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Synthesis of New Nonclassical Acridines Quinolines and Quinazolines Derived from Dimedone for Biological Evaluation.

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Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
519
Full Paper
Synthesis of New Nonclassical Acridines, Quinolines, and
Quinazolines Derived from Dimedone for Biological
Evaluation
Osama I. El-Sabbagh1, Mohamed A. Shabaan2, Hanan H. Kadry2, and Ehab Saad Al-Din3
1
Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
3
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
2
New nonclassical acridines, quinolines, and quinazolines were prepared starting from cyclic bdiketones, namely dimedone, through application of Hantzsch addition, Michael addition, and
Mannich reactions, respectively. The antimicrobial activity revealed that decahydroacridin-1,8dione 2e bearing a 3-nitrophenyl group and hexahydroquinoline 4e having a 2,4-dichlorophenyl
moiety were the most active compounds against both Gram-positive and -negative bacteria based
upon using the disc diffusion method. Cytotoxic activity studies for decahydroacridin-1,8-diones 2a–e
against liver carcinoma cells (HepG2) using the MTT cell viability assay revealed that decahydroacridin1,8-dione bearing a 4-methylphenyl moiety 2d showed a higher cytotoxic activity (IC50 ¼ 4.42 mg/mL)
than the other derivatives.
Keywords: Acridines / Antimicrobial / Cytotoxic activity / Quinolines / Quinazolines
Received: December 6, 2009; Accepted: March 5, 2010
DOI 10.1002/ardp.200900296
Introduction
Cyclic b-diketones, especially dimedone, were used as precursors for the preparation of biologically active heterocyclic
compounds such as acridine [1–4], quinoline [5], and quinazoline [6] derivatives. A series of hexahydroacridine derivatives
A [1] and many of the decahydroacridines B [2, 3] (Fig. 1) were
prepared from dimedone and most of them were found to
exhibit a broad spectrum of antimicrobial activities.
Acridine derivatives are known as DNA-intercalators, such
as nitracrine [7] and amsacrine [8, 9] which exhibit cytotoxic
activity. Amsacrine C (Fig. 2) was one of the first DNA-intercalating agents to be considered as a topoisomerase-II inhibitor [9]. A series of acridine derivatives D (Fig. 2) were prepared
starting from dimedone [4] and most of them were found to
possess cytotoxic activity against hepatoma cell lines (HepG2)
at 10 mmol/mL.
On the other hand, several drugs such as sparofloxacin and
ciprofloxacin E (Fig. 3), which are used clinically as antibacterial agents, are chemically quinoline derivatives [10–12].
Moreover, several quinazolines were reported to possess antimicrobial activity [13, 14] in addition to other quinazolines F
(Fig. 3) derived from dimedone were found to have antibacterial activity [6].
X
NO2
R
O
N
H
A
R = o-OH
R = p-Cl
Correspondence: Osama I. El-Sabbagh, Department of Medicinal
Chemistry, Faculty of Pharmacy, Zagazig University, 44511, Zagazig,
Egypt.
E-mail: elsabbagh_59@yahoo.com
Fax: þ20 55 230-3266
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
O
O
O
O
N
N
OR
Cl
B
2e
X = Cl, NO 2
R = H, CH 2COOC2H5,
CH2CONHNH2,
CH2CONHN=CHAr
Figure 1. Structures of hexahydroacridine derivatives A, decahydroacridines B, and of compound 2e.
520
O. I.-E. Sabbagh et al.
Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
CH 3
R
H3 CO
NHSO 2CH 3
O
O
O
O
HN
N
N
N
O
OC2 H5
Cl
Amsacrine
C
D
2d
R= H,Br, Cl, OH, OCH3
Figure 2. Structures of amsacrine C, acridine derivatives D, and 2d.
Based on the above findings coupled with our interest in
the chemistry of dimedone gave us the chance to prepare new
nonclassical decahydroacridin-1,8-diones, hexahydroquinolin-5-ones, and octahydroquinazolines structurally similar
to the aforementioned ones hoping to possess antimicrobial
activity. In addition, we evaluated the cytotoxic activity of the
decahydroacridin-1,8-dione derivatives.
Results and discussion
Chemistry
To prepare the target acridine, quinoline, and quinazoline
derivatives, the reactions presented in Scheme 1were performed. The enaminone starting material 1 was prepared
in 87% yield by condensation of equimolar amounts of 5,5dimethyl-1,3-cyclohexandione (dimedone) with 4-chloroaniline via heating the reactants under reflux in toluene using
the reported method [15, 16].
In the present work, the novel decahydroacridin-1,8-dione
derivatives 2a–f were prepared through a Hantzsch reaction
by cyclocondensation of enaminone 1 with half an equivalent
of aromatic aldehyde via heating the reactants under reflux
in acetic acid for 4 h. This method enables the formation of
acridines in one-step with higher yields (75 to 85%) than the
previously reported method [17]. Moreover, acetic acid was
Cl
R
O
F
HN
N
COOH
NH
N
Ciprofloxacin
E
Cl
O
O
N
H
X
N
NH 2
F
X= O, S
R=H,Cl
Cl
4e
Figure 3. Structures of ciprofloxacin E, quinazolines F, and 4e.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
found to be the solvent of choice for conducting the cyclocondensation by providing the reaction with a higher
temperature necessary for its completion and also maintaining the expelled amine residue, thus, it favors the formation
of acridines.
The formed decahydroacridin-1,8-dione derivatives 2a–f
were established by an indirect synthesis route as shown
in Scheme 2 through the reaction of dimedone with half
an equivalent of p-bromobenzaldehyde to afford the xanthenes derivative G [18]. The later was further reacted with
4-chloroaniline by heating the compounds together at reflux
in acetic acid for 10 h to give the target decahydroacridin-1,8dione 2a. The obtained product 2a was matched with that
isolated from the former method using thin-layer chromatography (TLC) technique. The indirect method requires a
prolonged time and gives the decahydroacridin-1,8-dione 2a
in lower yield (60%) than the former method (75%).
In the present work, we unexpectedly obtained hexahydroquinolines 4a–h rather than the target hexahydroquinolinecarboxamide derivatives 5 upon using Michael-addition
reaction of the enaminone 1 to the Michael acceptors 2cyano-3-substituted phenylacrylamide 3a–h [19–22] by stirring the reactants for 12 h in ethanol containing sodium
ethoxide at room temperature.
The structures of the novel hexahydroquinolines 4a–h
were elucidated using microanalytical and spectral data.
The IR spectrum for compound 4a for example, illustrated
the absence of the carbonyl absorption band at y ¼ 1670–
1680 cm1 suggesting the removal of the carboxamide group
from the expected quinolinecarboxamide 5. This assumption
is confirmed by the mass spectrum which showed a molecular ion peak at m/z ¼ 457 [Mþ]. In addition, the 1H-NMR
showed a new signal at 4.80 ppm indicating a vinylic hydrogen at the 3-position. The postulated mechanism of the
reaction sequence forming the unexpected hexahydroquinolines 4a–h, is illustrated in Fig. 4. The 1H-NMR proved the
structure of the hexahydroquinoline derivatives 4a–h. It
showed the disappearance of both singlets at d ¼ 7.85 ppm
ppm of the NH group and a singlet at d ¼ 5.65 ppm of the
vinylic hydrogen for the starting enaminone. Moreover, the
appearance of a singlet at d ¼ 4.80 ppm indicating the presence of the vinylic proton at the 3-position and another
singlet at d ¼ 5.33 ppm due to the benzylic proton at the
4-position as well as a broad singlet at d ¼ 6.33 ppm for the
NH2 group.
In this work, the octahydroquinazoline 6 was prepared in
our laboratory [16] in an one-pot synthesis through a double
Mannich reaction by refluxing a mixture of enaminone 1, paminophenol, and two mol of formol in ethanol containing a
catalytic amount of acetic acid. Ester 7 was obtained by
stirring equimolar amounts of the corresponding octahydroquinazoline
6
and
ethyl
bromoacetate
in
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Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
Synthesis of Nonclassical Acridines
OCH 2CONHNH 2
O
O
r
S o NC
CH 2
H
cO
CH 2
Cl
l Ah
N
1 NC
R
N
m
/1 x2
OH f lu
Et r e
O
O
O
N
N
H
H
N
Et
O
NHR1
H,
r
N
2
ef
lu
x
H
2
2h
OCH 2COOC 2 H5
O
Cl
X
NH
8
N
N
N
Cl
7
Cl
BrCH 2 COOC H
2 5
9a-d
9a:
9b:
9c:
9d:
521
R1
4-OCH 3 -C6 H4
4-CH 3-C6H 4
C 6H 5
ClCH2CH2
X
S
S
S
O
DMF/ K 2CO 3 ,
stir, rt, 24h
OH
O
O
OH
H2 N
NH
N
2CH2O/EtOH
1ml AcOH / reflux
N
1
Cl
ArCHO
O
Ar
6 Cl
AcOH,
reflux
R2
EtOH
EtONa
stir, rt
O
NH2
H
O
CN
3a-h
N
R2
Cl
2
2a-f
2a:
2b:
2c:
2d:
2e:
2f:
Ar
4-Br-C 6 H4
2,4-diCl-C 6H3
2-F-C 6H 4
4-CH 3 -C6H 4
3-NO2 -C6H 4
2-thienyl
R2
O
N
Cl
NH2
R
4a: 3-Br
4b: 4-Br
4c: 2-Cl
4d: 4-Cl
4e: 2,4-diCl
4f: 3-CH 3 O
4g: 4-CH 3 O
4h: H
4a-h
O
CONH 2
N
5
NH2
Cl
Scheme 1. Synthetic pathway to the acridines 2a–f, quinolines 4a–h, and quinazolines 9a–d.
dimethylformamide (DMF) containing K2CO3 at room
temperature for 24 h [16]. This ester 7 was condensed with
hydrazine hydrate in refluxing ethanol to give the desired
hydrazide intermediate 8 [16]. The reaction of the hydrazide 8
with the appropriate isothiocyanate or isocyanate derivatives
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
was conducted through heating the reactants in ethanol in
the presence of glacial acetic acid for 2 h to give the novel
thiosemicarbazide 9a–c or semicarbazide derivatives 9d. The
structure of the novel compounds was confirmed using
microanalytical and IR and 1H-NMR spectral data.
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522
O. I.-E. Sabbagh et al.
Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
Br
Br
O
O
O
Br
H
CHO
OH
acetonitrile
reflux
H
O
H2N
O
Cl
O
N
AcOH/reflux10h
Xanthene
Dimedone
G
Scheme 2. Indirect method for the preparation of decahydroacridin-1,8-dione 2a.
Cl
Decahydroacridin-1,8-dione
(2a)
Biological evaluation
Antimicrobial activity
derivatives 9a–d did not show any activity against Gramnegative bacteria.
Most compounds presented in Table 1 were devoid of any
antifungal activity except those having chloro (2b, 4c, 4d, and
4e) or fluoro (2c) atoms. It was further observed that an
increase in the number of chloro atoms led to an increase
in the antifungal activity against Candida albicans to reach its
maximum in case of quinoline 4e bearing the 2,4-dichlorophenyl moiety.
The preliminary antimicrobial activity for decahydroacridin1,8-diones 2a–f, hexahydroquinolines 4a–h, and octahydroquinazoline derivatives 9a–d was carried out using the disc
diffusion method [23].
Table 1 revealed that the acridine derivatives 2b, 2c, and 2e
exhibited a high antibacterial activity especially against
Bacillus subtilus and Staphylococcus aureus. Acridine derivative
2e bearing a nitro group was the most active one in this series
against Gram-negative bacteria having nearly the same
activity as the reference drug ciprofloxacin.
Regarding quinolines 4a–h, it was observed that those
having a chloro moiety, especially 4e, showed higher antibacterial activity than other quinolines. It was also noted that
the bromo quinolines 4a and 4b as well as thiosemicarbazide
O
O
O
+
Ph
H
O
O
NH2
C N
N
Cl
O
Ph
O
+H+
N
NH2
NH2
-CO2
_
+H+
Ph
H
O
_
+H+
NH2
N
N
Cl
Ph
N
Ph
The effect of decahydroacridin-1,8-diones 2a–e on the proliferation of liver carcinoma (HepG2) cells was measured after
48 h of incubation using the MTT (3-[4,5-dimethylthiazole-2yl]-2,5-diphenyltetrazolium bromide) cell viability assay [24].
NH2
NH H
O
H
Cytotoxic activity
NH
Cl
_
+H+
Ph
O
O
O
N
NH2
Ph
O
NH2
NaOEt
N
NH2
+EtOH
+EtOCl
Cl
Na + +NH 3 + EtOH +
Cl
Cl
Figure 4. The postulated mechanism for the formation of unexpected quinoline 4a–h.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
Synthesis of Nonclassical Acridines
523
Table 1. Antimicrobial activity evaluation for compounds 2a–f, 4a–h, and 9a–d expressed by diameter of inhibition zone (mm).
Compound
Diameter of inhibition zone (mm)
Gram-positive
Ciprofloxacin
Nystatin
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
4g
4h
9a
9b
9c
9d
Gram-negative
Fungi
Staphylococcus aureus
Bacillus subtilis
Escherichia. coli
Candida albicans
18 0.6
–
6 0.2
16 0.3
14 0.6
6 0.2
16 0.8
8 0.01
10 0.1
12 0.18
13 0.14
14 0.3
16 0.5
6 0.09
6 0.06
8 0.2
8 0.1
7 0.12
10 0.1
4 0.03
20 0.5
–
8 0.3
18 0.2
18 0.3
8 0.2
20 0.8
8 0.09
10 0.3
10 0.1
14 0.18
15 0.25
18 0.9
7 0.4
6 0.2
8 0.3
10 0.11
8 0.16
12 0.2
4 0.01
14 0.3
–
–
8 0.1
8 0.2
–
12 0.4
6 0.08
–
–
10 0.1
10 0.16
12 0.12
4 0.04
4 0.1
6 0.2
–
–
–
–
–
20 0.7
–
§
8 0.2
§
6 0.1
–
–
–
–
–
8 0.19§
10 0.2§
14 0.3§
–
–
–
–
–
–
–
Values were expressed as mean standard deviation;
P > 0.001 versus ciprofloxacin; § P > 0.001 versus nystatin.
It can be observed from Table 2 that the tested compounds
2a–e caused an inhibition of the proliferation of HepG2 cells.
This phenomena got more pronounced in case of decahydroacridin-1,8-dione bearing 4-methylphenyl moiety 2d
(Fig. 5) as concluded by its low IC50 value (4.42 mg/mL), which
revealed the highest cytotoxic activity against hepatic carcinoma cell lines. It was also noted that the compounds 2a, 2b,
2c, and 2e revealed a low cytotoxic effect on HepG2 cells as
indicated from their relatively high IC50 values 39.67, 43.11,
60.76, and 63.78 mg/mL, respectively.
droquinolines 4a–h, and octahydroquinazolines 9a–d were
prepared. The antimicrobial evaluation revealed that decahydroacridin-1,8-dione 2e bearing a 3-nitrophenyl group and
the hexahydroquinoline 4e having a 2,4-dichlorophenyl
moiety showed high antibacterial activity upon testing with
the disc diffusion method. Evaluation of the cytotoxic activity
of decahydroacridin-1,8-diones 2a–e against liver carcinoma
(HepG2) cells revealed that decahydroacridin-1,8-dione
Compound 2d
100
Conclusion
y = -0.4925x + 52.177
Starting from dimedone, different new heterocyclic derivatives such as decahydroacridin-1,8-diones 2a–e, hexahyTable 2. Cytotoxic evaluation for compounds 2a–e against liver
carcinoma (HepG2) cell lines.
Compound
60
40
IC50 (mg/mL)
20
39.67
43.11
60.76
4.42
63.78
0
2a
2b
2c
2d
2e
Cell viability %
80
IC50: Dose required to inhibit cell growth by 50%.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0
20
40
60
80
100
Concentration (µg/ml)
Figure 5. Plots of the percentage viability of liver carcinoma
(HepG2) versus drug concentration for compound 2d.
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524
O. I.-E. Sabbagh et al.
bearing the 4-methylphenyl moiety 2d was the most active
one having an IC50 value equal to 4.42 mg/mL.
Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
538 [M þ 1] (8.20), 537 [Mþ] (9.70), 382 (100.00). Anal. calcd.
for C29H29BrClNO2: C, 64.63; H, 5.42; N, 2.60. Found: C, 64.13;
H, 5.52; N, 2.62.
Experimental
Chemistry
Melting points were determined with a Gallenkamp melting
point apparatus (London, UK) and are uncorrected. IR spectra
(KBr, cm1) were recorded on Bruker Vector, 22FT-IR spectrometer (Bruker, Germany). 1H-NMR and 13C-NMR spectra were
recorded on a Varian Gemini-200 (200 MHz, Foster City, CA, USA)
Mac NMR5.3-AC250 (250 MHz), and Varian Mercury-300
(300 MHz; Palo Alto, CA, USA) spectrometers using CDCl3 or
dimethylsulphoxide (DMSO)-d6 as a solvent and tetramethylsilane (TMS) as an internal standard (Chemical shift in d, ppm).
Mass spectra were determined using mass spectrometer GC/MS
Shimadzu QP 1000 EX with ionization energy 70 eV (Shimadzu,
Japan). Elemental analyses were determined using Manual
Element Analyzer (Heraeus, Germany) and Automatic Element
Analyzer CHN Model 2400 (Perkin Elmer, USA) at the
Microanalytical Center, Faculty of Science, Cairo University,
Cairo, Egypt. All results of the elemental analyses corresponded
to the calculated values within experimental error. Progress of
the reaction was monitored by thin-layer chromatography (TLC)
using precoated TLC sheets with Ultraviolet (UV) fluorescent
silica gel (Merck, 60F254); the spots were visualized by iodine
vapors or irradiation with UV light (254 nm). Dimedone and
other chemicals were purchased from Sigma-Aldrich (USA).
The enaminone of dimedone 1, 1-(4-chlorophenyl)-7,7dimethyl-5-oxo-3-(4-hydroxyphenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline 6, its ester derivative 7, and also its corresponding
hydrazide intermediate 8 had been previously prepared in our
laboratory [16]. Moreover, xanthene derivative G [18] and the
intermediates 2-cyano-3-substituted phenylacrylamide 3a–h
[19–22] were prepared according to the reported procedures.
General procedure for preparation of compounds 2a–f
Method A (compounds 2a–f): A solution of enaminone 1 (0.58 g,
2.32 mmol) and half an equivalent of aromatic aldehyde
(1.16 mmol) in glacial acetic acid (15 mL) was heated under
reflux for 4 h. The reaction mixture was diluted with water,
and then allowed to cool to room temperature. The obtained
solid was filtered, washed with water, and crystallized from
aqueous acetic acid.
(Method B) compound 2a: A solution of xanthene G (0.86 g,
2 mmol) and 4-chloroaniline (0.26 g, 2 mmol) in glacial acetic
acid (10 mL) was heated under reflux for 10 h. The reaction
mixture was diluted with water and then allowed to cool to
room temperature. The obtained solid was filtered, washed with
water, and crystallized from aqueous acetic acid. Yield: 0.65 g,
(60%), m. p.: 2888C.
9-(4-Bromophenyl)-10-(4-chlorophenyl)-3,3,6,6tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8dione 2a
Yield: 75% (method A); m. p.: 288–2898C; IR n: 3080 (CH, aro1 1
matic), 2957 (CH, aliphatic), 1642 (C –
– O), 1579 (C –
– C) cm ; HNMR (200 MHz, CDCl3) d: 0.73, 0.88 (2s, 12H, 4 CH3), 1.77–1.94 (2s,
4H, 2 CH2), 1.99–2.09 (m, 4H, 2 CH2), 5.13 (s, 1H, 9-H acridine),
7.08–7.49 (m, 8H, ArH) ppm; MS m/z (rel. int.): 539 [M þ 2] (13.00),
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
10-(4-Chlorophenyl)-9-(2,4-dichlorophenyl)-3,3,6,6tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8dione 2b
Yield: 70%; m. p.: 305–3068C; IR n: 3075 (CH, aromatic), 2956 (CH,
1 1
aliphatic), 1641 (C –
– O), 1580 (C –
– C) cm ; H-NMR (200 MHz,
CDCl3) d: 0.86, 0.94 (2s, 12H, 4 CH3), 1.83–1.93 (2s, 4H, 2 CH2),
2.13–2.12 (d, 4H, 2 CH2), 5.38 (s, 1H, 9-H acridine), 7.16–7.65 (m,
8H, ArH) ppm. Anal. calcd. for C29H28Cl3NO2: C, 65.86; H, 5.34; N,
2.65. Found: C, 65.76; H, 4.98; N, 2.63.
10-(4-Chlorophenyl)-9-(4-fluorophenyl)-3,3,6,6tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8dione 2c
Yield: 78%; m. p.: 274–2758C; IR n: 3085 (CH, aromatic), 2956 (CH,
1 1
aliphatic), 1643 (C –
– O), 1578 (C –
– C) cm ; H-NMR (200 MHz,
CDCl3) d: 0.86, 1.02 (2s, 12H, 4CH3), 1.91, 2.08 (2s, 4H, 2 CH2),
2.07–2.22 (d, 4H, 2 CH2), 5.29 (s, 1H, 9-H acridine), 6.97–7.63 (m,
8H, ArH) ppm. Anal. calcd. for C29H29FClNO2: C, 72.87; H, 6.12; N,
2.93. Found: C, 72.81; H, 6.10; N, 2.97.
10-(4-Chlorophenyl)-9-(4-methylphenyl)-3,3,6,6tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8dione 2d
Yield: 80%; m. p.: 268–2698C; IR n: 3075 (CH, aromatic), 2956 (CH,
1 1
aliphatic), 1641 (C –
– O), 1579 (C –
– C) cm ; H-NMR (200 MHz,
CDCl3) d: 0.83, 0.96 (2s, 12H, 4 CH3), 1.78, 2.09 (2d, 4H, 2 CH2),
1.91–2.01 (d, 4H, 2 CH2), 2.26 (s, 3H, CH3), 5.23 (s, 1H, 9-H acridine), 7.04–7.56 (m, 8H, ArH) ppm. Anal. calcd. for C30H32ClNO2:
C, 76.01; H, 6.80; N, 2.95. Found: C, 76.20; H, 6.51; N, 2.62.
10-(4-Chlorophenyl)-9-(3-nitrophenyl)-3,3,6,6-tetramethyl1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8-dione 2e
Yield: (85%); m. p.: 285–2868C; IR n: 3050 (CH, aromatic), 2961
(CH, aliphatic), 1640 (C –
– O) 1579 (C –
– C) and 1527, 1363 (NO2)
cm1; 1H-NMR (300 MHz, DMSO-d6) d: 0.72, 0.91 (2s, 12H, 4
CH3), 1.84 (d, 2H, J ¼ 17 Hz, acridine H2a,2e), 2.03 (d, 2H,
J ¼ 16 Hz, acridine H4a,4e), 2.22 (d, 2H, J ¼ 16 Hz,
acridine H5a,5e), 2.24 (d, 2H, J ¼ 17 Hz, acridine H7a,7e), 5.17 (s,
1H, 9-H acridine), 7.47 (d, 2H, J ¼ 8.7 Hz, H-2 and H-6 4-ClC6H5),
7.57 (m, 1H, H-5 3-NO2C6H5), 7.68 (d, 2H, J ¼ 8.7 Hz, H-3, H-5 4ClC6H5), 7,78 (d, 1H, H-6 3-NO2C6H5), 7.98 (d, 1H, H-4 3-NO2C6H5),
8.14 (s, 1H, H-2 3-NO2C6H5) ppm; 13C-NMR (DMSO-d6) d: 25.8, 28.9
(4 CH3), 31.8, 32.2 (2 C(CH3)2), 40.7 (2 CH2), 49.2 (2 CH2), 112.1
(2 Csp2), 120.5–150.6 (2 Csp2, C-NO2, Ph-C), 194.8 (2 C –
– O); MS m/z
(rel. int.): 506 [M þ 2] (10.90), 505 [M þ 1] (15.20), 504 [Mþ] (4.30),
382 (100.00). Anal. calcd. for C29H29ClN2O4: C, 68.97; H, 5.79; N,
5.55. Found: C, 68.89; H, 6.00; N, 5.25.
10-(4-Chlorophenyl)-9-(2-thienyl)-3,3,6,6-tetramethyl1,2,3,4,5,6,7,8,9,10-decahydroacridin-1,8-dione 2f
Yield: 81%; m. p.:278–2798C; IR n: 3075 (CH, aromatic), 2957 (CH,
1 1
aliphatic), 1641 (C –
– O), 1579 (C –
– C) cm ; H-NMR (200 MHz,
CDCl3) d: 0.88, 0.99 (2s, 12H, 4 CH3), 1.86, 2.07 (2s, 4H, 2 CH2),
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Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
2.15–2.23 (d, 4H, 2 CH2), 5.67 (s, 1H, 9-H acridine), 6.87–7.57 (m,
8H, ArH) ppm. Anal. calcd. for C27H28ClNO2S: C, 69.58; H, 6.06; N,
3.01. Found: C, 69.80; H, 6.24; N, 2.81.
General procedure for the preparation of compounds 4a–h
A mixture of enaminone 1 (1 g, 4 mmol), and the appropriate 2cyano-3-substituted phenylacrylamide 3a–h (4 mmol) was stirred
at room temperature in ethanol (10 mL) containing sodium
metal (0.18 g, 8 mmol) for 12 h. The product was filtered and
crystallized from toluene.
2-Amino-4-(3-bromophenyl)-1-(4-chlorophenyl)-7,7dimethyl-1,4,5,6,7,8-hexahydroquinolin-5-one 4a
Yield: 67%; m. p.: 191–1928C; IR n: 3240, 3178 (NH2), 3098 (CH,
1
aromatic), 2956 (CH, aliphatic), 1624 (C –
– O), 1572 (C –
– C) cm ; MS
m/z (rel. int.): 457 [Mþ] (60.00), 248 (100.00). Anal. calcd.
for C23H22BrClN2O: C, 60.34; H, 4.84; N, 6.12. Found: C, 60.51;
H, 4.54; N, 5.98.
2-Amino-4-(4-bromophenyl)-1-(4-chlorophenyl)-7,7dimethyl-1,4,5,6,7,8-hexahydroquinolin-5-one 4b
Yield: 73%; m. p.: 205–2068C; IR n: 3470, 3348 (NH2), 3097 (CH,
1 1
aromatic), 2960 (CH, aliphatic), 1646 (C –
– O), 1581 (C –
– C) cm ; HNMR (200 MHz, DMSO-d6) d: 0.87, 1.02 (2s, 6H, 2 CH3), 2.06 (s, 2H,
CH2), 2.38 (s, 2H, CH2), 4.86 (s, 1H, vinylic H), 5.33 (s, 1H, benzylic
H), 6.33 (s, 2H, NH2), 7.09–7.65 (m, 8H, ArH) ppm. Anal. calcd.
for C23H22BrClN2O: C, 60.34; H, 4.84; N, 6.12. Found: C, 60.61; H,
5.09; N, 5.91.
2-Amino-4-(2-chlorophenyl)-1-(4-chlorophenyl)-7,7dimethyl-1,4,5,6,7,8-hexahydroquinolin-5-one 4c
Yield: 65%; m. p.: 198–1998C; IR n: 3248, 3168 (NH2), 3093 (CH,
1 1
aromatic), 2952 (CH, aliphatic), 1597 (C –
– O), 1564 (C –
– C) cm ; HNMR (200 MHz, DMSO-d6) d: 0.88, 1.02 (2s, 6H, 2 CH3), 1.92–2.38
(m, 4H, 2 CH2), 4.88 (s, 1H, vinylic H), 5.32 (s, 1H, benzylic H), 6.40
(s, 2H, NH2), 7.127–7.669 (m, 8H, ArH) ppm. Anal. calcd.
for C23H22Cl2N2O: C, 66.83; H, 5.36; N, 6.78. Found: C, 67.09;
H, 5.32; N, 6.45.
2-Amino-4-(4-chlorophenyl)-1-(4-chlorophenyl)-7,7dimethyl-1,4,5,6,7,8-hexahydroquinolin-5-one 4d
Yield: 70%; m. p.: 202–2038C; IR n: 3470, 3350 (NH2), 3100 (CH,
aromatic), 2950 (CH, aliphatic), 1646 (C ––O), 1580 (C ––C) cm1; 1HNMR (300 MHz, DMSO-d6) d: 0.97, 1.02 (2s, 6H, 2 CH3), 2.06 (s, 2H,
CH2), 2.37 (s, 2H, CH2), 4.88 (s, 1H, vinylic H), 5.32 (s, 1H, benzylic H),
6.22 (s, 2H, NH2), 7.03–7.63 (m, 8H, ArH) ppm; 13C-NMR (DMSO-d6) d:
25.7, 27.9 (2 CH3), 31.7 (C(CH3)2), 33.8 (benzylic C), 42.1 (CH2), 50.2
(CH2), 97.3 (Csp2), 120.7–138.3 (Csp2, Ph-C), 159.6 (C-N), 195.4 (C –– O). MS
m/z (rel. int.): 414 [M þ 2] (28.00), 413 [M þ 1] (76.80), 412 [Mþ]
(33.20), 411 (100.00). Anal. calcd. for C23H22Cl2N2O: C, 66.83; H,
5.36; N, 6.78. Found: C, 67.09; H, 5.32; N, 6.45.
2-Amino-1-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-7,7dimethyl-1,4,5,6,7,8-hexahydroquinolin-5-one 4e
Yield: 75%; m. p.: 206–2078C; MS m/z (rel. int.): 448 [M þ 2] (22.30),
447 [M þ 1] (49.00), 446 [Mþ] (54.70), 410 (100.00). Anal. calcd.
for C23H21Cl3N2O: C, 61.69; H, 4.73; N, 6.26. Found: C, 62.04; H,
5.09; N, 6.44.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Synthesis of Nonclassical Acridines
525
2-Amino-1-(4-chlorophenyl)-7,7-dimethyl-4-(4methoxyphenyl)-1,4,5,6,7,8-hexahydroquinolin-5-one 4f
Yield: 75%; m. p.: 230–2318C; IR n: 3242, 3178 (NH2), 3098 (CH,
1
aromatic), 2956 (CH, aliphatic), 1642 (C –
– O), 1572 (C –
– C) cm ; MS
m/z (rel. int.): 41 [M þ 2] (2.40), 409 [M þ 1] (6.0), 408 [Mþ] (5.40),
77 (100.00). Anal. calcd. for C24H25ClN2O2: C, 70.49; H, 6.16; N,
6.85. Found: C, 70.61; H, 6.27; N, 6.67.
2-Amino-1-(4-chlorophenyl)-7,7-dimethyl-4-(4methylphenyl)-1,4,5,6,7,8-hexahydroquinolin-5-one 4g
Yield: 78%; m. p.: 200–2018C; IR n: 3240, 3178 (NH2), 3098 (CH,
1
aromatic), 2956 (CH, aliphatic), 1624 (C –
– O), 1572 (C –
– C) cm ; MS
þ
m/z (rel. int.): 393 [M þ 1] (15.40), 392 [M ] (16.90), 77 (100.00).
Anal. calcd. for C24H25ClN2O: C, 73.36; H, 6.41; N, 7.13. Found: C,
73.52; H, 6.18; N, 6.77.
2-Amino-1-(4-chlorophenyl)-7,7-dimethyl-4-phenyl1,4,5,6,7,8-hexahydroquinolin-5-one 4h
Yield: 60%; m. p.: 210–2118C; IR n: 3468, 3360 (NH2), 3090 (CH,
1
aromatic), 2950 (CH, aliphatic), 1646 (C –
– O), 1581 (C –
– C) cm ; MS
m/z (rel. int.): 380 [M þ 2] (16.50), 379 [M þ 1] (21.40), 378 [Mþ]
(27.20), 51 (100.00). Anal. calcd. for C23H23ClN2O: C, 72.91; H,
6.12; N, 7.39. Found: C, 73.08; H, 6.06; N, 6.95.
1-(4-Chlorophenyl)-7,7-dimethyl-5-oxo-3-(4hydroxyphenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline 6
To a solution of enaminone 1 (1.70 mmol) in ethanol (30 mL), the
appropriate aromatic amines (1.70 mmol), 40% formalin
(3.40 mmol), and glacial acetic acid (1 mL) were added. The reaction
mixture was heated under reflux for 2 h and then left to stand
overnight at room temperature. The reaction mixture was diluted
with water (40 mL), basified with NH4OH to pH ¼ 8, and then left
in refrigerator for 3 h. The separated product was filtered, washed
with water (20 mL), and crystallized from ethanol. Yield: 85%; m. p.:
195–1968C; IR n: 3259 (OH), 3060 (CH, aromatic), 2924 (CH,
aliphatic), 1605 (CO), 1556 (C –– C) cm1. 1H-NMR (250 MHz,
CDCl3) d: 0.878 (s, 6H, 2 CH3), 1.947 (s, 2H, CH2), 2.264 (s, 2H,
CH2), 4.297 (s, 2H, CH2), 4.888 (s, 2H, CH2), 6.754–6.876 (m, 4H,
ArH), 7.254–7.337 (m, 4H, ArH), 8.20 (brs, 1H, OH) ppm; 13C-NMR d:
28.33 (2 CH3), 32.87 (C(CH3)2), 41.14 (CH2), 45.34 (CH2), 49.58 (CH2),
72.34 (CH2), 104.14 (Csp2), 116.14–158.87 (Csp2 þ phenyl-C), 195.08
(C –– O) ppm; MS m/z (rel. int.): 384 [M þ 2] (7.4), 383 [M þ 1] (8.9), 382
[Mþ] (19.40), 260 (54.30), 226 (100.00). Anal. calcd. for C22H23ClN2O2:
C, 69.01; H, 6.05; N, 7.32. Found: C, 68.71; H, 5.83; N, 7.80.
1-(4-Chlorophenyl)-3-[4-(ethyoxycarbonylmethoxy)
phenyl]-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8octahydroquinazolin 7
A mixture of compound 6 (5.24 mmol), ethyl bromoacetate
(6.28 mmol), and K2CO3 (10.48 mmol) was stirred in DMF
(10 mL) at room temperature for 24 h. The reaction mixture
was filtered, poured in ice water (20 mL) and left in the refrigerator overnight. The formed product was filtered and crystallized
from ethanol. Yield: 81.3%; m. p.: 808C; IR n: 3061 (CH, aromatic),
1 1
2941 (CH, aliphatic), 1751, 1605 (CO), 1513(C –
– C) cm ; H-NMR
(200 MHz, CDCl3) d: 0.911 (s, 6H, 2 CH3), 1.213–1.285 (t, 3H,
J ¼ 7 Hz, CH3 ester), 1.946 (s, 2H, CH2), 2.196 (s, 2H, CH2),
4.191–4.273 (m, 4H, J ¼ 7 Hz, OCH2 þ CH2 ester), 4.521 (s, 2H,
CH2), 4.788 (s, 2H, CH2), 6.746–7.303 (m, 8H, ArH) ppm; MS m/z
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526
O. I.-E. Sabbagh et al.
(rel. int.): 470.84 [M þ 2] (3.70), 469.85 [M þ 1] (10.50), 468.81
[Mþ] (10.20), 394.86 (2.70), 317.70 (1.50), 273.89 (19.10), 225.96
(36.50), 206.95 (100.00). Anal. calcd. for C26H29ClN2O4: C, 66.59;
H, 6.23; N, 5.97. Found: C, 66.26; H, 6.01; N, 5.90.
1-(4-Chlorophenyl)-3-[4-(hydrazinocarbonylmethoxy)phenyl]7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline 8
A mixture of ester 7 (2.14 mmol) and hydrazine hydrate
(6.42 mmol) in ethanol (10 mL) was refluxed for 2 h. The reaction
mixture was evaporated under reduced pressure and then
poured on crushed ice. The separated product was filtered and
crystallized from ethanol. Yield: 72%; m. p.: 908C; IR n: 3420,
3340, 3240 (NH, NH2), 3020 (CH, aromatic), 2930 (CH, aliphatic),
1 1
1667, 1601 (CO), 1563 (C –
– C) cm ; H-NMR (200 MHz, CDCl3) d:
0.899 (s, 6H, 2 CH3), 1.943 (s, 2H, CH2), 2.181 (s, 2H, CH2), 3.095
(brs, 2H, NH2, exch.), 4.176 (s, 2H, OCH2), 4.461 (s, 2H, CH2), 4.778
(s, 2H, CH2), 6.717–7.304 (m, 8H, ArH), 7.730 (s, 1H, NH, exch.)
ppm. Anal. calcd. for C24H27ClN4O3: C, 63.36; H, 5.98; N, 12.31.
Found: C, 63.60; H, 5.98; N, 12.62.
General procedure for preparation of compounds 9a–d
A mixture of hydrazide intermediate 8 (0.5 g, 1.1 mmol) and
substituted phenyl isothiocyanate or ethyl chloroisocyanate
(1.1 mmol) in ethanol (10 mL) containing 1 mL glacial acetic
acid was heated under reflux for 2 h. The formed product was
filtered and crystallized from aqueous ethanol.
1-(4-Chlorophenyl)-3[(N2-(N-4methoxyphenylaminocarbonothioyl)
hydrazinecarbonylmethoxy)phenyl]-7,7-dimethyl-5-oxo1,2,3,45,6,7,8-octahydroquinazoline 9a
Yield: 78%; m. p.: 165–1668C; IR n: 3350 (NH), 3030 (CH, aromatic),
1 1
2930 (CH, aliphatic), 1640–1601 (2 C –
– O), 1561 (C –
– C) cm ; HNMR (300 MHz, DMSO-d6) d: 0.86 (s, 6H, 2 CH3), 2.02 (s, 2H, CH2),
2.09 (s, 2H, CH2), 4.07 (s, 3H, OCH3), 4.30 (s, 2H, CH2), 4.39 (s, 2H,
CH2), 4.90 (s, 2H, CH2), 6.83–7.46 (m, 14H, ArH þ 2 NH), 9.21 (brs,
1H, NH) ppm; 13C-NMR (DMSO-d6) d: 27.8 (2 CH3), 32.4 (C(CH3)2),
45.4 (CH2), 49.6 (CH2), 66.7 (CH2), 69.8 (CH2), 104.3 (Csp2), 114.7–
152.1 (2 Csp2, C –– N, Ph-C), 156.0 (C ¼ S), 166.7 (C–OH), 192.5
(C –– O). Anal. calcd. for C32H34ClN5O4S: C, 61.97; H, 5.53; N,
11.29. Found: C, 62.10; H, 5.64; N, 11.50.
2
1-(4-Chlorophenyl)-3[(N -(N-4methylphenylaminocarbonothioyl)
hydrazinecarbonylmethoxy)phenyl]-7,7-dimethyl-5-oxo1,2,3,4,5,6,7,8-octa hydroquinazoline 9b
Yield: 75%; m. p.: 160–1618C; IR n: 3325 (NH), 3007 (CH, aromatic),
2955 (CH, aliphatic), 1695–1675 (C –– O), 1556 (C –– C) cm1; 1H-NMR
(200 MHz, CDCl3) d: 0.95 (s, 6H, 2 CH3), 1.20 (s, 2H, CH2), 2.24 (s, 2H,
CH2), 2.34 (s, 3H, CH3), 4.24 (s, 2H, CH2), 4.57 (s, 2H, CH2), 4.85 (s, 2H,
CH2), 6.89–7.36 (m, 12H, ArH), 8.37 (s, 1H, NH), 9.10 (s, 1H, NH), 9.72
(s, 1H, NH) ppm. Anal. calcd. for C32H34ClN5O3S: C, 63.62; H, 5.67; N,
11.59. Found: C, 63.42; H, 5.51; N, 11.91.
1-(4-Chlorophenyl)-3[(N2-(N-phenylaminocarbonothioyl)
hydrazinecarbonylmethoxy)phenyl]-7,7-dimethyl-5-oxo1,2,3,4,5,6,7,8-octahydro quinazoline 9c
Yield: 70%; m. p.: 158–1598C; IR n: 3300 (NH), 3040 (CH, aromatic),
1
2950 (CH, aliphatic), 1660–1620 (2 C –
– O) and 1511 (C –
– C) cm ;
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
1
H-NMR (200 MHz, CDCl3) d: 0.85 (s, 6H, 2 CH3), 2.02 (s, 2H, CH2),
2.09 (s, 2H, CH2), 4.09 (s, 2H, CH2), 4.54 (s, 2H, CH2), 4.94 (s, 2H,
CH2), 6.91–7.44 (m, 13H, ArH þ NH), 9.73 (s, 1H, NH), 10.24 (s, 1H,
NH) ppm. Anal. calcd. for C31H32ClN5O3S: C, 63.09; H, 5.47; N,
11.87. Found: C, 63.20; H, 5.48; N, 12.14.
1-(4-Chlorophenyl)-3[(N2-(N-ethylchloroaminocarbonyl)
hydrazinecarbonylmethoxy)phenyl]-7,7-dimethyl-5-oxo1,2,3,4,5,6,7,8-octahydro quinazoline 9d
Yield: 72%; m. p.: 110–1118C; IR n: 3261 (NH), 3040 (CH, aromatic),
1
2956 (CH, aliphatic), 1689–1649 (2 C ¼ O) and 1510 (C –
– C) cm ;
1
H-NMR (200 MHz, CDCl3) d: 0.92 (s, 6H, 2 CH3), 2.02 (s, 2H, CH2),
2.25 (s, 2H, CH2), 3.59 (brs, 4H, 2 CH2), 4.24 (s, 2H, CH2), 4.59 (s, 2H,
CH2), 4.84 (s, 2H, CH2), 5.80 (s, 1H, NH, D2O exch.), 6.83–7.37 (m,
9H, ArH þ NH), 8.40 (s, 1H, NH, exch.) ppm. Anal. calcd.
for C27H31Cl2N5O4: C, 57.86; H, 5.57; N, 12.50. Found: C, 58.14;
H, 5.47; N, 12.35.
Biological evaluation
Antimicrobial activity
The chosen new compounds were dissolved in DMF at concentration 10 mg/mL. The antibacterial ciprofloxacin (disc, 5 mg;
Oxoid, UK) and the antifungal nystatin were used as references
drugs at the same dose level while DMF was used as a negative
control [23]. The discs were saturated with 5 mg from the newly
synthesized compounds and dried in an oven at 608C before
loading on the surface of the seeded Mueller–Hinton agar
medium (Oxoid, UK). The agar was seeded with Staphylococcus
aureus as Gram-positive cocci and Bacillus subtilus as Gram-positive
rods, Escherichia coli as Gram-negative rods as well as Candida
albicans as fungi. The plates were incubated at 378C for 24 h
and the diameters of the inhibition zone were measured
in mm. The results of antimicrobial activity for the new compounds are recorded in Table 1. Bacterial and fungal strains were
isolated and identified by the Department of Microbiology,
National Research Center, Dokki, Giza, Egypt.
Cytotoxic activity
Cell culture
The human hepatocarcinoma cell line (HepG2),
which was provided from ATCC, USA, was used to evaluate the
cytotoxic effect of the tested compounds. Cells were routinely
cultured in DMEM (Dulbeco’s Modified Eagle’s Medium), which
was supplemented with 10% fetal bovine serum (FBS), 2 mL
glutamine containing 100 units/mL penicillin G sodium,
100 units/mL
streptomycin
sulphate,
and
250 ng/mL
amphotericin B. Cells were maintained at subconfluence at
378C in humidified air containing 5% CO2. For subculturing,
monolayer cells were harvested after trypsin/EDTA treatment
at 378C. Cells were used when confluence had reached 75%.
The test compounds were dissolved in dimethyl sulphoxide
(DMSO) and then diluted in the assay. All cell culture
materials were obtained from Cambrex BioScience
(Copenhagen, Denmark). All chemicals were purchased from
Sigma/Aldrich, USA, except mentioned. All experiments were
repeated three times, unless mentioned.
As reagents, we used MTT solution: 5 mg/mL of MTT in 0.9%
NaCl and acidified isopropanol: 0.04 N HCl in absolute
isopropanol.
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Arch. Pharm. Chem. Life Sci. 2010, 9, 519–527
Synthesis of Nonclassical Acridines
Cells (0.5 105 cells/well), in serum-free media, were plated in
a flat bottom 96-well microplate and treated with 20 mL of
different concentrations of each tested compounds for 48 h at
378C in a humidified 5%-CO2 atmosphere [24]. After incubation,
media were removed and 40 mL MTT solution/well were added
and then incubated for an additional 4 h. The blue crystals were
solubilized by adding 180 mL of acidified isopropanol/well and
plate was shacked at room temperature, followed by photometric determination of the absorbance at 570 nm using microplate ELISA reader. Triplicates were performed for each
concentration and the average was calculated. Data were
expressed as the percentage of relative viability compared with
the untreated cells or the vehicle control. Cytotoxicity indicated
by <100% relative viability.
Calculation
Percentage of relative viability was calculated using the following equation:
½Absorbance of treated cells=Absorbance of control cellsÞ 100
(1)
Then the half-maximal inhibitory concentration (IC50) was
calculated from the equation of the dose-response curve.
Statistical analysis
Data were analyzed using the computer program SPSS (SPSS Inc.,
Chicago, IL, USA). The differences in mean values were determined by analysis of variance (one-way ANOVA) followed by least
significant difference (LSD).
The authors would like to express their thanks to Dr. Amira Gamal El-Din,
Lecturer in the Biochemistry Department, National Research Center, for
performing the cytotoxic evaluation, and also Raaed Said Mahmud,
Assistant Lecturer in the Microbiology Department, National Research
Center for carrying out the antimicrobial activity tests.
The authors have declared no conflict of interest.
References
[1] V. Nadaraj, S. T. Selvi, S. Mohan, Eur. J. Med. Chem. 2009, 44,
976–980.
[2] E. H. Abdel Aal, Zag. J. Pharm. Sci. 2005, 14, 33–42.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
527
[3] M. I. Al-Ashmawi, M. A. El-Sadek, M. A. El-Bermawy, O. I. ElSabbagh, Zag. J. Pharm. Sci. 1994, 3, 144–150.
[4] O. I. El-Sabbagh, H. M. Rady, Eur. J. Med. Chem. 2009, 44, 3680–
3686.
[5] M. E. El-Sadek, M. Aboukull, O. I. El-Sabbagh, H. M. Shallal,
Monatsh. Chem. 2007, 138, 219–225.
[6] M. Kidwai, S. Saxena, M. K. R. Khan, S. S. Thukral, Eur. J. Med.
Chem. 2005, 40, 816–819.
[7] H. H. Lee, W. R. Wilson, D. M. Ferry, P. Vanzijl, et al., J. Med.
Chem. 1996, 39, 2508–2517.
[8] M. Kimura, I. Okabayashi, A. Kato, Chem. Pharm. Bull. 1989, 37,
697–701.
[9] I. Sanchez, R. Reches, D. H. Caignard, P. Renard, M. D. Pujol,
Eur. J. Med. Chem. 2006, 41, 340–352.
[10] B. K. Srivastava, M. Solanki, B. Mishra, R. Soni, et al., Bioorg.
Med. Chem. Lett. 2007, 17, 1924–1929.
[11] S. Jazayeri, M. H. Moshafi, L. Firoozpour, S. Emami, et al. Eur.
J. Med. Chem. 2009, 44, 1205–1209.
[12] N. Rameshkumar, M. Ashokkumar, E. H. Subramanian, Eur.
J. Med. Chem. 2003, 38, 1001–1004.
[13] A. M. S. El-Sharief, Y. A. Ammar, M. A. Zahran, A. H. Ali, M. S.
A. El-Gaby, Molecules 2001, 6, 267–278.
[14] L. Kubicová, M. Sustr, K. Král’ová, V. Chobot, et al. Molecules
2003, 8, 756–769.
[15] N. Viswanathan, N. N. Rawle, D. H. Gawad, J. Chem. Res. 1985,
244–245.
[16] M. A. Shabaan, O. I. El-Sabbagh, H. H. Kadri, E. Saad Al-Din,
Az. J. Pharm. Sci. 2008, 38, 81–96.
[17] M. I. Al-Ashmawi, S. M. Sakr, E. H. Abdel-Aal, A. Abou Sier,
Bull. Fac. Pharm. 1991, 29, 9–13.
[18] S. Kantevari, R. Bantu, L. Nagaraupu, J. Mol. Catal. 2007, 269
(A), 53–57.
[19] T. I. Reddy, R. S. Verma, Tetrahedron Lett. 1997, 38, 1721–1724.
[20] J. W. Karras, N. A. Lindquist, D. R. Camenisch, L. Elam, et al.,
Pure Appl. Chem. 1998, A35, 395–400.
[21] S. A. El Batran, A. E. N. Osman, M. M. Ismail, A. M. El Sayed,
Inflammopharmacology 2006, 14, 62–71.
[22] R. M. Kumbhare, M. Sridhar, Catal. Commun. 2008, 9, 403–
405.
[23] H. M. Ericsson, J. C. Sherris, Acta Pathol. Microbiol. Scand. 1971,
217 (Suppl. B), 1–90.
[24] M. B. Hansen, S. E. Nielsen, K. Berg, J. Immunol. Methods 1989,
119, 203–210.
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