Synthesis and antimicrobial activities of novel bisacridine-1,8-dione derivatives

Article abstract of DOI:10.1007/s00044-010-9321-6

A series of bisacridine-1,8-dione derivatives were synthesized by one-pot reaction of aromatic dialdehydes, dimedone or cyclohexane-1,3-dione and primer aromatic amines in acetonitrile to utilizing Amberlyst-15 as a heterogeneous catalyst. The structures

Full text of DOI:10.1007/s00044-010-9321-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:293–299
DOI 10.1007/s00044-010-9321-6
ORIGINAL RESEARCH
Synthesis and antimicrobial activities of novel
bisacridine-1,8-dione derivatives
•
•
Muharrem Kaya Yılmaz Yıldırır
¨
Gokc¸en Y. C¸ elik
Received: 19 May 2009 / Accepted: 12 February 2010 / Published online: 27 February 2010
Ó Springer Science+Business Media, LLC 2011
Abstract A series of bisacridine-1,8-dione derivatives
were synthesized by one-pot reaction of aromatic dialde-
hydes, dimedone or cyclohexane-1,3-dione and primer
aromatic amines in acetonitrile to utilizing Amberlyst-15 as
a heterogeneous catalyst. The structures of compounds
were characterized by FT-IR, NMR, and elemental analy-
sis. Antimicrobial activities of these compounds were
determined by using the disc diffusion method against to
these gram-positive and gram-negative bacteria and yeast.
The results were compared with reference discs.
2001), fungicidal (Wainwright, 2001; Srivastava and Ni-
zamuddin, 2004), anti-multidrug-resistant (Gallo et al.,
2003), and widely prescribed as calcium b-blockers (Bos-
sert and Vater, 1971, 1989; Berkan et al., 2002). They have
similarities in structure to the biologically important
compounds NADH and NADPH (Singh et al., 1982;
Odabasoglu et al., 2007; Srividya et al., 1996).
As for the preparation of acridine-1,8-dione derivatives,
generally similar methods have been employed under tra-
ditional heating condition including a two-step procedure
and complex operation (Murugan and Ramakrishnan, 1997,
2001; Shanmugasundaram et al., 1997; Kaya et al., 2009).
In addition, synthesis of only very few bisacridine-1,8-
dione derivatives reported in the literature for microwave-
heating synthesis in solid phase (Hua et al., 2005). Each of
these methods have their own advantages but also suffer
from one or more disadvantages such as long reaction time,
complex processes, low yield, and hazardous reaction
conditions. Recently, heterogeneous catalysts have been
used widely as organic transformations in organic reactions
(Sirivinas and Das, 2003; Ramesh et al., 2003; Das et al.,
2004a, b; 2006). These methods have advantages process
clean, safe, high-yielding, and inexpensive. Due to these
advantages, we have used to efficient method as reported in
literature for the synthesis of acridine-1,8-diones (Das
et al., 2006). In this method using Amberlsyt-15 catalyst
has some properties such as easily run, inexpensiveness,
non-toxicity, removable easily from reaction medium, and
utility several times. In this study, bisacridine-1,8-diones
were synthesized via one-pot reaction of dimedone, aro-
matic dialdehydes, and primer amines. Amberlyst-15 (in
acetonitrile) was used as catalyst in these syntheses. As a
result, we have performed the synthesis of bisacridine-1,8-
dione derivatives in high yields using Amberlyst-15 as a
heterogeneous solid acid.
Keywords Bisacridine-1,8-diones ꢀ
Antimicrobial activity ꢀ Antibiotics
Introduction
Acridine and acridine-1,8-dione derivatives are important
compounds because these compounds have pharmaceutical
properties such as antitumor (Mikata et al., 1998), cyto-
toxic (Antonini et al., 1999), anticancer (Gamega et al.,
1999), antimicrobial (Ngadi et al., 1990; Wainwright,
M. Kaya
Faculty of Science and Arts, Chemistry Department, Dumlupınar
University, 43100 Ku¨tahya, Turkey
Y. Yıldırır (&)
Faculty of Science and Arts, Chemistry Department,
Gazi University, Teknikokullar, 06500 Ankara, Turkey
e-mail: yildirir@gazi.edu.tr
G. Y. C¸ elik
Faculty of Science and Arts, Biology Department, Nigde
˘
University, 51240 Nigde, Turkey
˘
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Med Chem Res (2011) 20:293–299
Antimicrobial activity
The newly synthesized bisacridine-1,8-dione com-
pounds 4a–o were evaluated for their antimicrobial activity
against Shigella sonnei, Salmonella 21.3, Bacillus subtilis,
B. cereus, Staphylococcus aureus, Escherichia coli,
Staphylococcus epidermidis, Pseudomonas aeruginosa,
Candida albicans, and Saccharomyces cerevisiae. These
compounds were active on both Gram-positive (Bacillus
subtilis, B. cereus, Staphylococcus aureus, Staphylococcus
epidermidis) and Gram-negative (Shigella sonnei, Salmo-
nella, Escherichia coli, Pseudomonas aeruginosa) bacteria.
As seen in Table 2, all the compounds except compound 4e
showed antibacterial and antifungal activity against test
microorganisms. Compounds 4a, b, c, h, i, n, and 4o were
not active against B. subtilis and B. cereus. Also compound
4a was not active against S. epidermidis. Compound 4f had
no inhibition effect against B. cereus and S. cerevisiae
while compound 4g was not active against Shigella sonnei
and S. aureus. Compound 4j showed activity against only
S. sonnei, B. cereus, E. coli, and P. aeruginosa while
compound 4k showed activity against all the test micro-
organisms. Compound 4l had no inhibition effect against S.
aureus, P. aeruginosa and 4m only was not active against
S. epidermidis. From antifungal assay, it was observed that
all the compounds show significant activity against
C. albicans and S. cerevisiae. Table 2 showed that most of
compounds show more inhibition effect against tested
bacteria and yeast and these activities could reach the
effectiveness of the conventional reference antibiotics.
Acridines are known to be biologically versatile com-
pounds possessing several pharmacological activities,
including antimicrobial (Wainwright, 2001; Ngadi
et al.,1990). Some researchers reported that all of the
synthesized acridine derivatives exhibited moderate anti-
bacterial and antifungal activity (Patel et al. 2006).
Result and discussion
Chemistry
In this study, 15 bisacridine-1,8-dione derivatives were pre-
pared via one-pot reaction in acetonitrile to utilizing Am-
berlyst-15 as a heterogeneous catalyst. The structures of the
synthesized bisacridinedione derivatives, 4a–o, were con-
firmed by IR, 1H NMR spectra, and elemental analysis data.
The IR spectra of the compounds were showed the sharp
peaks for the carbonyl groups in region between 1720 and
1633 cm-l. The compounds 4a, b, h, i were measured
peaks belong to CN group in the range 2233–2229 cm-1
.
Besides, in the IR spectra of the compounds, aliphatic C–H
stretching bands at 2962–2942 cm-1 and aromatic C–H
stretching bands at 3065–3021 cm-1 were observed.
1
Experimental
The H NMR spectra of these compounds were showed
singlet peaks belong to protons of the methyl groups in
1
positions 3 and 6 at 0.66 and 0.94 ppm. In the H NMR
Chemistry
spectra, multiple peaks were showed in the range
1.65–2.96 ppm for the CH2 group protons of the cyclo-
hexane rings. The signals for the CH protons at
4.53–5.41 ppm and signals for the aromatic protons in the
range 6.32–8.30 ppm were observed. Acid protons of
compounds 4f, g, l, m gave broad signals at 12.27, 12.33,
12.40, and 12.62 ppm, respectively.
The chemicals used in the synthesis of the novel bisacri-
dine-1,8-dione compounds were purchased from Aldrich
Chemical Company. All chemicals and solvents used for
the synthesis were spectroscopic reagent grade. Melting
points were measured on a Bibby Stuart Scientific appa-
ratus. FT-IR spectra were recorded from Bruker Optics,
Vertex 70 FT-IR spectrometer using ATR diamond crystal.
1H NMR spectra were recorded on a Bruker DPX-400
FT-NMR instrument with chloroform-d (CDCl3) and
dimethyl sulfoxide (DMSO-d6) as solvent with trimethylsi-
lane as the internal reference. Chemical shifts are expressed
in d units (ppm). The elemental analyses (C, H, N) were
recorded on an Elemental Analyzer LECO CHNS-932.
The yield, melting points, and elemental analyses values
of compounds 4a–o are given in Table 1.
R3
R1
R1
N
R1
R1
OHC-R2 -CHO
O
(2)
O
O
R2
O
O
Amberlsyt-15
+
4
R1
CH3CN, Reflux
Typical procedure for preparation of bisacridine-1,
8-diones (4a–o)
O
R1
2
3R-NH2
(1)
R1
R1
(3)
N
1
1
R
R
R3
A mixture of aromatic dialdehydes (1.0 mmol), cyclohex-
ane-1,3-dione or dimedone (4.0 mmol), aromatic amines
(2 mmol), and Amberlyst-15 (400 mg) in acetonitrile
(20 mL) were stirred at reflux for 4 h. The progress of the
(4)
Scheme 1 Synthesis scheme of novel bisacridine-1,8-dione
derivatives
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295
Table 1 Preparation of 4a–o promoted by Amberlyst-15 in CH3CN and elemental analyses of compounds 4a–o
Entry
R1
OHC–R2–CHO
R3
Yield (%)
m.p. (°C)
Elemental analyses (%) Calc./Found
C
H
N
4a
4b
4c
4d
4e
4f
H
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,3-(OHC)2C6H4
1,4-(OHC)2C6H4
1,4-(OHC)2C6H4
3-CNC6H4
81
74
80
72
77
76
73
79
80
71
78
77
75
82
84
180a
153a
216a
167a
260a
327a
298a
290–291
221
77.73/77.56
77.73/77.63
76.50/76.42
76.64/76.41
76.64/76.49
73.78/73.61
73.78/73.59
78.80/78.63
78.80/78.60
77.85/77.70
77.85/77.75
75.33/75.49
75.33/75.17
74.18/74.03
67.10/67.01
5.39/5.36
5.39/5.42
6.13/6.09
6.15/6.12
6.15/6.10
5.38/5.34
5.38/5.33
6.61/6.57
6.61/6.59
7.26/7.21
7.26/7.22
6.56/6.53
6.56/6.58
6.46/6.41
5.85/5.80
7.88/7.81
7.88/7.82
8.11/8.08
3.89/3.87
3.89/3.85
3.74/3.76
3.74/3.70
6.81/6.75
6.81/6.76
3.36/3.38
3.36/3.33
3.25/3.23
3.25/3.22
3.33/3.30
3.01/2.97
H
2-CNC6H4
H
6-CH3Prydine
3-CH3OC6H4
2-CH3OC6H4
4-HOOCC6H4
3-HOOCC6H4
3-CNC6H4
H
H
H
4g
4h
4i
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2-CNC6H4
4j
3-CH3OC6H4
2-CH3OC6H4
4-HOOCC6H4
3-HOOCC6H4
4-ClC6H4
228
4k
4l
265
320a
256a
282a
210a
4m
4n
4o
a
4-BrC6H4
Decomposition
reaction was monitored by TLC. After completion of the
reactions, the mixture was filtered and cooled to room
temperature. The crude products were purified by recrys-
tallization from ethyl acetate–methanol. Data all of the
compounds are shown below.
1H NMR (400 MHz, CDCl3) d: 1.84–1.87 (m, 4H,
2 9 CH2), 1.95–2.00 (m, 4H, 2 9 CH2), 2.21–2.35 (m,
12H, 6 9 CH2), 2.48–2.58 (m, 4H, 2 9 CH2), 2.59 (s, 3H,
CH3), 4.72 and 5.35 (2 9 d, 2H, J = 18.0 Hz, CH), 6.85
(m, 2H, ArH), 6.95–7.15 (m, 3H, ArH), 7.25–7.32 (m, 2H,
ArH), 7.41–7.48 (m, 1H, ArH), 7.78–7.38 (m, 2H, ArH).
9,90-(1,3-phenylene)bis(10-(3-methoxyphenyl)-3,4,6,7-
tetrahydroacridine-1,8(2H,5H,9H,10H)-dione) (4d): IR
(KBr) m: 3055 (aromatic CH), 2942 (aliphatic CH), 1634
3,30-(9,90-(1,3-phenylene)bis(1,8-dioxo-1,2,3,4,5,6,7,8-
octahydroacridine-10,9(9H)-diyl))dibenzonitrile (4a): IR
(KBr) m: 3062 (aromatic CH), 2946 (aliphatic CH), 2232
(CN), 1634 (C=O), 1576 (aromatic C=C), 1229 (CN)
1
1
cm-1. H NMR (400 MHz, CDCl3) d: 1.82–1.96 (m, 6H,
(C=O), 1571 (aromatic C=C), 1229 (CN) cm-1. H NMR
3 9 CH2), 2.03–2.10 (m, 6H, 3 9 CH2), 2.20–2.41 (m,
8H, CH2), 2.54–2.60 (m, 2H, CH2), 2.69–2.75 (m, 2H,
CH2), 4.79 and 5.36 (2 9 d, 2H, J = 10.4 Hz, CH), 6.91
(m, 1H, ArH), 7.02–7.19 (m, 3H, ArH), 7.20–7.25 (m, 2H,
ArH), 7.40–7.75 (m, 4H, ArH), 7.83 (t, 2H, J = 6.1 Hz,
ArH).
2,20-(9,90-(1,3-phenylene)bis(1,8-dioxo-1,2,3,4,5,6,7,8-
octahydroacridine-10,9(9H)-diyl))dibenzonitrile (4b): IR
(KBr) m: 3059 (aromatic CH), 2947 (aliphatic CH), 2230
(CN), 1636 (C=O), 1575 (aromatic C=C), 1230 (CN)
cm-1. 1H NMR (400 MHz, CDCl3) d: 1.76–2.05 (m, 10H,
5 9 CH2), 2.25–2.40 (m, 10H, 5 9 CH2), 2.53–2.56
(d 9 t, 2H, CH2), 2.66–2.70 (d 9 t, 2H, CH2), 4.73 and
5.32 (2 9 d, 2H, J = 12.8 Hz, CH), 6.87 (d, 1H,
J = 7.8 Hz, ArH), 7.01–7.11 (m, 2H, ArH), 7.21–7.35
(m, 3H, ArH), 7.60–7.66 (m, 2H, ArH), 7.83–7.93 (m, 4H,
ArH).
(400 MHz, CDCl3) d: 1.74–1.92 (m, 4H, 2 9 CH2),
1.95–2.10 (m, 4H, 2 9 CH2), 2.22–2.40 (m, 12H,
6 9 CH2), 2.49–2.58 (m, 2H, CH2), 2.70–2.76 (m, 2H,
CH2), 3.88 (s, 6H, 2 9 OCH3), 4.80 and 5.38 (2 9 d, 2H,
J = 18.8 Hz, CH), 6.71–6.83 (m, 4H, ArH), 7.03–7.25
(m, 6H, ArH), 7.41–7.55 (m, 2H, ArH).
9,90-(1,3-phenylene)bis(10-(2-methoxyphenyl)-3,4,6,7-
tetrahydroacridine-1,8(2H,5H,9H,10H)-dione) (4e): IR
(KBr) m: 3060 (aromatic CH), 2944 (aliphatic CH), 1634
1
(C=O), 1574 (aromatic C=C), 1229 (CN) cm-1. H NMR
(400 MHz, DMSO-d6) d: 1.65–1.99 (m, 8H, 4 9 CH2),
2.07–2.31 (m, 12H, 6 9 CH2), 2.50–2.52 (m, 2H, CH2),
2.64–2.69 (m, 2H, CH2), 3.91 (s, 6H, 2 9 OCH3), 4.56
and 5.14 (2 9 d, 2H, J = 15.6 Hz, CH), 6.53–6.78 (m,
2H, ArH), 6.93–7.14 (m, 5H, ArH), 7.23–7.56 (m, 5H,
ArH).
4,40-(9,90-(1,3-phenylene)bis(1,8-dioxo-1,2,3,4,5,6,7,8-
octahydroacridine-10,9(9H)-diyl))dibenzoic acid (4f): IR
(KBr) m: 3365 (COOH), 2952 (aliphatic CH), 1717 and
9,90-(1,3-phenylene)bis(10-(6-methylpyridin-2-yl)-3,4,6,
7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione) (4c): IR
(KBr) m: 3056 (aromatic CH), 2945 (aliphatic CH), 1668
1
1640 (C=O), 1596 (aromatic C=C), 1235 (CN) cm-1. H
and 1636 (C=O), 1562 (aromatic C=C), 1175 (CN) cm-1
.
NMR (400 MHz, DMSO-d6) d: 1.66–1.71 (m, 2H, CH2),
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297
1.84–1.98 (m, 8H, 4 9 CH2), 2.21–2.34 (m, 10H,
5 9 CH2), 2.49–2.51 (m, 2H, CH2), 2.61–2.65 (m, 2H,
CH2), 4.55 and 5.15 (2 9 d, 2H, J = 19.2 Hz, CH), 6.55
(d, 1H, J = 8.5 Hz, ArH), 6.92–7.29 (m, 3H, ArH), 7.61
(d, 4H, J = 8.7 Hz, ArH), 8.10 (d, 4H, J = 8.7 Hz, ArH),
12.27 (br, 2H, COOH).
9,90-(1,3-phenylene)bis(10-(2-methoxyphenyl)-3,3,6,6-
tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,
10H)-dione) (4k): IR (KBr) m: 3045 (aromatic CH), 2957
(aliphatic CH), 1636 (C=O), 1585 (aromatic C=C),
1
1221(CN) cm-1. H NMR (400 MHz, CDCl3) d: 0.75 (s,
9H, 3 9 CH3), 0.87 (s, 12H, 4 9 CH3), 1.01 (s, 3H, CH3),
1.78–1.82 (m, 4H, 2 9 CH2), 2.03–2.16 (m, 8H,
4 9 CH2), 2.33–2.48 (m, 4H, 2 9 CH2), 3.57 (s, 6H,
2 9 OCH3), 4.64 and 5.19 (2 9 d, 2H, J = 12.4 Hz,
2 9 CH), 6.77–7.07 (m, 4H, ArH), 7.35–7.64 (m, 4H,
ArH), 7.78–7.98 (m, 2H, ArH), 8.12–8.30 (m, 2H, ArH).
4,40-(9,90-(1,3-phenylene)bis(3,3,6,6-tetramethyl-1,8-
dioxo-1,2,3,4,5,6,7,8-octahydroacridine-10,9(9H)-diyl))
dibenzoic acid (4l): IR (KBr) m: 3048 (aromatic CH),
2961(aliphatic CH), 1720 and 1638 (C=O), 1603 (aro-
3,30-(9,90-(1,3-phenylene)bis(1,8-dioxo-1,2,3,4,5,6,7,8-
octahydroacridine-10,9(9H)-diyl))dibenzoic acid (4g): IR
(KBr) m: 3050 (aromatic CH), 2948 (aliphatic CH), 1718
and 1633 (C=O), 1586 (aromatic C=C), 1231 (CN) cm-1
.
1H NMR (400 MHz, CDCl3 and DMSO-d6) d: 1.73–2.00
(m, 8H, 4 9 CH2), 2.19–2.25 (m, 8H, 4 9 CH2),
2.50–2.61 (m, 4H, 2 9 CH2), 2.78–2.90 (m, 4H,
2 9 CH2), 4.56 and 5.19 (2 9 d, 2H, J = 18.8 Hz, CH),
6.88–7.06 (m, 4H, ArH), 7.39–7.68 (m, 4H, ArH),
7.85–7.90 (m, 2H, ArH), 8.07 (d, 2H, J = 7.55, ArH),
12.40 (br, 2H, COOH).
matic C=C), 1221 (CN) cm-1 1H NMR (400 MHz,
.
CDCl3 and DMSO-d6) d: 0.70 (s, 9H, 3 9 CH3), 0.84 (s,
12H, 4 9 CH3), 1.00 (s, 3H, CH3), 1.76–1.82 (m, 4H,
2 9 CH2), 1.93–2.11 (m, 8H, 4 9 CH2), 2.49–2.51 (m,
4H, 2 9 CH2), 4.60 and 5.08 (2 9 d, 2H, J = 10.0 Hz,
2 9 CH), 6.74 (d, 1H, J = 7.9 Hz, ArH), 6.96–7.14 (m,
2H, ArH), 7.32–7.48 (m, 5H, ArH), 8.16 (d, 4H,
J = 8.0 Hz, ArH), 12.62 (br, 2H, COOH).
3,30-(9,90-(1,3-phenylene)bis(3,3,6,6-tetramethyl-1,8-dioxo-1,
2,3,4,5,6,7,8-octahydroacridine-10,9(9H)-diyl))dibenzonit-
rile (4h): IR (KBr) m: 3051(aromatic CH), 2959 (aliphatic CH),
2233 (CN), 1640 (C=O), 1580 (aromatic C=C), 1219 (CN)
cm-1. 1H NMR (400 MHz, CDCl3) d: 0.71 (s, 9H, 3 9 CH3),
0.85 (s, 12H, 4 9 CH3), 0.98 (s, 3H, CH3), 1.68 (t, 4H,
J = 17.0 Hz, 2 9 CH2), 1.94–2.12 (m, 10H, 5 9 CH2), 2.36
(q, 2H, J = 8.4 Hz, CH2), 4.59 and 5.15 (2 9 d, 2H,
J = 11.6 Hz, 2 9 CH), 6.68 (d, 1H, J = 7.8 Hz, ArH), 6.99 (t,
1H, J = 6.2 Hz, ArH), 7.03–7.12 (s, 2H, ArH), 7.20 (m, 1H,
ArH), 7.34 (m, 1H, ArH), 7.41–7.46 (m, 2H, ArH), 7.67–7.52
(m, 4H, ArH).
3,30-(9,90-(1,3-phenylene)bis(3,3,6,6-tetramethyl-1,8-
dioxo-1,2,3,4,5,6,7,8-octahydroacridine-10,9(9H)-diyl))
dibenzoic acid (4m): IR (KBr) m: 3041 (aromatic CH),
2958 (aliphatic CH), 1717 and 1637 (C=O), 1585 (aro-
matic C=C), 1220 (CN) cm-1 1H NMR (400 MHz,
.
CDCl3) d: 0.66 (s, 9H, 3 9 CH3), 0.79 (s, 12H,
4 9 CH3), 0.95 (s, 3H, CH3), 1.71 (d, 4H, J = 17.0 Hz,
2 9 CH2), 1.94–2.07 (m, 8H, 4 9 CH2), 2.24–2.50 (m,
4H, 2 9 CH2), 4.53 and 5.04 (2 9 d, 2H, J = 11.2 Hz,
2 9 CH), 6.72 (d, 1H, J = 7.8 Hz, ArH), 6.90–7.08 (m,
4H, ArH), 7.42–7.56 (m, 3H, ArH), 7.71–7.98 (m, 2H,
ArH), 8.07 (d, 2H, J = 7.7 Hz, ArH), 12.33 (br, 2H,
COOH).
2,20-(9,90-(1,3-phenylene)bis(3,3,6,6-tetramethyl-1,8-
dioxo-1,2,3,4,5,6,7,8-octahydroacridine-10,9(9H)-diyl))
dibenzonitrile (4i): IR (KBr) m: 3053 (aromatic CH),
2959 (aliphatic CH), 2229 (CN), 1639 (C=O), 1579
1
(aromatic C=C), 1220 (CN) cm-1. H NMR (400 MHz,
CDCl3) d: 0.75 (s, 9H, 3 9 CH3), 0.87 (s, 12H,
4 9 CH3), 0.98 (s, 3H, CH3), 1.60–1.77 (m, 4H,
2 9 CH2), 1.96–2.19 (m, 8H, 4 9 CH2), 2.32–2.45 (m,
4H, 2 9 CH2), 4.62 and 5.14 (2 9 d, 2H, J = 10.0 Hz,
2 9 CH), 6.73 (d, 1H, J = 7.8 Hz, ArH), 6.97–7.08 (m,
2H, ArH), 7.10–7.19 (s, 1H, ArH), 7.22–7.31 (m, 2H,
ArH), 7.58–7.64 (m, 2H, ArH), 7.79–7.86 (m, 3H, ArH),
8.20 (d, 1H, J = 7.7 Hz, ArH).
9,90-(1,4-phenylene)bis(10-(4-chlorophenyl)-3,3,6,6-tet-
ramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-
dione) (4n): IR (KBr) m: 3021(aromatic CH), 2960 (ali-
phatic CH), 1637 (C=O), 1579 (aromatic C=C), 1220 (CN)
cm-1 1H NMR (400 MHz, CDCl3) d: 0.81 (s, 12H,
.
4 9 CH3), 0.92 (s, 12H, 4 9 CH3), 1.78–2.15 (m, 14H,
7 9 CH2), 2.87–2.96 (m, 2H, CH2), 5.27 (s, 2H, 2 9 CH),
7.13–7.24 (m, 8H, ArH), 7.70 (d, 4H, J = 8.1 Hz,
ArH).
9,90-(1,4-phenylene)bis(10-(4-bromophenyl)-3,3,6,6-tet-
ramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-
dione) (4o): IR (KBr) m: 3023 (aromatic CH), 2962 (ali-
phatic CH), 1637 (C=O), 1578 (aromatic C=C), 1221(CN)
.
cm-1 1H NMR (400 MHz, CDCl3) d: 0.83 (s, 12H,
4 9 CH3), 0.95 (s, 12H, 4 9 CH3), 1.79 (d, 4H, 2 9 CH2),
1.91–2.22 (m, 12H, 6 9 CH2), 5.31 (s, 2H, 2 9 CH),
7.12–7.23 (m, 8H, ArH), 7.77 (d, 4H, J = 7.9 Hz, ArH).
9,90-(1,3-phenylene)bis(10-(3-methoxyphenyl)-3,3,6,6-
tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,
10H)-dione) (4j): IR (KBr) m: 3043 (aromatic CH), 2956
(aliphatic CH), 1664 (C=O), 1572 (aromatic C=C), 1224
1
(CN) cm-1. H NMR (400 MHz, CDCl3 and DMSO-d6)
d: 0.88 (s, 9H, 3 9 CH3), 0.94 (s, 12H, 4 9 CH3), 0.99 (s,
3H, CH3), 1.91–2.02 (m, 10H, 5 9 CH2), 2.21–2.34 (m,
4H, 2 9 CH2), 2.41–2.43 (m, 2H, CH2), 3.62 (s, 6H,
2 9 OCH3), 4.92 and 5.41 (2 9 d, 2H, J = 12.4 Hz,
2 9 CH), 6.32–6.77 (m, 8H, ArH), 6.87–6.92 (m, 2H,
ArH), 7.02–7.07 (m, 2H, ArH).
123

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References
Biology
Antonini I, Polucci P, Kelland LR, Menta E, Pescalli N, Martelli S
(1999) 2,3-Dihydro-1H, 7H-pyrimido[5,6,1-de]acridine-1,3,7-tri-
one derivatives, a class of cytotoxic agents active on multidrug-
resistant cell lines: synthesis, biological evaluation, and structure-
activity relationships. J Med Chem 42(14):2535–2541
Berkan O, Sarac B, Simsek R, Yildirim S, Sariogli Y, Safak C (2002)
Vasorelaxing properties of some phenylacridine type potassium
channel openers in isolated rabbit thoracic arteries. Eur J Med
Chem 37(6):519–523
Bossert F, Vater W (1971) Dihydropyridines, a new group of strongly
effective coronary therapeutic agents. Naturwis 58(11):578
Bossert F, Vater W (1989) 1,4-Dihydropyridines—a basis for
developing new drugs. Med Res Rev 9(3):291–324
Das B, Banerjeee J, Ravindranath N (2004a) A simple and facile
stereoselective synthesis of (Z)- and (E)-allyl halides catalyzed
by silica supported sodium hydrogen sulfate: factors influencing
the yields and stereochemistry of allyl halides. Tetrahedron
60:8357–8361
Test microorganisms
The bacterial subcultures for Shigella sonnei RSKK 877,
Salmonella 21.3, Bacillus subtilis RSKK 240, B. cereus
RSKK 863, Staphylococcus aureus ATCC 25923, Esche-
richia coli ATCC 35218, Staphylococcus epidermidis Mu
30, Pseudomonas aeruginosa ATCC 27853, Candida
albicans 16231, and Saccharomyces cerevisiae TP (3–2)
were obtained from Gazi University, Biology Department.
Bacterial strains were cultured overnight at 37°C in
Nutrient Broth and the yeast were cultured overnight at
30°C in Sabouraud Dextrose Broth for antibacterial and
antifungal activity tests. These stock cultures were stored in
the dark at 4°C during the survey.
Das B, Mahender G, Kumar VS, Chowdary N (2004b) Chemoselec-
tive deprotection of tritylethers using silica-supported sodium
hydrogen sulfate. Tetrahedron Lett 45:6709–6711
Biological screening
Das B, Thirupati P, Mahender I, Reddy VS, Rao KY (2006) Amberlyst-
15: an efficient reusable heterogeneous catalyst for the synthesis
of 1,8-dioxo-octahydroxanthenes and 1,8-dioxo-decahydroacri-
dines. J Mol Catalysis A: Chemical 247(1–2):233–239
Gallo S, Atifi S, Mohamoud A, Santelli-Rouvier C, Wolfart K,
Molnar J, Barbe J (2003) Synthesis of aza mono, bi and tricyclic
compounds. Evaluation of their anti MDR activity. Eur J Med
Chem 38(1):19–26
Gamega SA, Spicer JA, Atwell GJ, Finlay GJ, Baguley BC, Deny WA
(1999) Structure-activity relationships for substituted bis(acri-
dine-4-carboxamides): a new class of anticancer agents. J Med
Chem 42(13):2383–2393
Antibacterial activities of the compounds were determined
by using the disc diffusion method (NCCLS 1997). The
antimicrobial screening was performed using Mueller–
Hinton Agar for bacteria and Sabouraud Dextrose Agar for
yeast. The culture suspensions were prepared and adjusted
by comparing against 0.5 Mc Farland turbidity standard
tubes. Mueller–Hinton Agar (20 ml) was poured into each
sterile Petri dish after injecting cultures (100 ll) of micro-
organisms and distributing medium in Petri dish homoge-
neously. Compounds were filtered with a pore size of
0.45 lm. Compounds 4a, b, c, d were dissolved in CHCl3 of
5 mg ml-1. All of the other compounds were dissolved in
Hua GP, Zhang XJ, Shi F, Tu SJ, Xu JN, Wang Q, Zhu XT, Zhang JP,
Ji SJ (2005) One-pot synthesis of 10-methyl-1,2,3,4,5,6,7,8,9,10-
decahydroacridine-1,8-dione derivatives under microwave heat-
ing without catalyst. Chin J Chem 23(12):1646–1650
DMSO of 5 mg ml-1 (Katırcıoglu et al., 2007; Logoglu
˘
˘ ˘
¨
˘
˘ ˘
Katırcıoglu H, Logoglu E, Tilki T, Oktemer A (2007) Synthesis of
2,4-dihalogenofluorobenzenes and their antimicrobial and anti-
fungal activity studies. Med Chem Res 16:205–221
Kaya M, Yildirir Y, Tu¨rker L (2009) Synthesis and laser activity of
halo-acridinedione derivatives. J Heterocyclic Chem 46(2):294–
297
¨
et al., 2007; Unlu¨soy et al., 2007). Empty sterilized discs of
6 mm (Whatman No: 1) were each impregnated with 20 ll
of compounds. Discs were placed on agar plates, and the
plates were incubated at 37°C for 24 h. Inhibition zones
formed on the medium were evaluated in millimeters.
Studies performed in duplicate and the inhibition zones were
compared with those of reference discs. The solvents control
(CHCl3, DMSO) did not show any antimicrobial activity.
¨
˘ ˘
˘
Logoglu E, Katırcıoglu H, Tilki T, Oktemer A (2007) Synthesis,
biological activity studies of di- and mono- halogenofluoro
benzenes. Asian J Chem 19(3):2029–2035
Mikata Y, Yokoyama M, Mogami K, Kato M, Okura I, Chikira M,
Yano S (1998) Intercalator-linked cisplatin: synthesis and
antitumor activity of cis-dichloroplatinum(II) complexes con-
nected to acridine and phenylquinolines by one methylene chain.
Inorg Chim Acta 279(1):51–57
Murugan P, Ramakrishnan VT (1997) Synthesis of acridinediones and
bis-acridinediones. Indian J Heterocyclic Chem 7(1):31–34
Murugan P, Ramakrishnan VT (2001) Synthesis of 9,90-bisacridin-
ediones. Indian J Heterocyclic Chem 40(1):78–81
NCCLS (National Committee for Clinical Laboratory Standards)
(1997) Performance standards for antimicrobial disk suscepti-
bility test, 6th Ed., Wayne PA: Approved standard. M2-A6
Ngadi L, Galy AM, Galy JP, Barbe J, Cremieux A, Chevalier J,
Sharples D (1990) Some new 1-nitro acridine-derivatives as
antimicrobial agents. Eur J Med Chem 25(1):67–70
Conclusion
In this study, 15 novel bisacridine-1,8-dione derivatives
were synthesized using Amberlyst-15 as a heterogeneous
catalyst and their antimicrobial activities evaluated. All the
compounds except compound 4e showed antibacterial and
antifungal activity against test microorganisms.
Acknowledgment The authors are very grateful to Dumlupınar
University Research Fund for providing financial support for this
project (Grant No. 2008-4).
Odabasoglu M, Kaya M, Buyukgungor O, Yildirir Y (2007) 10-(4-
Bromophenyl)-9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-
123

Med Chem Res (2011) 20:293–299
299
3,4,6,7-tetrahydro-acridine-1,8(2H, 5H, 9H, 10H)-dione. Acta
Cryst E 63:2162–2164
Patel BB, Patel RG, Patel MP (2006) Synthesis and studies of the
biological activity of novel pyrimido fused acridine derivatives.
J Serb Chem Soc 71:1015–1023
Ramesh C, Ravindranath N, Das B (2003) Simple, efficient, and
selective deprotection of phenolic methoxymethyl ethers using
silica-supported sodium hydrogen sulfate as a heterogeneous
catalyst. J Org Chem 68:7101–7103
Shanmugasundaram P, Murugan P, Ramakrishnan VT, Srividya N,
Ramamurthy P (1997) Synthesis of acridinedione derivatives as
laser dyes. Heteroatom Chem 7(1):17–22
Sirivinas KVNS, Das B (2003) A highly convenient, efficient, and
selective process for preparation of esters and amides from
carboxylic acids using Fe3?-K-10 montmorillonite clay. J Org
Chem 68:1665–1667
Srivastava A, Nizamuddin A (2004) Synthesis and fungicidal activity
of some acridine derivatives. Indian J Heterocyclic Chem
13(3):261–264
Srividya N, Ramamurthy P, Shanmugasundaram P, Ramakrishnan VT
(1996) Synthesis, characterization, and electrochemistry of some
acridine-1,8-dione dyes. J Org Chem 61(15):5083–5089
¨
˘
Unlu¨soy MC, Bozdag OD, Altanlar N, Ertan R (2007) Studies on the
synthesis of some new substituted benzylamino and phenyl-
acrylamido-methyl flavone derivatives. Med Chem Res 16:
170–178
Singh S, China S, Sharma VK, Sachdev SS (1982) Cationic
hydrogenation of benzyl alcohols and arylethylenes using
acridane derivatives as hindered NADH models. J Chem Soc
Chem Commun 8:453–454
Wainwright MJ (2001) Acridine—a neglected antibacterial chromo-
phore. J Antimicrob Chemother 47(1):1–13
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