Synthesis, antiviral, and cytotoxic investigation of imidazo[4,5-a]acridones

Article abstract of DOI:10.1007/s00044-015-1438-1

The importance of virus infections and the early successes with some antiviral drugs have prompted the search for new agents, and it has been focused on compounds that are active against herpesviruses, retroviruses, and rhinoviruses. In this paper, 3H-imi

Full text of DOI:10.1007/s00044-015-1438-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1438-1
ORIGINAL RESEARCH
Synthesis, antiviral, and cytotoxic investigation
of imidazo[4,5-a]acridones
Leila Rezaei Daghigh1 Mehdi Pordel1 Abolghasem Davoodnia1 Maryam Jajarmi2
•
•
•
Received: 24 February 2015 / Accepted: 17 August 2015
Ó Springer Science+Business Media New York 2015
Abstract The importance of virus infections and the
early successes with some antiviral drugs have prompted
the search for new agents, and it has been focused on
compounds that are active against herpesviruses, retro-
viruses, and rhinoviruses. In this paper, 3H-imidazo[4,5-
a]acridones are introduced as new antiviral agents against a
panel of DNA and RNA viruses, including herpes simplex
virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus,
vesicular stomatitis virus, and herpes simplex virus-1 TK-
Introduction
An intensive search for drugs effective in chemotherapy of
viral infections and/or various cancers has been underway
for decades. Nitrogen-containing heterocycles have diverse
applications, from drugs used as antitumor agents and
enzyme inhibitors (Dell’Erba et al., 1992; De Angelis
et al., 2005; Iida et al., 2005) to optical materials used in
light-emitting diodes and conducting polymers (Cornil
et al., 2001). For example, benzo[c]isoxazole derivatives
are prescribed as antipsychotic risperidone drugs (Szarf-
man et al., 2006) and play a key role in many organic
reactions (Loudon and Tennant, 1964), notably those
leading to anthranilic acids. Also, acridine derivatives, such
as acridones, pyridoacridines, and imidazoacridines, are
one of the oldest classes of bioactive compounds that are
widely used as antibacterial (Mitra et al., 2014), antiprion
(Kukowska-Kaszuba and Dzierzbicka 2007), antimalarial
(Joshi and Viswanathan, 2006; Winter et al., 2008) anti-
cancer (Kamal et al., 2004; Belmont et al., 2007), and
antitumor (Qiao et al., 2012; Lang et al., 2013) agents.
Recently, various derivatives of the acridine series also
demonstrated significant inhibitory activities toward Plas-
modium (Girault et al., 2000, 2001), Trypanosoma (Gam-
age et al., 1997) and Leishmania (Werbovetz et al., 1994;
Di Giorgio et al., 2003) parasites, as well as potent antiviral
properties (Lowden and Bastow, 2003; Goodell et al.,
2006).
r
KOS ACV . Also, these compounds were cytostatic in the
higher micromolar range. 3H-imidazo[4,5-a]acridones
were synthesized by Tanasescu reaction of 3H-imi-
dazo[40,50:3,4]benzo [c]isoxazoles in concentrated sulfuric
acid containing nitrous acid in excellent yields. The
advanced compounds were obtained from the reaction of
N-alkyl-5-nitrobenzimidazoles with different aryl acetoni-
triles under basic conditions. Structures of all newly syn-
1
thesized compounds were confirmed by IR, H NMR, and
mass spectral data. The results indicated that the title
compounds have mild-to-potent activities in comparison
with their appropriate reference standards.
Keywords 5-Nitrobenzimidazoles Á
3H-imidazo[40,50:3,4]benzo [c] isoxazole Á
Imidazo[4,5-a]acridone Á Cytotoxic Á Antiviral
Recently, we reported synthesis of new derivatives of
imidazo[4,5-a]acridines as very effective antibacterial
agents (Sadeghian et al., 2012; Rahimizadeh et al., 2009).
In continuation of our research work on the synthesis of
bioactive nitrogen heterocyclic compounds (Rahimizadeh
et al., 2009, 2010; Sadeghian et al., 2010; Bakavoli et al.,
2010; Pordel et al., 2013), in this study, we explored the
& Mehdi Pordel
mehdipordel58@mshdiau.ac.ir
1
Department of Chemistry, Mashhad Branch, Islamic Azad
University, Mashhad, Iran
2
Khorasan Razavi Rural Water and Wastewater Co.,
Mashhad, Iran
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Med Chem Res
8-(4-Chlorophenyl)-3-methyl-3H-imidazo[40,50:3,4]benzo
[c]isoxazole (3b) Pale yellow crystals (methanol); m.p.:
293–295 °C (lit. [Rahimizadeh et al., 2009] m.p.:
preparation and investigation of some imidazo[4,5-a]acri-
dones as potential antiviral agents against different viral
strains. Furthermore, the cytotoxic activity of these com-
pounds was also determined.
1
292–294 °C); H NMR (400 MHz, CDCl3) d 3.92 (s, 3H,
N-CH3), 7.42 (d, J = 9.5 Hz, 1H, Ar H), 7.58 (d,
J = 9.5 Hz, 1H, Ar H), 7.67 (d, J = 8.8 Hz, 2H, Ar H),
7.89 (s, 1H, Ar H), 8.87 (d, J = 8.8 Hz, 2H, Ar H). 13C
NMR (100 MHz, CDCl3): d = 162.9 (C, C-5), 157.3 (C,
C-8), 153.2 (C, C-2), 149.0 (CH, C-7), 135.3 (CH, C-14),
133.9 (C, C-9), 131.2 (CH, C-12, C-13), 129.9 (CH, C-10,
C-11), 125.6 (C, C-1), 120.2 (CH, C-4), 115.5 (CH, C-6),
102.8 (C, C-3), 35.6 (CH3, N–CH3).
Experimental
Materials, methods, and instruments
Methanol, N,N-dimethylformamide (DMF), methyl iodide,
n-propyl bromide, n-butyl bromide, isobutyl bromide,
phenyl acetonitrile, 2-(4-chlorophenyl)acetonitrile, and
2-(4-bromophenyl)acetonitrile were purchased from Mer-
ck. Potassium hydroxide was purchased from Sigma–
Aldrich. All solvents were dried according to standard
procedures. Compounds 1a–d were synthesized as descri-
bed in the literature (Preston, 2009).
8-Phenyl-3-propyl-3H-imidazo[40,50:3,4]benzo[c]isoxazole
(3c) Pale yellow crystals (methanol); m.p.: 121–122 °C
[lit.(Rahimizadeh et al., 2009) m.p.: 119–122 °C]; 1H
NMR (400 MHz, CDCl3) d 0.99 (t, J = 7.0 Hz, 3H, CH2–
CH3), 1.77–2.12 (m, 2H, CH2–CH3), 4.21 (t, J = 7.0 Hz,
2H, N–CH2), 7.47–7.69 (m, 6H, Ar H), 7.89 (s, 1H, Ar H),
8.89 (d, J = 8.0 Hz, 1H, Ar H). 13C NMR (100 MHz,
CDCl3): d = 163.7 (C, C-8), 162.7 (C, C-5), 148.4 (CH,
C-7), 147.3 (C, C-2), 133.8 (C, C-9), 130.3 (CH, C-14),
129.5 (CH, C-12, C-13), 127.9 (CH, C-10, C-11), 123.0 (C,
C-1), 120.4 (CH, C-4), 111.2 (CH, C-6), 102.8 (C, C-3),
49.3 (CH2, N–CH2), 21.9 (CH2, CH2–CH3), 13.0 (CH3,
CH2–CH3).
Melting points were measured on an electrothermal
type-9100 melting-point apparatus. The IR (as KBr disks)
spectra were obtained on a Tensor 27 spectrometer, and
only noteworthy absorptions are listed. The 13C NMR
(100 MHz) and 1H NMR (400 MHz) spectra were recorded
on a Bruker Avance DRX-400 FT spectrometer in CDCl3
and DMSO-d6. Chemical shifts are reported in ppm
downfield from TMS as internal standard; coupling con-
stant J is given in Hz. The mass spectra were recorded on a
Varian Mat, CH-7 at 70 eV. Elemental analysis was per-
formed on a Thermo Finnigan Flash EA microanalyzer. All
measurements were carried out at room temperature.
8-(4-Chlorophenyl)-3-propyl-3H-imidazo[40,50:3,4]benzo[c]
isoxazole (3d) Pale yellow crystals (methanol); m.p.:
160–163 °C [lit.(Rahimizadeh et al., 2009) m.p.:
158–160 °C]; 1H NMR (400 MHz, CDCl3) d 1.05 (t,
J = 7.3 Hz, 3H, CH2–CH3), 1.85–2.21 (m, 2H, CH2–CH2–
CH3), 4.18 (t, J = 7.3 Hz, 2H, N–CH2), 7.40 (d,
J = 9.5 Hz, 1H, Ar H), 7.56 (d, J = 9.5 Hz, 1H, Ar H),
7.62 (d, J = 8.6 Hz, 2H, Ar H), 7.86 (s, 1H, Ar H), 8.89 (d,
J = 8.6 Hz, 2H, Ar H). 13C NMR (100 MHz, CDCl3):
d = 162.7 (C, C-5), 158.73 (C, C-8), 148.9 (CH, C-7),
147.1 (C, C-2), 133.4 (CH, C-14), 130.5 (CH, C-12, C-13),
129.7 (CH, C-10, C-11), 129.5 (C, C-9), 122.7 (C, C-1),
120.4 (CH, C-4), 112.0 (CH, C-6), 103.3 (C, C-3), 49.5
(CH2, N–CH2), 22.3(CH2, CH2–CH3), 13.1 (CH3, CH2–
CH3).
General procedure for the synthesis of compounds
3a–j
With stirring to a solution of KOH (13 g, 231 mmol) in
methanol (50 mL), 1-alkyl-5-nitrobenzimidazole 1a–
d (10 mmol) and aryl acetonitriles 2a–c (12 mmol) were
added. The mixture was refluxed for 4 h and then poured
into water. The precipitate was collected by filtration,
washed with water, and air-dried to give 3a–j. Further
purification was achieved by crystallization from suitable
solvent such as EtOH.
3-Butyl-8-phenyl-3H-imidazo[40,50:3,4]benzo[c]isoxazole
(3e) Pale yellow crystals (methanol); m.p.: 113–115 °C
[lit.(Rahimizadeh et al., 2009) m.p.: 110–112 °C]; 1H
NMR (400 MHz, CDCl3) d 0.97 (t, J = 7.0 Hz, 3H, CH2–
CH3), 1.21–1.56 (m, 2H, CH2–CH2–CH3), 1.81–2.09 (m,
2H, CH2–CH2–CH2–CH3), 4.23 (t, J = 7.0 Hz, 2H, N–
CH2), 7.47–7.69 (m, 6H, Ar H), 7.88 (s, 1H, Ar H), 8.89 (d,
J = 8.0 Hz, 1H, Ar H). 13C NMR (100 MHz, CDCl3):
d = 162.3 (C, C-5), 159.6 (C, C-8), 148.6 (C, C-2), 146.0
(CH, C-7), 132.5 (C, C-9), 131.2 (CH, C-14), 129.2 (CH,
C-12, C-13), 128.6 (CH, C-10, C-11), 121.1 (CH, C-4),
3-Methyl-8-phenyl-3H-imidazo[40,50:3,4]benzo[c]isoxazole
(3a) Pale yellow crystals (methanol); m.p.: 267–269 °C
[lit.(Rahimizadeh et al., 2009) m.p.: 266–268 °C]; 1H
NMR (400 MHz, CDCl3) d = 3.43 (s, 3H, N–CH3), 7.41
(d, J = 8.0 Hz, 1H, Ar H), 7.55–7.81 (m, 7H, Ar H). 13C
NMR (100 MHz, CDCl3): d = 162.4 (C, C-5), 159.7 (C,
C-8), 153.6 (C, C-2), 149.4 (CH, C-7), 132.5 (C, C-9),
130.9 (CH, C-14), 129.3 (CH, C-12, C-13), 128.4 (CH,
C-10, C-11), 125.8 (C, C-1), 120.5 (CH, C-4), 115.6 (CH,
C-6), 103.1 (C, C-3), 35.1 (CH3, N–CH3).
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Med Chem Res
123.5 (C, C-1), 113.9 (CH, C-6), 103.2 (C, C-3), 48.3
(CH2, N–CH2), 31.0(CH2, CH2–CH2), 21.9 (CH2, CH2–
CH2), 13.8 (CH3, CH2–CH3).
0.92 (t, J = 7.0 Hz, 3H, CH2–CH3), 1.4 (m, 2H, CH2–
CH2–CH3), 1.95 (m, 2H, CH2–CH2–CH2–CH3), 4.23 (t,
J = 7.0 Hz, 2H, N–CH2), 7.44 (d, J = 9.0 Hz, 1H, Ar H),
7.57 (d, J = 9.0 Hz, 1H, Ar H), 7.71 (d, J = 9.0 Hz, 2H,
Ar H), 7.83 (s, 1H, Ar H), 8.78 (d, J = 9.0 Hz, 2H, Ar H)
ppm. 13C NMR (100 MHz, CDCl3): d = 162.3 (C, C-5),
156.3 (C, C-8), 148.0 (CH, C-7), 146.1 (C, C-2), 134.5
(CH, C-12, C-13), 131.1 (CH, C-10, C-11), 130.4 (C, C-9),
126.2 (C, C-1), 125.4 (CH, C-14), 120.3 (CH, C-4), 115.9
(CH, C-6), 100.3 (C, C-3), 49.0 (CH2, N–CH2), 31.4 (CH2,
CH2–CH2), 22.5 (CH2, CH2–CH2), 13.7 (CH3, CH2–CH3).
MS (70 eV): m/z 372 [M ? 2] ? (3), 91 (100). Anal.
Calcd for C18H16BrN3O (370.2): C, 58.39; H, 4.36; N,
11.35. Found: C, 58.12; H, 4.32; N, 11.23.
3-Butyl-8-(4-chlorophenyl)-3H-imidazo[40,50:3,4]benzo[c]
isoxazole (3f) Pale yellow crystals(methanol); m.p.:
155–157 °C [lit.(Rahimizadeh et al., 2009) m.p.:
157–159 °C]; 1H NMR (400 MHz, CDCl3) d 0.98 (t,
J = 7.0 Hz, 3H, CH2–CH3), 1.23–1.58 (m, 2H, CH2–CH2–
CH3), 1.82–2.10 (m, 2H, CH2–CH2–CH2–CH3), 4.24 (t,
J = 7.0 Hz, 2H, N–CH2), 7.41 (d, J = 9.5 Hz, 1H, Ar H),
7.56 (d, J = 9.5 Hz, 1H, Ar H), 7.61 (d, J = 8.6 Hz, 2H,
Ar H), 7.90 (s, 1H, Ar H), 8.87 (d, J = 8.6 Hz, 2H, Ar H).
13C NMR (100 MHz, CDCl3): d = 162.8 (C, C-5), 157.5
(C, C-8), 155.0 (C, C-2), 149.8 (CH, C-7), 134.1 (CH,
C-14), 132.0 (C, C-9), 131.0 (CH, C-12, C-13), 129.9 (CH,
C-10, C-11), 122.7 (CH, C-4), 123.7 (C, C-1), 114.8 (CH,
C-6), 103.2 (C, C-3), 48.7 (CH2, N–CH2), 31.5(CH2, CH2–
CH2), 22.0 (CH2, CH2–CH2), 13.9 (CH3, CH2–CH3).
8-(4-Bromophenyl)-3-isobutyl-3H-imidazo [40,50:3,4] benzo
[c] isoxazole (3j) Pale yellow crystals (ethanol); yield
(78 %), m.p.: 153–155 °C; 1H NMR (400 MHz, CDCl3): d
1.01 (d, J = 7.2 Hz, 6H, CH(CH3)2), 2.22 (m, 1H,
CH(CH3)2), 4.04 (d, J = 7.2 Hz, 2H, N–CH2), 7.46 (d,
J = 9.2 Hz, 1H, Ar H), 7.57 (d, J2 = 9.2 Hz, 1H, Ar H),
7.75 (d, J = 8.8 Hz, 2H, Ar H), 7.86 (s, 1H, Ar H), 8.81 (d,
J = 8.8 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3):
d = 162.6 (C, C-5), 156.3 (C, C-8), 148.1 (CH, C-7), 146.3
(C, C-2), 134.7 (CH, C-12, C-13), 131.3 (CH, C-10, C-11),
130.5 (C, C-9), 126.7 (C, C-1), 125.0 (CH, C-14), 120.9
(CH, C-4), 116.3 (CH, C-6), 99.8 (C, C-3), 53.8 (CH2, N–
CH2), 28.8 (CH, CH(CH3)2), 18.6 (CH3, CH(CH3)2). MS
(70 eV): m/z 372 [M ? 2] ? (1), 91 (100). Anal. Calcd for
C18H16BrN3O (370.2): C, 58.39; H, 4.36; N, 11.35. Found:
C, 58.18; H, 4.31; N, 11.12.
8-(4-Bromophenyl)-3-methyl-3H-imidazo[40,50:3,4]benzo
[c]isoxazole (3g) Pale yellow crystals (ethanol); yield
(79 %), m.p.: 277–280 °C; 1H NMR (400 MHz, CDCl3): d
3.92 (s, 3H, N–CH3), 7.40 (d, J = 9.0 Hz, 1H, Ar H), 7.53
(d, J = 9.0 Hz, 1H, Ar H), 7.7 (d, J = 8.0 Hz, 2H, Ar H),
7.83 (s, 1H, Ar H), 8.75 (d, J = 8.0 Hz, 2H, Ar H) ppm.
13C NMR (100 MHz, CDCl3): d = 162.8 (C, C-5), 153.5
(C, C-2), 153.2 (C, C-8), 149.7 (CH, C-7), 134.1 (CH,
C-12, C-13), 130.7 (CH, C-10, C-11), 130.1 (C, C-9), 126.0
(C, C-1), 124.6 (CH, C-14), 120.1 (CH, C-4), 115.0 (CH,
C-6), 100.8 (C, C-3), 35.3 (CH3, N–CH3). MS (70 eV): m/z
330 [M ? 2] ? (7), 91 (100). Anal. Calcd for C15H10-
BrN3O (328.2): C, 54.90; H, 3.07; N, 12.80. Found: C,
54.60; H, 3.02; N, 13.01.
General procedure for the synthesis of 4a–j
8-(4-Bromophenyl)-3-propyl-3H-imidazo[40,50:3,4]benzo[c]
isoxazole (3h) Pale yellow crystals (ethanol); yield
(72 %), m.p.: 170–172 °C; 1H NMR (400 MHz, CDCl3): d
0.97 (t, J = 7.2 Hz, 3H, CH2–CH3), 1.95 (m, 2H, CH2–
CH2–CH3), 4.18 (t, J = 7.2 Hz, 2H, N–CH2), 7.43 (d,
J = 9.0 Hz, 1H, Ar H), 7.55 (d, J = 9.0 Hz, 1H, Ar H),
7.75 (d, J = 8.8 Hz, 2H, Ar H), 7.85 (s, 1H, Ar H), 8.75 (d,
J = 8.8 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3):
d = 162.5 (C, C-5), 156.1 (C, C-8), 148.1 (CH, C-7), 146.9
(C, C-2), 134.7 (CH, C-12, C-13), 130.8 (CH, C-10, C-11),
130.5 (C, C-9), 126.1 (C, C-1), 124.9 (CH, C-14), 120.1
(CH, C-4), 115.7 (CH, C-6), 100.5 (C, C-3), 49.3 (CH2, N–
CH2), 22.1 (CH2, CH2–CH3), 13.3 (CH3, CH2–CH3). MS
(70 eV): m/z 358 [M ? 2] ? (5), 91 (100). Anal. Calcd for
C17H14BrN3O (356.2): C, 57.32; H, 3.96; N, 11.80. Found:
C, 56.96; H, 3.93; N, 11.65.
To a solution of 3a–j (10 mmol) in concentrated sulfuric
acid (100 mL) maintained at -10 °C, sodium nitrite (5 g,
150 mmol) was added with stirring over a half-hour period.
After the addition was completed, the mixture was allowed
to warm to room temperature and to stand at room tem-
perature for 48 h. After pouring this mixture into crushed
ice and water (500 mL), the solid which precipitated was
removed by filtration, was washed with water and then
acetone, and dried to give 4a–j.
3-Methyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4a) Yellowish needles (EtOH ? CH3CN); m.p.:
[300 °C [lit.(Rahimizadeh et al., 2009) m.p.: [300 °C];
1
IR (KBr): 3420 cm-1 (NH), 1660 cm-1 (C=O). H NMR
(400 MHz, DMSO-d6): d 3.92 (s, 3H, N–CH3), 7.41 (d,
J = 8.9 Hz, 1H, Ar H), 7.45–7.85 (m, 5H, Ar H), 8.33 (s,
1H, Ar H), 11.79 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d = 175.1 (C = O, C9), 141.6 (C, C-11),
140.3 (CH, C-7), 140.6 (C, C-1), 129.1 (CH, C-12), 127.7
(C, C-10), 126.7 (CH, C-15), 122.4 (C, C-2), 120.0 (CH,
8-(4-Bromophenyl)-3-butyl-3H-imidazo[40,50:3,4]benzo[c]
isoxazole (3i) Pale yellow crystals (ethanol); yield
(75 %), m.p.: 155–157 °C; 1H NMR (400 MHz, CDCl3): d
123

Med Chem Res
C-13), 119.3 (CH, C-6), 117.9 (CH, C-4), 117.5 (CH,
C-14), 117.0 (CH, C-5), 107.7 (CH, C-3), 33.3 (CH3, N–
CH3). MS (70 eV): m/z 249 [M] ? (3), 91 (100); Anal.
Calcd for C15H11N3O (249.3): C, 72.28; H, 4.45; N, 16.86.
Found: C, 72.01; H, 4.42; N, 17.04.
139.6 (C, C-1), 137.4 (CH, C-12), 128.4 (C, C-10), 126.1
(CH, C-15), 121.9 (C, C-2), 119.1 (CH, C-13), 119.0 (CH,
C-6), 117.7 (CH, C-4), 117.1 (CH, C-14), 115.2 (CH, C-5),
106.7 (CH, C-3), 52.8 (CH2, N–CH2), 21.6 (CH2, CH2–
CH3), 10.1 (CH3, CH2–CH3). MS (70 eV): m/z 313
[M ? 2] ? (1), 91 (100); Anal. Calcd for C17H14ClN3O
(311.8): C, 65.49; H, 4.53; N, 13.48. Found: C, 65.23; H,
4.51; N, 13.69.
8-Chloro-3-methyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-
11-one (4b) Yellowish needles (EtOH ? CH3CN); m.p.:
[300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.:
[300 °C]; IR (KBr): 3415 cm-1 (NH), 1660 cm-1
3-Butyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4e) Yellowish needles (EtOH ? CH3CN); m.p.:
[300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.:
[300 °C]; IR (KBr): 3415 cm-1 (NH), 1660 cm-1 (C=O).
1H NMR (400 MHz, DMSO-d6) d 0.87 (t, J = 7.0 Hz, 3H,
CH2–CH3), 1.16–1.51 (m, 2H, CH2–CH2–CH3), 1.75–2.03
(m, 2H, CH2–CH2–CH2–CH3), 4.30 (t, J = 7.0 Hz, 2H, N–
CH2), 7.10–8.10 (m, 6H, Ar H), 8.31 (s, 1H, Ar H), 11.81
(br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d = 175.1 (C = O, C9), 140.3 (C, C-11), 138.9 (CH, C-7),
138.0 (C, C-1), 129.3 (CH, C-12), 127.2 (C, C-10), 126.2
(CH, C-15), 122.1 (C, C-2), 119.5 (CH, C-13), 118.9 (CH,
C-6), 117.3 (CH, C-4), 117.0 (CH, C-14), 116.6 (CH, C-5),
107.0 (CH, C-3), 49.7 (CH2, N–CH2), 30.8 (CH2, CH2–
CH2), 20.4 (CH2, CH2–CH2), 11.1 (CH3, CH2–CH3). MS
(70 eV): m/z 291 [M] ? (5), 91 (100); Anal. Calcd for
C18H17N3O (291.3): C, 74.21; H, 5.88; N, 14.42. Found: C,
73.97; H, 5.85; N, 14.50.
1
(C = O). H NMR (400 MHz, DMSO-d6) d 4.04 (s, 3H,
N–CH3), 7.32 (dd, J = 9.5 Hz, J = 2.1 Hz, 1H, Ar H),
7.78 (d, J = 9.4 Hz, 1H, Ar H), 7.85 (d, J = 9.4 Hz, 1H,
Ar H), 8.12 (d, J = 2.1 Hz, 1H, Ar H), 8.25 (d,
J = 9.5 Hz, 1H, Ar H) 8.45 (s, 1H, Ar H), 11.83 (br s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d = 175.1
(C = O, C9), 141.9 (C, C-11), 141.4 (CH, C-7), 140.6 (C,
C-1), 138.2 (CH, C-12), 127.0 (C, C-10), 126.4 (CH,
C-15), 122.2 (C, C-2), 119.9 (CH, C-13), 119.2 (CH, C-6),
117.9 (CH, C-4), 117.3 (CH, C-14), 117.0 (CH, C-5), 107.4
(CH, C-3), 33.4 (CH3, N–CH3). MS (70 eV): m/z 285
[M ? 2] ? (1), 91 (100); Anal. Calcd for C15H10ClN3O
(283.7): C, 63.50; H, 3.55; N, 14.81. Found: C, 63.43; H,
3.52; N, 14.89.
3-Propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4c) Yellowish needles (EtOH ? CH3CN); m.p.:[300 °C
(decomp) [lit.(Rahimizadeh et al., 2009) m.p.:[300 °C]; IR
(KBr): 3415 cm-1 (NH), 1660 cm-1 (C=O). 1H NMR
(400 MHz, DMSO-d6) d 0.79 (t, J = 7.0 Hz, 3H, CH2–CH3),
1.71–2.06 (m, 2H, CH2–CH2–CH3), 4.26 (t, J = 7.0 Hz, 2H,
N–CH2), 7.15–8.15 (m, 6H, Ar H), 8.30 (s, 1H, Ar H), 11.86
(br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d = 175.0
(C = O, C9), 140.2 (C, C-11), 139.4 (CH, C-7), 138.5 (C,
C-1), 129.3 (CH, C-12), 127.1 (C, C-10), 126.1 (CH, C-15),
122.1 (C, C-2), 119.5 (CH, C-13), 118.8 (CH, C-6), 117.2
(CH, C-4), 117.0 (CH, C-14), 116.6 (CH, C-5), 106.9 (CH,
C-3), 52.5 (CH2, N–CH2), 21.6 (CH2, CH2–CH3), 10.0 (CH3,
CH2–CH3). MS (70 eV): m/z 277 [M] ? (3), 91 (100); Anal.
Calcd for C17H15N3O (277.3): C, 73.63; H, 5.45; N, 15.15.
Found: C, 73.49; H, 5.41; N, 15.41.
3-Butyl-8-chloro-6,11-dihydro-3H-imidazo[4,5-a]acridin-
11-one (4f) Yellowish needles (EtOH ? CH3CN); m.p.:
[300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.:
[300 °C]; 1H NMR (400 MHz, DMSO-d6) d 0.86 (t,
J = 6.5 Hz, 3H, CH2–CH3), 1.13–1.48 (m, 2H, CH2–CH2–
CH3), 1.73–2.01 (m, 2H, CH2–CH2–CH2–CH3), 4.33 (t,
J = 6.5 Hz, 2H, N–CH2), 7.21(dd, J = 9.5 Hz,
J = 2.1 Hz, 1H, Ar H), 7.58 (d, J = 9.4 Hz, 1H, Ar H),
7.65 (d, J = 9.4 Hz, 1H, Ar H), 8.15 (d, J = 2.1 Hz, 1H,
Ar H), 8.25 (d, J = 9.5 Hz, 1H, Ar H) 8.30 (s, 1H, Ar H),
11.91 (br s, 1H, NH); IR (KBr): 3415 cm-1 (NH),
1660 cm-1 (C = O).);13C NMR (100 MHz, DMSO-d6):
d = 175.1 (C = O, C9), 140.3 (C, C-11), 139.7 (CH, C-7),
139.1 (C, C-1), 137.4 (CH, C-12), 128.4 (C, C-10), 126.2
(CH, C-15), 121.9 (C, C-2), 119.2 (CH, C-13), 119.0 (CH,
C-6), 117.7 (CH, C-4), 117.2 (CH, C-14), 115.2 (CH, C-5),
107.4 (CH, C-3), 49.9 (CH2, N–CH2), 30.7 (CH2, CH2–
CH2), 20.4 (CH2, CH2–CH2), 11.1 (CH3, CH2–CH3). MS
(70 eV): m/z 327 [M ? 2] ? (2), 91 (100); Anal. Calcd for
C18H16ClN3O (325.8): C, 66.36; H, 4.95; N, 12.90. Found:
C, 66.03; H, 4.94; N, 13.09.
8-Chloro-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-
11-one (4d) Yellowish needles (EtOH ? CH3CN); m.p.:
[300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.:
[300 °C]; IR (KBr): 3415 cm-1 (NH), 1660 cm-1 (C=O).
1H NMR (400 MHz, DMSO-d6) d 0.83 (t, J = 7.1 Hz, 3H,
CH2–CH3), 1.69–1.95 (m, 2H, CH2–CH2–CH3), 4.29 (t,
J = 7.1 Hz, 2H, N–CH2), 7.25 (dd, J = 9.5 Hz,
J = 2.1 Hz, 1H, Ar H), 7.68 (d, J = 9.4 Hz, 1H, Ar H),
7.75 (d, J = 9.4 Hz, 1H, Ar H), 8.17 (d, J = 2.1 Hz, 1H,
Ar H), 8.25 (d, J = 9.5 Hz, 1H, Ar H), 8.35 (s, 1H, Ar H),
11.80 (br s, 1H, NH);. 13C NMR (100 MHz, DMSO-d6):
d = 175.1 (C = O, C9), 140.2 (C, C-11), 140.0 (CH, C-7),
8-Bromo-3-methyl-3H-imidazo[4,5-a]acridin-11(6H)-one
(4g) Yellowish needles (EtOH ? CH3CN); yield (70 %),
m.p.:[300 °C (decomp); IR(KBr): 3400 cm-1 (NH), 1632
1
(C=O) cm-1. H NMR (400 MHz, DMSO-d6): d 3.93 (s,
123

Med Chem Res
3H, N–CH3), 7.24 (dd, J = 8.4 Hz, J0 = 1.2 Hz, 1H, Ar
H), 7.66 (d, J = 9.2 Hz, 1H, Ar H), 7.85 (d, J = 9.2 Hz,
1H, Ar H), 7.94(s, 1H, Ar H), 8.05 (d, J = 1.2 Hz, 1H, Ar
H), 8.43 (d, J = 8.4 Hz, 1H, Ar H), 11.8 (br s, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 175.1 (C=O,
C9), 148.7 (CH, C-10), 143.4 (C, C-11), 141.9 (CH, C-7),
140.2 (C, C-1), 138.8 (CH, C-12), 129.5 (C, C-14), 125.1
(CH, C-15), 124.2 (C, C-2), 117.1 (CH, C-13), 119.0 (CH,
C-6), 117.1 (CH, C-4), 117.6 (CH, C-5), 107.8 (CH, C-3),
33.9 (CH3, N–CH3). MS (70 eV): m/z 330 [M ? 2] ? (5),
91 (100). Anal. Calcd for C15H10BrN3O (328.2): C, 54.90;
H, 3.07; N, 12.80. Found: C, 54.70; H, 3.02; N, 12.69.
8-Bromo-3-isobutyl-3H-imidazo
[4,5-a]acridin-11(6H)-
one (4j) Yellowish needles (EtOH ? CH3CN); yield
(72 %), m.p.: [300 °C (decomp); IR(KBr): 3391 cm-1
(NH), 1633 (C=O) cm-1. 1H NMR (400 MHz, DMSO-d6):
d 0.67 (d, J = 7.0 Hz, 6H, CH(CH3)2), 1.98 (m, 1H,
CH(CH3)2), 4.14 (d, J = 7.0 Hz, 2H, N–CH2), 7.27 (d,
J = 8.8 Hz, 1H, Ar H), 7.31 (d, J = 8.8 Hz, 1H, Ar H),
7.62 (s, 1H, Ar H), 7.95 (dd, J = 8.4 Hz, J0 = 1.2 Hz, 1H,
Ar H), 8.2 (d, J = 8.4 Hz, 1H, Ar H), 8.37 (d, J = 1.2 Hz,
1H, Ar H), 11.81 (br s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6): d = 175.3 (C=O, C9), 148.5 (CH, C-10), 143.8
(C, C-11), 142.0 (CH, C-7), 140.4 (C, C-1), 138.7 (CH,
C-12), 129.7 (C, C-14), 125.6 (CH, C-15), 124.9 (C, C-2),
117.8 (CH, C-13), 119.3 (CH, C-6), 117.0 (CH, C-4), 117.2
(CH, C-5), 107.4 (CH, C-3), 54.6 (CH2, N–CH2), 29.5 (CH,
CH(CH3)2), 18.5 (CH3, CH(CH3)2). MS (70 eV): m/z 372
[M ? 2] ? (2), 91 (100); Anal. Calcd for C18H16BrN3O
(370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.21; H,
4.33; N, 11.19.
8-Bromo-3-propyl-3H-imidazo [4,5-a]acridin-11(6H)-one
(4h) Yellowish needles (EtOH ? CH3CN); yield (65 %),
m.p.:[300 °C (decomp); IR(KBr): 3392 cm-1 (NH), 1633
1
(C=O) cm-1. H NMR (400 MHz, DMSO-d6): d 0.86 (t,
J = 6.8 Hz, 3H, CH2–CH3), 1.84 (m, 2H, CH2–CH2–CH3),
4.31 (t, J = 6.8 Hz, 2H, N–CH2), 7.38 (d, J = 8.8 Hz, 1H,
Ar H), 7.41 (d, J = 8.8 Hz, 1H, Ar H), 7.74 (s, 1H, Ar H),
8.08 (dd, J = 8.4 Hz, J0 = 1.2 Hz, 1H, Ar H), 8.18 (d,
J = 8.4 Hz, 1H, Ar H), 8.35 (d, J = 1.2 Hz, 1H, Ar H),
11.8 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d = 175.3 (C=O, C9), 148.5 (CH, C-10), 143.7 (C, C-11),
141.9 (CH, C-7), 140.5 (C, C-1), 138.4 (CH, C-12), 129.7
(C, C-14), 125.3 (CH, C-15), 124.4 (C, C-2), 117.4 (CH,
C-13), 119.1 (CH, C-6), 117.2 (CH, C-4), 117.9 (CH, C-5),
107.8 (CH, C-3), 53.5 (CH2, N–CH2), 21.7 (CH2, CH2–
CH3), 10.0 (CH3, CH2–CH3). MS (70 eV): m/z 358
[M ? 2] ? (4), 91 (100); Anal. Calcd for C17H14BrN3O
(356.2): C, 57.32; H, 3.96; N, 11.80. Found: C, 57.70; H,
4.05; N, 11.56.
Biological evaluations
Antiviral assay (MIC or EC50) (Clercq et al., 1980, 1987)
Confluent cell cultures in microtiter 96-well plates were
inoculated with 100 CCID50 of virus, one CCID50 being the
virus dose required to infect 50 % of the cell cultures. After
1–2 h of virus adsorption period, residual virus was
removed, and the cell cultures were incubated at 37 °C in
the presence of varying concentrations of the test com-
pounds (dilutions were made based upon CTC50). Viral
cytopathogenicity was recorded as soon as it reached
completion in the control virus infected cell cultures that
were not treated with the test compounds after 4–5 days of
post infection, microscopically. The antiviral activity of the
compounds 4a–j was expressed as the effective concen-
tration required for inhibiting the viral cytopathic effect by
50 % (MIC or EC50). The CTC50 and MIC of the test
compounds were compared with the standard drugs bri-
vudine (BVDU), cidofovir, acyclovir, and ribavirin under
similar conditions. By adopting the above procedure, the
MIC or EC50 for all the compounds 4a–j was determined.
8-Bromo-3-butyl-3H-imidazo [4,5-a]acridin-11(6H)-one
(4i) Yellowish needles (EtOH ? CH3CN); yield (67 %),
m.p.:[300 °C (decomp); IR(KBr): 3423 cm-1 (NH), 1636
1
(C=O) cm-1. H NMR (400 MHz, DMSO-d6): d 0.90 (t,
J = 6.7 Hz, 3H, CH2–CH3), 1.26 (m, 2H, CH2–CH2–CH3),
1.83 (m, 2H, CH2–CH2–CH2–CH3), 4.41 (t, J = 6.7 Hz,
2H, N–CH2), 7.43 (d, J = 7.0 Hz, 1H, Ar H), 7.53 (d,
J = 7.0 Hz, 1H, Ar H), 7.8 (s, 1H, Ar H), 8.15 (dd,
J = 8.4 Hz, J0 = 1.2 Hz, 1H, Ar H), 8.25 (d, J = 8.4 Hz,
1H, Ar H), 8.86 (d, J = 1.2 Hz, 1H, Ar H), 12.06 (br s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d = 175.4 (C=O,
C9), 148.6 (CH, C-10), 143.9 (C, C-11), 142.3 (CH, C-7),
140.6 (C, C-1), 138.3 (CH, C-12), 129.7 (C, C-14), 125.4
(CH, C-15), 124.6 (C, C-2), 117.8 (CH, C-13), 119.3 (CH,
C-6), 117.1 (CH, C-4), 117.4 (CH, C-5), 107.0 (CH, C-3),
49.5 (CH2, N–CH2), 30.5 (CH2, CH2–CH2), 20.3 (CH2,
CH2–CH2), 11.0 (CH3, CH2–CH3). MS (70 eV): m/z 372
[M ? 2] ? (3), 91 (100); Anal. Calcd for C18H16BrN3O
(370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.67; H,
4.39; N, 11.25.
Cytotoxicity activity assay (Piotrowska et al., 2012)
Murine leukemia L1210, human T-lymphocyte CEM,
human cervix carcinoma (HeLa), and human lung fibrob-
last (HEL) cells were suspended at 300,000–500,000 cells/
mL of culture medium, and 100 lL of a cell suspension
was added to 100 lL of an appropriate dilution of the test
compounds in wells of 96-well microtiter plates. After
incubation at 37 °C for two (L1210) or three (CEM, HeLa,
123

Med Chem Res
Scheme 1 Synthesis of compounds 3a–j and 4a–j
Table 1 Antiviral activity of compounds 4a–j in E6SM cell cultures
Compound
Minimum inhibitory concentrationa (lM)
Herpes simplex
virus-1 (KOS)
Herpes simplex
virus-2 (G)
Vaccinia
virus
Vesicular
stomatitis virus
Herpes simplex virus-1
TK-KOS ACVr
4a
[80b
35.0
19.0
15.1
20.0
12.0
[100b
55.0
35.0
40.0
0.04
1.5
[80b
35.0
19.0
13.2
20.0
8.0
[100b
50.0
30.0
40.0
150
[150b
45.0
26.0
25.0
25.0
15.0
[100b
75.0
40.1
40.0
12
[80b
80.0
[80b
35.0
23.0
23.0
23.0
23.0
[100b
60
4b
4c
45.0
4d
45.0
4e
45.0
4f
45.0
4g
[100b
[100
[100
[100
[300
[300
[300
180
4h
4i
45.0
40.0
45
4j
Brivudine
Cidofovir
Acyclovir
Ribavirin
a
3
25
1.5
0.5
0.5
[300
30
70
180
180
180
Required to reduce virus-induced cytopathogenicity by 50 %
b
Compound precipitated out under assay conditions
HEL) days, the cell number was determined using a
Coulter counter. The IC50 was defined as the compound
concentration required to inhibit cell proliferation by 50 %.
2012) (Scheme 1). Derivatives of 3a–j were converted to
3H-imidazo[4,5-a]acridones 4a–j in concentrated sulfuric
acid containing nitrous acid at room temperature by
Tanasescu reaction (Tanasescu 1927) in fairly good yields
(Scheme 1). Compounds 3g–j and 4g–j are new hetero-
cyclic compounds. The structures of compounds 3g–j and
4g–j were unambiguously characterized on the basis of
Results and discussion
Chemistry
1
their IR, H NMR and mass spectra.
Initially, N-alkyl-5-nitrobenzimidazoles 1a–d were
obtained from 5-nitrobenzimidazole using different alkyl
halides treatment in DMF and KOH as previously descri-
bed (Preston, 2009). 3H-imidazo[40,50:3,4]benzo [c] isoxa-
zoles 3a–j were accessed through the nucleophilic
substitution of hydrogen of N-alkyl-5-nitrobenzimidazoles
1a–d with aryl acetonitriles 2a–c under basic conditions
(Rahimizadeh et al., 2009; Sahraei et al., 2013; Pordel
Antiviral and cytostatic evaluation
Compounds 4a–j were evaluated for antiviral and cyto-
static activity using the method described in experimental
section. The results of antiviral screening of compounds
4a–j against herpes simplex virus-1 (KOS), herpes simplex
virus-2 (G), vaccinia virus, vesicular stomatitis virus, and
r
herpes simplex virus-1 TK-KOS ACV are shown in
123

Med Chem Res
Table 2 Cytostatic activity of compounds 4a–j
Compound
CCa50 (lM)
L1210
CEM
HeLa
HEL
4a
4b
4c
4d
4e
4f
4g
4h
4i
135
120
110
85
180
179
190
100
140
110
190
180
150
145
150
130
150
100
95
85
60
75
60
95
75
75
90
60
120
120
110
90
200
180
150
125
100
90
85
4j
65
a
50 % inhibitory concentration or compound concentration required to inhibit cell proliferation by 50 %
Table 1. The results of assay indicate that all the com-
pounds have shown varying degree of cytotoxicity (i.e.,
from 90 to 200 lM). Based on the CTC50 non-toxic con-
centrations, all the synthesized compounds were subjected
for antiviral activity determination against different viral
strains. The results of antiviral activity (Table 1) indicated
that all 3H-imidazo[4,5-a]acridones 4a–j exhibited good-
to-moderate antiviral activity against mentioned organisms
from approximately 8 to 150 lM which is comparable with
the reference drug Ribavirin.
The antiviral screening for all 3H-imidazo[4,5-a]acridones
(4a–j) against a broad panel of DNA and RNA viral strains
indicated that these compounds emerged as promising
antiviral activity against different viral strains. Addition-
ally, compounds 4a–j proved slightly cytostatic (middle to
higher micromolar range: 60–200 lM).
Such compounds could be selected as lead compounds
for the development of novel antiviral agents active against
herpes simplex virus, vaccinia virus, and vesicular stom-
atitis virus.
Also, the results revealed that compounds 4b, 4d, and 4f
in which the R2 substituent is a chlorine function displayed
greater antiviral activity than did others. Compound 4f
(R2 = Cl and R1 = Bu) was the most potent of the tested
compounds against viral strains. It might be due to the
chain lengths and chlorine substituent that change the
binding characteristics of ligands to their respective
receptors and, thereby, improve the biological activities.
The cytotoxicity of the tested compounds toward the unin-
fected host cells was defined as the minimum compound con-
centration (MCC) that caused a microscopically detectable
alteration of normal cell morphology. The 50 % cytostatic
concentration (CC50), causing a 50 % decrease in cell prolif-
eration, was determined against murine leukemia L1210,
human lymphocyte CEM, human cervix carcinoma HeLa, and
human lung fibroblast HEL cells. All of the tested compounds
affected cell morphology of HEL, HeLa, Vero, MDCK, and
CrFK cells at concentrations ranging from 60 to 200 lM for
HeLa cells, L1210, CEM, and HEL cells (Table 2).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict
of interest.
Research involving human participants and/or animals This
article does not contain any studies with human participants or ani-
mals performed by any of the authors.
Informed consent For this type of study, formal consent is not
required.
References
Bakavoli M, Bagherzadeh G, Vaseghifar M, Shiri A, Pordel M,
Mashreghi M, Pordeli P, Araghi M (2010) Molecular iodine
promoted synthesis of new pyrazolo[3,4-d]pyrimidine derivatives
as potential antibacterial agents. Eur J Med Chem 45:647–650
Belmont P, Bosson J, Godet T, Tiano M (2007) Acridine and acridone
derivatives, anticancer properties and synthetic methods: Where
are we now? Anti-Cancer Agents Med Chem 7:139–169
Clercq ED, Descamps J, Verhelst G, Walker RT, Jones AS, Torrence
PF, Shuger D (1980) Comparative efficacy of antiherpes drugs
against different strains of herpes simplex virus. J Infect Dis
141:563–574
In conclusion, we synthesized a series of 3-alkyl-6,11-
dihydro-3H-imidazo[4,5-a]acridin-11-one, 8-chloro-3-pro-
pyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one,
and
new 8-bromo-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]
Clercq ED, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I,
Holy A (1987) Antiviral activity of phosphonylmethoxyalkyl
derivatives of purine and pyrimidines. Antiviral Res 8:261–272
acridin-11-one, which were structurally confirmed by IR,
1H NMR, 13C NMR, elemental, and MS spectral analysis.
123

Med Chem Res
Cornil J, Beljonne D, Calbert JP, Bredas JL (2001) Interchain
interactions in organic p-conjugated materials: impact on
electronic structure, optical response, and charge transport.
Adv Mater 13:1053–1067
De Angelis M, Stossi F, Carlson KA, Katzenellenbogen BS,
Katzenellenbogen JA (2005) Indazole estrogens: highly selective
ligands for the estrogen receptor ß. J Med Chem 48:1132–1144
Dell’Erba C, Novi M, Petrillo G, Tavani C (1992) Behaviour of
arylazo tert-butyl sulfides with ketone enolates. competition
between srn1 a-arylation and azocoupling reactions. Tetrahedron
48:325–334
dialkoxylated, 1-hydroxyacridone derivatives. Antiviral Res
59:143–154
Mitra P, Chakraborty PK, Saha P, Ray P, Basu S (2014) Antibacterial
efficacy of acridine derivatives conjugated with gold nanopar-
ticles. Int J Pharm 473:636–643
Piotrowska DG, Balzarini J, Gowacka IE (2012) Design, synthesis,
antiviral and cytostatic evaluation of novel isoxazolidine
nucleotide analogues with a 1,2,3-triazole linker. Eur J Med
Chem 47:501–509
Pordel M (2012) Synthesis of new fluorescent compounds from
benzimidazole. J Chem Res 36:595–597
Di Giorgio C, Delmas F, Filloux N, Robin M, Seferian L, Azas N,
Gasquet M, Timon-David P, Galy JP (2003) In vitro activities of
7-substituted 9-chloro and 9-amino-2-methoxyacridines and
their bis- and tetra-acridine complexes against leishmania
infantum. Antimicrob Agents Chemother 47:174–180
Gamage SA, Figgit DP, Wojcik SJ, Ralph RK, Ransijn A, Mauel J,
Yardley V, Snowdon D, Croft SL, Denny W (1997) Structure-
activity relationships for the antileishmanial and antitrypanoso-
mal activities of 10-substituted 9-anilinoacridines. J Med Chem
40:2634–2642
Pordel M, Abdollahi A, Razavi B (2013) Synthesis and biological
evaluation of novel isoxazolo[4,3-e]indoles as antibacterial
agent. Russ J Bioorg Chem 39:211–214
Preston PN (2009) The chemistry of heterocyclic compounds,
benzimidazoles and cogeneric tricyclic compounds, Part 1, vol
40. Wiley, London, pp 87–105
Qiao X, Zeitany AE, Wright MW, Essader AS, Levine KE, Kucera
GL, Bierbach U (2012) Analysis of the DNA damage produced
by a platinum-acridine antitumor agent and its effects in NCI-
H460 lung cancer cells. Metallomics 4:645–652
Girault S, Grellier P, Berecibar A, Maes L, Mouray E, Lemiere P,
Debreu MA, Davioud-Charvet E, Sergheraert C (2000) Anti-
malarial, antitrypanosomal, and antileishmanial activities and
cytotoxicity of bis (9-amino-6-chloro-2-methoxyacridines):
influence of the linker. J Med Chem 43:2646–2654
Girault S, Delarue S, Grellier P, Berecibar A, Maes L, Quirijnen L,
Lemiere P, Debreu-Fontaine MA, Sergheraert C (2001) Anti-
malarial in vivo activity of bis (9-amino-6-chloro-2-methoxy-
acridines. J Pharm Pharmacol 53:935–938
Goodell JR, Madhok AA, Hiasab H, Ferguson DM (2006) Synthesis
and evaluation of acridine- and acridone-based anti-herpes
agents with topoisomerase activity. Bioorg Med Chem
14:5467–5480
Rahimizadeh M, Pordel M, Bakavoli M, Bakhtiarpoor Z, Orafaie A
(2009) Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-
a]acridines as potential antibacterial agents. Monatsh Chem
140:633–638
Rahimizadeh M, Pordel M, Bakavoli M, Rezaeian Sh, Sadeghian A
(2010) Synthesis and antibacterial activity of some new deriva-
tives of pyrazole. World J Microbiol Biotechnol 26:317–321
Sadeghian H, Sadeghian A, Pordel M, Rahimizadeh M, Jahandari P,
Orafaie A, Bakavoli M (2010) Design, synthesis, and structure–
activity relationship study of 5-amido-1-(2,4-dinitrophenyl)-1H-
4-pyrazolecarbonitrils as DD carboxypeptidase/penicillin-bind-
ing protein inhibitors with Gram-positive antibacterial activity.
Med Chem Res 19:103–119
Iida T, Satoh H, Maeda K, Yamamoto Y, Ki Asakawa, Sawada N,
Wada T, Kadowaki C, Itoh T, Mase T, Weissman SA, Tschaen
D, Krska S, Volante RP (2005) Practical synthesis of a
neuropeptide y antagonist via stereoselective addition to a
ketene. J Org Chem 70:9222–9229
Sadeghian A, Pordel M, Safdari H, Fahmidekar MA, Sadeghian H
(2012) 11-Chloro-3-methyl-3H-imidazo[4,5-a]acridine (CMIA)
as a potent and selective antimicrobial agent against clinical
isolates of highly antibiotic-resistant Acinetobacter baumannii.
Med Chem Res 21:3897–3901
Joshi AA, Viswanathan CL (2006) Recent developments in anti-
malarial drug discovery. Anti-Infect Agents Med Chem
5:105–122
Kamal A, Srinivas O, Ramulu P, Ramesh G, Kumar PP (2004)
Synthesis of C8linked pyrrolo [2,1-c][1,4] benzodiazepine-
acridone/acridine hybrids as potential DNA-binding agents.
Bioorg Med Chem Lett 14:4107–4111
Kukowska-Kaszuba M, Dzierzbicka K (2007) Synthesis and struc-
ture-activity studies of peptide-acridine/acridone conjugates.
Curr Med Chem 14:3079–3104
Sahraei R, Pordel M, Behmadi H, Razavi B (2013) Synthesis of a new
class of strongly fluorescent heterocyclic compounds: 3H-
imidazo[4,5 a]acridine-11-carbonitriles. J Lumin 136:334–338
Szarfman A, Tonning J, Levine J, Doraiswamy P (2006) Atypical
antipsychotics and pituitary tumors: a pharmacovigilance study.
Pharmacotherapy 26:748–758
Tanasescu I (1927) Preparation of acridones (and 10-hydroxy-
acridones) from o-nitrobenzaldehyde and a halobenzene in the
presence of concentrated sulfuric acid containing nitrous acid as
catalyst. Bull Soc Chim Fr 41:528–532
Lang X, Li L, Chen Y, Sun Q, Wu Q, Liu F, Tan Ch, Liu H, Gao Ch,
Jiang Y (2013) Novel synthetic acridine derivatives as potent
DNA-binding and apoptosis-inducing antitumor agents. Bioorg
Med Chem 21:4170–4177
Loudon JD, Tennant G (1964) Substituent interactions in ortho-
substituted nitrobenzenes. Quart Rev Chem Soc 18:389–413
Lowden CT, Bastow KF (2003) Cell culture replication of herpes
simplex virus and or human cytomegalovirus is inhibited by 3,7-
Werbovetz KA, Spoors PG, Pearson RD, Macdonald TL (1994)
Cleavable complex formation in Leishmania chagasi treated with
anilinoacridines. Mol Biochem Parasitol 65:1–10
Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D, Riscoe
MK (2008) Antimalarial quinolones: synthesis, potency, and
mechanistic studies. Exp Parasitol 118:487–497
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