Synthesis and Bioassay of Novel Substituted Pyrano[2,3-f]cinnoline-2-ones

Article abstract of DOI:10.1002/jhet.2482

A new series of 9-substituted-4,10-dimethylpyrano[2,3-f]cinnolin-2-ones (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m) were synthesized via intramolecular cyclization of the respective acyl amidrazone derivatives (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m), catalyzed by polyphosphoric acid. Compounds (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m) were synthesized through direct interaction of coumarin-7-yl hydrazonoyl chloride (3) with the corresponding cyclic sec-amines in the presence of triethylamine. The structures of the new compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m was evaluated in vitro on breast cancer cell line (MCF-7) by a cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Among the compounds tested, compounds 5d, 5f, 5k, and 5h showed potential anti-MCF-7 activity and were able to reduce the viability after 72 h to less than 50%.

Full text of DOI:10.1002/jhet.2482

Month 2015 Synthesis and Bioassay of Novel Substituted Pyrano[2,3-f]cinnoline-2-ones
Abla S. Al-zagameem,a Mustafa M. El-Abadelah,a Malek A. Zihlif,b Randa G. Naffa,c Musa L. Al-Smadi,d
a
*
and Mohammad S. Mubarak
aDepartment of Chemistry, The University of Jordan, Amman 11942, Jordan
bDepartment of Pharmacology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
cLaboratory of Molecular Biology Research, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan
dChemistry Department, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan
*
E-mail: mmubarak@ju.edu.jo
Received January 22, 2015
DOI 10.1002/jhet.2482
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 9-substituted-4,10-dimethylpyrano[2,3-f]cinnolin-2-ones (5a–m) were synthesized via in-
tramolecular cyclization of the respective acyl amidrazone derivatives (4a–m), catalyzed by polyphosphoric
acid. Compounds (4a–m) were synthesized through direct interaction of coumarin-7-yl hydrazonoyl chloride
(3) with the corresponding cyclic sec-amines in the presence of triethylamine. The structures of the new
compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of
compounds 5a–m was evaluated in vitro on breast cancer cell line (MCF-7) by a cell viability assay utilizing
the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Among the compounds
tested, compounds 5d, 5f, 5k, and 5h showed potential anti-MCF-7 activity and were able to reduce the
viability after 72 h to less than 50%.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
[10]. Recently, several 3-(4-(substituted)-piperazin-1-yl)
cinnolines have been prepared and their antitumor and
antifungal activities evaluated [1].
The benzo[c]pyridazine nucleus, better known as
cinnoline, and its derivatives have received considerable at-
tention from chemists and medicinal chemists because of
their wide range of pharmacological profiles, for example,
antibacterial, antitumor, antifungal, and anti-inflammatory
activities [1]. Furthermore, various derivatives of the
cinnoline series possess antithrombotic [2], antituberculosis
[3], anesthetizing [4], and sedative [5] activity, in addition
to their use as agrochemicals [6]. In general, cinnolines
are valuable heterocyclic compounds that exhibit multidi-
rectional biological activities. The significant commercial
interest in the development of benzopyridazine derivatives,
particularly pharmaceutical uses of cinnolines, is mani-
fested by the large number of patents filed in this area [7].
Their ring system is an isosteric relative to either quinoline
or isoquinoline; therefore, in many cases, the synthesized
compounds were designed as analogs of previously ob-
tained quinoline or isoquinoline derivatives; for example,
cinoxacin (1) is a cinnoline analog of quinoline antibacte-
rials used for urinary tract infection [8], while ICI-D-7569
(2) is an anxiolytic agent [9] (Fig. 1). Meanwhile, attention
has been paid to the synthesis of heterocyclic compounds
bearing a cinnoline moiety; an excellent review on the syn-
thesis and characteristics of cinnolines has been published
On the other hand, coumarins (also named 2-oxo-2H-
chromenes or 2H-1-benzopyran-2-ones) occur naturally
as secondary metabolites in several plant species. They
exist in nature with wide distribution and constitute an
important class of oxygen heterocycles with low toxicity
[11,12]. Coumarin derivatives have drawn considerable
attention from researchers because of their role in natural
and synthetic organic chemistry and their interesting biolo-
gical activities. Compounds containing a coumarin nucleus
exhibit various biological activities, such as anticoagulant
and antithrombotic properties [13] and also found numer-
ous therapeutic applications in photochemo- [14], antitumor
[15], and anti-HIV therapy [16], while others have served as
antibacterial [17], antifungal [18], anti-inflammatory [19],
antiviral (including HIV [20]), anticoagulant [21] agents,
antitubercular [22–24], and dyes [25]. Interestingly,
7-amino-4-methylcoumarin (AMC) is employed for label-
ing L-α-amino acids (AA) via coupling of the respective
AA-carboxyl and AMC-7-amino functions [26]; these
labeled α-amino acids are utilized as synthetic fluorogenic
and highly specific substrates for aminopeptidases, in which
case hydrolysis of the amide bond results in liberation of the
fluorescent. As a result, such substrates offer rapid detection,
© 2015 HeteroCorporation

A. S. Al-zagameem, M. M. El-Abadelah, M. A. Zihlif, R. G. Naffa,
M. L. Al-Smadi, and M. S. Mubarak
Vol 000
solution was freshly prepared by diazotization of 7-amino-
4-methylcoumarin which, in turn, was prepared from
m-aminophenol according to literature procedure [13]. On the
other hand, synthesis of the respective amidrazones 4a–m,
was achieved in good yield, via interaction of hydrazonoyl
chloride (3) in ethanol in the presence of triethylamine,
with the appropriate secondary amines at 0°C. Intramolecular
cyclization of amidrazones (4a–m) was accomplished in
polyphosphoric acid (PPA) at 130°C for 5–6h, to produce
the corresponding pyrano-cinnolines (5a–m).
Figure 1. Cinoxacine (1) and ICI-D-7569 (2).
visualization, and assay of various aminopeptidases from
animal or plant extracts [26].
The newly synthesized compounds 5a–m were charac-
terized by elemental analyses, NMR, and high resolution
mass spectral data. These data, detailed in the experimental
part, are consistent with the suggested structures. Thus, the
mass spectra display the correct molecular ion peaks for
which the measured high resolution (HRMS) data are in
good agreement with the calculated values. DEPT experi-
ments were used to distinguish secondary hydrogens from
In view of the interest in the activity spectrum and profile
of cinnolines and coumarins, and in continuation of our work
on the synthesis and bioassay of new compounds of pharma-
cological and biological interest [1,13,26–28], we describe
herein the preparation and characterization of some novel 9-
substituted-4,10-dimethylpyrano[2,3-f]cinnolin-2-ones along
with their antitumor activities.
1
primary and tertiary ones. The H NMR spectra for the
target compounds show the vinylic proton at position 3
as singlet in the range from 6.47 to 6.63ppm, protons of
the methyl groups at C-4 and C-10 appear as singlets at
about 2.5 and 3.0 ppm, respectively, while protons at
positions 5 and 6 appear as doublets at about 8.21 and
7.73ppm, respectively (J=9.1Hz). The fluorine atom causes
the characteristic C-F coupling in compounds 5g and 5h. In
compound 5g, C-3’’/C-5’’ appear as doublet at 115.5ppm
(2JC-F =21.9Hz), C-2’’/C-6’’ resonate at 118.1 (3JC-F =7.5Hz),
and C4’’ resonates at 157.4ppm (1JC-F = 238.0Hz). In com-
pound 5h, on the other hand, C-3’’ resonates at 116.2 as
doublet (2JC-F = 20.0Hz), C-5’’ at 119.1 (4JC-F = 3.0Hz),
C-4’’ appears at 122.7 (3JC-F = 8.0Hz), and C-6’’ appears
at 124.5 (3JC-F =3.4Hz), whereas C-1’’ appears as doublet
at 155.8ppm (1JC-F =240.0Hz). The piperazinyl’s carbons
appear at 50.5 (C-2’/ C-6’) and 50.8ppm (C-3’’/C-5’’).
The effect of the fluorine atom on the piperazinyl protons
is clear, splitting the piperazinyl signals into multiplet,
resulting from the long-range coupling.
RESULT AND DISCUSSION
Chemistry. The N-(4-methyl-2-oxo-2H-chromen-7-yl)-
2-oxopropanehydrazonoyl chloride synthon (3), required in
this study, was prepared via diazotization of 7-amino-4-
methylcoumarin, followed by coupling with 3-chloro-2,4-
pentanedione (Japp–Klingemann reaction) in basic medium
(NaOAc or pyridine) [13,26] (Scheme 1). The resulting
orange-colored solid precipitate was collected, washed
several times with water, dried, and recrystallized from
acetonitrile. The intermediate arenediazonium chloride
Scheme 1. Synthesis of Pyrano[2,3-f]cinnolines 5a-m.
Biology.
The antitumor activity of the newly
synthesized compounds 5a–m was characterized by
conducting cell viability assays using the tetrazolium
dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT). Cultures of breast cancer cells MCF-7
were treated with the target compounds at two
concentrations of 10 and 50μM, and the results are shown
in Table 1. It can be seen that at 50μM concentration, four
compounds (5d, 5f, 5h, and 5k) displayed anti-MCF-7
activity. These compounds were able to reduce the viability
after 72h to less than 50%. However, none of the
compounds retained the activity at 10μM. Furthermore, we
determined IC50 values for the potential compounds against
the MCF-7 and the results are shown in Table 2. In
addition, the antileukemic effects of these four potential
compounds were tested against the leukemic cell line
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Bioassay of Novel Substituted Pyrano[2,3-f]cinnoline-2-ones
Table 1
were visualized under UV light (where appropriate).
Preparative thick layer (0.25 mm) chromatography was
performed on silica gel glass plates (60 F-254, 20×20cm,
Scharlau). Melting points (uncorrected) were determined
on a Stuart scientific melting point apparatus in open capil-
Survival percentage of MCF-7 cells after an exposure of compounds
5a–5m for 72 h at concentrations of 10 and 50 μM, respectively.
Doxorubicin was used as a positive control.
% Survival at 10 μM
% Survival at 50 μM
1
lary tubes. H and13C-NMR spectra were recorded on a
Compound
( SD)
( SD)
400 MHz spectrometer (Bruker DPX-400, Germany) with
5a
5b
5c
5d
5e
5f
5g
5h
5i
92.55
82.36
95.47
88.14
88.35
86.16
97.22
71.76
92.83
80.21
71.97
88.35
89.60
(0.65)
(0.29)
(1.32)
(1.23)
(1.36)
(2.79)
(0.84)
(1.33)
(1.36)
(2.18)
(0.37)
(1.54)
(0.86)
77.02
59.15
78.71
48.20
55.68
49.24
55.90
49.22
85.03
63.04
45.81
55.68
62.69
(0.87)
(1.82)
(0.81)
(1.19)
(1.05)
(1.12)
(0.86)
(1.36)
(1.05)
(0.28)
(0.64)
(1.10)
(0.99)
TMS as internal standard. Chemical shifts are expressed
1
1
in δ units; H-1H, H-F, and 13C-F coupling constants are
given in Hertz. High resolution mass spectra (HRMS) were
acquired by electrospray ionization (ESI) technique with the
aid of a Bruker APEX (IV) mass spectrometer (Bremen,
Germany). The samples were dissolved in acetonitrile,
diluted in spray solution (methanol/water 1:1v/v+0.1%
formic acid) and infused using a syringe pump with a flow
rate of 2μL/min. External calibration was conducted using
arginine cluster in a mass range m/z 175–871. Microanalyses
(for C, H, and N) were performed on a Euro Vector elemental
analyzer, model EA 3000 (Milan, Italy), and the results
agreed with the calculated percentages to within the experi-
5j
5k
5l
5m
Table 2
mental error ( 0.4%).
General preparative procedures. Preparation of 7-amino-4-
methylcoumarin. This synthon, required in the present
IC50 determinations of bioactive pyrano-cinnoline-2-ones 5d, 5f, 5h, and
5k against MCF-7 and K562 cells. Doxorubicin was used as a positive
control.
study, was prepared according to a literature procedure
[29,30], which involves reaction of m-aminophenol with
methoxycarbonyl chloride as the initial step; the resulting
N-protected m-aminophenol underwent cyclocondensation
upon reaction with ethyl acetoacetate and conc. sulfuric
acid, followed by removal of the N-protecting group (via
treatment with sodium hydroxide) to afford the title
Compound
IC50 MCF-7 (μM)
IC50 K562 (μM)
5d
5f
5 h
5 k
33.33 5.44
44.36 3.21
37.60 6.12
32.15 1.93
0.31 0.01
>100
89.61 20.64
>100
>100
1.41 0.31
Doxorubicin
compound; mp=224–226°C (lit. mp= 226–227°C) [29,30].
Preparation of N-(4-methyl-2-oxo-2H-chromen-7-yl)-2-oxo-
propanehydrazonoyl chloride (3). 7-Amino-4-methylcoumarin
K562, and only compound 5k was able to show a week
(17.5g, 0.10mol) was dissolved in 17% aqueous hydrochloric
acid (160mL). To this cooled solution, dropwise added, a
solution of sodium nitrite (7.6g, 0.11 mol) in water (15 mL)
with efficient stirring at 0–5°C. Stirring was continued
for 20–30 min, and the resulting fresh cold 4-methyl-2-
oxo-2H-chromene-7-diazonium chloride solution was used
immediately as such for the following coupling reaction. A
cold (0–5°C) freshly prepared solution of 4-methyl-2-oxo-
2H-chromene-7-diazonium chloride (0.1 mol) was poured
onto a cold solution (0 to À10°C, ice-salt bath) of 3-
chloropentan-2,4-dione (13.5g, 0.10mol) in pyridine/water
(160mL, 3:2v/v) with vigorous stirring. The resulting
orange-colored mixture was further stirred until a solid
precipitate was formed (5–10min). The reaction mixture
was then diluted with cold water (200mL). The solid
product was collected by suction filtration, washed several
times with cold water, dried, and recrystallized from
acetonitrile. Yield 22.8g (82%), mp 271–273°C. The
identity of the desired compound was confirmed with the
activity as shown in Table 2.
CONCLUSION
In summary, we have synthesized a novel series of
pyrano[2,3-f]cinnolin-2-ones through cyclization of the ap-
propriate acetyl amidrazones using polyphosphoric acid as
cyclizing agent. The new compounds, with N-piperazinyl
appendages at C-9, were tested in vitro for their antitumor
activity against breast cancer MCF-7 cell line. Results
revealed that at 50 μM concentration, four of the synthe-
sized compounds (5d, 5f, 5k, and 5h) showed potential
anti-MCF-7 activity and were able to reduce the viability
after 72h to less than 50%.
EXPERIMENTAL
All chemicals used were obtained from commercial
sources and were used as received without further purifica-
tion. The progress of reactions was monitored by thin layer
chromatography (TLC), carried out on TLC sheets that
1
aid of MS, H NMR, and 13C NMR data that were in
excellent agreement with previous work [26].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. Al-zagameem, M. M. El-Abadelah, M. A. Zihlif, R. G. Naffa,
M. L. Al-Smadi, and M. S. Mubarak
Vol 000
General procedure for the synthesis of compounds 4a–m. Com-
pounds 4a-m were synthesized according to the following
general literature procedure [13]. To a stirred cold
suspension (0 to À10°C) of compound 3 (1.0g, 3.6mM) in
20mL of ethanol, a solution of the appropriate piperazine
or secondary amine (2.0mM) and triethylamine (3mL) in
10mL of ethanol was added. Stirring was continued at 0 to
5°C for 2–4h, followed by 10–12h at ambient temperature.
The solvent was then removed under reduced pressure, and
the residue was treated with water (15mL). The resulting
crude solid product was collected by suction filtration, washed
with water, dried, and purified on preparative silica gel TLC
plates. Using the same general procedure, compounds 4a–j
were prepared and showed identical properties to those
previously described [13]. In addition, the following new
compounds were also prepared:
J= 1.2Hz, 3H, CH3-4), 2.49 (s, 3H, CH3-CO), 3.28 (m, 4H,
H2-2’+H2-6’), 3.35 (m, 4H, H2-3’+H2-5’), 6.17 (s, 1H,
H-3),
6.92–7.15
(m,
5H,
1H-6 + 1H-2’’+1H-
3’’ +1H-5’’+1H-6’’), 7.24 (d, J= 2.4 Hz, 1H, H-8), 7.34
(t, J= 7.2 Hz, 1H, H-4’’), 7.55 (d, J= 8.4Hz, 1H, H-5), 9.29
(s, 1H, H-N) ppm; 13C NMR (100Hz, CDCl3): δ 18.5
(CH3), 26.6 (CH3), 47.8 (CH2), 48.7 (CH2), 101.1 (CH),
111.2 (CH), 111.7 (CH), 113.9 (C), 116.0 (CH), 119.3 (CH),
126.9 (CH), 129.4 (CH), 144.7 (C), 147.4 (C), 151.7 (C),
153.8 (C), 155.1 (C), 160.7 (C), 195.5 (C) ppm; HRMS
(ESI) m/z: calcd. for C23H25N4O3 [M + H]+ 405.19267,
found 405.19212. Anal. Calcd for C23H24N4O3: C, 68.36; H,
5.98; N, 13.85. Found: C, 68.15; H, 5.94; N, 13.79.
General procedure for the synthesis of 4-methyl-3-[(4-
substituted)piperazin-1-yl]cinnolines (5a-m).
Compounds
5a–m were synthesized according to the following
general procedure [1]: A solution of the appropriate
amidrazone 4a–m (2.5 mM) in 12.0 g of PPA was stirred
at 130°C for 5–6 h. The reaction mixture was cooled to
room temperature, treated with 10g of crushed ice, and
neutralized with 10% of aqueous sodium bicarbonate
solution. The mixture was then extracted with ethyl
acetate (3× 50mL), and the combined organic extracts
were evaporated under reduced pressure to afford crude
residues of the respective title compounds, which were
purified by column chromatography using silica gel.
Using the same general procedure, the following
compounds were synthesized:
7-{2-[1’-(4’-(4’’-Chlorophenylpiperazin-1-yl))-2-oxopropylide
ne]hydrazinyl}-4-methyl-2H-chromen-2-one (4k).
Yield
(0.66g, 75%); mp 248–250°C; 1H NMR (400MHz,
CDCl3): δ 2.43 (d, J=0.8Hz, 3H, CH3-4), 2.49 (s, 3H,
CH3-CO), 3.28 (m, 8H, H2-2’+H2-3’+, H2-5’+H2-6’),
6.16 (d, J= 0.8Hz, 1H, H-3), 6.91 (d, J= 2Hz, 2H,
H-2’’+H-6’’), 6.07 (dd, J=8.8Hz, 2.4Hz, 1H, H-6), 7.26
(d, J= 2.4Hz, 1H, H-8), 7.26 (d, J =2Hz, 2H,
H-3’’+H-5’’), 7.54 (d, J=8.8Hz, 1H, H-5) ppm; 13C
NMR (100 Hz, CDCl3): δ 18.6 (CH3), 26.6 (CH3), 47.6
(CH2), 48.5 (CH2), 101.1 (CH), 111.3 (CH), 111.7 (CH),
113.9 (C), 117.4 (CH), 122.7 (C), 126.9 (CH), 129.1
(CH), 144.6 (C), 147.3 (C), 150.5 (C), 153.9 (C), 155.1
(C), 160.7 (C), 195.3 (C) ppm; HRMS (ESI) m/z: calcd.
for C23H24ClN4O3 [M+H]+ 439.15369, found 439.15314.
Anal. Calcd for C23H23ClN4O3: C, 62.94; H, 5.28; N,
12.77. Found: C, 62.65; H, 5.24; N, 12.53.
4,10-Dimethyl-9-morpholino-2H-pyrano[2,3-f]cinnolin-2-
one (5a).
Yield (0.23 g, 30%); mp 235–236°C; 1H
NMR (400 MHz, CDCl3): δ 2.58 (d, J = 1.2 Hz, 3H,
CH3-4), 3.02 (s, 3H, CH3-10), 3.46 (t, J = 4.8 Hz, 4H,
H2-2’ + H2-6’), 3.98 (t, J = 4.8 Hz, 4H, H2-3’ + H2-5’),
6.50 (d, J = 1.2 Hz, 1H, H-3), 7.78 (d, J = 8.8 Hz, 1H,
H-6), 8.25 (d, J = 8.8 Hz, 1H, H-5) ppm; 13C NMR
(100 Hz, CDCl3): δ 17.5 (CH3), 19.7 (CH3), 51.2
(CH2), 67.0 (CH2), 115.9 (CH), 118.3 (C), 119.9 (C),
122.6 (CH), 123.2 (C), 126.2 (CH), 148.4 (C), 151.0 (C),
7-{2-[1’-(4’-(4’’-Methoxyphenylpiperazin-1-yl))-2-oxopropylid
ene]hydrazinyl}-4-methyl-2H-chromen-2-one (4l).
Yield
(0.59g, 68%); mp 244–245°C; 1H NMR (400MHz,
CDCL3): δ 2.43 (s, 3H, CH3-4), 2.49 (s, 3H, CH3-CO),
3.23 (m, 4H, H2-3’+H2-5’), 3.28 (m, 4H, H2-2’+, H2-6’),
3.81 (s, 3H, CH3-O), 6.16 (s, 1H, H-3), 6.89 (d, J=8.4Hz,
2H, H-2’’+H-6’’), 6.99 (d, J=8.4Hz, 2H, H-3’’+H-5’’),
7.07 (dd, J = 8.8 Hz, 2.4 Hz, 1H, H-6), 7.22 (d, J = 2.0 Hz,
1H, H-8), 7.54 (d, J = 8.8 Hz, 1H, H-5), 9.28 (s, 1H, H-
N) ppm; 13C NMR (100 Hz, CDCl3): δ 18.6 (CH3), 26.6
(CH3), 47.9 (CH2), 50.0 (CH2), 56.6 (CH3), 101.1 (CH),
111.2 (CH), 111.7 (CH), 113.8 (C), 114.7 (C), 118.0
(CH), 126.9 (CH), 144.8 (C), 146.2 (C), 147.4(C), 153.4
(C), 153.9 (C), 155.1 (C), 160.7 (C), 195.5 (C) ppm;
HRMS (ESI) m/z: calcd. for C23H25N4O3 [M + H]+
435.20323, found 435.20268. Anal. Calcd for
C24H26N4O4: C, 66.34; H, 6.03; N, 12.89. Found: C,
66.08; H, 5.91; N, 12.64.
152.9 (C), 159.6 (C), 161.2 (C) ppm; HRMS (ESI) m/z:
+
calcd. for C17H18N3O3 [M+H]
312.13482, found
312.13427. Anal. Calcd for C17H17N3O3: C, 65.58; H,
5.50; N, 13.50. Found: C, 65.33; H, 5.44; N, 13.69.
4,10-Dimethyl-9-thiomorpholino-2H-pyrano[2,3-f]cinnolin-
2-one (5b).
Yield (0.36 g, 44%); mp 236–237°C; 1H
NMR (400 MHz, CDCl3): δ 2.43 (d, J = 1.2 Hz, 3H,
CH3-4), 2.46 (s, 3H, CH3-10), 2.79 (t, J = 2.4 Hz, 4H,
H2-3’ + H2-5’), 3.33 (t, J = 2.4 Hz, 4H, H2-2’ + H2-6’),
6.17 (d, J = 1.2 Hz, 1H, H-3), 7.55 (d, J = 9.2 Hz, 1H,
H-6), 8.26 (d, J = 9.2 Hz, 1H, H-5) ppm; 13C NMR
(100 Hz, CDCl3): δ 18.7 (CH3), 25.8 (CH3), 28.5 (CH2),
50.3 (CH2), 101.6 (CH), 110.7 (CH), 112.2 (C), 119.6
(C), 123.0 (C), 125.9 (CH), 145.4 (C), 145.6 (C), 152.4
(C), 155.3 (C), 161.1 (C-9) ppm; HRMS (ESI) m/z:
calcd. for C17H18N3O2S [M + H]+ 328.11142, found
7-{2-[1-(4-Phenylpiperazin-1-yl)-2-oxopropylidene]hydrazinyl}-
4-methyl-2H-chromen-2-one (4m). Yield (0.66g, 82%); mp
263–266°C; 1H NMR (400MHz, CDCl3): δ=2.43 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Bioassay of Novel Substituted Pyrano[2,3-f]cinnoline-2-ones
328.11197. Anal. Calcd for C17H17N3O2S: C, 62.36; H,
5.23; N, 12.83. Found: C, 62.15; H, 5.11; N, 12.64.
4,10-Dimethyl-9-(piperidin-1’-yl)-2H-pyrano[2,3-f]cinnolin-
(CH3), 20.0 (CH2), 50.6 (CH2), 53.3 (CH2), 60.8 (CH2),
115.9 (CH), 118.3 (C), 120.0 (C), 122.2 (CH), 122.7
(C), 126.2 (CH), 148.2 (C), 151.1 (C), 153.0 (C), 159.8
(C), 161.4 (C) ppm; HRMS (ESI) m/z: calcd. for
C20H25N4O2 [M + H]+ 353.19775, found 353.19720.
Anal. Calcd for C20H24N4O2: C, 68.16; H, 6.86; N,
15.90. Found: C, 68.27; H, 6.80; N, 15.72.
2-one (5c).
Yield (0.70 g, 90%); mp 198–199°C; 1H
NMR (400 MHz, CDCl3): δ 1.71 (m, 2H, H2-4’), 1.83
(m, 4H, H2-3’ + H2-5’), 2.58 (s, 3H, CH3-4), 2.99 (s, 3H,
CH3-10), 3.38 (t, J = 14.0 Hz, 4H, H2-2’ + H2-6’), 6.48
(s, 1H-3), 7.72 (d, J = 9.1 Hz, 1H, H-6), 8.22 (d,
J = 9.1 Hz, 1H, H-5) ppm; 13C NMR (100 Hz, CDCl3): δ
17.6 (CH3), 19.7 (CH3), 24.4 (CH2), 26.2 (CH2), 52.1
(CH2), 114.4 (C), 115.7 (CH), 118.1 (C), 120.1 (C),
122.1 (CH), 126.1 (CH), 147.9 (C), 151.1 (C), 153.0
(C), 159.8 (C), 162.5 (C) ppm; HRMS (ESI) m/z: calcd.
for C18H20N3O2 [M + H]+ 310.15555, found 310.15500.
Anal. Calcd for C18H20N3O2: C, 69.88; H, 6.19; N,
9-(4-(4’-Fluorophenyl)piperazin-1’-yl)-4,10-dimethyl-2H-
pyrano[2,3-f]cinnolin-2-one (5g).
Yield (0.52 g, 51%);
mp 251–252°C; 1H NMR (400 MHz, CDCl3): δ 2.56
(s, 3H, CH3-4), 3.01 (s, 3H, CH3-10), 3.37 m, 4H, H2-
3’ + H2-5’), 3.59 (m, 4H, H2-2’ + H2-6’), 6.48 (s, 1H,
H-3), 6.96 (m, 2H, 1H-2’’ + 1H-6’’), 6.99 (m, 2H, 1H-
3’’ + 1H-5’’), 7.73 (d, J = 9.1 Hz, 1H, H-6), 8.21 (d, J =
9.1 Hz, 1H, H-5) ppm; 13C NMR (100 MHz, CDCl3): δ
17.6 (CH3), 19.8 (CH3), 50.5 (CH2), 50.8 (CH2), 115.5
13.58. Found: C, 69.76; H, 6.14; N, 13.34.
4,10-Dimethyl-9-(4’-methylpiperazin-1’-yl)-2H-pyrano[2,3-
f]cinnolin-2-one (5d). Yield (0.39g, 48%); mp 192–193°C;
2
(d, JC-F =21.9Hz, C-3’’/C-5’’), 115.9 (C), 118.1 (d,
3JC-F =7.5Hz, C-2’’/C-6’’), 118.3 (CH), 120.0 (C), 122.6
1H NMR (400 MHz, CDCl3) : δ 2.38 (s, 3H, CH3-4), 2.56
(s, 3H, CH3-10), 2.64 (m, 4H, H2-3’ + H2-5’), 2.94 (s, 3H,
CH3-N), 3.45 (m, 4H, H2-2’ + H2-6’), 6.44 (s, 1H, H-3),
7.70 (d, J = 9.1 Hz, 1H, H-6), 8.19 (d, J = 9.1 Hz, 1H,
H-5) ppm; 13C NMR (100 MHz, CDCl3): δ 17.6 (CH3),
19.8 (CH3), 46.2 (CH3), 50.5 (CH2), 55.1 (CH2), 115.8
(C), 118.2 (CH), 120.0 (C), 122.4 (C), 122.9 (CH),
126.2 (CH), 148.2 (C), 151.0 (C), 153.0 (C), 159.8 (C),
161.4 (C) ppm; HRMS (ESI) m/z: calcd. for
C18H21N4O2 [M + H]+ 325.16645, found 325.16590.
Anal. Calcd for C18H20N4O2: C, 66.65; H, 6.21; N,
17.27. Found: C, 66.52; H, 6.25; N, 17.03.
4
(C), 123.2 (CH), 126.3 (CH), 148.2 (d, JC-F =2.7Hz,
C-1’’), 150.1 (C), 151.1 (C), 153.0 (C), 157.4 (d,
1JC-F =237.6Hz, C-4’’), 159.7 (C), 161.3 (C)ppm; HRMS
(ESI) m/z: calcd. for C23H22FN4O2 [M+H]+ 405.17268,
found 405.17213. Anal. Calcd for C23H21FN4O2: C, 68.30;
H, 5.23; N, 13.85. Found: C, 68.13; H, 5.25; N, 13.68.
9-(4’-(2’’-Fluorophenyl)piperazin-1’-yl)-4,10-dimethyl-2H-
pyrano[2,3-f]cinnolin-2-one (5h). Yield (0.52g, 51%); mp
1
251–252°C; H NMR (400MHz, CDCl3): δ 2.56 (s, 3H,
CH3-4), 3.01 (s, 3H, CH3-10), 3.37 (m, 4H, H2-2’+H2-6’),
3.59 (m, 4H, H2-3’+H2-5’), 6.47 (s, 1H, H-3), 6.96 (m,
4H, H2-2’’+H2-6’’), 6.99 (m, 4H, H2-3’’+H2-5’’), 7.73
(d, J=9.1Hz, 1H, H-6), 8.21 (d, J=9.1Hz, 1H, H-5) ppm;
13C NMR (100MHz, CDCl3): δ 17.6 (CH3), 19.7 (CH3),
50.7 (CH2), 50.9 (CH2), 114.5 (C), 115.8 (CH), 116.2 (d,
9-(4’-Ethylpiperazin-1’-yl)-4,10-dimethyl-2H-pyrano[2,3-
f]cinnolin-2-one (5e).
Yield (0.48 g, 57%); mp
177–179°C; 1H NMR (400 MHz, CDCl3): δ 1.18 (d,
J = 7.1 Hz, H3, CH2-CH3), 2.54 (s, 3H, CH3-4), 2.56
(q, J = 7.1 Hz, 2H, CH2-N), 2.73 (m, 4H, H2-3’ + H2-
5’), 2.94 (s, 3H, CH3-10), 3.48 (m, 4H, H2-2’ + H2-6’),
6.44 (s, 1H-3), 7.70 (d, J = 9.1 Hz, 1H, H-6), 8.18 (d,
J = 9.1 Hz, 1H, H-5) ppm; 13C NMR (100 MHz,
CDCl3): δ 11.9 (CH3), 17.7 (CH3), 19.8 (CH3), 50.5
(CH2), 52.5 (CH2), 52.8 (CH2), 115.8 (C), 118.2 (CH),
120.0 (C), 122.4 (C), 122.8 (CH), 126.2 (CH), 148.2
(C), 151.0 (C), 153.0 (C), 159.8 (C), 161.3 (C) ppm;
HRMS (ESI) m/z: calcd. for C19H23N4O2 [M + H]+
339.18210, found 339.18160. Anal. Calcd for
C19H22N4O2: C, 67.44; H, 6.55; N, 16.56. Found: C,
4
2JC-F =20.0Hz, C-3’’), 118.4 (C), 119.1 (d, JC-F =3.0Hz,
3
C-5’’), 120.5 (C), 122.5 (C), 122.7 (d, JC-F =8.0Hz,
3
C-4’’), 123.1 (CH), 124.5 (d, JC-F =3.4Hz, C-6’’), 126.2
2
(CH), 140.1 (d, JC-F =9.0Hz, C-1’’), 148.3 (C), 151.0
1
(C), 153.0 (C), 155.8 (d, JC-F =244.0Hz, C-2’’), 159.8
(C), 161.3 (C) ppm; HRMS (ESI) m/z: calcd. for
C23H22FN4O2 [M+H]+ 405.17268, found 405.17213.
Anal. Calcd for C23H21FN4O2: C, 68.30; H, 5.23; N,
13.85. Found: C, 68.08; H, 5.18; N, 13.58.
9-(4’-Benzylpiperazin-1’-yl)-4,10-dimethyl-2H-pyrano[2,3-
f]cinnolin-2-one (5i). Yield (0.77g, 77%); mp 208–210°C;
1H NMR (400 MHz, DMSO): δ 2.52 (s, 3H, CH3-4), 2.60
(m, 8H, H2-2’ + H2-3’ + H2-5’ + H2-6’), 2.83 (s, 3H,
CH3-10), 3.56 (s, 2H, CH2-Ph), 6.60 (s, 1H, H-3),
7.25–7.34 (m, 5H, H-2’’ + H-3’’ + H-4’’ + H-5’’ + H-6’’),
7.93 (d, J = 9.1 Hz, 1H, H-6), 8.13 (d, J = 9.1 Hz, 1H,
H-5) ppm; 13C NMR (100 MHz, CDCl3): δ 18.7 (CH3),
25.9 (CH3), 48.0 (CH2), 53.7 (CH2), 63.1 (CH2), 110.6
(CH), 112.1 (CH), 114.4 (C), 125.8 (CH), 127.2 (CH),
128.3 (CH), 129.1 (CH), 137.9 (C), 144.9 (C), 145.2
(C), 145.8 (C), 152.4 (C), 154.2 (C), 155.3 (C), 161.2
(C) ppm; HRMS (ESI) m/z: calcd. for C24H25N4O2
67.22; H, 6.44; N, 16.35.
4,10-Dimethyl-9-(4’-propylpiperazin-1’-yl)-2H-pyrano[2,3-
f]cinnolin-2-one (5f). Yield (0.78 g, 89%); mp 129–131°C;
1H NMR (400 MHz, CDCl3): δ 0.51 (d, J = 8.0 Hz, 3H,
CH3-CH2), 1.67 (m, 2H, CH2-CH3), 2.36 (t, J = 8.0 Hz,
CH2-N), 2.53 (m, 4H, H2-3’ + H2-5’), 2.59 (s, 3H,
CH3-4), 2.99 (s, 3H, CH3-10), 3.55 (m, 4H,
H2-2’ + H2-6’), 6.49 (s, 1H, H-3), 7.76 (d, J = 10.2 Hz,
1H, H-6), 8.24 (d, J = 10.2 Hz, 1H, H-5) ppm; 13C NMR
(100 MHz, CDCl3): δ 12.0 (CH3), 17.6 (CH3), 19.7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. Al-zagameem, M. M. El-Abadelah, M. A. Zihlif, R. G. Naffa,
M. L. Al-Smadi, and M. S. Mubarak
Vol 000
[M + H]+ 401.19775, found 401.19720. Anal. Calcd for
C24H24N4O2: C, 71.98; H, 6.04; N, 13.99. Found: C,
72.11; H, 6.10; N, 14.09.
9-(4’-(4’’-Chlorophenyl)piperazin-1’-yl)-4,10-dimethyl-2H-
pyrano[2,3-f]cinnolin-2-one (5k). Yield (0.87g, 83%); mp
273–276°C; H NMR (400MHz, DMSO): δ 2.54 (s, 3H,
1
CH3-4), 2.92 (s, 3H, CH3-10), 3.36 (m, 8H, H2-2’+H2-3’+
H2-5’+H2-6’), 6.63 (s, 1H, H-3), 7.03 (d, J=12.0Hz, 2H,
H-3’’+H-5’’), 7.25 (d, J=12.1Hz, 2H, H-2’’ +H-6’’), 7.98
(d, J=12.1Hz, 1H, H-6), 8.17 (d, J= 12.0Hz, 1H, H-5)
ppm; 13C NMR (100MHz, CDCl3): δ 17.5 (CH3-10), 19.7
(CH3), 49.5 (CH2), 50.7 (CH2), 115.9 (CH), 117.5 (C), 118.3
(C), 120.0 (C), 122.6 (CH), 123.2 (C), 124.9 (C), 126.3
(CH), 129.0 (C), 148.4 (C), 150.0 (C), 151.0 (C), 152.9
4,10-Dimethyl-9-(4’-(pyrimidin-2’’-yl)piperazin-1’-yl)-2H-
pyrano[2,3-f]cinnolin-2-one (5j). Yield (0.30 g, 31%); mp
232–234°C; H NMR (400MHz, CDCl3): δ 2.56 (s, 3H,
1
CH3-4), 3.04 (s, 3H, CH3-10), 3.49 (m, 4H, H2-2’+H2-6’),
4.09 (m, 4H, H2-3’+H2-5’), 6.47 (s, 1H, H-3), 6.52 (t, J=
4.7 Hz, 1H, H-4’’), 7.75 (d, J=9.1Hz, 1H, H-6), 8.23 (d,
J= 9.1 Hz, 1H, H-5), 8.34 (d, J=4.7Hz, 2H, 1H-3’’ +1H-
5’’) ppm; 13C NMR (100 MHz, CDCl3): δ 17.6 (CH3), 19.7
(CH3), 43.9 (CH2), 50.7 (CH2), 110.2 (CH), 115.9 (CH),
118.3 (C), 120.0 (C), 122.5 (CH), 123.2 (C), 126.2 (CH),
148.4 (C), 151.1 (C), 152.9 (C), 157.8 (CH), 159.7 (C),
161.5 (C), 161.9 (C) ppm; HRMS (ESI) m/z: calcd. for
(C), 159.7 (C), 161.2 (C) ppm; HRMS (ESI) m/z: calcd. for
+
C23H22ClN4O2 [M+H]
421.14313, found 421.14258.
Anal. Calcd for C23H21ClN4O2: C, 65.63; H, 5.03; N,
13.31. Found: C, 65.29; H, 5.08; N, 13.19.
+
C21H21N6O2 [M+ H] 389.17260, found 389.17205ppm.
9-(4’-(4’’-Methoxyphenyl)piperazin-1’-yl)-4,10-dimethyl-2H-
pyrano[2,3-f]cinnolin-2-one (5l). Yield (0.42 g, 40%); mp
Anal. Calcd for C23H20N6O2: C, 64.94; H, 5.19; N, 21.64.
Found: C, 64.76; H, 5.02; N, 21.52.
1
172–174°C; H NMR (400MHz, CDCl3): δ 2.56 (s, 3H,
Figure 2. Growth inhibitory curves on MCF-7 cells for Doxorubicin (positive control), 5d, 5f, 5h, and 5k on MCF-7 breast cancer cells.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Bioassay of Novel Substituted Pyrano[2,3-f]cinnoline-2-ones
CH3-4), 3.00 (s, 3H, CH3-10), 3.32 (m, 4H, H2-2’+H2-6’),
3.59 (m, 4H, H2-3’+H2-5’), 3.78 (s, 3H, O-CH3), 6.48 (s,
1H, H-3), 6.79-7.01 (m, 5H, 1H-2’’+1H-3’’+1H-5’’+1H-
6’’), 7.75 (d, J=9.1Hz, 1H, H-6), 8.14 (d, J=9.1Hz, 1H,
H-5) ppm; 13C NMR (100MHz, CDCl3): δ 18.7 (CH3-10),
25.9 (CH3), 48.2 (CH2), 51.6 (CH2), 110.7 (CH), 112.2
(CH), 114.5 (CH), 118.6 (CH), 120.0 (C), 125.8 (CH),
123.2 (C), 124.9 (C), 129.2 (CH), 144.9 (C), 145.6 (C),
145.7 (C), 152.4 (C), 155.3 (C), 161.2 (C) ppm; HRMS
(ESI) m/z: calcd. for C24H25N4O3 [M+H]+ 417.19267,
found 417.19212. Anal. Calcd for C24H24N4O3: C, 69.21;
H, 5.81; N, 13.45. Found: C, 65.03; H, 5.78; N, 13.29.
obtained from the dose–response curves (Fig. 2) using
Graph Pad Prism Software 5 (San Diego California USA,
www.graphpad.com).
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4,10-Dimethyl-9-(4’-phenylpiperazin-1’-yl)-2H-pyrano[2,3-
f]cinnolin-2-one (5m).
Yield (0.34 g, 35%); mp 224–
226°C; 1H NMR (400 MHz, DMSO): δ 2.54 (s, 3H,
CH3-4), 2.92 (s, 3H, CH3-10), 3.36 (m, 8H, H2-2’ + H2-
3’ + H2-5’ + H2-6’), 6.63 (s, 1H, H-3), 6.79 (t, J = 8.0 Hz,
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(CH2), 50.1 (CH2), 63.1 (CH2), 110.7 (CH), 112.2
(CH), 115.7 (C), 118.3 (CH), 125.8 (CH), 129.2 (CH),
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+
calcd. for C23H23N4O2 [M + H]
387.1821, found
387.18155. Anal. Calcd for C23H22N4O2: C, 71.48; H,
5.74; N, 14.50. Found: C, 71.41; H, 5.65; N, 14.
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Cell lines and cell culture. MCF-7 breast cancer cells
were obtained from American Type culture collections
and were cultured in DMEM/F12. The K562 leukemia cell
line was obtained from Dr. Mona Hassona (Department of
Biological Sciences, Faculty of Science, The University of
Jordan) and was cultured in RPMI. All media were
supplemented with 10% heat-inactivated fetal bovine
serum (Gibco Invitrogen), 1% of 2mML-glutamine
(Lonza), 50IU/mL penicillin (Lonza), and 50mg/mL
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96-well plates in appropriate media, respectively. The
cells were then treated with 10 and 50 μM concentrations
of the tested compounds. The drugs were dissolved in
DMSO immediately before addition to the cell cultures,
and equal amounts of the solvent were added to control
cells. Cell viability was assessed after 3 days of treatment
with the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide obtained from Sigma
(Dorset, UK). For the IC50 determination, the cells were
treated with increasing concentrations of the tested
compound (1.56–100 μM). IC50 concentrations were
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet