Synthesis and anticancer activity of some novel tetralin-6-yl-pyrazoline, 2-thioxopyrimidine, 2-oxopyridine, 2-thioxo-pyridine and 2-iminopyridine derivatives

Article abstract of DOI:10.3390/molecules16043410

The title compounds were prepared by reaction of 6-acetyltetralin (1) with different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflourobenzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding α,β-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b, 2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared compounds were evaluated for anticancer activity against two human tumor cell lines. Compound 3a showed the highest potency with IC₅₀ = 3.5 and 4.5 μg/mL against a cervix carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.

Full text of DOI:10.3390/molecules16043410

Molecules 2011, 16, 3410-3419; doi:10.3390/molecules16043410
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Anticancer Activity of Some Novel
Tetralin-6-yl-pyrazoline, 2-Thioxopyrimidine, 2-Oxopyridine,
2-Thioxo-pyridine and 2-Iminopyridine Derivatives
Ebtehal S. Al-Abdullah
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia; E-Mail: ealabdullah@ksu.edu.sa
Received: 7 March 2011; in revised form: 29 March 2011 / Accepted: 8 April 2011 /
Published: 20 April 2011
Abstract: The title compounds were prepared by reaction of 6-acetyltetralin (1) with
different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflouro-
benzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding
α,β-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield
the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford
the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic
aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the
presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b,
2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared
compounds were evaluated for anticancer activity against two human tumor cell lines.
Compound 3a showed the highest potency with IC50 = 3.5 and 4.5 μg/mL against a cervix
carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.
Keywords: tetrahydronaphthalenes; 2-pyrazoline; 2-thioxopyrimidine; 2-oxopyridine;
2-thioxopyridine; 2-iminipyridine; anticancer activity
1. Introduction
Cancer is presently responsible for about 25% of deaths in developed countries and for 15% of all
deaths worldwide. It can therefore be considered as one of the foremost health problems, with about
1.45 million new cancer cases expected yearly. Antitumor chemotherapy is nowadays a very active
field of research, and a huge amount of information on the topic is generated every year [1,2].

Molecules 2011, 16
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Although there is a large amount of information available dealing with clinical aspects of cancer
chemotherapy, we felt that there was a clear need for an updated treatment from the point of view of
medicinal chemistry and drug design [3]. Diverse chemotherapeutic activities were ascribed to
substituted tetralin (tetrahydronaphthalene)-heterocycles [4,5] and tetrahydronaphthalene derivatives,
especially those incorporated into heterocyclic systems [6]. It has been reported that this type of
compounds possess a wide variety of biological activities including anti-HIV [5], antibacterial [4,7],
hypotensive [8], antiarrythmic [9], molluscicidal [10], antiplatelet aggregation [11,12], anxiolytic and
antidepressant [13,14] and anticancer [15,16] effects. Pyridin-2(1H)-ones are known to possess a range
of biological activities such as analgesic, antifungal, antimalarial, antiinflammatory, antibacterial,
anti-HIV, phytotoxic, antitumoral and antiviral properties [17-24]. Thus, it was of interest to synthesize
some new heterocyclic derivatives carrying a tetrahydronaphthale moiety for evaluation as potential
anticancer agents.
2. Results and Discussion
2.1. Chemistry
α,β-Unsaturated ketons (chalcones) are active intermediates and excellent starting materials for the
synthesis of several heterocyclic systems. Thus, a Claisen-Schmidt reaction of 1-(1,2,3,4-tetrahydro-
naphthaline-6-yl)ethanone (1), prepared following the previously reported method of Allinger and Jones [25],
with 2,6-dichlorobenzaldehyde (2a), 2,6-diflourobenzaldehyde (2b) or 3-ethoxy-4-hydroxybenzaldehyde
(2c), in 10% ethanolic sodium hydroxide afforded the corresponding α,β-unsaturated ketons 3a-c in 53, 42
and 80% yields, respectively. Condensation of the chalcone analogue 3b with hydrazine hydrate in acetic acid
yielded the corresponding 1-acetyl-2-pyrazoline derivative 4 in 92% yield. Meanwhile, the interaction of the
chalcone analogues 3a,b with thiourea in aqueous potassium hydroxide yielded the corresponding
2-thioxopyrimidines 5a,b in 20 and 28% yields, respectively (Scheme 1, Table 1).
Scheme 1. Synthetic pathways to compounds 3a-c, 4 and 5a,b.
O
O
OHC
Na+OH-
EtOH
CH3
+
X
X
3a-c
1
2a-c
NH2CSNH2
K+OH-
EtOH
2
2
H
O
c
A
S
F
F
HN
N
O
N
N
CH3
5a,b
X
4

Molecules 2011, 16
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Table 1. Melting points, crystallization solvents, yields, molecular formulae and molecular
weights of newly synthesized compounds 3a-c, 4, 5a,b , 6a,b, 7a-c and 8a,b.
Comp.
No.
Yield
(%)
Molecular Formula
(Mol. Wt.)
X
Mp (ºC)
Cryst. Solv.
3a
3b
3c
4
2,6-Cl2
2,6-F2
71-3
250-2
77-9
EtOH
EtOH
53
42
80
95
20
28
18
30
25
53
90
26
34
C19H16Cl2O (331.24)
C19H16F2O (298.34)
3-EtO,4-OH
-
EtOH
C20H20O2 (292.38)
> 300
> 300
253-5
252-4
250-2
150-2
124-6
226-8
193-5
100-2
AcOH
C21H20F2N2O (354.40)
C20H16Cl2 N2S (387.33)
C20H16F2 N2S (354.42)
C22H16Cl2 N2O (395.29)
C22H16F2 N2O (362.38)
C22H16Cl2 N2S (411.36)
C22H16F2 N2S (378.45)
C23H20 N2OS (372.49)
C22H17Cl2 N3 (394.31)
C22H17F2 N3 (361.40)
5a
5b
6a
6b
7a
7b
7c
8a
8b
2,6-Cl2
2,6-F2
EtOH/H2O
EtOH/H2O
AcOH
2,6-Cl2
2,6-F2
AcOH
2,6-Cl2
2,6-F2
AcOH
AcOH
3-EtO-4-OH
2,6-Cl2
2,6-F2
AcOH
AcOH
AcOH
Condensation of compound 1 and the aromatic aldehydes 2a or 2b with ethyl cyanoacetate in
presence of excess ammonium acetate in n-butanol afforded the corresponding 3-cyano-2-(1H)-
oxopyridines 6a and 6b in a one pot reaction. Similarly, the reaction of compound 1 and the aromatic
aldehydes 2a-c with 2-cyanothioacetamide yielded the corresponding 3-cyano-2-(1H)-thioxopyridines
7a-c in 25, 53 and 90% yields, respectively. The 3-cyano-2-(1H)-iminopyridines 8a and 8b were also
prepared in fair yields by applying the aforementioned one pot reaction of the compound 1, the
corresponding aldehyde and malononitrile (Scheme 2, Table 1). The structures of the newly
1
synthesized compounds were confirmed on the basis of their elemental analysis and IR, H-NMR,
13C-NMR and mass spectral data.
Scheme 2. Synthetic pathways of compounds 6a,b, 7a-c and 8a,b.
X
O
OHC
CH3
NCCH2COOEt
+
AcO-NH4
+
CN
O
X
1
2a-c
N
NCCH2CN
H
AcO-NH4
+
6a,b
2
X
-
X
2
+
4
CN
S
CN
N
N
NH
8a,b
H
H
7a-c

Molecules 2011, 16
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2.2. Anticancer Screening
All the newly synthesized compounds were tested at the Department of Tumor Pathology, National
Cancer Institute, Cairo, Egypt. Two cell lines were used for the evaluation – human cervix carcinoma
cell line (Hela) and human breast carcinoma cell line (MCF7). The newly synthesized analogs 3a-c, 4,
5a,b, 6a,b, 7a-c and 8a,b were tested for in vitro cytotoxic activity against these cell lines, which were
obtained frozen in liquid nitrogen (-180 °C) from the American Type Culture Collection [26]. The
tumor cell lines were maintained in the National Cancer Institute, Cairo, Egypt, by serial sub-culturing.
The results (Table 2) are expressed in the form of the concentration of compound that causes 50%
inhibition of cells growth. The in vitro evaluation revealed that all the newly synthesized compounds
showed certain activity against tumor cell lines tested, although the activity was generally higher
towards the cervical cancer line than the breast cancer one. Compound 3a showed potent and broad
antitumor activity against the two tumor cell lines tested (IC50 = 3.5 against Hela and IC50 = 4.5 against
MCF7) compared to the potent anticancer drug 5-flourouracil (5-FU) used as a reference standard [27].
Substitution of the side chain with different ring systems like in the oxopyridine or thioxopyridine
compounds 6a,b and 7a,b resulted in moderate activity against the Hela cell line and marked activity
against the MCF-7 cell line. Meanwhile, substitution of the side chain with iminopyridine,
thioxopyrimidine and/or pyrazoline rings resulted in low activity against the two tumor cell lines.
These results demonstrated that changing the molecular conformation and orientation could influence
markedly the antitumor activity against the two tested cell types.
Table 2. Effect of compounds 3a-c, 4, 5a,b, 6a,b, 7a-c and 8a,b on cervix carcinoma cell
line (Hela) and breast carcinoma cell line (MCF7).
IC50(μg/mL)
Compound No.
Hela
3.5
MCF7
4.5
3a
3b
3c
10.5
12.5
11.3
10.7
11.9
7.1
15
18.3
19
4
5a
20.5
17.3
12
5b
6a
6b
7a
10.9
8.1
17.5
16
7b
7c
5.9
12.5
16
6.5
8a
12.1
12.1
-
22.3
21.7
3.5
8b
5-FU

Molecules 2011, 16
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3. Experimental
3.1. General
Melting points (°C, uncorrected) were measured in open glass capillaries using a Barnstead 9001
electrothermal melting point apparatus. Infrared spectra (ν, cm-1) were recorded on a Jasco
1
FT/IR-330E, Fourier Transform Infrared Spectrometer using KBr discs. H-NMR spectra were
1
determined using a Bruker AC 500 Ultra Shield NMR spectrometer operating at 500.13 MHz for H
and 125.76 MHz for 13C, the chemical shifts are expressed in δ (ppm) downfield from
tetramethylsilane (TMS) used as internal standard. Electron impact mass spectra (EI-MS) were
recorded on a Shimadzu GC-MS-QP 5000 instrument at 70 eV. Elemental analyses (C, H, N) were in
full agreement with the proposed structures within ±0.4% of the theoretical values. Monitoring the
reactions and checking the purity of the final products were carried out by thin layer chromatography
(TLC) using silica gel precoated aluminum sheets (60 F254, Merck) and visualization with ultraviolet
light (UV) at 365 and 254 nm.
3.2. 3-Aryl-1-(1,2,3,4-tetrahydronaphthalen-6-yl)prop-2-en-1-ones 3a-c
A mixture of 6-acetyltetraline 1 (4.9 g, 0.028 mol), the appropriate aldehyde 2a-c (0.028 mol) and
10% ethanolic sodium hydroxide solution (15 mL) in ethanol (30 mL) was stirred for 12 h. The
reaction mixture was then warmed at 40 °C for 10 min. and the separated precipitate was filtered off
and recrystallized from ethanol.
3-(2,6-Dichlorophenyl)-1-(1,2,3,4-tetrahydronaphthalen-6-yl)prop-2-en-1-ones (3a): IR: 1690 (C=O),
1
1650 (C=C). H-NMR (DMSO-d6): δ 1.7-1.73 (m, 4H, tetralin CH2), 2.76-2.8 (m, 4H, tetralin CH2),
7.21 (d, 1H, CH=, J = 10.4 Hz), 7.54 (d, 1H, CH=, J = 10.4 Hz), 7.37-7.8 (m, 6H, Ar-H). 13C-NMR: δ
22 (tetralin CH2), 29 (tetralin CH2), 125.5 (CH=), 143.2 (CH=), 129.01, 129.25, 130.59, 130.83,
132.11, 134.37, 134.3, 135.07, 136.2, 137.3 (Ar-C), 188.5 (C=O). MS, m/z (rel. int.): 334 (M+, 0.3),
176 (50), 175 (75), 173 (100), 138 (5).
3-(2,6-Difluorophenyl)-1-(1,2,3,4-tetrahydronaphthalen-6-yl)prop-2-en-1-ones (3b): IR: 1651 (C=O),
1548 (C=C), 1H-NMR (DMSO-d6): δ 1.7 (m, 4H, tetralin CH2), 2.5 (m, 4H, tetralin CH2), 7.24 (d, 1H,
13
CH=, J = 8.3 Hz), 7.84 (d, 1H, CH=, J = 8.3 Hz), 6.66-7.6 (m, 6H, Ar-H); C-NMR: δ 22 (tetralin
CH2), 29 (tetralin CH2), 129.3 (CH=), 136.6 (CH=), 111.2, 112.3, 126.7, 129.9, 131.16, 134.26, 134.3,
135.9, 142.5, 157.3 (Ar-C), 186.9 (C=O). MS, m/z (rel. int.): 298 (M+, 0.2), 165 (19), 139 (2), 137
(100), 131 (3), 75 (5).
3-(3-Ethoxy-4-hydroxyphenyl))-1-(1,2,3,4-tetrahydronaphthalen-6-yl)prop-2-en-1-ones (3c): IR: 3420
(OH), 1634 (C=O) 1539 (C=C). 1H-NMR: δ 1.35 (t, 3H, CH3, J = 7.1 Hz ), 1.70-1.73 (m, 4H, tetralin
CH2), 2.5 (m, 4H, tetralin CH2), 4.08 (q, 2H, CH2, J = 11.05 Hz), 7.15 (d, 1H, CH=, J = 9.4 Hz), 7.40
13
(d, 1H, CH=, J = 9.4 Hz), 6.97-7.4 (m, 6H, Ar-H), 9.75 (s, 1H, OH). C-NMR: δ 14.49 (CH3), 22.2
(tetralin CH2), 28.8 (tetralin CH2), 125.7 (CH=), 147.2 (CH=), 111.8, 113.3, 115.6, 123.7, 126.2,
128.4, 129.8, 136.7, 137.01, 141.9, 149.8, 153.2 (Ar-C), 188.56 (C=O). MS, m/z (rel. int.): 174 (30),
166 (67), 159 (100), 137 (100), 131 (17).

Molecules 2011, 16
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3.3. 1-Acetyl-4-(2,6-difluorophenyl)-3-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-pyrazoline 4
Hydrazine hydrate (99%, 1.0 mL) was added to a solution of compound 3b (2.98 g, 0.01 mol) in
acetic acid (30 mL) and the mixture was heated under reflux for 6 h. and the excess solvent was
distilled in vacuo. Cold water (30 mL) was then added to the remaining residue and the separated
crude product was filtered, washed with water, dried and crystallized from acetic acid. IR: 2880-2910
1
(tetralin CH2 & CH3), 1710 (C=O). H-NMR (DMSO-d6): δ 1.76-1.87 (m, 4H, tetralin CH2), 4.1 (dd,
2H, pyrazoline CH2, J = 14.2 Hz), 2.15 (s, 3H, CH3), 2.75-2.8 (m, 4H, tetralin CH2), 6.5-6.9 (m, 1H,
13
pyrazoline CH), 7.0-7.5 (m, 6H, Ar-H). C-NMR: δ 22.3 (tetralin CH2), 24.4 (CH3), 28.92 (tetralin
CH2), 38.67 (pyrazoline CH2), 39.67 (pyrazoline CH), 111.8, 123.7, 126.2, 128.4, 129.8, 136.7,
137.01, 149.8, 141.9, 153.2 (Ar-C), 157.3 (imine C), 168.2 (C=O). MS m/z (rel. int.): 169 (72), 141
(40), 116 (20), 96 (46), 74 (100).
3.4. 4-Aryl-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-1,2-dihydropyrimidine-2-thiones 5a,b
A solution of potassium hydroxide (1.7 g, 0.03 mol) in water (4 mL) was added to a mixture of the
appropriate α,β-unsaturated ketone 3a,b (0.01 mol) and thiourea (0.9 g, 0.012 mol), in ethanol (50 mL)
and the mixture was heated under reflux for 24 h. The excess of solvent was then distilled off and the
residue was acidified with dilute hydrochloric acid. The separated crude product was filtered, washed
with water, dried and crystallized from aqueous ethanol.
4-(2,6-Dichlorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-1,2-dihydropyrimidine-2-thione
(5a):
1
IR: 3400 (NH), 2888-2921 (tetralin CH2), 1050 (C=S). H-NMR (DMSO-d6): δ 1.67-1.7 (m, 4H,
tetralin CH2), 2.49-2.52 (m, 4H, tetralin CH2), 3.55 (s, 1H, NH), 5.5 (s, 1H, pyrimidine CH), 6.6-7.1
(m, 6H, Ar-H). MS, m/z (rel. int.): 159 (100), 131 (19), 91 (40), 78 (60).
4-(2,6-Difluorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-1,2-dihydropyrimidine-2-thione
(5b):
1
IR: 3400 (NH), 2880-2925 (tetralin CH2), 1050 (C=S). H-NMR (DMSO-d6): δ 1.65-1.66 (m, 4H,
tetralin CH2), 2.4-2.5 (m, 4H, tetralin CH2), 3.5 (s, 1H, NH), 5.5 (s, 1H, pyrimidine CH), 6.57-7.14 (m,
6H, Ar-H). 13C-NMR: δ 22 (tetralin CH2), 29 (tetralin CH2), 104 (pyrimidine CH), 105.5, 111.2, 126.7,
129.6, 131.16, 134.26, 134.3, 135.9, 142.5, 157.3 (Ar-C), 185 (C=S). MS, m/z (rel. int.): 131 (8), 113 (2),
112 (4), 96 (31), 76 (7).
3.5. 4-Aryl-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 6a,b
A mixture of 6-acetyltetraline 1 (1.74 g, 0.01 mol), ethyl cyanoacetate (1.13 g, 0.01 mol), the
appropriate aldehyde 2a,b, and ammonium acetate (6.0 g), was heated in n-butanol (40 mL) under
reflux for 3 h. On cooling, the separated yellow solid was filtered, washed with water and crystallized.
4-(2,6-Dichlorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
1
(6a): IR: 3330 (NH), 2987-2910 (tetralin CH2), 2228 (CN), 1616 (C=O). H-NMR (CDCl3): δ
1.79-1.82 (m, 4H, tetralin CH2), 2.76-2.82 (m, 4H, tetralin CH2), 7.25-7.48 (m, 7H, Ar-H), 7.75 (s, 1H,
13
NH). C-NMR: δ 22 (tetralin CH2), 28 (tetralin CH2), 114.4 (CN), 105.5, 123.5, 127.4, 127.7, 130.4,

Molecules 2011, 16
3416
132.7, 133.7, 127.8, 129.5, 138.4, 141.6, 151.5, 156.4, 165.5 (Ar-C & pyridine-C), 162.69 (C=O). MS,
m/z (rel. int.): 398 (M+, 0.7), 205 (100), 174 (4), 148 (3), 131 (11), 91 (20), 65 (3).
4-(2,6-Difluorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile
1
(6b): IR: 3430 (NH), 2990-2995 (tetralin CH2), 2217 (CN), 1600 (C=O). H-NMR (CDCl3): δ
1.75-1.82 (m, 4H, tetralin CH2), 2.76-2.81 (m, 4H, tetralin CH2), 6.8-7.2 (m, 7H, Ar-H), 7.61 (s, 1H,
NH). MS, m/z (rel. int.): 362 (M+, 0.5), 174 (26), 166 (100), 159 (100), 131 (4), 118 (5).
3.6. 4-Aryl-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles 7a-c
A mixture of 6-acetyltetraline 1 (1.74 g, 0.01 mol), 2-cyanothioacetamide (1 g, 0.01 mol), the
appropriate aldehyde 2a-b, and ammonium acetate (6.0 g), was heated under reflux in n-butanol (40 mL)
for 3 h. On cooling, the separated yellow solid was filtered, washed with water and crystallized.
4-(2,6-Dichlorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile
(7a): IR: 3450 (NH), 2988-2995 (tetralin CH2), 2240 (CN), 1340 & 1140 (C=S). 1H-NMR (DMSO-d6):
δ 1.8-1.82 (m, 4H, tetralin CH2), 2.77-2.81 (m, 4H, tetralin CH2), 6.5 (s, 1H, NH), 7.2-7.6 (m, 7H,
13
Ar-H & pyridine-H). C-NMR: δ 22 (tetralin CH2), 30 (tetralin CH2), 115.5 (CN), 105, 123.5, 127.4,
127.7, 130.4, 132.7, 133.7, 127.8, 129.5, 138.4, 141.6, 105.5, 151.5, 156.4 (Ar-C & pyridine-C), 164
(C=S). MS, m/z (rel. int.): 281 (20), 207 (35), 147 (23), 135 (32).
4-(2,6-Difluorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile
(7b): IR: 3450 (NH), 2910-2985 (tetralin CH2), 2240 (CN), 1310 & 1090 (C=S). 1H-NMR (DMSO-d6):
δ 1.73-1.8 (m, 4H, tetralin CH2), 2.74-2.8 (m, 4H, tetralin CH2), 5.18 (s, 1H, NH), 7.15-7.82 (m, 7H,
Ar-H & pyridine-H). MS, m/z (rel. int.): 378 (M+, 2.7), 361 (2), 207 (16), 159 (29), 78 (75).
4-(3-Ethoxy-4-hydroxyphenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-thioxo-1,2-dihydropyridine-3-
carbonitrile (7c): IR: 3470 (NH), 3310 (OH), 2820-2995 (tetralin CH2, CH3, CH2), 2250 (CN), 1310 &
1
1110 (C=S). H-NMR (DMSO-d6): δ 1.33-1.35 (t, 3H, CH3, J = 2.93 Hz), 1.73-1.8 (m, 4H, tetralin
CH2), 2.76-2.8 (m, 4H, tetralin CH2), 4.11 (q, 2H, CH2CH3, J = 2.93 Hz), 9.7 (s, 1H, NH), 7.0-7.6 (m,
7H, Ar-H & pyridine-H). 13C-NMR: δ 15.5 (CH3), 22 (tetralin CH2), 30 (tetralin CH2), 58.5 (CH2CH3),
115.5 (CN), 102.5, 104.0, 110.5, 129.4, 133.7, 135.4, 138.7, 140.7, 127.8, 128.5, 142.4, 145.6, 105.5,
153.5, 158.4, 166.5 (Ar-C & pyridine-C), 168 (C=S). MS, m/z (rel. int.): 174 (33), 159 (100), 131 (20),
104 (2).
3.7. 4-Aryl-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-imino-1,2-dihydropyridine-3-carbonitriles 8a,b
A mixture of 6-acetyltetraline 1 (1.74 g, 0.01 mol), malononitrile (0.66 g, 0.01 mol), the appropriate
aldehyde 2a-b, and ammonium acetate (6.0 g), was heated under reflux in n-butanol (40 mL) for 3 h.
On cooling, the separated yellow solid was filtered, washed with water and crystallized.
4-(2,6-Dichlorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-imino-1,2-dihydropyridine-3-carbonitrile
1
(8a): IR: 3500, 3450 (NH), 2820-2995 (tetralin CH2), 2250 (CN). H-NMR (CDCl3): δ 1.79-1.82 (m,
4H, tetralin CH2), 2.1 (s, 1H, NH), 2.81-2.83 (m, 4H, tetralin CH2), 5.61 (s, 1H, NH), 7-7.6 (m, 7H,

Molecules 2011, 16
3417
13
Ar-H & pyridine-H). C-NMR: δ 22.2 (tetralin CH2), 28.7 (tetralin CH2), 114.9 (CN), 104.0 123.7,
127.4, 127.6, 128.8, 130.01, 133.2, 136.8, 149.9, 159.06, 110.9, 128.6, 159.9, 162.0, 166.5 (Ar-C &
pyridine-C), 176.06 (C=NH). MS, m/z (rel. int.): 207 (100), 159 (98), 151 (8), 131 (15), 119 (3).
4-(2,6-Difluorophenyl)-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-2-imino-1,2-dihydropyridine-3-carbonitrile
(8b): IR: 3470, 3450 (NH), 2820-2990 (tetralin CH2), 2250 (CN). 1H-NMR (CDCl3): δ 1.81-1.826 (m,
4H, tetralin CH2), 2.1 (s, 1H, NH), 2.81-2.83 (m, 4H, tetralin CH2), 5.61 (s, 1H, NH), 6.9-7.67 (m, 7H,
Ar-H & pyridine-H). 13C-NMR: δ 22.36 (tetralin CH2), 28.91 (tetralin CH2), 115.8 (CN), 104.5,
111.37, 111.68, 112.14, 123.98, 127.64, 129.15, 129.54, 131.03, 131.12, 137.23, 155.5, 1157.6, 161.3,
166.6 (Ar-C & pyridine-C), 174.1 (C=NH). MS, m/z (rel. int.): 194 (5), 131 (100), 127 (100), 104 (100).
3.8. Determination of the anticancer activity [26]
Cell monolayers were fixed with 10% (w/v) trichloroacetic acid and stained for 30 minutes with 0.4%
(wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid. Unbound dye was removed by four
washes with 1% acetic acid, and protein-bound dye was extracted with 10 mM unbuffered Tris base [tris
(hydroxymethyl) aminomethane] for determination of optical density in a computer-interfaced, 96-well
microtiter plate reader at 510 nm.
4. Conclusions
New tetrahydronaphthaline derivatives bearing different heterocyclic moieties were tested for
in vitro antitumor activity. The results indicated that the 2,6-dihaloarylchalcone derivatives 3a,b, the
cyanopyridone derivatives 6a,b and thioxopyridine derivatives 7a-c were the most effective against the
cervix cell line (Hela), showing IC50 values of 3.5, 10.5, 7.1, 10.9, 8.1, 5.9 and 6.5 μg/mL,
respectively. All the tested compounds showed moderate to marginal activity against the breast
carcinoma cell line MCF-7. Compound 3a was the most potent, with an IC50 value of 3.5 μg/mL
against Hela and 4.5 μg/mL against MCF7 cell line. Compound 3a seems a promising new lead
compound with a novel skeleton for further development towards a new potential clinical
trials candidate.
Acknowledgements
The author would like to thank Abdelhamid Emwas, King Abdullah University for Science and
Technology, Jeddah, Saudi Arabia, for recording the NMR spectra.
References
1. Balunas, M.J.; Kinghorn, A.D. Drug Discovery from medicinal plants. Life Sci. 2005, 78, 431-441.
2. Parkin, D.M. Global cancer statistics in the year 2000. Lancet Oncol. 2001, 2, 533-543.
3. Carmen, A.J.; Carlos, M. Medicinal Chemistry of Anticancer Drugs, 1st ed.; Elsevier: Amsterdam,
The Netherlands, 2008; pp.1-8.

Molecules 2011, 16
3418
4. Ferrante, A.; Augliera J.; Lewis, K. Cloning of an organic solvent-resistance gene in Escherichia
coli: The unexpected role of alkylhydroperoxide reductase. Proc. Natl. Acad. Sci. USA 1995, 92,
7617-7621.
5. Hara, H.; Fujihashi, T.; Sakata, T. Tetrahydronaphthalene lignan compounds as potent anti-HIV
type 1 agents. AIDS Res. Hum. Retroviruses 1997, 13, 695-705.
6. Ebeid, M.Y.; El-Zahar, M.I.; Kamel, M.M.; Omar, M.T.; Anwar, M.M. Novel 5,6,7,8-
tetrahydronaphth-2-ylheterocycles of possible biological activity. Egypt. Pharm. J. NRC 2004, 3,
49-65.
7. Nabih, I.; Zayed, A.; Kamel, M.M.; Motawie, M.S. Synthesis of new tetrahydronaphthyl-1,2,4-
triazines of potensial antimicrobial activity. Egypt. J. Chem. 1986, 29, 101-106.
8. Hussain, R.A.; Dickey, J.K.; Rosser, M.P.; Matson, J.A.; Kozlowski, M.R.; Brittain, R.J.; Webb,
M.L.; Rose, P.M.; Fernandes, P.A. Novel class of non-peptidic endothelin antagonists isolated
from the medicinal herb phyllanthus niruri. J. Nat. Prod. 1995, 58, 1515-1520.
9. Chalina, E.G.; Chakarova, L. Synthesis, hypotensive and antiarrhythmic activities of 3-alkyl-1-(2-
hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-3-naphthalenyl)ureas or thioureas and their guanidine
analogues. Eur. J. Med. Chem. 1998, 33, 975-983.
10. Kamel, M.M.; Michael, J.M. Synthesis and moulscicidal activity of some salicylamido tetralins.
Egypt. J. Bilharziasis 1988, 10, 121-125.
11. Cimetière, B.; Dubuffet, T.; Muller, O.; Descombes, J.; Simonet, S.; Laubie, M.; Verbeuren, T.J.;
Lavielle, G. Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as
thromboxane receptor antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 1375-1340.
12. Takami, M.; Tsukada, W. Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and
spasmogen-induced bronchoconstriction in rodents. Eur. J. Pharmacol. 1999, 366, 253-259.
13. Rogóz, Z.; Skuza, G.; Kodziñska, A. Anxiolytic-and antidepressant-like effects of 7-OH DPAT,
preferential dopamine D3 receptor agonist in rats. Pol. J. Pharmacol. 2004, 56, 519-529.
14. Kitamura, Y.; Araki, H.; Shibata, K.; Gomita, Y.; Tanizaki, Y. 5-HT1A receptor full agonist,
8-OH-DPAT, exerts antidepressant-like effects in the forced swim test in ACTH-treated rats. Eur.
J. Pharmacol. 2003, 481, 75-77.
15. Amin, K.M.; El-Zahar, M.I.; Anwar, M.; Kamel, M.; Mohamad, M. Synthesis and anticancer
activity of novel tetralin-6-yl pyridine and tetralin-6-yl pyrimidine derivatives. Acta Pol. Pharm.
2009, 66, 279-291.
16. Dong, Y.Z.; Shi, Q.; Nakagawa-Goto, K.; Wu, P.C.; Bastow, K.F.; Morris-Natschke, S.L.; Lee,
K.H. Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as a new class
of potent antitumor agents. Bioorg. Med. Chem. Lett. 2009, 19, 6289-6292.
17. Öztürk, G.; Erol, D.D.; Uzbay, T.; Aytemir, M.D. Synthesis of 4(1H)-pyridinone derivatives and
investigation of analgesic and antiinflammatory activities. Farmaco 2001, 56, 251-256.
18. Findlay, J.A.; Tam, W.H.J.; Krepinsky, J. The chemistry of some 6-methyl-4-hydroxy-2-pyridones.
Can. J. Chem. 1978, 56, 613-616.
19. Abadi, A.; Al-Deeb, O.; Al-Afify, A.; El-Kashef, H. Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-
2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents. Farmaco 1999,
54, 195-201.

Molecules 2011, 16
3419
20. Storck, P.; Aubertin, A.; Grierson, D.S. Tosylation/mesylation of 4-hydroxy-3-nitro-2-pyridinones
as an activation step in the construction of dihydropyrido[3,4-b] benzo[f][1,4]thiazepin-1-one
based anti-HIV agents. Tetrahedron Lett. 2005, 46, 2919-2922.
21. Macdonald, G.E.; Puri, A.; Shilling, D.G. Interactive effect of photoperiod and fluridone on
growth, reproduction, and biochemistry of dioecious hydrilla (Hydrilla Verticillata). Weed Sci.
2008, 56, 189-195.
22. Evidente, A.; Fiore, M.; Bruno, G.; Sparapano, L.; Motta, A. Chemical and biological
characterisation of sapinopyridione, a phytotoxic 3,3,6-trisubstituted-2,4-pyridione produced by
Sphaeropsis sapinea, a toxigenic pathogen of native and exotic conifers, and its derivatives.
Phytochemistry 2006, 67, 1019-1028.
23. Cocco, M.T.; Congiu, C.; Onnis, V. Synthesis and antitumour activity of 4-hydroxy-2-pyridone
derivatives. Eur. J. Med. Chem. 2000, 35, 545-552.
24. Cocco, M.T.; Congiu, C.; Onnis, V. New bis(pyridyl)methane derivatives from 4-hydroxy-2-
pyridones: synthesis and antitumoral activity. Eur. J. Med. Chem. 2003, 38, 37-47.
25. Allinger, N.L.; Jones, E.S. Synthesis of some functionally substituted benzocyclanones. J. Org.
Chem. 1962, 27, 70-76.
26. Storeng, P.; Ritsa, S.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch,
H.; Kenney, S.; Boyd, M.R. Anticancer-drug screening. J. Natl. Cancer Inst. 1990, 82, 1107-1112.
27. Ghoshal, K.; Jacob, S.T. An alternative molecular mechanism of action of 5-fluorouracil, a potent
anticancer drug. Biochem. Pharmacol. 1997, 53, 1569-1575.
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