0.13
6.71 0.11
5.57 0.1
1.87 0.2
wa
4.07 0.3
1.23 0.1
21.1 0.05
38 0.03
19.5 0.2
7.95 0.02
33.6 0.03
2.05 0.12
w
3.35 0.50
3.35 0.50
3.35 0.50
3.82 0.50
3.96 0.50
3.87 0.50
3.96 0.50
3.82 0.50
3.53 0.53
4.23 0.66
3-ClC6H4
4-ClC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
2,5-Cl2C6H3
2,6-Cl2C6H3
3,4-Cl2C6H3
4-BrC6H4
1.41 0.18
12.1 0.1
11.5 0.12
36.3 0.06
2.44 0.11
NAa
3g
3h
3i
38.2 0.04
3.08 0.13
34.8 0.15
10.8 0.11
3j
2,3,5-
10.4 0.05
5.73 0.07
MeOBr2C6H2
5a
5b
5c
5d
5e
5f
2-ClC6H4
8.8 0.16
0.9 0.07
10.2 0.04
2.47 0.13
1.18 0.14
7.76 0.12
w
7.94 0.3
3.04 0.2
12.1 0.11
7.94 0.05
3.01 0.22
12.2 0.02
34.3 0.04
18.6 0.13
5.81 0.11
3.72 0.15
4.62 0.11
0.7 0.06
11.9 0.07
1.48 0.11
0.87 0.12
11.5 0.14
44.5 0.12
3.98
5.66 0.16
2.67 0.07
22.1 0.04
15.6 0.13
1.79 0.14
8.23 0.12
24.3 0.12
14.4 0.15
3.1 0.01
4.10 0.70
4.10 0.70
4.10 0.70
4.57 0.70
4.71 0.70
4.62 0.70
4.71 0.70
4.57 0.70
4.28 0.74
4.98 0.84
3-ClC6H4
4-ClC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
2,5-Cl2C6H3
2,6-Cl2C6H3
3,4-Cl2C6H3
4-BrC6H4
5g
5h
5i
7.96 0.15
0.99 0.01
8.09 0.2
0.13
1.23 0.03
8.97 0.12
5j
2,3,5-
2.28 0.12
MeOBr2C6H2
7a
7b
7c
7d
7e
7f
2-ClC6H4
2.56 0.22
5.79 0.01
27.9 0.12a
1.52 0.1
36 0.13
5.92 0.2
w
33.9 0.2
21.4 0.1
15.8 0.2a
39.5 0.4
45.5 0.2
35.8 0.12
w
14.5 .21
3.01 .11
1.8 .15
5.39 .1
23.9 0.14
10.5 0.3
w
27.8 0.22
24 0.01
w
3.81 0.50
3.81 0.50
3.81 0.50
4.28 0.50
4.42 0.50
4.33 0.50
4.42 0.50
4.28 0.50
3.99 0.53
4.69 0.66
3-ClC6H4
4-ClC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
2,5-Cl2C6H3
2,6-Cl2C6H3
3,4-Cl2C6H3
4-BrC6H4
31.8 0.1
36.6 0.13
22.4 0.2
w
7g
7h
7i
1.24 0.3
38.9 0.14a
4.95 0.15
23.7 0.04
22.8 0.13a
42.2 0.2
1.83 0.2
5.5 0.13
9.38 0.14
13.7 0.3
36.7 0.14
22.2 0.15
7j
2,3,5-
MeOBr2C6H2
V
C
–
–
6.1 0.01
2.6 0.04
4.6 0.11
10.6 0.13
3.78 0.01
21.3 0.03
–
–
17.7 0.03
42.8 0.08
IC50 values expressed in µg/ml as the mean values of triplicate wells from at least three experiments and are reported as the mean standard error
a
[1a]
w weak activity (IC50 > 50 µg/ml), NA not active, V Vinblastine, C Colchicine

Med Chem Res
with 6-Cl resulted in reduction of potency for the compound
9-H for compound 3 with 9-Me resulted in improvement
of antitumor activities of compound 7. Compounds 7c, h,
5. Compounds 5e, b, j exhibited near activities (IC50
=
3.01–3.72 μg/ml) and the other compounds 5i, a, d, c, f, h, g
exhibited moderate to lower activities (IC50 = 5.81–34.3 μg/ml)
b
exhibited good activities (IC50 = 1.5–3.01 μg/ml)
against HepG-2 as compared to Vinblastine (IC50 = 4.6
μg/ml), while compounds 7d, i, j, f, a, e exhibited near or
moderate to lower activities (IC50 = 5.39–23.9 and >50
μg/ml) and compounds 7c, h, b, d, i, j, f (IC50 = 1.5-10.5
μg/ml) showed good activities against HepG-2 as com-
pared to Colchicine (IC50 = 10.6 μg/ml) and the other
compounds 7a, e, g with increasing of partition coefficient
as shown in Table 1, suggesting that the monochloro
atom at 4-position or 3-position and the dichloro atoms at
3,4-position have the more variable influence on the
cytotoxic activity against HepG-2 than the another
groups.
against HCT-116 as compared to Vinblastine (IC50
=
2.6 μg/ml), while compounds 5e, b, j, i, a, d, c, f, h, g
exhibited good activity (IC50 = 3.01–34.3 μg/ml) against
HCT-116 as compared to Colchicine (IC50 = 42.8 μg/ml)
with decreasing of partition coefficient as shown in Table 1,
suggesting that the dichloro atoms at 2,4-position and the
monochloro atom at 3-position have the more variable
influence on the cytotoxic activity against HCT-116 than
the another groups. In addition, replacement of the 9-H for
compound 3 with 9-Me resulted in more reduction of
antitumor activities of compound 7. Compounds 7c, b, i, h,
j, a, f, d, e, g exhibited near or moderate to lower activities
(IC50 = 15.8–45.5 and >50 μg/ml) against HCT-116 as
compared to Vinblastine (IC50 = 2.6 μg/ml), while com-
Finally, compounds 3b, h (IC50 = 1.23 and 2.05 μg/ml)
showed a significant antitumor activities against lung
carcinoma (A549) as compared to Vinblastine (IC50
=
pounds 7c, b, i, h, j, a, f, d exhibited good activity (IC50
=
3.79 μg/ml) and the other compounds 3a, j, f, e, c, g, d, i
(IC50 = 4.07–38 and >50 μg/ml), while compounds 3b, h,
a, j, f, e, c (IC50 = 1.23–21.1 μg/ml) exhibited good
activities as compared to Colchicine (IC50 = 21.3 μg/ml)
and the other compounds 3g, d, i (IC50 = 33.6, 38 and
>50 μg/ml) with increasing of partition coefficient as
shown in Table 1. This is due to the presence of the
monochloro atom at 3-position and the dichloro atoms at
3,4-position which have the more variable influence on
the cytotoxic activity against A549 than the another
groups. Replacement of the 6-H for compound 3 with 6-Cl
resulted in improvement of potency for the compound 5.
15.8–39.5 μg/ml) against HCT-116 as compared to Col-
chicine (IC50 = 42.8 μg/ml) with increasing of partition
coefficient as shown in Table 1, suggesting that monochloro
atom at 4-position or 3-position and the monobromo atom at
4-position is preferred over another groups.
Furthermore, compounds 3d, b, h (IC50 = 1.41–2.44
μmol/l) showed good antitumor activities against hepato-
cellular carcinoma (HepG-2) as compared to Vinblastine
(IC50 = 4.6 μg/ml) and the other compounds 3a, j, f, e, g, c
(IC50 = 5.57–36.3 and >150 μg/ml) and compound 3i was
inactive, while compounds 3d, b, h, a, j (IC50
=
1.41–5.57 μg/ml) exhibited good antitumor activities
against HepG-2 as compared to Colchicine (IC50 = 10.6
Compounds 5e, j, b, i exhibited good activities (IC50 =
1.79–3.1 μg/ml) and the other compounds 5a, f, h, d, c, g
exhibited moderate to lower activities (IC50 = 5.66–24.3
μg/ml) and the other compounds 3f, e, g, c (IC50
=
11.5–36.3 and >150 μg/ml) and compound 3i was inac-
tive with decreasing of partition coefficient as shown in
Table 1, suggesting that the dichloro atoms at 2,3-posi-
tion, 3,4-position and the monochloro atom at 3-position
have the more variable influence on the cytotoxic activity
against HepG-2 than the another groups. Replacement of
the 6-H for compound 3 with 6-Cl resulted in improve-
ment of potency for the compound 5. Compounds 5b, e, i,
d, h, a exhibited good activities (IC50 = 0.7–4.62 μg/ml)
and the other compounds 5j, f, c, g exhibited moderate to
lower activities (IC50 = 8.97–44.5 μg/ml) against HepG-2
as compared to Vinblastine (IC50 = 4.6 μg/ml), while
compounds 5b, e, i, d, h, a, j exhibited good activity
(IC50 = 0.7–8.97 μg/ml) against HepG-2 as compared to
Colchicine (IC50 = 10.6 μg/ml) with increasing of parti-
tion coefficient as shown in Table 1, suggesting that the
monochloro/bromo atom at 3-position or 4-position, the
dichloro atoms at 2,4-position, 2,3-position have the more
variable influence on the cytotoxic activity against HepG-
2 than the another groups. In addition, replacement of the
μg/ml) against A549 as compared to Vinblastine (IC50
3.79 μg/ml), while compounds 5e, j, b, i, a, f, h, d (IC50
=
=
1.79–15.6 μg/ml) showed good activities against A549 as
compared to Colchicine (IC50 = 21.3 μg/ml) and the other
compounds 5c, g (IC50 = 22.1 and 24.3 μg/ml) with
increasing of partition coefficient as shown in Table 1,
suggesting that the dichloro atoms at 2,4-position and the
trisubstituted have the higher influence on the cytotoxic
activity against A549 than the another groups. Further-
more, replacement of the 9-H for compound 3 with 9-Me
resulted reduction of antitumor activities of compound 7.
All the compound 7 exhibited lower activities (IC50
=
13.7–36.7 and >50 μg/ml) against A549 as compared to
Vinblastine (IC50 = 3.79 μg/ml), while compound 7h
showed good activity against A549 as compared to
Colchicine (IC50 = 21.3 μg/ml) and the other compounds
7j, f, b, a, d, e, i, c, g (IC50 = 22.2–36.7 and >50 μg/ml)
with increasing of partition coefficient as shown in
Table 1, suggesting that the dichloro atoms at 3,4-position
is preferred over than the another groups.

Med Chem Res
Conclusions
aryl-6-chloro-4H-pyrano[3,2-h]quinoline-3-carbonitrile (5a–j)
and 2-amino-4-aryl-9-methyl-4H-pyrano[3,2-h]quinoline-3-
carbonitrile derivatives (7a–j).
In conclusion, halogenated 4H-pyrano[3,2-h]quinoline-3-
carbonitrile derivatives 3a–j, 5a–j, and 7a–j was synthe-
sized. Structures of the synthesized compounds were elu-
A
solution of 8-hydroxyquinoline 1, 5-chloro-8-
hydroxyquinoline 4, or 8-hydroxy-2-methyl-quinoline 6
(0.01 mol) in EtOH (30 mL) was treated with α-cyanomono,
di or trisubstituted cinnamonitriles 2a–j (0.01 mol) and
piperidine (0.5 mL). The reaction mixture was heated under
reflux with stirring for 1 h. The solid product formed was
collected by filtration and recrystallized from a suitable
solvent to give 3a–j, 5a–j, and 7a–j. The physical and
spectral data of compounds 3a–j, 5a–j, and 7a–j are as
follows:
cidated on the basis of IR, H NMR, 13C NMR, and MS
1
data. Among the newly synthesized compounds 3d, b, h, a,
5b, i, e, d, 7h, d, a, j, b, f and 3d, b, h, a, j, f, 5b, i, e, d, f,
h, j, a, c, 7h, d, a, j, b, f showed highest inhibition against
MCF-7 as compared to Vinblastine and Colchicine
respectively, while compounds 3d, b, 5e, b, j and 3d, b, h,
a, j, f, c, e, g, 5e, b, j, i, a, d, c, f, h, g, 7c, b, i, h, j, a, f, d
exhibited the best growth inhibitory activity against HCT-
116 as compared to the standard drugs Vinblastine and
Colchicine respectively, and compounds 3d, b, h, 5b, e, i,
d, h, a, 7c, h, b and 3d, b, h, a, j, 5b, e, i, d, h, a, j, 7c, h, b,
d, i, j, f exhibited the best growth inhibitory activity against
HepG-2 as compared to Vinblastine and Colchicine,
respectively, while compounds 3b, h, 5e, j, b, i and 3b, h, a,
j, f, e, c, 5e, j, b, i, a, f, h, d, 7h showed highest inhibition
against A549 as compared to Vinblastine and Colchicine,
respectively. On the basis of SAR, lipophilicity and the
partition coefficient (Log P) are beneficial for antitumor
activity. The highest inhibition activity of the halogenated
4H-pyrano[3,2-h]quinoline derivatives 3a–j, 5a–j and 7a–j
is in the following order:
2-amino-4-(2-chlorophenyl)-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (3a)
Yellow crystals from ethanol; yield 87 %; m.p. 289–290 °C;
IR (KBr, υmax cm−1): 3478, 3323, 3195 (NH2), 2196
(CN), 1658 (C=N) 1H NMR (500 MHz, DMSO-d6) δ:
8.96–7.06 (m, 9H, aromatic), 7.29 (bs, 2H, NH2), 5.44 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.50 (C-
2), 150.27 (C-9), 143.27 (C-10b), 137.35 (C-10a), 136.24
(C-7), 128.92 (C-5), 127.93 (C-6a), 124.34 (C-4a), 123.88
(C-8), 122.88 (C-6), 120.51 (CN), 54.63 (C-3), 38.48 (C-
4), 142.05, 132.10, 129.83, 128.09, 127.83, 126.09 (aro-
matic), MS m/z (%): 335 (M++2, 5.51), 333 (M+,17.23)
with a base peak at 222 (100); anal. calcd. for
C19H12ClN3O: C, 68.37; H, 3.62; N, 12.59. Found: C,
68.41; H, 3.64; N, 12.63 %.
6-Cl analogs 5a–j > unsubstituted analogs 3a–j >9-Me
analogs 7a–j
Further investigations are essential to gain deeper insight
into structure–activity aspects and to predict the optimal
structural parameters, which could be beneficial in devel-
opment of antitumor therapeutics.
2-amino-4-(3-chlorophenyl)-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (3b)
Experimental
Yellow crystals from ethanol; yield 88 %; m.p. 240-241 °C;
IR (KBr, υmax cm−1): 3407, 3322, 3205 (NH2), 2196
(CN), 1656 (C=N); 1H NMR (500 MHz, DMSO-d6) δ:
8.20–7.08 (m, 9H, aromatic), 7.22 (bs, 2H, NH2), 4.89 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.41 (C-
2), 150.28 (C-9), 143.04 (C-10b), 136.44 (C-10a), 136.00
(C-7), 128.26 (C-5), 127.80 (C-6a), 124.28 (C-4a), 123.75
(C-8), 122.23 (C-6), 120.25 (CN), 55.41 (C-3), 40.80 (C-
4), 148.02, 134.82, 130.84, 130.17, 127.06, 126.71 (aro-
matic), MS m/z (%): 335 (M++2, 2.95), 333 (M+,8.32)
with a base peak at 222 (100); anal. calcd. for
C19H12ClN3O: C, 68.37; H, 3.62; N, 12.59. Found: C,
68.40; H, 3.64; N, 12.61 %.
All chemicals were purchased from Sigma-Aldrich Che-
mical Co. Melting points were determined with a Stuart
Scientific Co. Ltd apparatus and are uncorrected. IR spectra
were determined as KBr pellets on a Jasco FT/IR 460 plus
spectrophotometer. H NMR and 13C NMR spectra were
1
recorded using a BRUKER AV 500/600 MHz spectrometer.
13C NMR spectra were obtained using APT, with this
technique, the signals of CH and CH3 carbon atoms appears
normal (up) and the signal of CH2 and Cq environments
appears negative (down). The MS were measured on a
Shimadzu GC/MS-QP5 spectrometer. Elemental analyses
were performed on a Perkin-Elmer 240 microanalyser.
Analytical thin layer chromatography (TLC) on silica gel-
precoated F254 Merck plates to check the purity of the
compounds.
2-amino-4-(4-chlorophenyl)-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (3c)
General procedure for the synthesis of 2-amino-4-aryl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (3a–j), 2-amino-4-
Prepared as previously described (El-Agrody and Al-
Ghamdi 2011).

Med Chem Res
2-amino-4-(2,3-dichlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (3d)
149.78, 131.55, 130.67, 130.12, 129.65, 127.87 (aromatic);
MS m/z (%): 371 (M++4, 2.76), 369 (M++2, 14.64), 367
(M+,23.66) with a base peak at 222 (100); anal. calcd. for
C19H11Cl2N3O: C, 61.98; H, 3.01; N, 11.41. Found: C,
61.95; H, 3.06; N, 11.46 %.
Yellow crystals from benzene; yield 87 %; m.p. 281–283 °C;
IR (KBr, υmax cm−1): 3466, 3349, 3188 (NH2), 2186 (CN),
1
1646 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.97–7.08
(m, 8H, aromatic), 7.32 (bs, 2H, NH2), 5.56 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.54 (C-2), 150.35
(C-9), 143.36 (C-10b), 137.33 (C-10a), 136.29 (C-7),
129.17 (C-5), 128.75 (C-6a), 124.42 (C-4a), 123.87 (C-8),
122.90 (C-6), 119.99 (CN), 54.27 (C-3), 39.99 (C-4),
150.09, 133.95, 130.20, 129.51, 127.96, 125.99 (aromatic),
MS m/z (%): 371 (M++4, 2.15), 369 (M++2, 12.05), 366
(M+,18.29) with a base peak at 222 (100); anal. calcd. for
C19H11Cl2N3O: C, 61.98; H, 3.01; N, 11.41. Found: C,
61.94; H, 2.98; N, 11.38 %.
2-amino-4-(2,6-dichlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (3g)
Yellow crystals from benzene; yield 84 %; m.p. 295–296 °C;
IR (KBr, υmax cm−1): 3471, 3361, 3188 (NH2), 2196 (CN),
1
1660 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.96–6.96
(m, 8H, aromatic), 7.26 (bs, 2H, NH2), 6.03 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.88 (C-2), 150.34
(C-9), 143.95 (C-10b), 137.03 (C-10a), 136.04 (C-7),
128.69 (C-5), 128.00 (C-6a), 123.68 (C-4a), 122.26 (C-8),
119.75 (C-6), 118.21 (CN), 51.87 (C-3), 37.20 (C-4),
137.14, 135.63, 134.87, 130.83, 130.65, 130.08, 125.24
(aromatic); MS m/z (%): 371 (M++4, 4.32), 369 (M++2,
23.64), 367 (M+, 34.64) with a base peak at 222 (100); anal.
calcd. for C19H11Cl2N3O: C, 61.98; H, 3.01; N, 11.41.
Found: C, 61.92; H, 3.10; N, 11.50 %.
2-amino-4-(2,4-dichlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (3e)
Yellow crystals from ethanol; yield 86 %; m.p. 238–240 °C;
IR (KBr, υmax cm−1): 3472, 3322, 3210 (NH2), 2192 (CN),
1
1657 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.94–7.02
(m, 8H, aromatic), 7.32 (bs, 2H, NH2), 5.42 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.50 (C-2), 150.13
(C-9), 143.32 (C-10b), 137.32 (C-10a), 136.05 (C-7),
128.52 (C-5), 128.11 (C-6a), 125.93 (C-4a), 123.79 (C-8),
122.83 (C-6), 119.93 (CN), 54.23 (C-3), 38.12 (C-4),
149.99, 135.95, 132.97, 131.82, 130.65, 127.75 (aromatic).
In 13CNMR-APT spectrum CH, CH3 [positive (up)], CH2,
Cq [negative (down)], revealed the following signals at δ:
160.50 (C-2 ↓), 150.13 (C-9 ↑), 149.99 (aromatic ↓),
143.32 (C-10b ↓), 137.32 (C-10a ↓), 136.05 (C-7 ↑),
135.95 (aromatic ↓), 132.97 (aromatic ↑), 131.82 (aromatic
↑), 130.65 (aromatic ↑), 128.52 (C-5 ↑), 128.11 (C-6a ↓),
127.75 (aromatic ↓), 125.93 (C-4a ↓), 123.79 (C-8 ↑),
122.83 (C-6 ↑), 119.93 (CN ↓), 54.23 (C-3 ↓), 38.12 (C-4
↑); MS m/z (%): 371 (M++4, 1.28), 369 (M++2, 7.59), 367
(M+,11.82) with a base peak at 222 (100); anal. calcd. for
C19H11Cl2N3O: C, 61.98; H, 3.01; N, 11.41. Found: C,
62.00; H, 3.05; N, 11.45 %.
2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (3h)
Yellow crystals from benzene/ethanol; yield 84 %; m.p.
289–290 °C; IR (KBr, υmax cm−1): 3430, 3371, 3196 (NH2),
1
2187 (CN), 1666 (C=N); H NMR (500 MHz, DMSO-d6)
δ: 8.97–7.09 (m, 8H, aromatic), 7.32 (bs, 2H, NH2), 5.46 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.57 (C-2),
150.36 (C-9), 143.76 (C-10b), 137.29 (C-10a), 136.03 (C-
7), 129.02 (C-5), 127.99 (C-6a), 125.98 (C-4a), 123.85 (C-
8), 122.35 (C-6), 119.91 (CN), 53.83 (C-3), 38.88 (C-4),
143.40, 132.29, 131.81, 131.09, 130.80, 130.08 (aromatic);
MS m/z (%): 371 (M++4, 2.18), 369 (M++2, 11.75), 367
(M+, 18.14) with a base peak at 255 (100); anal. calcd. for
C19H11Cl2N3O: C, 61.98; H, 3.01; N, 11.41. Found: C,
62.07; H, 3.09; N, 11.48 %.
2-amino-4-(4-bromophenyl)-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (3i)
2-amino-4-(2,5-dichlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (3f)
Prepared as previously described (El-Agrody and Al-
Ghamdi 2011).
Yellow crystals from benzene/ethanol; yield 84 %; m.p.
293–294 °C; IR (KBr, υmax cm−1): 3475, 3330, 3188 (NH2),
2198 (CN), 1656 (C=N); H NMR (500 MHz, DMSO-d6)
2-amino-4-(3,5-dibromo-2-methoxyphenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (3j)
1
δ: 8.92–7.05 (m, 8H, aromatic), 7.13 (bs, 2H, NH2), 5.41 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.53 (C-2),
151.15 (C-9), 143.38 (C-10b), 137.39 (C-10a), 136.15 (C-
7), 128.72 (C-5), 128.18 (C-6a), 126.03 (C-4a), 123.99 (C-
8), 122.91 (C-6), 119.99 (CN), 54.65 (C-3), 38.45 (C-4),
Pale yellow crystals from ethanol; yield 81 %; m.p. 224–
226 °C; IR (KBr, υmax cm−1): 3435, 3337, 3200 (NH2), 2190
(CN), 1657 (C=N); 1H NMR (500 MHz, DMSO-d6) δ:
8.97–7.27 (m, 7H, aromatic), 7.35 (bs, 2H, NH2), 5.13 (s, 1H,

Med Chem Res
H-4), 3.59 (s, 3H, OCH3); 13C NMR (125 MHz, DMSO-d6)
δ: 160.23 (C-2), 151.01 (C-9), 142.21 (C-10b), 137.99 (C-
10a), 133.91 (C-7), 132.06 (C-5), 127.93 (C-6), 125.13 (C-
6a), 124.70 (C-4a), 123.34 (C-8), 117.28 (CN), 61.35 (CH3),
54.35 (C-3), 36.88 (C-4), 153.32, 140.99, 132.45, 125.35,
120.11,118.56 (aromatic); MS m/z (%): 489 (M++4, 2.33),
487 (M++2, 4.63), 485 (M+, 2.37) with a base peak at 222
(100); anal. calcd. for C20H13Br2N3O2: C, 49.31; H, 2.69; N,
8.63. Found: C, 49.40; H, 2.71; N, 8.70 %.
140.47, 132.32, 130.50, 129.64, 127.93, 127.31 (aromatic),
MS m/z (%): 369 (M++2, 6.87), 367 (M+, 20.11) with a base
peak at 256 (100); anal. calcd. for C19H11Cl2N3O: C, 61.98;
H, 3.01; N, 11.41. Found: C, 61.87; H, 2.94; N, 11.25 %.
2-amino-6-chloro-4-(2,3-dichlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (5d)
Pale yellow crystals from benzene; yield 81 %; m.p.
298–300 °C; IR (KBr, υmax cm−1): 3479, 3324, 3182 (NH2),
1
2-amino-6-chloro-4-(2-chlorophenyl)-4H-pyrano[3,2-h]
2195 (CN), 1656 (C=N); H NMR (500 MHz, DMSO-d6)
quinoline-3-carbonitrile (5a)
δ: 9.55–7.11 (m, 8H, aromatic), 7.38 (bs, 2H, NH2), 5.56 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.30 (C-2),
151.26 (C-9), 143.79 (C-10b), 137.99 (C-10a), 130.34 (C-
7), 128.84 (C-5), 125.37 (C-6), 124.99 (C-6a), 123.54 (C-
8), 120.39 (C-4a), 119.65 (CN), 54.08 (C-3), 39.98 (C-4),
143.02, 132.53, 130.20, 129.82, 125.64 (aromatic), MS m/z
(%): 405 (M++4, 1.55), 403 (M++2, 9.12), 401 (M+, 14.02)
Yellow needles from benzene; yield 84 %; m.p. 298–300 °C;
IR (KBr, υmax cm−1): 3479, 3326, 3205 (NH2), 2198 (CN),
1
1659 (C=N); H NMR (500 MHz, DMSO-d6) δ: 9.06–7.19
(m, 9H, aromatic), 7.30 (bs, 2H, NH2), 5.44 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.25 (C-2), 151.17
(C-9), 142.88 (C-10b), 138.01 (C-10a), 132.45 (C-7),
130.08 (C-5), 125.22 (C-6), 124.85 (C-6a), 123.41 (C-8),
120.90 (C-4a), 119.75 (CN), 54.45 (C-3), 38.53 (C-4),
141.30, 132.12, 131.40, 129.25, 128.03, 125.66 (aromatic),
MS m/z (%): 369 (M++2, 5.1), 367 (M+,15.01) with a base
peak at 256 (100); anal. calcd. for C19H11Cl2N3O: C, 61.98;
H, 3.01; N, 11.41. Found: C, 61.92; H, 3.06; N, 11.49 %.
with
a base peak at 256 (100); anal. calcd. for
C19H10Cl3N3O: C, 56.67; H, 2.50; N, 10.44. Found: C,
56.79; H, 2.70; N, 10.60 %.
2-amino-6-chloro-4-(2,4-dichlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (5e)
Pale yellow crystals from benzene; yield 80 %; m.p.
2-amino-6-chloro-4-(3-chlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (5b)
277–279 °C; IR (KBr, υmax cm−1): 3471, 3327, 3196 (NH2),
2193 (CN), 1660 (C=N); H NMR (500 MHz, DMSO-d6)
1
δ: 9.06–7.20 (m, 8H, aromatic), 7.36 (bs, 2H, NH2), 5.44 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.23 (C-2),
151.21 (C-9), 142.95 (C-10b), 137.97 (C-10a), 132.82 (C-
7), 128.21 (C-5), 125.62 (C-6), 124.96 (C-6a), 123.48 (C-
8), 120.32 (C-4a), 119.64 (CN), 53.99 (C-3), 38.15 (C-4),
140.34, 133.14, 132.90, 132.47, 129.46, 125.31 (aromatic).
In 13CNMR-APT spectrum CH, CH3 [positive (up)], CH2,
Cq [negative (down)], revealed the following signals at δ:
160.23 (C-2 ↓), 151.21 (C-9 ↑), 142.95 (C-10b ↓), 140.34
(aromatic ↓), 137.97 (C-10a ↓), 133.14 (aromatic ↓),
132.90 (aromatic ↓), 132.82 (C-7 ↑), 132.47 (aromatic ↑),
129.46 (aromatic ↑), 128.21 (C-5 ↑), 125.62 (C-6 ↓),
125,31 (aromatic ↑), 124.96 (C-6a ↓), 123.48 (C-8 ↑),
120.32 (C-4a ↓), 119.64 (CN ↓), 53.99 (C-3 ↓), 38.15 (C-4
↑). MS m/z (%): 405 (M++4, 3.61), 403 (M++2, 20.48), 401
(M+, 31.19) with a base peak at 256 (100); anal. calcd. for
C19H10Cl3N3O: C, 56.67; H, 2.50; N, 10.44. Found: C,
56.47; H, 2.33; N, 10.31 %.
Yellow crystals from benzene; yield 85 %; m.p. 273–275 °C;
IR (KBr, υmax cm−1): 3441, 3321, 3205 (NH2), 2201 (CN),
1659 (C=N); H NMR (500 MHz, DMSO-d6) δ: 9.06-7.12
1
(m, 9H, aromatic), 7.34 (bs, 2H, NH2), 5.03 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.20 (C-2), 151.18
(C-9), 142.52 (C-10b), 138.14 (C-10a), 132.54 (C-7),
127.33 (C-5), 125.22 (C-6), 124.97 (C-6a), 123.44 (C-8),
121.74 (C-4a), 119.97 (CN), 55.23 (C-3), 40.32 (C-4),
147.47, 133.39, 130.90, 127.44, 126.53, 126.34 (aromatic),
MS m/z (%): 369 (M++2, 15.3), 367 (M+, 45.03) with a base
peak at 256 (100); anal. calcd. for C19H11Cl2N3O: C, 61.98;
H, 3.01; N, 11.41. Found: C, 62.07; H, 3.23; N, 11.61 %.
2-amino-6-chloro-4-(4-chlorophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (5c)
Yellow crystals from benzene; yield 81 %; m.p. 276–278 °C;
IR (KBr, υmax cm−1): 3444, 3349, 3188 (NH2), 2199 (CN),
1
1657 (C=N); H NMR (500 MHz, DMSO-d6) δ: 9.01–7.02
2-amino-6-chloro-4-(2,5-dichlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (5f)
(m, 9H, aromatic), 7.12 (bs, 2H, NH2), 5.01 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.26 (C-2), 151.23
(C-9), 142.55 (C-10b), 138.66 (C-10a), 132.23(C-7),
127.33 (C-5), 125.89 (C-6), 125.05 (C-6a), 123.49 (C-8),
121.84 (C-4a), 120.07 (CN), 55.28 (C-3), 40.11 (C-4),
Pale yellow crystals from benzene; yield 82 %; m.p. > 300 °C;
IR (KBr, υmax cm−1): 3476, 3347, 3196 (NH2), 2196 (CN),
1650 (C=N); 1H NMR (500 MHz, DMSO-d6)

Med Chem Res
δ: 9.58–7.26 (m, 8H, aromatic), 7.38 (bs, 2H, NH2), 5.46 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.32 (C-2),
151.22 (C-9), 143.02 (C-10b), 137.95 (C-10a), 132.48 (C-
7), 129.31 (C-5), 125.37 (C-6), 124.95 (C-6a), 123.51 (C-
8), 119.83 (C-4a), 119.65 (CN), 53.62 (C-3), 38.89 (C-4),
142.94, 132.34, 132.00, 131.19, 131.04, 125.57 (aromatic);
MS m/z (%): 405 (M++4, 2.22), 403 (M++2, 12.26), 401
(M+, 18.11) with a base peak at 256 (100); anal. calcd. for
C19H10Cl3N3O: C, 56.67; H, 2.50; N, 10.44. Found: C,
56.70; H, 2.63; N, 10.54 %.
(C-9), 144.95 (C-10b), 137.47 (C-10a), 135.98 (C-7),
127.77 (C-5), 126.67 (C-6), 123.68 (C-6a), 122.20 (C-8),
121.30 (C-4a), 117.68 (CN), 55.59 (C-3), 40.50 (C-4),
143.03, 131.63, 129.94, 127.45, 121.78 (aromatic), MS m/z
(%): 380 (M+–Cl+4, 2.08), 378 (M+–Cl+2, 5.02), 376
(M+–Cl, 3.37) with a base peak at 222 (100); anal. calcd. for
C19H11BrClN3O: C, 55.30; H, 2.69; N, 10.18. Found: C,
55.37; H, 2.73; N, 10.23 %.
2-amino-6-chloro-4-(3,5-dibromo-2-methoxyphenyl)-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (5j)
2-amino-6-chloro-4-(2,6-dichlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (5g)
Pale yellow Crystals from ethanol; yield 81 %; m.p. 223-
225 °C; IR (KBr, υmax cm−1): 3432, 3337, 3182 (NH2),
1
Colorless needles from benzene; yield 82 %; m.p. > 300 °C;
IR (KBr, υmax cm−1): 3475, 3325, 3188 (NH2), 2199 (CN),
2192 (CN), 1657 (C=N); H NMR (500 MHz, DMSO-d6)
δ: 9.07–7.29 (m, 7H, aromatic), 7.39 (bs, 2H, NH2), 5.25 (s,
1H, H-4), 3.69 (s, 3H, OCH3); 13C NMR (125 MHz,
DMSO-d6) δ: 160.43 (C-2), 151.21 (C-9), 142.78 (C-10b),
138.06 (C-10a), 134.91 (C-7), 132.30 (C-5), 125.25 (C-6a),
124.90 (C-4a), 123.43 (C-8), 120.93 (C-6), 117.00 (CN),
61.32 (CH3), 54.19 (C-3), 36.78 (C-4), 154.34, 141.49,
132.50, 125.86, 120.00, 118.29 (aromatic); MS m/z (%):
490 (M+–Cl+6, 0.85), 488 (M+–Cl+4, 3.53), 486 (M+–Cl
+2, 4.41), 484 (M+–Cl, 2.19) with a base peak at 222 (100);
anal. calcd. for C20H12Br2 ClN3O2: C, 46.05; H, 2.32; 6.80;
N, 8.06. Found: C, 46.16; H, 2.41; N, 8.13 %.
1
1661 (C=N); H NMR (500 MHz, DMSO-d6) δ: 9.07–7.05
(m, 8H, aromatic), 7.42 (bs, 2H, NH2), 6.03 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.59 (C-2), 151.30
(C-9), 143.55 (C-10b), 137.71 (C-10a), 132.53 (C-7),
130.37 (C-5), 125.37 (C-6), 124.73 (C-6a), 123.49 (C-8),
119.38 (C-4a), 118.91 (CN), 51.95 (C-3), 37.04 (C-4),
136.56, 135.54, 134.96, 130.90, 128.85, 124.86 (aromatic);
MS m/z (%): 405 (M++4, 2.06), 403 (M++2, 11.77), 401
(M+, 18.14) with a base peak at 256 (100); anal. calcd. for
C19H10Cl3N3O: C, 56.67; H, 2.50; N, 10.44. Found: C,
56.80; H, 2.63; N, 10.60 %.
2-amino-4-(2-chlorophenyl)-9-methyl-4H-pyrano[3,2-h]
2-amino-6-chloro-4-(3,4-dichlorophenyl)-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (5h)
quinoline-3-carbonitrile (7a)
Yellow crystals from ethanol; yield 88 %; m.p. 238–239 °C;
IR (KBr, υmax cm−1): 3470, 3366, 3196 (NH2), 2195 (CN),
1659 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.46–6.82
Pale yellow needles from benzene; yield 82 %; m.p.
1
257–259 °C; IR (KBr, υmax cm−1): 3470, 3321, 3199 (NH2),
1
2199 (CN), 1658 (C=N); H NMR (500 MHz, DMSO-d6)
(m, 8H, aromatic), 7.16 (bs, 2H, NH2), 5.43 (s, 1H, H-4),
2.72 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ:
160.54 (C-2), 159.11 (C-9), 142.86 (C-10b), 136.91 (C-
10a), 136.30 (C-7), 128.90 (C-5), 125.21 (C-6a), 123.84 (C-
8), 122.93 (C-4a), 120.52 (C-6), 120.07 (CN), 54.73 (C-3),
38.56 (C-4), 24.84 (CH3) 142.16, 136.08, 131.97, 130.42,
129.84, 126.20 (aromatic), MS m/z (%): 349 (M++2, 1.56),
347 (M+,4.63) with a base peak at 236 (100); anal. calcd. for
C20H14ClN3O: C, 69.07; H, 4.06; N, 12.08. Found: C,
69.11; H, 4.14; N, 12.13 %.
δ: 9.04–7.27 (m, 8H, aromatic), 7.39 (bs, 2H, NH2), 5.06 (s,
1H, H-4); 13C NMR (125 MHz, DMSO-d6) δ: 160.18 (C-2),
151.11 (C-9), 145.97 (C-10b), 138.13 (C-10a), 132.44 (C-
7), 128.21 (C-5), 125.25 (C-6), 125.04 (C-6a), 123.40 (C-
8), 121.22 (C-4a), 119.89 (CN), 54.94 (C-3), 38.97 (C-4),
142.56, 131.34, 131.18, 129.99, 129.65, 126.23 (aromatic);
MS m/z (%): 405 (M++4, 1.52), 403 (M++2, 8.89), 401 (M+,
13.37) with a base peak at 256 (100); anal. calcd. for
C19H10Cl3N3O: C, 56.67; H, 2.50; N, 10.44. Found: C,
56.57; H, 2.38; N, 10.27 %.
2-amino-4-(3-chlorophenyl)-9-methyl-4H-pyrano[3,2-h]
2-amino-6-chloro-4-(4-bromophenyl)-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (7b)
quinoline-3-carbonitrile (5i)
Yellow crystals from ethanol; yield 87 %; m.p. 236–238 °C;
IR (KBr, υmax cm−1): 3464, 3346, 3200 (NH2), 2188 (CN),
1655 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.19–7.09
(m, 8H, aromatic), 7.17 (bs, 2H, NH2), 4.97 (s, 1H, H-4),
2.69 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6)
δ: 160.41 (C-2), 159.12 (C-9), 149.51 (C-10b), 137.09
Yellow crystals from ethanol; yield 86 %; m.p. 228-230 °C;
1
IR (KBr, υmax cm−1): 3445, 3330, 3182 (NH2), 2192 (CN),
1
1658 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.95–7.18
(m, 9H, aromatic), 7.25 (bs, 2H, NH2), 5.00 (s, 1H, H-4);
13C NMR (125 MHz, DMSO-d6) δ: 160.30 (C-2), 150.25

Med Chem Res
1
(C-10a), 135.18 (C-7), 128.92 (C-5), 125.79 (C-6a), 122.50
(C-4a), 123.54 (C-8), 121.45 (C-6), 120.38 (CN), 55.84 (C-
3), 40.54 (C-4), 144.76, 136.05, 129.58, 131.78, 128.60,
126.17 (aromatic), MS m/z (%): 349 (M++2, 4.35), 347
(M+, 13.27) with a base peak at 236 (100); anal. calcd. for
C20H14ClN3O: C, 69.07; H, 4.06; N, 12.08. Found: C,
69.14; H, 4.16; N, 12.15 %.
2194 (CN), 1656 (C=N); H NMR (500 MHz, DMSO-d6)
δ: 8.23–7.01 (m, 7H, aromatic), 7.23 (bs, 2H, NH2), 5.44 (s,
1H, H-4), 2.71 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-
d6) δ: 160.63 (C-2), 159.01 (C-9), 143.92 (C-10b), 136.85
(C-10a), 136.08 (C-7), 126.33 (C-5), 124.93 (C-6a), 123.64
(C-8), 123.01 (C-4a), 119.92 (C-6), 119.50 (CN), 55.85 (C-
3), 40.14 (C-4), 24.95 (CH3), 142.96, 132.27, 131.77,
131.01, 130.72, 128.95 (aromatic); MS m/z (%): 385
(M++4, 3.61), 383 (M++2, 20.48), 381 (M+, 31.19) with a
base peak at 236 (100); anal. calcd. for C20H13Cl2N3O: C,
62.84; H, 3.43; N, 10.99. Found: C, 62.79; H, 3.39; N,
10.71 %.
2-amino-4-(4-chlorophenyl)-9-methyl-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (7c)
Prepared as previously described (El-Agrody and Al-
Ghamdi, 2011).
2-amino-4-(2,6-dichlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7g)
2-amino-4-(2,3-dichlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7d)
Yellow crystals from benzene; yield 85 %; m.p. 289–290 °C;
IR (KBr, υmax cm−1): 3470, 3375, 3187 (NH2), 2189(CN),
1660 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.22–6.87
Yellow crystals from benzene; yield 87 %; m.p. 240–241 °C;
IR (KBr, υmax cm−1): 3458, 3323, 3196 (NH2), 2193 (CN),
1656 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.22–7.00
1
1
(m, 7H, aromatic), 7.18 (bs, 2H, NH2), 6.01 (s, 1H, H-4),
2.71 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ:
160.93 (C-2), 159.13 (C-9), 143.54 (C-10b), 136.59 (C-
10a), 135.64 (C-7), 126.36 (C-6a), 124.21 (C-5), 123.46 (C-
8), 122.95 (C-4a), 119.75 (C-6), 118.18 (CN), 52.02 (C-3),
37.24 (C-4), 24.97 (CH3), 137.27, 136.10, 134.83, 130.81,
130.01, 128.65 (aromatic). In 13CNMR-APT spectrum CH,
CH3 [positive (up)], CH2, Cq [negative (down)], revealed
the following signals at δ: 160.93 (C-2 ↓), 159.13 (C-9 ↓),
143.54 (C-10b ↓), 137.27 (aromatic ↓), 136.59 (C-10a ↓),
136.10 (aromatic ↓), 135.64 (C-7 ↑), 134.83 (aromatic ↓),
130.81 (aromatic ↑), 130.01(aromatic ↑), 128.65 (aromatic
↑), 126.36 (C-6a ↓), 124.21 (C-5 ↑), 123.46 (C-8 ↑),
122.95 (C-4a ↓), 119.75 (C-6 ↑), 118.18 (CN ↓), 52.02 (C-
3 ↓), 37.24 (C-4 ↑), 24.97 (CH3 ↑). MS m/z (%): 385
(M++4, 2.06), 383 (M++2, 11.77), 381 (M+, 18.14) with a
base peak at 236 (100); anal. calcd. for C20H13Cl2N3O: C,
62.84; H, 3.43; N, 10.99. Found: C, 62.88; H, 3.50; N,
11.05 %.
(m, 7H, aromatic), 7.23 (bs, 2H, NH2), 5.53 (s, 1H, H-4), 2.71
(s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ: 160.59 (C-
2), 159.17 (C-9), 144.69 (C-10b), 136.89 (C-10a), 136.10 (C-
7), 128.72 (C-5), 126.32 (C-6a), 123.66 (C-8), 123.01 (C-4a),
119.98 (C-6), 119.95 (CN), 54.38 (C-3), 40.08 (C-4), 24.97
(CH3), 142.94, 136.31, 132.32, 130.16, 129.47, 124.96
(aromatic); MS m/z (%): 385 (M++4, 1.21), 383 (M++2, 8.81),
381 (M+, 12.44) with a base peak at 236 (100); anal. calcd. for
C20H13Cl2N3O: C, 62.84; H, 3.43; N, 10.99. Found: C, 62.75;
H, 3.56; N, 11.06 %.
2-amino-4-(2,4-dichlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7e)
Yellow crystals from ethanol; yield 86 %; m.p. 249–250 °C;
IR (KBr, υmax cm−1): 3475, 3328, 3196 (NH2), 2193 (CN),
1
1660 (C=N); H NMR (500 MHz, DMSO-d6) δ: 8.44–7.02
(m, 7H, aromatic), 7.35 (bs, 2H, NH2), 5.44 (s, 1H, H-4),
2.73 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ:
160.52 (C-2), 159.18 (C-9), 144.13 (C-10b), 137.55 (C-
10a), 136.34 (C-7), 128.52 (C-5), 126.11 (C-6a), 123.79 (C-
8), 123.93 (C-4a), 122.89 (C-6), 120.03 (CN), 54.29 (C-3),
38.19 (C-4), 23.73 (CH3), 149.91, 134.75, 132.97, 131.66,
130.61, 127.45 (aromatic); MS m/z (%): 385 (M++4, 1.27),
383 (M++2, 7.74), 381 (M+, 12.2) with a base peak at 236
(100); anal. calcd. for C20H13Cl2N3O: C, 62.84; H, 3.43; N,
10.99. Found: C, 62.88; H, 3.50; N, 11.05 %.
2-amino-4-(3,4-dichlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7h)
Yellow crystals from benzene/ethanol; yield 83 %; m.p.
268–270 °C; IR (KBr, υmax cm−1): 3479, 3336, 3196 (NH2),
1
2190 (CN), 1664 (C=N); H NMR (500 MHz, DMSO-d6)
δ: 8.96–7.06 (m, 7H, aromatic), 7.30 (bs, 2H, NH2), 5.42 (s,
1H, H-4), 2.73 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-
d6) δ: 160.51 (C-2), 151.36 (C-9), 143.45 (C-10b), 137.56
(C-10a), 136.23 (C-7), 129.42 (C-5), 128.09 (C-6a), 126.08
(C-4a), 123.95 (C-8), 122.77 (C-6), 120.11 (CN), 53.88 (C-
3), 38.92 (C-4), 24.71 (CH3), 141.40, 132.39, 131.83,
131.19, 130.80, 129.03 (aromatic). MS m/z (%): 385
(M++4, 0.88), 383 (M++2, 4.93), 381 (M+, 7.91) with a base
2-amino-4-(2,5-dichlorophenyl)-9-methyl-4H-pyrano
[3,2-h]quinoline-3-carbonitrile (7f)
Yellow crystals from benzene/ethanol; yield 84 %; m.p.
266–268 °C; IR (KBr, υmax cm−1): 3471, 3356, 3179 (NH2),

Med Chem Res
h]quinoline-3-carbonitrile, 7H-pyrimido [4′,5′:6,5] pyrano[3,2-h]
quinoline, and 14H-Pyrimido[4′,5′:6,5]pyrano[3,2-h][1,2,4]tria-
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peak at 236 (100); anal. calcd. for C20H13Cl2N3O: C, 62.84;
H, 3.43; N, 10.99. Found: C, 62.85; H, 3.47; N, 11.03 %.
2-amino-4-(4-bromophenyl)-9-methyl-4H-pyrano[3,2-h]
quinoline-3-carbonitrile (7i)
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Prepared as previously described (El-Agrody and Al-
Ghamdi 2011).
2-amino-4-(3,5-dibromo-2-methoxyphenyl)-9-methyl-
4H-pyrano[3,2-h]quinoline-3-carbonitrile (7j)
Pale yellow crystals from ethanol; yield 81 %; m.p.
224–226 °C; IR (KBr, υmax cm−1): 3431, 3333, 3201 (NH2),
1
2191 (CN), 1659 (C=N); H NMR (500 MHz, DMSO-d6)
δ: 8.20–7.03 (m, 6H, aromatic), 7.23 (bs, 2H, NH2), 5.25 (s,
1H, H-4), 3.70 (s, 3H, OCH3), 2.70 (s, 3H, CH3); 13C NMR
(125 MHz, DMSO-d6) δ: 160.69 (C-2), 159.16 (C-9),
142.75 (C-10b), 142.44 (C-10a), 136.96 (C-7), 132.18 (C-
5), 126.22 (C-6a), 123.61 (C-8), 122.95 (C-4a), 120.49 (C-
6), 120.27 (CN), 61.36 (Me), 54.59 (C-3), 36.68 (C-4),
24.96 (CH3), 154.14, 136.09, 134.48, 118.26, 117.01
(aromatic); MS m/z (%): 503 (M++4, 1.65), 501 (M++2,
3.05), 499 (M+, 1.65) with a base peak at 236 (100); anal.
calcd. for C21H15Br2N3O2: C, 50.33; H, 3.02; N, 8.38.
Found: C, 50.40; H, 3.10; N, 8.50 %.
Antitumor screening
Cell culture and cytotoxicity evaluation using viability assay
Compounds 3a–j, 5a–j, and 7a–j were initially evaluated
for in vitro antitumor activity against three different human
cell lines: MCF-7, HCT-116, HepG-2, and A549 in com-
parison with Vinblastine and Colchicine. The measurements
of cell growth and the viabilities and in vitro cytotoxicity
evaluation using viability assay were determined as
described in the literature (Rahman et al. 2001) and the
result was cited in Table 1.
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Acknowledgments The author deeply thanks the Regional Center
for Mycology & Biotechnology (RCMP), Al-Azhar University, Cairo,
Egypt, for carrying out the antitumor study and also, Mr. Ali Y. A.
1
Alshahrani for making the H NMR and 13C NMR spectra.
Leonard JT, Roy K (2008) Exploring molecular shape analysis of
styrylquinoline derivatives as HIV-1 integrase inhibitors. Eur J
Med Chem 43:81–92
Compliance with ethical standards
Liu XH, Zhu J, Zhou AN, Song BA, Zhu HL, Bai LS, Bhadury PS,
Pan CX (2009) Synthesis, structure and antibacterial activity
of new 2-(1-(2-(substitutedphenyl)-5-methyloxazol-4-yl)-3-
(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-
1,2,3,4- tetrahydroisoquinoline derivatives. Bioorg Med Chem
17:1207–1213
Mallesha L, Kendagannaswamy BK, Mohana KN (2013) Synthesis
and in vitro antioxidant activity of quinolin-5-ylamine deriva-
tives. Curr Chem Lett 2:119–124
Conflict of interest The authors declare that they have no conflict of
interest.
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