Selenium-containing heterocycles: Synthesis and pharmacological activities of some new 4-methylquinoline-2(1H) selenone derivatives

Article abstract of DOI:10.1002/ardp.200700202

Several selenolo[2,3-b]quinolines and pyrimido[4′,5′:4,5] selenolo[2,3-b]quinolines were prepared by annulations via reaction of NaSeH with 2-chloro-3-cyano-4-methylquinoline 1 followed by reactions with aromatic aldehydes, cycloalkanones, and acetic anhy

Full text of DOI:10.1002/ardp.200700202

240
Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
Full Paper
Selenium-Containing Heterocycles: Synthesis and
Pharmacological Activities of Some New 4-Methylquinoline-
2(1H) Selenone Derivatives
Shams H. Abdel-Hafez1 and Mostafa A. Hussein2
1 Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt
2 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt
Several selenolo[2,3-b]quinolines and pyrimido[49,59:4,5]selenolo[2,3-b]quinolines were prepared
by annulations via reaction of NaSeH with 2-chloro-3-cyano-4-methylquinoline 1 followed by
reactions with aromatic aldehydes, cycloalkanones, and acetic anhydride. Spectroscopic (IR, 1H-
NMR, and MS) properties of the synthesized compounds are reported. Some selected compounds
5a, 7b, 7c, 8b–d, 9a, 11b, and 11d were investigated for their anti-inflammatory and analgesic
activities; in addition, the most active compounds were tested for their ulcerogenicity and acute
toxicity. Moreover, some of the test compounds 7c, 9a, 11b, and 11d were screened for their anti-
bacterial and antifungal activities.
Keywords: Fused quinolines / Pharmacological Screening / Pyrimidoselenolo quinolines / Quinolines /
Received: October 3, 2007; accepted: November 19, 2007
DOI 10.1002/ardp.200700202
nificant anti-inflammatory and analgesic activities with
Introduction
strong fungicidal effects [15]. This work attempts to fur-
ther expand the synthetic procedures of selenium- and/
or sulfur-containing heterocyclic compounds [16–23].
We investigated selenophene and quinoline systems
combined with a fused ring to give compact structures
and screened these compounds for their inflammatory
and analgesic effects. Prompted by these observations,
herein we report the reaction of sodium hydrogensele-
nide with 2-chloro-3-cyano-4-methylquinoline 1 to give a
new series of selenolo[2,3-b]quinoline derivatives and
their pharmacological activities.
Quinoline drugs, which include quinine, quinidine,
chloroquine, mefloquine, and halofantrine are widely
used as antimalarial agents [1, 2], also, quinoline deriv-
atives possess a broad spectrum of biological activities
such as antifungal [3], antibacterial [4], antileishmanial
[5] in addition to anti-arrhythmic [6]. On the other hand,
the introduction of selenium into organic compounds
often permits modification of their chemical properties
and biological activities [7–11]. A literature survey indi-
cates that only few publications have mentioned the
incorporation of a selenium atom in the quinoline
nucleus [12–14]. Consequently, synthesis and biological
screening of selenoquinoline derivatives may be consid-
ered a virgin research area. Previous work in our labora-
tory describes the synthesis of selenolo[2,3-c]pyridazine
derivatives, which indicate that certain compounds bear-
ing the selenophene and pyridazine nucleus possess sig-
Results and discussion
Chemistry
2-Chloro-3-cyano-4-methylquinoline
1
was prepared
according to a known method [24] and reacted with
sodium hydrogenselenide in ethanol to give 3-cyano-4-
methylquinoline-2(1H)selenone 2 in good yield (70%)
with diquinolinyl diselenide derivative 3 as a by-product
in moderate yield (22%). The two compounds 2 and 3
were isolated by fractional crystallization from ethanol.
Correspondence: Shams H. Abdel-Hafez, Department of Chemistry,
Faculty of Science, Assiut University, Assiut 71516, Egypt.
E-mail: shams@aun.edu.eg, Sabdel68@yahoo.co.uk
Fax: +20 882 342708
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
New 4-Methylquinoline-2(1H) Selenone Derivatives
241
Scheme 1. Synthesis route of compounds 1–7.
Scheme 3. Synthesis route of compounds 10 and 11.
(Scheme 1).
A new series of pyrimido[49,59:4,5]sele-
nolo[2,3-b]quinolines 8a–d were prepared by reaction of
3-amino-4-methylselenolo[2,3-b]quinoline-2-carbamide
7c with the appropriate aromatic aldehyde and/or cyclo-
hexanone or cyclopentanone reagents, to give the corre-
sponding spiro compounds 9a, b (Scheme 2). Further-
more, compound 7c was converted into various pyrimi-
dine derivatives of 11a–d through compound 10 by treat-
ment with acetic anhydride followed by alkyl halide in
the presence of anhydrous potassium carbonate in DMF
(Scheme 3).
The structures of the synthesized compounds were
characterized by their physical, analytical, and spectral
data. The IR spectrum of compound 10 showed character-
Scheme 2. Synthesis route of compounds 8 and 9.
Upon recrystallization, compound 2 crystallized from istic absorption bands at 3308 (NH) and 1660 cm– 1 (C=O),
ethanol as yellow crystals, while compound 3 crystallized whereas, in compounds 11a–d, the absence of the
from dioxane as red crystals. The structures of the absorption band of (NH). The results were displayed in
Table 1.
obtained products were established on the basis of their
mass spectra and elemental analyses. Refluxing of com-
pound 2 with chloro acetone or phenacyl bromide in Biological screening
ethanol in the presence of sodium acetate as a basic cata- Anti-inflammatory activity
In the present study, nine compounds, 5a, 7b, 7c, 8b–d,
lyst, afforded 2-acetyl(benzoyl)-3-amino-4-methyl sele-
nolo[2,3-b]quinoline 5a or 5b, respectively, in excellent 9a, 11b, and 11d were selected and tested for their anti-
yields, via the intermediates 4a or 4b. Furthermore, 3- inflammatory activity using the carrageenan-induced rat
paw edema method in comparison to indomethacin as a
cyano-4-methylquinoline-2(1H)selenone 2 reacted with
chloro acetonitrile or ethyl chloroacetate or chloro acet- reference drug [25]. The results are listed in Table 2, at a
amide under the same conditions and gave the corre- dose level of 0.028 lmol/kg. The results showed that after
sponding selenoloacetonitrile 6a, ethyl selenoloacetate 3 h the inhibition effect of compounds was about 53.5–
80.0% less of that of indomethacin. Compounds 7c, 9a,
6b, or selenoloacetamide 6c quinoline derivatives. Com-
pounds 6a–c underwent smooth Thorpe–Ziegler cycliza- 11b, and 11d are the most active ones. It is worth noting
tion, when treated with sodium ethoxide in ethanol, to that the conversion of 7b (R = COOEt) to compound 7c (R
give the corresponding compound derivatives 7a–c = CONH2) resulted in an enhancement of activity. In gen-
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242
S. H. Abdel-Hafez and M. A. Hussein
Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
Table 1. Physical and spectral data of compounds 2, 3, 4a, b, 5a,b, 6a–c, 7a–c, 8a–d, 9a,b, 10, and 11a–d.
Compound
Mp. (8C)
Yield (%)
Mol. formula
(M/wt)
IR (cm-1)
1H-NMR (d, ppm)
2a)
3a)
4a
4b
5a
5b
6a
6b
6c
298-300 (70)
A300 (22)
C11H8N2Se
(247.15)
C22H14N4Se2
(492.31)
C14H12N2OSe
(303.22)
C19H14N2OSe
(365.29)
C14H12N2OSe
(303.22)
C19H14N2OSe
(365.29)
2200 (CN)
DMSO-d6 : 14.95 (s, 1H SeH, exchangeable); 7.40–8.10
(m, 4H Ar-H); 2.70 (s, 3H, CH3)
DMSO-d6 : 7.20–760 (m, 8H Ar-H); 2.70 (s, 6H 2CH3)
2200 (CN), s. peak
2200 (CN),; 1685 (C=O)
2200 (CN), 1690 (C=O)
100–102 (85)
230–232 (78)
218–220 (75)
272–274 (75)
190–192 (75)
142–144 (80)
240–242 (85)
CDCl3 : 7.40 –7.90 (m, 4H Ar-H); 4.15 (s, 2H CH2); 2.80
(s,3H CH3); 2.40 (s, 3H CH3)
DMSO-d6 : 7.40–8.20 (m, 9H Ar-H); 4.90 (s, 2H CH2);
2.90 (s, 3H CH3)
DMSO-d6 : 7.50–8.10 (m, 4H Ar-H); 4.90 (s, 2H NH2);
2.98 (s, 3H CH3-quinoline) 2.40 (s, 3H CH3)
DMSO-d6 : 7.60–8.10 (m, 9H Ar-H); 4.950 (s, 2H NH2);
2.98 (s, 3H CH3-quinoline)
CDCl3 : 7.60 –8.30 (m, 4H Ar-H); 4.02 (s, 2H CH2); 2.75 (s,
3H CH3-quinoline)
CDCl3 : 7.70 –8.30 (m, 4H Ar-H); 4.50 (q, 2H CH2); 4.00
(s, 2H CH2 ); 3.20 (s, 3H CH3-quinoline); 1.60 (t, 3H CH3)
DMSO-d6 : 7.30–8.50 (m, 4H Ar-H); 7.10 (broad, 2H
NH2, exchangeable); 4.02 (s, 2H CH2); 2.75 (s, 3H CH3-
quinoline)
3320,3440 (NH2);
1645 (C=O)
3250, 3450 (NH2);
1640 (C=O)
C
13H9N3Se
2200 (CN), s. peak
(286.19)
C15H14N2O2Se
(333.24)
C13H11N3OSe
(304.21)
2200 (CN);
1710 (C=O ester)
3300,3430 (NH2);
1680 (C=O); 2200 (CN)
7a
A300 (70)
C13H9N3Se
(286.19)
C15H14N2O2Se
333.24)
3390,3200 (NH2);
2200 (CN)
3400,3200 (NH2) ;
1668 (C=O ester)
DMSO-d6 : 7.90–8.00 (m, 4H Ar-H); 7.40 (s, 2H NH2);
3.20 (s, 3H CH3-quinoline)
DMSO-d6 : 7.90–8.00 (m, 4H Ar-H); 6.60 (s, 2H NH2);
4.20–4.30 (q, 2H CH2); 3.30 (s, 3H CH3-quinoline); 1.28
(t, 3H CH3)
DMSO-d6 : 8.50 (s,2H CONH2); 7.90–8.00 (m, 4H Ar-H);
7.20 (s, 2H NH2); 3.20 (s, 3H CH3-quinoline)
DMSO-d6 : 8.65 (s, 1H NH); 7.6–8.50 (m , 9H Ar-H); 7.30
(d, 1H CH); 5.98 (d, 1H NH); 3.20 (s, 3H CH3-quinoline)
DMSO-d6 : 8.85 (s, 1H NH); 7.90–8.40 (m , 8H Ar-H);
7.40 (d, 1H CH); 6.15 (d, 1H NH); 2.00 (s, 3H CH3-quino-
line)
7ba)
280–282 (45)
7ca)
8a
275–277 (77)
A300 (80)
C13H11N3OSe
(304.21)
C20H15N3OSe
(392.31)
C20H14N4O3Se
(437.31)
3500,3450, 3300,
3250 (NH2); 1660 (C=O)
3400,3200 (2NH);
1640 (C=O)
3420, 3200 (2NH);
1660 (C=O)
8b
230–232 (83)
8c
A300 (72)
A300 (55)
A300 (76)
A300 (65)
C21H17N3O2Se
(422.34)
3400, 3200 (2NH);
1645 (C=O
DMSO-d6 : 9.40 (s, 1H NH); 7.00–8.80 (m, 8H Ar-H); 6.90
(d, 1H CH); 5.8 (d, 1H NH); 4.70 (s, 3H OCH3); 3.00 (s, 3H
CH3-quinoline)
DMSO-d6 : 8.40 (s, 1H NH); 7.30–8.20 (m, 7H Ar-H); 6.98
(d, 1H CH); 5.9(s, 2H CH2-aldehyde); 5.70 (d, 1H NH);
3.10 (s, 3H CH3-quinoline)
DMSO-d6 : 8.30 (s, 1H NH); 7.30–8.00 (m, 4H Ar-H); 6.00
(s, 1H NH); 3.20 (s, 3H CH3-quinoline); 1.5–2.4 (m, 10H-
cyclohexane)
DMSO-d6 : 8.30 (s, 1H NH); 7.30–8.00 (m, 4H Ar-H); 6.00
(s, 1H NH); 3.20 (s, 3H CH3-quinoline); 1.5–2.10 (m, 8H-
cyclopentane)
DMSO-d6 : 8.40 (d,1H NH); 7.80–7.98 (m, 4H Ar-H); 2.50
(s, 3H CH3-quinoline); 1.98 (s, 3H CH3)
CDCL3: 7.20–7.50 (m, 4H Ar-H); 3.50 (s, 3H CH3); 3.20
(s, 3H CH3); 2.50 (s, 3H CH3-)
CDCL3: 7.30–8.10 (m, 4H Ar-H); 4.00(q, 2H NCH2); 3.20
(s, 3H CH3-quinoline); 2.50 (s, 3H CH3-pyrimidine); 1.3
(t, 3H CH2CH3)
DMSO-d6 : 7.50–8.20 (m, 4H Ar-H); 4.20 (d, 2H NCH2);
3.30 (s, 3H CH3-quinoline); 2.55 (m, 2H CH2-propane) ;
1.48 (d, 3H CH3-pyrimidine); 1.00 (s, 3H CH3-propane)
TFA : 8.2–8.5 (m, 4H Ar-H); 5.01–6.01 (m, 5H allyl-H);
4.0 (s, 3H CH3-pyrimidine); 3.1 (s, 3H, CH3-quinoline)
8d
C21H15N3O3Se
(436.32)
3400, 3200 (2NH);
1655 (C=O
9aa)
9ba)
C19H19N3OSe
(384.33)
3350, 3150 (2NH);
1660 (C=O
C18H17N3OSe (370.31)
3300, 3100 (2NH);
1655 (C=O
10a)
300 (52)
C15H11N3OSe (328.23)
C16H13N3OSe (342.25)
C17H15N3OSe (356.28)
3200 (NH); 1670 (C=O)
1680 (C=O)
11aa)
11ba)
155–157 (60)
170–172 (75)
1680 (C=O)
11ca)
165–167 (63)
126–128 (70)
C18H17N3OSe (370.31)
C18H15N3OSe (368.29)
1675 (C=O)
1680 (C=O)
11da)
a)
For MS data of the respective compounds: see Experimental.
eral, it can be concluded that the presence of a selenium Analgesic activity
atom in cyclic structures afforded compounds, e.g. 7c, 9a, The most active anti-inflammatory compounds 7c, 9a,
11b, and 11d, with higher activity than the open struc- 11b, and 11d were tested for their analgesic properties
tures, e.g. 5a.
relative to acetyl salicylic acid as reference drug at a dose
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Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
New 4-Methylquinoline-2(1H) Selenone Derivatives
243
Table 2. Inhibitory effect of the test compounds and indometha-
cin upon carrageenan-induced paw edema in rats (% edema
inhibition).
Table 4. Gastric ulceration effects of compounds 11b and 11d.
Compound Ratio of ulcera- % Ulceration Ulceration in-
tion in animals
dex (M € S.E.)
Time
0.5 h 1 h
2 h
3 h
4 h
5 h
Compound
Indomethacin 6/6
100
50
33
1.08 l 0.2
1.05 l 0.4
1.04 l 0.2
11b
11d
3/6
2/6
5a
7b
7c
8b
8c
3.2
3.2
3.2
3.2
3.2
9.7
9.7
6.5
3.2
6.5
9.1 20.0 22.3 30.6 30.6
9.1 17.1 22.3 30.64 30.6
18.1 28.6 33.4 47.3 52.8
9.1 20.0 22.3 36.2 38.9
12.1 22.9 25.0 36.2 41.2
12.1 28.6 22.3 36.2 44.5
18.1 28.6 30.6 47.3 52.8
18.1 28.6 30.6 36.2 52.8
9.1 28.6 30.6 41.2 44.5
18.1 31.4 41.7 52.8 58.4
pounds 11b, 11d, and indomethacin showed a compara-
ble ulceration indix, see Table 4.
8d
9a
Acute toxicity (LD50)
11b
11d
Indomethacin
The medial lethal dose (LD50) of the most active com-
pound 11d was determined in mice according to a
reported procedure [28]. The animals were injected i.p.
with graded doses of the test compounds. Compound
11d was non toxic at doses up to 160 mg/kg.
level of 0.028 lmol/kg, according to the reported proce-
dures [26]. The results are given in Table 3.
The results showed that after 1 h, compounds 7c and
9a had about one-half the activity of the reference drug
while compounds 11b and 11d are the most active with
100.7% and 103.9%, respectively compared to the refer-
ence drug. After 5 h, compounds 11b and 11d were still
the most active of the tested compounds showing 114.8%
and 125.7% activity, respectively compared to the refer-
ence drug. Thus, cyclization of the amide derivative 7c
into pyrimidinone derivatives 11b and 11d greatly
improved the analgesic activity, in accordance with pre-
viously reported effects [26].
Antimicrobial effects
The most active anti-inflammatory and analgesic com-
pounds (7c, 9a, 11b, and 11d) were screened for their anti-
bacterial and antifungal activities according to reported
procedures [29] and the results are given in Table 5. The
data verify that none of the synthesized compounds has a
considerable antimicrobial activity, except for com-
pound 9a, which showed a moderate effect against Bacil-
lus cereus. On the other hand, the compounds show no
effect against the tested fungal species with the excep-
tion of 7c and 9a. A considerable antifungal effect against
Aspergillus flavus, Aspergillus niger, and Candida albicans
for compound 7c, and against Aspergillus flavus, Candida
albicans, and Fusarium oxysporum for 9a. Compound 11d
showed a moderate antifungal effect against Candida
albicans. The minimum inhibitory concentration (MIC)
of the most active compounds (7c and 9a) was
50 lg mL– 1. The experiments also reveal that com-
pounds 7c and 9a are completely inactive at 25 lg mL– 1
against all the tested fungi and bacteria. The activities
Ulcerogenicity
The following inflammatory and analgesic most active
compounds 11b and 11d were screened for their ulcero-
genicity using reported procedures [27]. The results are
listed in Table 4. The tested compounds are saver con-
cerning ulcerogenicity in animals: they showed 50% and
33% activity, respectively, for the applied doses, com-
pared to indomethacin (100%). However, the tested com-
Table 3. Analgesic activities of 7c, 9a, 11b, and 11d (on the hot plate).
Reaction
Timea)
0.5 h
1 h
2 h
3 h
4 h
5 h
Compound
Control
Aspirin
7c
9a
11b
20.1 l 0.30
35.1 l 0.72
25.1 l 0.63
21.9 l 0.32
38.2 l 0.65
37.2 l 0.53
20.2 l 0.62
54.8 l 0.83
27.3 l 0.55
28.5 l 0.34
55.2 l 0.60
56.5 l 0.45
20.3 l 0.81
46.5 l 1.11
25.2 l 0.47
30.5 l 0.30
60.5 l 0.61
58.1 l 0.00
20.1 l 0.61
36.5 l 1.02
23.4 l 0.33
30.4 l 0.42
40.1 l 0.65
50.2 l 0.60
20.1 l 0.34
34.2 l 0.98
21.7 l 0.45
23.6 l 0.40
39.1b)l 0.58
40.3 l 0.55
20.1 l 0.66
28.0b)l 0.72
20.1 l 0.40
20.2 l 0.45
32.0 l 0.60
35.2b)l 0.63
11d
a)
Each value represents the mean l S.E., all showed significant difference at least at p a 0.05 in comparison with the control group.
Not significant.
b)
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244
S. H. Abdel-Hafez and M. A. Hussein
Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
Table 5. Fungal and antimicrobial activities of compounds 7c, 9a and 11d.
Compound
Minimum inhibitory concentration (MIC) (lg mL– 1
)
Organism
7c
9a
50
11d
Reference drug*
100
50
100
100
100
50
25
Aspergillus flavus
Aspergillus niger
Candida albicans
Fusarium oxysporum
Bacillus cereus (+ve)
Escherichia coli (-ve)
P. aeruginosa (-ve)
S. marcescens (-ve)
Fungi
8
7
9
0
0
0
0
0
7
0
7
0
0
0
0
0
7
0
12
7
7
0
0
0
7
0
0
0
0
0
0
0
7
0
0
0
0
0
0
40
25
22
25
12
29
24
0
32
18
16
20
10
25
21
0
26
14
14
18
9
Bacteria
0
0
20
19
* Reference drug: antifungal: dermatin; antibacterial: ampicillin.
nacyl bromide (6 mmol) in 30 mL ethanol was heated under
reflux for 30 min. The reaction mixture was allowed to cool and
was then poured into 50 mL of ice water. The precipitate was col-
lected by filtration and recrystallized from EtOH.
of the tested compounds are considerably lower than
the standard antifungal and antibacterial agents.
The authors have declared no conflict of interest.
3-Amino-4-methyl-2-acetyl or -benzoylselenolo[2,3-
b]quinoline (C14H12N2OSe, C19H14N2OSe) 5a, 5b
Experimental
General procedure: Compounds 4a and 4b (6 mmol) and EtONa
(0.5 g Na in 10 mL EtOH) was refluxed for 1 h, and then cooled.
The precipitate was collected and recrystallized from dioxane.
Chemistry
Melting points were determined using a Kofler melting point
apparatus (C. Reichert, Vienna, Austria) and are uncorrected. IR
(KBr) spectra were recorded on a Pye-Unicam SP3-100 instrument
3-Cyano-4-methyl-2-substituted selenoquinolines
(C13H9N3Se, C15H14N2O2Se, C13H11N3OSe) 6a, 6b, 6c
General procedure: A mixture of compound 2 (0.5 g, 20 mmol),
fused sodium acetate (1.4 g, 17 mmol), and chloroacetonitrile,
ethyl chloroacetate or chloroacetamide (15 mmol), respectively,
and 30 mL ethanol was heated under reflux for 2 h. The reaction
mixture was allowed to cool and was then poured into 50 mL of
ice water. The precipitate was collected by filtration and recrys-
tallized from EtOH.
1
(Pye Unicam Ltd. Cambridge, England). H-NMR spectra were
obtained on a Varian EM 390 (Varian Inc., Palo Alto, CA, USA)
using tetramethylsilane as an internal reference. Mass spectra
were recorded on a JEOL-JMS-AX 500 (JEOL, Tokyo, Japan) at Cairo
National Research Center and Assiut University, Assiut, Egypt.
Elemental analyses were obtained on an Elementar Vario EL
1150C analyzer (Heraeus, Germany). The purity of the com-
pounds was checked by TLC.
3-Amino-4-methyl-2-cyano or -ethylcarboxylate or -
carboxamide selenolo[2,3-b]quinolines (C13H9N3Se,
C15H14N2O2Se, C13H11N3OSe) 7a, 7b, 7c
3-Cyano-4-methylquinoline-2(1H)selenone (C11H8N2Se) 2
A mixture of the corresponding chloroquinoline derivative 1
(2.02 g, 10 mmol), selenium metal (1.0 g, 12 mmol) and sodium
borohydride (1.2 g, 32 mmol) was refluxed in ethanol (50 mL) for
5 h. The mixture was cooled and poured in cold HCl. The solid
precipitate was filtered, dried, and recrystallized from ethanol.
MS m/z (% ref. int.): 248 (18) [M+], other important fragments 207
(5), 167 (25), 140 (100), 113 (20).
General procedure: Compounds 6a–c (6 mmol) and EtONa (0.5 g
Na in 10 mL EtOH) were refluxed for 1 h and then cooled. The
solid product was collected and recrystallized from dioxane.
7b: MS m/z 333 (50) [M+ – 1] and the other important frag-
ments are 260 (95), 182 (55), 140 (100).
7c: MS m/z 305 (100) [M+]; other important fragments are 288
(80), 260 (45), 140 (55).
2,29-Bis(3-cyano-4-methyl)diquinolinyl diselenide
(C22H14N4Se2) 3
2-Aryl-4-methyl-2,3-dihydropyrimido[49,59:4,5]-
selenolo[2,3-b]quinoline-11(1H)-ones 8a-d or 2-
Spiro(cycloalkane)-4-methyl-3(H)pyrimido[49,59:4,5]-
selenolo[2,3-b]quinoline-11(1H)-ones 9a, b
General procedure: A mixture of 7c (1 g, 33 mmol) and the corre-
sponding aromatic aldehydes or cycloalkanones (33 mmol) was
heated under reflux in glacial acetic acid (20 mL) for 5–7 h, the
solid was collected by filtration and recrystallized from acetic
acid.
The above described reaction mixture which precipitated dur-
ing refluxing now was recrystallized from dioxane. MS m/z (%
ref. int.): 494 (15) [M+], other important fragments 333 (55), 248
(25), 140 (100), 113 (20).
3-Cyano-4-methyl-2-substituted selenoquinolines
(C14H12N2OSe, C19H14N2OSe) 4a, 4b
General procedure: A mixture of 2 (1.48 g, 6 mmol), fused
sodium acetate (0.98 g, 12 mmol), and chloroacetone or phe-
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New 4-Methylquinoline-2(1H) Selenone Derivatives
245
9a: MS m/z 385 (53.8) [M+], 386 (100) [M+ + 1]; other important
fragments are 356 (59), 342 (46), 288 (61), 236 (28), 140 (43).
9b MS m/z 372 (5.6) [M+ + 1]; other important fragments are
370 (2.9), 353 (1.8), 185 (53.8), 149 (9.9), 93 (100), 78 (23.5).
icylic acid. The time taken by the mouse to lick its feet or to
jump within a plexiglas cylinder placed on a hot plate surface
(558C) was determined. This reaction time was taken as the end
point and the increase in hot plate latency was taken as a meas-
ure of the analgesic activity. Male adult albino mice (20–25 g)
were divided into six groups, each containing five animals. Four
test compounds and the reference drug were injected into the
animals i.p. at a dose level of 10 mg kg– 1. A control group of ani-
mals was similarly treated with 5% CMC in normal saline. The
reaction time was evaluated directly after 0.5, 1, 2, 3, 4, and 5 h
intervals after injection. The results of analgesic activity of the
test compounds and acetyl salicylic acid are displayed in Table 3.
2,4-Dimethylpyrimido[49,59:4,5]selenolo[2,3-b]quinoline-
11(1H)-one (C15H11N3OSe) 10
Compound 7c (1.0 g, 33 mmol) and redistilled acetic anhydride
(20 mL) were heated under reflux for 8 h, and then left to cool.
The precipitate was filtered and crystallized from EtOH.
10: MS m/z 328 (52) [M+], 329 (12) [M+], 330 (100) [M+] and the
other important fragments are 260 (16), 179 (5), 140 (37).
Gastric ulceration
N-Alkylsubstituted-2,4-dimethylpyrimido[49,59:4,5]-
Examination of the gastrointestinal mucosa for the presence of
lesions following oral administration of graded doses of the test
compounds as well as the reference drug has been taken as an
indication for ulcerogenic effects. Both, the frequency of ulcera-
tion (expressed as ratio of ulcerated animals) and the severity of
ulceration (expressed as ulcer index) were used for comparison
of the tested compound and indomethacin [27].
Three groups of six male adult albino mice each were fasted
for 24 h. Compounds 11b and 11d and indomethacin were
administered orally in doses of 10, 30, and 50 mg kg– 1, as sus-
pensions in 5% CMC normal saline solution. After 6 h, the ani-
mals were killed, the stomachs were removed and gastric lesions
on the mucosa were determined using a stereoscopic micro-
scope. Ulcer was defined as one lesion that was at least 0.5 mm
or more in length. All lesions of more than 0.1 mm in length
were summed to obtain the ulcer index; results are displayed in
Table 4.
selenolo[2,3-b]quinoline-11(1H-ones 11a–d
General procedure: To a solution of 10 (0.5 g, 15 mmol) in DMF,
anhydrous K2CO3 (0.5 g) and the suitable alkyl halide (15 mmol)
were added. The reaction mixture was heated on a water bath
for 8–10 h, cooled, and then diluted with ice water (20 mL). The
precipitate was collected by filtration and recrystallized from
EtOH.
11a: MS m/z 343 (2.4) [M+], 342 (4.2) [M+ – 1].
11b: MS m/z 357 (6.5) [M+].
11c: MS m/z 369 (2.4) [M+ – 2].
11d: MS m/z 369 (88) [M+ + 1]; other important fragments are
330 (60), 300 (35), 259 (40), 140 (100).
Biological screening
The biological screening was carried out at the Department of
Pharmacology, Faculty of Medicine, Assiut University, Assiut,
Egypt. Animals were obtained from the animal house of the Fac-
ulty of Medicine. The experiments were performed with albino
rats of Wister strain of either sex, weighing 100–120 g. The ani-
mals were maintained at 258C l 28C, 50% l 2% relative humid-
ity, and a 12 h light/dark cycle. Food and water were freely avail-
able up to the time of experiments. The test compounds were
dissolved in 1% carboxyl methyl cellulose (CMC) solution.
Determination of acute toxicity (LD50)
The median lethal dose (LD50) of the most active and safe com-
pound 11d was determined in mice. Groups – each consisting of
five animals – of male adult albino mice (20–25 g), were
injected i.p. with graded doses of the test compound. The per-
centage of mortality was determined 72 h, after the injection.
Computation of LD50 was processed by a graphical method [28].
Anti-inflammatory activity
The anti-inflammatory activities of compounds 5a, 7b, 7c, 8b–d,
9a, 11b, and 11d were evaluated according to the method
described by Winter et al. [25], where a pedal inflammation in
rat paws was induced by subplantar injection of 0.2 mL carra-
geenan suspension (0.2%) into the right hind paw of the rats.
Male adult albino rats (100–120 g) were divided into eleven
groups, of five animals each. The thickness of rat paw was meas-
ured by a Veriner caliper (SMIEC, China) before and 1 h after
injection, to detect the inflammation induced by carrageenan.
Test compounds at doses of 10 mg kg– 1 were injected i. p. to nine
groups of rats 1 h after injection of carrageenan. The control
group received the vehicle (5% CMC), while the reference group
received indomethacin at 10 mg kg– 1. The difference between
the thicknesses of the two paws was taken as a measure of
edema. The measurement was carried out at 0.5, 1, 2, 3, 4, and
5 h intervals, after injection of the test compounds, the refer-
ence drug, and the vehicle. The results are displayed in Table 2.
Antibacterial activity
Four bacterial species representing both Gram-positive and
Gram-negative strains were used to test the antibacterial activ-
ities of the target compounds 7c, 9a, 11b, and 11d in vitro, in
comparison to ampicillin as a reference drug using the standard
agar paper disc diffusion method: Bacillus cereus (P-70) (Gram-pos-
itive bacteria), Escherichia coli (P-69), Pseudomonas aeruginosa (P-
72), Serratia marcescens (P-67) (Gram-negative bacteria).
Cell suspensions of bacterial stains were prepared from 48-h
old cultures grown on potato dextrose agar (PDA) or Sabouraud
agar (SA) media. One mL of the cell suspension was added to Petri
dishes of 9 cm in diameter, and then, 15 mL of nutrient agar was
poured onto the plates. Plates were shaken gently to homoge-
nize the innoculum. Sterile 5 mm filter paper (Whatmann, UK)
was saturated with 10 lg L– 1 of the test compound, ampicillin
solutions (100, 50, 25 lg mL– 1 concentrations) as reference
drug, or DMSO as negative control. Impregnated discs were then
dried for 1 h and placed in the centre of each plate. The seeded
plates were incubated at 358C l 28C for 24–48 h. The radii of the
inhibition zones in mm of triplicate sets were measured and the
results are given in Table 5.
Analgesic activity
The analgesic activity of 7c, 9a, 11b, and 11d was determined in
mice using the hot-plate method [26] in comparison to acetyl sal-
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246
S. H. Abdel-Hafez and M. A. Hussein
Arch. Pharm. Chem. Life Sci. 2008, 341, 240–246
[9] F. T. Burling, B. M. Goldstein, J. Am. Chem. Soc. 1992, 114,
Antifungal activity
2313–2320.
Compounds 7c, 9a, 11b, and 11d were screened for their antifun-
gal activity in vitro, in comparison to fluconazole as a reference
drug using the standard agar paper disc diffusion method
against four fungi: Aspergillus flavus (3372), Aspergillus niger
(3364), Candida albicans (421), and Fusarium oxysporum (208).
A spore suspension in sterile distilled water was prepared
from 2-3 days old culture of the fungi growing on potato dex-
trose agar (PDA) or Sabouraud agar (SA) media. The final spore
concentration was 56104 spores mL– 1. About 15 mL of the
growth medium was placed into sterile petri dishes of 9 cm in
diameter and incubated with 1 mL of the spore suspension.
Plates were shaken gently to homogenize the innoculum.
Sterile 5 mm filter paper (Whatmann, UK) was saturated with
10 mg L– 1 of the test compound, fluconazole solution (100, 50,
25 lg mL– 1 concentrations) as reference drug or DMSO as nega-
tive control. Impregnated discs were then dried for 1 h and
placed in the centre of each plate. The seeded plates were incu-
bated at 288C l 28C for 7 days. The radii of the inhibition zones
in mm of triplicate sets were measured and the results had
shown inhibition activity at 40, 25, and 22 mm, respectively.
The results are listed in Table 5.
[10] K. Burger, M. Gold, H. Neuhauser, M. Rudolph, E. Hoess,
Synthesis 1992, 11, 1145–1150.
[11] M. Piatek, E. Zeslawska, Phosphorus, Sulfur, Silicon, Relat.
Elem 1996, 117, 55–56.
[12] B. Prabhuswamy, Indian Heterocycl Chem. 2002, 1, 245–246.
[13] S. K. Nandeeshaiah, S. Y. Ambekar, Synth. Commun. 1995,
25, 451–459.
[14] E. Lukevics, I. Shestakova, I. Domracheva, A. Nesterova, et
al., Chemistry of Heterocyclic Compounds, 2006, 42(1), 53–56.
[15] S. H. Abdel-Hafez, Eur. J. Med. Chem., in press.
[16] S. H. Abdel–Hafez, Phosphorus, Sulfur, Silicon, Relat. Elem
2003, 178, 2563–2579.
[17] S. H. Abdel-Hafez, Russ. J. Org. Chem. 2005, 41, 396–401.
[18] S. H. Abdel-Hafez, H. W. Anthosen, H. R. Sliwka, V. Partali,
Phosphorus, Sulfur, Silicon, Relat. Elem 2005, 180, 2217–2224.
[19] B. G. Mohamed, A. M. Abdel-Alim, M. A. Hussein, Acta
Pharm. 2006, 56, 31–48.
[20] H. M. Abdel-Rahman, M. A. Hussein, Arch. Pharm 2006, 339,
378–387.
[21] M. A. Abbady, S. H. Abdel-Hafez, M. M. Kandeel, M. I. Abdel-
Monem, Molecules 2003, 8, 622–641.
References
[22] M. A. Abbady, S. H. Abdel-Hafez, Phosphorus, Sulfur, Silicon,
Relat. Elem 2000, 160, 121–139.
[1] R. Assan, C. Perronne, L. Chotard, E. Larger, J. L. Vilde, Dia-
bete Metab. 1995, 21, 54–58.
[23] S. H. Abdel-Hafez, S. A. Abdel-Mohsen, Y. A. El-Ossaily, Phos-
phorus, Sulfur, Silicon, Relat. Elem 2006, 181, 2297–2305.
[2] M. G. Fiona, M. E. D. Timothy, E. H. Claire, A. Clark, M. A.
Frances, Br. Pharmacol. 2000, 131, 756–760.
[24] A. M. Kamal El-Dean, A. A. Geies, Y. A. El-Ossaily, Phospho-
rus, Sulfur, Silicon, Relat. Elem 2006, 181, 2013–2022.
[3] R. Musiol, J. Jampilek, V. Buchta, L. Silva, et al., J. Bioorg.
Med. Chem. 2006, 14, 3592–3598.
[25] L. V. G. Nargund, G. R. N. Reedy, V. Haripbasad, J. Pharm.
Sci. 1994, 83, 246–248.
[4] V. Thiery, C. W. Rees, T. Besson, G. Cottenceau, A. M. Pons,
Eur. J. Med. Chem. 1998, 33, 149–153.
[26] E. A. Boyle, F. R. Mangan, R. E. Markwell, S. A. Smith, et al.,
J. Med. Chem. 1986, 29, 894–897.
[5] Z. Dardari, M. Lemrani, A. E. Bahloul, A. E. Sebban, et al.,
Farmaco 2004, 59, 195–199.
[27] B. Tozkoparan, G. Akaty, E. Yesilada, Farmaco 2002, 57,
154–156.
[6] F. E. Goda, A. A. M. Abdel-Aziz, H. A. Ghoneim, Bioorg. Med.
Chem 2005, 13, 3175–3183.
[28] F. Sztaricskai, I. E. Takacs, F. Pusztai, G. Szabo, I. Csipo,
[7] V. P. Litvinov, V. D. Dyachenko, Russ. Chem. Rev. 1997, 66,
Arch. Pharm. Med. Chem. 1999, 332, 321–326.
923–951.
[29] H. William Microbiological assay. An introduction to quantita-
tive principles and evaluation, Academic press, New York,
1997.
[8] P. K. Atanassov, A. Linden, H. Heimgartner, Heterocycles
2003, 61, 569–579.
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