New synthetic approach to coumarino[4,3-b]pyridine systems and potential cytotoxic evaluation

Article abstract of DOI:10.1007/s00044-013-0859-y

The reaction of 4-aminocoumarin (2) with appropriate α,β- unsaturated ketones gave the corresponding coumarin [4,3- b]pyridines. Thus, treatment of 2 with ( E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one, (1 E,4E)-1,5-diphenylpenta-1,4-dien-3-one, (Z)-ethyl 3-(4-chloro-phenyl)-2- cyanoacrylate, and (2E,6E)-2,6-dibenzylidenecyclohexanone (3, 6 and 12) afforded the corresponding coumarino[4,3-b]pyridines 5, 7 and coumarino[4,3-b] quinoline derivatives 13, respectively. Heterocyclic annulations of coumarino [5,4- b]pyridine system were achieved via reaction of 2 (in situ) with benzylidene derivatives of indandione to give 15 which was also obtained by multicomponent condensation reaction of 2 (in situ) with indandione and benzaldehyde. A representative sample of new synthesized compounds was evaluated as cytotoxic agents. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0859-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2615–2621
DOI 10.1007/s00044-013-0859-y
ORIGINAL RESEARCH
New synthetic approach to coumarino[4,3-b]pyridine systems
and potential cytotoxic evaluation
•
Wafaa S. Hamama Mona E. Ibrahim
•
•
Asmaa E. Metwalli Hanafi H. Zoorob
Received: 21 July 2013 / Accepted: 17 October 2013 / Published online: 27 October 2013
Ó Springer Science+Business Media New York 2013
Abstract The reaction of 4-aminocoumarin (2) with
appropriate a,b-unsaturated ketones gave the correspond-
ing coumarin [4,3-b]pyridines. Thus, treatment of 2 with
(E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one, (1E,4E)-
1,5-diphenylpenta-1,4-dien-3-one, (Z)-ethyl 3-(4-chloro-
phenyl)-2-cyanoacrylate, and (2E,6E)-2,6-dibenzylidene-
cyclohexanone (3, 6 and 12) afforded the corresponding
coumarino[4,3-b]pyridines 5, 7 and coumarino[4,3-b]
quinoline derivatives 13, respectively. Heterocyclic
annulations of coumarino [5,4-b]pyridine system were
achieved via reaction of 2 (in situ) with benzylidene
derivatives of indandione to give 15 which was also
obtained by multicomponent condensation reaction of 2
(in situ) with indandione and benzaldehyde. A represen-
tative sample of new synthesized compounds was evalu-
ated as cytotoxic agents.
increasing roles in synthetic approaches to promising
compounds in the field of medicinal chemistry (Sun et al.,
2006; Stachulski et al., 2006; Garino et al., 2005; Narender
et al., 2004).
The incorporation of other heterocyclic moiety either as
substituent group or as a fused component into parent
coumarin alters the property of parent coumarin and con-
verts it into a more useful product (Brahnbhatt et al., 2007).
Fused coumarin is interesting due to their significant
antibacterial (El-Saghier et al., 2007; Okumura et al. 1961;
Cingolani et al. 1969; Rao et al., 1983; El-NaggarA et al.,
1981; Moustafa, 1991) and novobiocin activities (Kaczka
et al., 1955). Substituted chromenopyridones were syn-
thesized and evaluated in vitro for the cytotoxic activity
against various human cancer cell lines such as prostate
(PC-3), breast (MCF-7), CNS (IMR-32), cervix (Hela), and
liver (Hep-G2) (Singh et al., 2013).
Keywords Coumarin ꢀ Regioselective ꢀ Annulation ꢀ
Biselectrophiles ꢀ Cytotoxic activity (in vitro)
As a result, a number of methodologies have been
developed to synthesize coumarin compounds (Shi et al.,
2003; Kidwai et al., 2005; Makarem et al., 2008,). Spe-
cifically, those bearing a benzopyrone-pyridine or piperi-
dine skeleton were found to interact with DNA (Gutam
et al., 2009).
Introduction
Coumarins are an important group of heterocyclic com-
pounds due to their important functions in nature and their
pharmacological applications. Coumarin constitutes occur
in alkaloids, flavonoids, tocopherols, and anthocyanins.
Moreover, functionally substituted coumarin has played
Cyclocondensation of enamino skeleton has multiple
competing sites for ring-annulation reaction toward the
biselectrophiles. The b-position of the exocyclic enamino
group is the most nucleophilic and attacks the most elec-
trophilic carbon atom of the reactants with a,b-unsaturated
ketones or their synthetic precursor aldehydes and ketones
containing at least two active hydrogen atoms are the most
widespread and investigated pathways to fused dihydro-
azaheterocycles (Hamama et al., 2007; Chebanov et al.,
2010; Chebanov and Desenko, 2006), In most cases, both
the types of reaction pathways, i.e., a sequential protocol
involving the initial synthesis of the a,b-unsaturated
W. S. Hamama (&) ꢀ M. E. Ibrahim ꢀ A. E. Metwalli ꢀ
H. H. Zoorob
Department of Chemistry, Faculty of Science, Mansoura
University, Mansoura 35516, Egypt
e-mail: wshamama@yahoo.com; wshamama53@gmail.com
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Med Chem Res (2014) 23:2615–2621
NO2
N
HN
O
Autooxidation
O
3
OH
O
O
O
NO2
O
NO2
Ph
N
4
5
O
1
Ph
Ph
AcONH4
6
Ph
O
O
O
7
NH2
Cl
N
O
O
C
NH2
O
2
CO2Et
Cl
ArCHO
8
2
O
O
O
NH2
9
NH2
O
OEt
N
O
Cl
O
10
O
O
O
HN
O
O
O
O
O
11
Scheme 1 Pyridine ring formation through nucleophilic attack and cyclization reactions followed by auto-oxidation
ketonic compounds and the other pathway is the three-
component reaction, yield the same products (Lipson et al.,
2003). However, in rare cases, the direct multicomponent
procedure may lead to the formation of different products
(Desenko et al., 1993). It was felt interesting to synthesize
fused heterocyclic systems incorporating coumarin moiety
and evaluate their biological activity. Our interest was
directed to synthesize pyridine derivatives fused to cou-
marin rings, which is mainly caused by the known bio-
logical activity of these systems (Yamamori et al., 1985).
Indandiones are very important synthons for synthesis of
fused compounds containing indandione moiety, which are
evaluated as inhibitors of human papillomavirus type II
(Yoakim et al., 2003; Goudreau et al., 2007) and as anti-
microbial agents (El-Ossaily, 2007).
Results and discussion
Chemistry
4-hydroxycoumarin (Manolov and DanchevN, 1999) (1)
was reacted with ammonium acetate to give 4-amino-
coumarin (2) in situ or can be separated in pure form,
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Med Chem Res (2014) 23:2615–2621
2617
Scheme 2 The pyridine ring
formation either through
reaction of 2 with 2,6-
dibenzylidenecyclohexanone or
via a multicomponent reaction
Ph
N
O
Ph
Ph
Ph
12
O
O
13
NH2
O
O
O
O
2
N
Ph 14
O
Ph
O
CHO
O
O
or
+
15
O
which has two competing sites for ring-annulation reaction
toward biselectrophiles. One of them is the b-position of
the enamino group, and the other site is the amino group
itself. Therefore, cyclocondensation reaction of 2 with (E)-
3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (3) in a mix-
ture of ethanol/acetic acid (1:1) furnished the couma-
rin[4,3-b]pyridine derivative 5. We have found that
condensation between 2 and 3 was regioselective. (con-
cordant with similar reactions of aminoisoxazole and bis-
electrophiles (Lipson et al., 2003) (Scheme 1).
potential of compound 2 has been explored for other syn-
theses through annulation of 2 via one step cyclocondensa-
tion reaction with 2-benzylidene-2H-indene-1,3-dione, in
ethanol/acetic acid mixture to afford regioselective penta-
cyclic derivative 15, indeno [30,20:5,6]pyrido[3,2-c]couma-
rin, in high yield (Scheme 2). Similarly, multicomponent
condensation reaction of 2 with a mixture of indandione and
benzaldehyde led to dihydropyrido[2,3-a]inden-5-one
derivative 15.
From the literature survey (Navarrete-Encina et al.,
2010) synthesized Chromeno[4,3-b]pyridine-3-carbox-
ylate derivatives from anisaldehyde derivatives and
ethylaminocrotonate.
An efficient method for selective synthesis of 2-sty-
rylcoumarino [4,3-b]pyridine derivatives 7 was achieved by
the Micheal addition of 2 to 1,5-diphenyl-1,4-pentadiene-3-
one (6) in a mixture of ethanol/acetic acid (1:1) via cyclo-
condensation reaction through removal of water molecule
followed by auto-oxidation. (Scheme 1). Whereas, amino-3-
((4-amino-2-oxo-2H-Coumarin-3-yl)(4-chlorophenyl)methyl)
-2H-Coumarin-2-one:(9) was obtained by the reaction of 2
with ((E)-ethyl 3-(4-chlorophenyl)-2-cyanoacrylate (8) in
ethanol/glacial acetic acid (1:1) instead of the expected
coumarino[4,3-b]pyridine derivative 10.
Assignment of the new synthesized compounds was
1
based on elemental analyses, IR, H NMR, 13C NMR, and
mass spectral data (C.f. ‘‘Experimental’’ Section).r
Biological activity
Effect of drugs on the viability of Ehrlich ascites carcinoma
cells (EAC) in vitro
Also, fusion of diethyl malonate with 2 led to 1H-cou-
marin[4,3-b]pyridine -2,4,5(3H)-trione (11) (Scheme 1). In
addition, the reaction of 2 with (2E,6E)-2,6-dibenzylidene-
cyclohexanone (12) in DMF afforded (11E)-11-benzylidene-
8,9,10,11-tetrahydro-7-phenyl-7H-coumarino[4,3-b]quin-
olin-6(12H)-one (13) (Scheme 2). Also, the synthetic
Five coumarino pyridines and its annulated analogues were
tested for potential antitumor activity against EAC in vitro
(Dashora et al., 2011). Results for the IC100, IC50, and IC25
values of the active compounds are summarized in Table 1.
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Med Chem Res (2014) 23:2615–2621
The data showed clearly that all the tested compounds
showed more toxicity than the 5-FU in vitro studies.
Interestingly, compounds 5, 7, 9, 13, and 15 were increased
around three times more toxic than the 5-FU. Experimental
potential antitumor activity of the compounds reported in
this study to their structures, the following structure
activity relationships (SAR’s) were postulated: (a) com-
pounds 5 and 7 contain pyridine moiety and this is in
agreement with that reported by (Hamama et al., 2012).
(b) Also, in case of compound 9 and 13, the high cytotoxic
activity may be attributed to the presence of bis-coumarin
and quinoline moiety, respectively, which is in agreement
with that reported (Gouda et al., 2012; Al-Said et al.,
2011). (c) Moreover, the high cytotoxic activity of com-
pound 15 may be attributed to the presence of indandione
moiety; similar results have been reported (Hamama et al.,
2012) (Fig. 1).
Conclusions
Modification of coumarin derivatives produced compounds
with potential development as anticancer agents. The
screening results of compounds 5, 7, 9, 13, and 15 showed
significant activities in certain cancer cells. Additional
research, including mode of action studies, is planned to
accurately establish relative activity for SAR’s and rational
design. The cancer chemopreventive effects of coumarin
derivatives have been intensively investigated. Coumarin
derivatives exhibited pronounced antitumor activities by
triggering apoptosis in human tumor cells (Weinman and
Ottow, 2007). Studies are underway to investigate the
apoptosis-inducing activity of compounds found to be
cytotoxic in this study.
Experimental
Table 1 In vitro potential antitumor activity of coumarin analogues
using EAC assay
All melting points are in degree centigrade (uncor-
rected) and were determined on Gallenkamp electric
melting point apparatus. Elemental analyses were car-
ried out at Micro analytical Center, Faculty of Science,
Cairo University. IR spectra were recorded (KBr), (m
cm-1) on a Mattson 5000 FTIR Spectrophotometer at
Micro analytical Center Faculty of Science, Mansoura
University. 1H NMR Spectra were measured on a
Varian Spectrophotometer at 300 MHz, using TMS as
an internal reference and DMSO-d6 or CDCl3 as solvent
at Chemistry Department, Faculty of Science, Cairo
University. 13C NMR (100 MHz) was recorded in
DMSO-d6 using a Bruker AV 400 spectrometer at
Chemistry Department, Faculty of Science, Assiut
Compound no
Death
IC100 (lM)
IC50 (lM)
IC25 (lM)
5-FU
5
0.77
0.25
0.27
0.25
0.24
0.27
0.38
0.12
0.13
0.12
0.12
0.13
0.19
0.06
0.06
0.06
0.06
0.06
7
9
13
15
IC100, IC50, and IC25 are the inhibitive concentration at 25, 50, and
100 lM, respectively, of the compounds used. 5-FU is 5-fluorouracil
as a well known cytotoxic agent
Fig. 1 Structure of the most potent
compounds 5, 7, 9, 13 and 15
Cl
NO2
Ph
NH2
O
O
N
N
O
Ph
Ph
O
NH2
Ph
O
O
O
O
9
5
7
O
N
O
N
O
Ph
Ph
O
O
15
13
123

Med Chem Res (2014) 23:2615–2621
2619
University. Mass spectra were recorded on (Kratos,
70 eV) MS equipment and/or a Varian MAT 311 a
Spectrometer, at Microanalytical Center, Faculty of
Science, Cairo University. Reaction mixtures were
monitored by thin layer chromatography using EM
science silica gel-coated plates with visualization by
irradiation with ultraviolet lamp. Biological testing was
carried out at Drug Department, Faculty of Pharmacy,
Mansoura University, Mansoura, Egypt.
Yield 76 % (pale brown powder); m.p. 96–98 °C
(methanol); Rf = 0.65 [pet. ether (60–80): ethyl acetate
(3:2)]; IR (KBr): m/cm-1 = 1677 (O–C=O),1602 (C=N);
1H NMR (CDCl3) d:6.61(d, 1H, J = 8 Hz, CHAr), 6.93 (d,
1H, J = 8 Hz, CH=CHAr,) 6.81–7.99 (m, 10H, CHAr); MS
(EI, 70 eV) m/z (%) = 377 (M??2, 2.7), 376
(M??1,3.95), 375 (M?, 4.22), 374 (M?-1, 9.6), 300 (2.8),
298 (8.4), 272 (2.8), 249 (30.2), 223 (6.7), 195 (3.5), 191
(12),178 (17.6), 162 (14.0), 121 (77.8), 103 (59.2), 92
(88.1),77 (100.0, base peak); Anal. Calcd. for C26H17NO2
(375.42): C, 83.18; H, 4.56; Found: C, 83.09; H, 4.50.
2-(4-Nitrophenyl)-4-phenyl-5H coumarino[4,3-
b]pyridin-5-one (5)
4-Amino-3-((4-amino-2-oxo-2H-coumarin-3-yl)
A mixture of 1 (0.3 g, 1.85 mmol) and ammonium acetate
(0.28 g, 3.64 mmol) in ethanol/glacial acetic acid (20 ml;
1:1) was refluxed for 4 h. (E)-3-(4-Nitro phenyl)-1-phe-
nylprop-2-en-1-one (3) (0.47 g, 1.85 mmol) was then
added and further refluxed for 7 h. After cooling, the
reaction mixture was poured onto ice and allowed to stand
at room temperature. The formed precipitate was filtered
off, washed with water, and recrystallized from methanol
to give product 5.
(4-chlorophenyl) methyl)-2H-Coumarin-2-one (9)
A mixture of 2 (0.3 g, 1.85 mmol) and (E)-ethyl 3-(4-
chlorophenyl)-2-cyanoacrylate (0.44 g, 1.85 mmol) in
ethanol/glacial acetic acid (20 ml; 1:1) was refluxed for
9 h. White flakes of product was formed during reflux.
After cooling, the mixture was poured onto ice and allowed
to stand. The formed precipitate was filtered off, washed
with water, and recrystallized from ethanol to give product
9.
Yield 58 % (yellowish brown crystals); m.p.
120–121 °C (methanol); Rf = 0.65[pet. ether (60–80):
ethyl acetate (3:2)]; IR (KBr): m/cm-1 = 1668 (O–
C=O),1610 (C=N); 1H NMR (DMSO-d6) d: 7.97 (d,
J = 8.4 Hz, 6H, CHAr a),7.78 (t, 2H, CHAr b),7.43–7.62
(m, 6H, 5H CHAr ? 1H pyridine; 13C NMR (100 MHz,
DMSO-d6): d ppm = 106.7 (C-3), 116.1 (C-4a), 123.1
(2CHAr), 123.5 (CHAr), 123.9 (CHAr), 125.5 (2CHAr),
126.1 (CHAr), 127.9 (CHAr), 128.9 (2CHAr), 132.1
(2CHAr), 133.5 (C-10a), 136.4(CAr), 137.1(CAr), 141.2
(CAr), 145.8 (CAr), 148.1 (C-10b), 150.9 (C-6a), 152.1 (C-
4), 158.2 (C-5), 161.1 (C-2); MS (EI, 70 eV) m/
z (%) = 395 (M??1, 1.7), 380 (1.3), 303 (1.0), 259 (1.2),
253 (37.5), 237 (5.0), 236 (19.5), 223 (4.6),221 (1.4),207
(9.8), 206 (23.7),178 (22.2), 162 (15.6), 159 (1.2), 122
(6.4), 121 (18.8),120 (33.8),105 (57.9), 92 (40.0), 77
(100.0, base peak); Anal. Calcd. for C24H14N2O4 (394.09) :
C, 73.09; H, 3.58; Found: C, 73.03; H, 3.62.
1
Yield 70 % (white sheet); m.p. [300 °C (ethanol); H
NMR (DMSO-d6) d:8.08 (d, 4H, J = 7.8 Hz, HAr a), 7.72
(s, 1H, CH), 7.67 (t, 4H, HAr b),7.33 (d, 2H J = 8.7 Hz,
2Hc), 7.13 (d, 2H J = 8.4 Hz, 2Hd), 5.91 (s, 4H, 2NH2):
13C NMR (100 MHz, DMSO-d6): d 36.9 (CH), 94.1(2C-3),
114.5 (2CAr), 116.8 (2C-4a), 123.9 (2C-8), 127.9(2C-6),
128.5(2C-7), 130.1(2CHAr), 1316 (CHAr), 132.4(2CHAr),
137.2(CAr), 152.1(2C-8a), 154.2 (2C-4), 163.9(2C-2); MS
(EI, 70 eV) m/z (%) = 400 (M??5, 4.9), 399 (M??4,
8.3), 284 (36.8), 283(59), 282 (91.7), 281(100, base peak),
280 (25), 161 (93.8), 160 (54.9),121 (17.4), 112 (29.2),
111(15.3),77(54.9); Anal. Calcd. for C25H18N2O4 (410.42):
C, 73.16; H, 4.42; Found: C, 73.09; H, 4.38.
1H-Coumarino [4,3-b]pyridine-2,4,5(3H)-trione (11)
A mixture of 2 (0.3 g, 1.85 mmol) and diethyl malonate
(0.32 g, 1.85 mmol) was fused in oil bath at 180 °C for
6 h. The formed precipitate was washed with ethanol, fil-
tered off to give product 11 which was washed by boiling
in ethanol.
4-Phenyl-2-styryl-5H-coumarino [4,3-b]pyridin-5-one
(7)
A mixture of 1 (0.3 g, 1.85 mmol) and ammonium acetate
(0.28 g, 3.64 mmol) in ethanol/glacial acetic acid (20 ml;
1:1) was refluxed for 4 h.; then dibenzalacetone (0.29 g,
1.85 mmol) was added and further refluxed for 7 h. After
cooling, the mixture was poured onto ice and allowed to
stand at room temperature. The formed precipitate was
filtered off, washed with water, and recrystallized from
methanol to give product 7.
Yield 73 % (deep brown crystals); m.p. [300 °C (eth-
anol); Rf = 0.54 [pet. ether (60–80): ethyl acetate (3:2)];
IR (KBr): m/cm-1 = 3392 (NH), 1690 (true C=O), 1647,
1614 (C=O),1559 (C=N); MS (EI, 70 eV) m/z (%) = 230
(M??1, 13.8), 229 (M?, 100.0, base peak), 228 (M?-1,
5.6), 200 (48.4), 199 (3.1), 160 (1.7), 146 (16.6), 145(38.1),
113(1.7), 77 (10.5), 53(18.9). Anal. Calcd. for C12H7NO4
(229.19): C, 62.89; H, 3.08; Found: C, 62.81; H, 3.17.
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Med Chem Res (2014) 23:2615–2621
(E)-11-Benzylidene-8,9,10,11-tetrahydro-7-
synthesized compounds have a direct cytotoxic effect on
Ehrlich ascites carcinoma cells (Dashora et al., 2011), via-
bility was estimated by the trypan blue (Sheeja et al., 1997),
exclusion test. The desired concentration of tumor cells
(2 9 106 cells per 0.2 ml) was obtained by dilution with
saline solution (0.9 % sodium chloride). Viability of tumor
cells obtained and used in this experiment was always higher
than 90 %. Below this percentage, the cells were discarded
and the entire procedure was repeated.
phenylcoumarino[4,3-b]quinolin-6-one (13)
A mixture of 2 (0.3 g, 1.85 mmol) and dibenzylidene cyclo-
hexanone (0.5 g, 1.85 mmol) in DMF (20 ml) was refluxed for
30 h. Cooling the reaction mixture then poured onto ice cold
water. The formed precipitate was filtered off, washed with
water, and recrystallized using ethanol to give product 13.
Yield 73 % (deep brown crystals). m.p. 76–78 °C (ethanol);
Rf = 0.79 [pet. ether (60–80): ethyl acetate (3:2)]; IR (KBr):
1
m/cm-1 = 1626 (O–C=O),1608 (C=N); H NMR (CDCl3)
References
d:1.56 (m, 2H, CH2), 1.9 (t, 2H, CH2), 6.60 (s,1H, C=CHAr),
6.97–7.98 (m, 14H, CHAr); MS (EI, 70 eV) m/z (%) =
418.1(M??3, 14.5), 388 (2.7), 342 (12.5), 341 (43.5), 327
(5.4), 287 (3.0), 263 (3.8), 249 (18.6), 213 (6.3), 162 (9.9), 144
(2.7), 129.2 (19.7), 122 (8.6) 107 (4.4), 92 (48.1), 91 (69.1), 89
(20.5), 77 (100.0, base peak); Anal. Calcd. for C29H21N O2
(415.48): C, 83. 83; H, 5.09; Found: C, 83.76; H, 5.01.
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(a) A mixture of 1 (0.3 g, 1.85 mmol) and ammonium
acetate (0.28 g, 3.64 mmol) in ethanol/glacial acetic
acid (20 ml; 1:1) was refluxed for 4 h. The arylidene
of indandione 14 (0.43 g, 1.85 mmol) was added then
further refluxed for 1 h, whereby yellow needles of
product 15 were formed.
(b) A mixture of 1 (0.3 g, 1.85 mmol) and ammonium
acetate (0.28 g, 3.64 mmol) in ethanol/glacial acetic
acid (20 ml; 1:1) was refluxed for 4 h.; then indan-
dione (0.27 g, 1.85 mmol) followed by benzaldehyde
(0.19 g, 1.85 mmol) were added and further refluxed
until a violet color disappeared after (1 h); then
yellow needles of product 15 were formed.
El-Ossaily YA (2007)
A Convenient synthesis of some new
indeno[1,2-b]pyridines and indeno[1,2-b] thieno[3,2-e]pyridine
derivatives with potential biological activity phosphorus. Sulfur
Silicon 182:1109–1117
Yield 73 %/81 % (yellow needles); m.p. 286–288 °C (chlo-
roform);Rf = 0.78[pet. ether(60–80):ethyl acetate (3:2)];IR
(KBr): m/cm-1 = 1712 (C=O), 1668 (O–C=O) 1544 (C=N);
1HNMR(DMSO-d6)d:7.99(d, J = 7.2 Hz, 4H, CHAr a),7.78
(t, 4H, CHAr b),7.43–7.62 (m, 5H, CHAr); MS (EI, 70 eV) m/
z (%) = 375 (M?, 9.2), 374(M?-1, 8.8), 359 (90.7),
358(22.3), 301 (12.2), 244(13.5), 198 (48), 161(11.7), 154
(19.2), 124 (20.6), 108 (17.4), 93 (56.9), 90 (45.7),78 (21.4),
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