Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-a]acridines as potential antibacterial agents

Article abstract of DOI:10.1007/s00706-009-0109-7

New imidazo[4,5-a]acridone derivatives were synthesized from the rearrangement of 3H-imidazo[4′,5′:3,4]benzo[c]isoxazoles. New imidazo[4,5-a]acridines were obtained from the reaction of imidazo[4,5-a] acridones in boiling POCl₃. All of these co

Full text of DOI:10.1007/s00706-009-0109-7

Monatsh Chem (2009) 140:633–638
DOI 10.1007/s00706-009-0109-7
ORIGINAL PAPER
Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-a]acridines
as potential antibacterial agents
Mohammad Rahimizadeh Æ Mehdi Pordel Æ
Mehdi Bakavoli Æ Zahra Bakhtiarpoor Æ
Ala Orafaie
Received: 15 September 2008 / Accepted: 24 November 2008 / Published online: 20 February 2009
Ó Springer-Verlag 2009
Abstract New imidazo[4,5-a]acridone derivatives were
synthesized from the rearrangement of 3H-imidazo
[40,50:3,4]benzo[c]isoxazoles. New imidazo[4,5-a]acridines
were obtained from the reaction of imidazo[4,5-a]acri-
dones in boiling POCl3. All of these compounds exhibited
antimicrobial activities comparable to streptomycin as
reference drug.
inhibit topoisomerase enzymes. Also acridines with a
suitable functionalization can be used as a fluorophore for
fluorescence lifetime studies [15] and fluorescent sensors
for anions [16].
There are several methods for the synthesis of these
useful compounds, including the Bernthsen reaction [17] as
the oldest method for the synthesis of acridines. Other
reactions by Ullmann [18], Meyer [19], Koller [20], and
several new methods [21–26] have also been cited in the
literature. In 1937, Tanasescu and Suciu [27] described a
synthetic approach to acridones through rearrangement of
benzo[c]isoxazoles (anthranil) in the presence of concen-
trated sulfuric acid containing nitrous acid as catalyst.
A literature survey disclosed that 3H-imidazo[40,50:3,4]
benzo[c]isoxazoles have not been converted to imi-
dazo[4,5-a]acridones by the Tanasescu reaction yet. Owing
to our growing interest in the synthesis of bioactive
heterocycles [28–33] and evaluation of their biological
activities, we became interested in examining the trans-
formation of 3H-imidazo[40,50:3,4]benzo[c]isoxazoles 3a–f
to their new imidazo[4,5-a]acridones 4a–f by this method.
Keywords Imidazo[4, 5-a]acridone ꢀ
Imidazo[4, 5-a]acridine ꢀ Antibacterial agents ꢀ
Tanasescu reaction
Introduction
Acridine derivatives, such as acridones, pyridoacridines,
and imidazoacridines, are one the oldest classes of bioac-
tive compounds that are widely used as antibacterial [1, 2],
antiviral [3, 4], antiprion [5], and antimalarial [6–10]
agents. Some work in these areas continues, but recent
research has focused mainly on their utility as anticancer
[11, 12] and antitumor [13, 14] drugs. This is because of
the ability of the acridine and acridone chromophore to
intercalate within the double-stranded DNA structure and
Results and discussion
Chemistry
M. Rahimizadeh ꢀ M. Pordel ꢀ M. Bakavoli (&) ꢀ
Z. Bakhtiarpoor
Department of Chemistry, School of Sciences,
Ferdowsi University of Mashhad,
91775-1436 Mashhad, Iran
The new key compounds 3a–f were obtained via the
nucleophilic substitution of hydrogen of N-alkyl-5-nitro-
benzimidazoles 1a–c with arylacetonitriles 2a, b in basic
MeOH solution [34, 35] (Scheme 1).
e-mail: mbakavoli@yahoo.com
Compounds 3a–f underwent rearrangement in high
yields to their corresponding imidazo[4,5-a]acridones 4a–f
in concentrated sulfuric acid containing nitrous acid at
room temperature (Scheme 2).
A. Orafaie
Department of Biology, School of Sciences,
Ferdowsi University of Mashhad,
91775-1436 Mashhad, Iran
123

634
M. Rahimizadeh et al.
R2
Biological activities
The synthesized compounds 4a–f and 5a–f were screened
for antibacterial activity against Escherichia coli HB101
(BA-7601C), Staphylococcus aureus (PTCC-1074), Pseu-
domonas aeruginosa (PTCC 1431), and Bacillus subtilis
(PTCC 1365) by filter paper disk diffusion method [36, 37].
Mueller-Hinton agar media were sterilized (15 min at
121 °C) and poured into the plates to a uniform depth of
5 mm and allowed to solidify. The microbial suspension
(15 9 108 CFU mL-1) (0.5 McFarland Nephelometery
Standards) was streaked over the surface of media using a
sterile cotton swab (15 min at 180 °C) to ensure confluent
growth of the organisms. The bacteria were grown on agar
media (pH = 7.4 0.2 at 25 °C). The disks used were
Whatman no. 1 filter papers (6.25 mm in diameter). Stock
solutions of compounds 4a–f and 5a–f with dimethylsulf-
oxide (DMSO) were prepared and diluted with ethanol
96% (50–250 lg cm-3). The prepared discs were impreg-
nated with these prepared solutions of compounds 4a–f and
5a–f and then placed on the previously inoculated agar
surface. The plates were inverted and incubated for 24 h at
37 °C. The negative control of inhibition zones of growth
for ethanol and DMSO were studied. All the experiments
were conducted three times. Antimicrobial activity was
indicated by the assessment of clear inhibition zones
around the spot, and the disk diameters were compared
with streptomycin (10 lg cm-3) as standard drug. Solvent
effects and growth controls were kept, and the zones of
inhibition in millimeter were studied as a criterion for its
antimicrobial activity. The results of these evaluations are
given in Table 1.
R2
O
N
O2N
N
N
N
N
R1
KOH, MeOH
4 h, reflux
R1
CH2CN
3a:R1=Me, R2=H
3b:R1=Me, R2=Cl
3c:R1=Pr, R2=H
3d:R1=Pr, R2=Cl
3e:R1=Bu, R2=H
3f:R1=Bu, R2=Cl
1a:R1=Me
1b:R1=Pr
1c:R1=Bu
2a:R2=H
2b:R2=Cl
Scheme 1
R2
R2
O
O
N
c. H2SO4, NaNO2
48 h, rt
4a:R1=Me, R2=H
4b:R1=Me, R2=Cl
4c:R1=Pr, R2=H
HN
N
N
N
N
R1
4d:R1=Pr, R2=Cl
4e:R1=Bu, R2=H
4f:R1=Bu, R2=Cl
R1
4a-f
3a-f
Scheme 2
The latter compounds decomposed above 300 °C, and
they were very insoluble in organic solvents except DMF
and DMSO. The structural assignments of compounds 4a–f
were based on the analytical and spectral data. For exam-
ple, in the 1H NMR spectrum of 4a, the signal at
11.79 ppm is attributed to one exchangeable proton (NH
group). Moreover, the FT-IR spectrum of 4a in KBr
showed two absorption bands at 3,420 and 1,660 cm-1
assignable to NH and C=O groups. All this evidence plus
microanalytical data strongly support the cyclic structure
of 4a.
As can be concluded from the data in Table 1, imi-
dazo[4,5-a]acridines 5a–f have shown the higher sensitivity
against Escherichia coli HB101 (BA-7601C), Staphylo-
coccus aureus (PTCC-1074), Pseudomonas aeruginosa
(PTCC 1431), and Bacillus subtilis (PTCC 1365) than
imidazo[4,5-a]acridones 4a–f. Compounds 5b, d, and f
have shown the highest sensitivity against Escherichia coli
HB101 (BA-7601C), Staphylococcus aureus (PTCC-1074),
Pseudomonas aeruginosa (PTCC 1431), and Bacillus sub-
tilis (PTCC 1365). All the other compounds were found to
exhibit moderate activities against the mentioned organ-
isms. These results clearly demonstrate that halogen
substituted imidazo[4,5-a]acridines exhibited better acti-
vity than other substituted imidazo[4,5-a]acridones and
imidazo[4,5-a]acridines.
Treatment of imidazo[4,5-a]acridones 4a–f in boiling
POCl3 gave imidazo[4,5-a]acridines 5a–f in excellent
yields (Scheme 3).
R2
R2
O
Cl
POCl3
3 h, reflux
5a:R1=Me, R2=H
5b:R1=Me, R2=Cl
5c:R1=Pr, R2=H
5d:R1=Pr, R2=Cl
5e:R1=Bu, R2=H
5f:R1=Bu, R2=Cl
HN
N
N
N
R1
N
N
R1
Experimental
5a-5f
4a-4f
Melting points were recorded on an Electrothermal type
9100 melting point apparatus. The IR spectra were
Scheme 3
123

Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-a]acridines
Table 1 Antibacterial data of 4a–f and 5a–f
635
Compound
Escherichia coli
HB101 (BA-7601C)
Pseudomonas
aeruginosa (PTCC-1431)
Staphylococcus
aureus (PTCC 1074)
Bacillus sabtilis
(PTCC 1365)
4a
12 (?)
14 (?)
12 (?)
12 (?)
12 (?)
13 (?)
13 (?)
15 (??)
14 (?)
16 (??)
14 (?)
17 (??)
17
13 (?)
12 (?)
13 (?)
12 (?)
12 (?)
12 (?)
13 (?)
13 (?)
15 (?)
14 (?)
16 (??)
14 (?)
16 (??)
15
12 (?)
14 (?)
12 (?)
13 (?)
13 (?)
14 (?)
13 (?)
14 (?)
14 (?)
16 (??)
14 (?)
17 (??)
10
4b
14 (?)
4c
12.5 (?)
12.5 (?)
12 (?)
4d
4e
4f
14 (?)
5a
13.5 (?)
15 (??)
15 (??)
17 (??)
15 (??)
17 (??)
10
5b
5c
5d
5e
5f
Streptomycin (standard)
Zones of inhibition in millimeters
(??) Highly sensitive = inhibition zone 15
(?) Moderately sensitive = inhibition zone 12–14
8-(4-Chlorophenyl)-3-methyl-3H-imidazo
[40,50:3,4]benzo[c]isoxazole (3b, C15H10ClN3O)
obtained on a 4300 Shimadzu spectrometer, and only
noteworthy absorptions are listed. The 13C NMR
(125 MHz) spectra were recorded on a Bruker Avance
Compound 3b was obtained as pale yellow crystals
(methanol), yield 86%, m.p.: 292–294 °C; 1H NMR
(100 MHz, CDCl3): d = 3.92 (s, 3H), 7.42 (d,
J = 9.5 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.67 (d,
J = 8.8 Hz, 2H), 7.89 (s, 1H), 8.87 (d, J = 8.8 Hz, 2H)
ppm; MS (70 eV): m/z = 285 (M ? 2).
1
DRX-500 spectrometer. The H NMR (100 MHz) spectra
were recorded on a Bruker AC 100 spectrometer. Chemical
shifts are reported in ppm downfield from TMS as internal
standard; coupling constants J are given in Hz. The mass
spectra were scanned on a Varian Mat CH-7 at 70 eV.
Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyzer, and results agreed favorably with
calculated values. Compounds 1a–c [38] were obtained
according to published methods. Other reagents were
commercially available.
8-Phenyl-3-propyl-3H-imidazo[40,50:3,4]benzo[c]isoxazole
(3c, C17H15N3O)
Compound 3c was obtained as pale yellow crystals
(ethanol), yield 73%, m.p.: 119–122 °C; 1H NMR
(100 MHz, CDCl3): d = 0.99 (t, J = 7.0 Hz, 3H), 1.77–
2.12 (m, 2H), 4.21 (t, J = 7.0 Hz, 2H), 7.47–7.69 (m, 6H),
7.89 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H) ppm; MS (70 eV):
m/z = 277 (M?).
General procedure for the synthesis of 3a–f from 1a–c
Compounds 1a–c (10 mmol) and 2a, b (12 mmol) were
added with stirring to a solution of 20 g KOH (357 mmol)
in 80 cm3 methanol. The mixture was refluxed with stirring
for 4 h and then poured into water. The precipitate was
collected by filtration, washed with water, and air-dried to
give 3a–f.
8-(4-Chlorophenyl)-3-propyl-3H-imidazo
[40,50:3,4]benzo[c]isoxazole (3d, C17H14ClN3O)
Compound 3d was obtained as pale yellow crystals
(ethanol), yield 67%, m.p.: 158–160 °C; 1H NMR
(100 MHz, CDCl3): d = 1.05 (t, J = 7.3 Hz, 3H), 1.85–
2.21 (m, 2H), 4.18 (t, J = 7.3 Hz, 2H), 7.40 (d, J = 9.5 Hz,
1H), 7.56 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H),
7.86 (s, 1H), 8.89 (d, J = 8.6 Hz, 2H) ppm; MS (70 eV):
m/z = 313 (M ? 2).
3-Methyl-8-phenyl-3H-imidazo[40,50:3,4]benzo[c]
isoxazole (3a, C15H11N3O)
Compound 3a was obtained as pale yellow crystals
(methanol), yield 81%, m.p.: 266–268 °C; 1H NMR
(100 MHz, CDCl3): d = 3.43 (s, 3H), 7.41 (d,
J = 8.0 Hz, 1H), 7.55–7.81 (m, 7H) ppm; MS (70 eV):
m/z = 249 (M?).
3-Butyl-8-phenyl-3H-imidazo[40,50:3,4]benzo[c]isoxazole
(3e, C18H17N3O)
Compound 3e was obtained as pale yellow crystals
(ethanol), yield 82%, m.p.: 110–112 °C; 1H NMR
123

636
M. Rahimizadeh et al.
(100 MHz, CDCl3): d = 0.97 (t, J = 7.0 Hz, 3H), 1.21–
1.56 (m, 2H), 1.81–2.09 (m, 2H), 4.23 (t, J = 7.0 Hz, 2H),
7.47–7.69 (m, 6H), 7.88 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H)
ppm; MS (70 eV): m/z = 291(M?).
3-Propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4c, C17H15N3O)
Compound 4c was obtained as yellow crystals
(EtOH ? CH3CN), yield 80%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 0.79 (t, J = 7.0 Hz,
3H), 1.71–2.06 (m, 2H), 4.26 (t, J = 7.0 Hz, 2H), 7.15–
8.15 (m, 6H), 8.30 (s, 1H), 11.86 (br s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 175.0, 140.2, 139.4, 138.5,
129.3, 127.1, 126.1, 122.1, 119.5, 118.8, 117.2, 117.0,
116.6, 106.9, 52.5, 21.6, 10.0 ppm; IR (KBr): vꢀ = 3,415
(NH), 1,660 (C=O) cm-1; MS (70 eV): m/z = 277 (M?).
3-Butyl-8-(4-chlorophenyl)-3H-imidazo
[40,50:3,4]benzo[c]isoxazole (3f, C18H16ClN3O)
Compound 3f was obtained as pale yellow crystals
(ethanol), yield 83%, m.p.: 157–159 °C; 1H NMR
(100 MHz, CDCl3): d = 0.98 (t, J = 7.0 Hz, 3H), 1.23–
1.58 (m, 2H), 1.82–2.10 (m, 2H), 4.24 (t, J = 7.0 Hz, 2H),
7.41 (d, J = 9.5 Hz, 1H), 7.56(d, J = 9.5 Hz, 1H), 7.61 (d,
J = 8.6 Hz, 2H), 7.90 (s, 1H), 8.87 (d, J = 8.6 Hz, 2H)
ppm; MS (70 eV): m/z = 327 (M ? 2).
8-Chloro-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]
acridin-11-one (4d, C17H14ClN3O)
Compound 4d was obtained as yellow crystals
(EtOH ? CH3CN), yield 73%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 0.83 (t, J = 7.1 Hz,
3H), 1.69–1.95 (m, 2H), 4.29 (t, J = 7.1 Hz, 2H), 7.25 (dd,
J = 9.5 Hz, J = 2.1 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.75
(d, J = 9.4 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.25 (d,
J = 9.5 Hz, 1H), 8.35 (s, 1H), 11.80 (br s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 175.1, 140.2, 140.0,
139.56, 137.4, 128.4, 126.1, 121.9, 119.1, 119., 117.7,
117.1, 115.2, 106.7, 52.8, 21.6, 10.1 ppm; IR (KBr):
vꢀ = 3,415 (NH), 1,660 (C=O) cm-1; MS (70 eV):
m/z = 313 (M ? 2).
General procedure for the synthesis of 4a–f from 3a–f
Sodium nitrite (5 g, 150 mmol) was added with stirring
over half an hour period to a solution of 3a–f (7 mmol) in
100 cm3 concentrated sulfuric acid maintained at -10 °C.
After the addition was completed, the mixture was allowed
to warm to room temperature and to stand at room tem-
perature for 17 h. After pouring this mixture into 500 cm3
crushed ice and water, the solid that precipitated was
removed by filtration, was washed with water, and dried to
give 4a–f.
3-Methyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4a, C15H11N3O)
3-Butyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one
(4e, C18H17N3O)
Compound 4a was obtained as yellow crystals
(EtOH ? CH3CN), yield 90%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 3.92 (s, 3H), 7.41 (d,
J = 8.9 Hz, 1H), 7.45–7.85 (m, 5H), 8.33 (s, 1H), 11.79 (br
s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 175.1,
141.6, 140.3, 140.6, 129.1, 127.7, 126.7, 122.4, 120.0,
119.3, 117.9, 117.5, 117.0, 107.7, 33.3 ppm; IR (KBr):
vꢀ = 3,420 (NH), 1,660 (C=O) cm-1; MS (70 eV):
m/z = 249 (M?).
Compound 4e was obtained as yellow crystals
(EtOH ? CH3CN), yield 87%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 0.87 (t, J = 7.0 Hz,
3H), 1.16–1.51 (m, 2H), 1.75–2.03 (m, 2H), 4.30 (t,
J = 7.0 Hz, 2H), 7.10–8.10 (m, 6H), 8.31 (s, 1H), 11.81 (br
s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 175.1,
140.3, 138.9, 138.0, 129.3, 127.2, 126.2, 122.1, 119.5,
118.9, 117.3, 117.0, 116.6, 107.0, 49.7, 30.8, 20.4,
11.1 ppm; IR (KBr): vꢀ = 3,415 (NH), 1,660 (C=O)
cm-1; MS (70 eV): m/z = 291(M?).
8-Chloro-3-methyl-6,11-dihydro-3H-imidazo[4,5-a]
acridin-11-one (4b, C15H10ClN3O)
3-Butyl-8-chloro-6,11-dihydro-3H-imidazo[4,5-a]
acridin-11-one (4f, C18H16ClN3O)
Compound 4b was obtained as yellow crystals
(EtOH ? CH3CN), yield 85%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 4.04 (s, 3H), 7.32
(dd, J = 9.5 Hz, J = 2.1 Hz, 1H), 7.78 (d, J = 9.4 Hz,
1H), 7.85 (d, J = 9.4 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H),
8.25 (d, J = 9.5 Hz, 1H) 8.45 (s, 1H), 11.83 (br s, 1H)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 175.1, 141.9,
141.4, 140.6, 138.2, 127.0, 126.4, 122.2, 119.9, 119.2,
117.9, 117.3, 117.0, 107.4, 33.4 ppm; IR (KBr): vꢀ = 3,415
(NH), 1,660 (C=O) cm-1; MS (70 eV): m/z = 285
(M ? 2).
Compound 4f was obtained as yellow crystals
(EtOH ? CH3CN), yield 80%, m.p.: [300 °C (decomp);
1H NMR (100 MHz, DMSO-d6): d = 0.86 (t, J = 6.5 Hz,
3H), 1.13–1.48 (m, 2H), 1.73–2.01 (m, 2H), 4.33 (t,
J = 6.5 Hz, 2H), 7.21(dd, J = 9.5 Hz, J = 2.1 Hz, 1H),
7.58 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 9.4 Hz, 1H), 8.15 (d,
J = 2.1 Hz, 1H), 8.25 (d, J = 9.5 Hz, 1H) 8.30 (s, 1H),
11.91 (br s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 175.1, 140.3, 139.7, 139.1, 137.4, 128.4, 126.2, 121.9,
119.2, 119.0, 117.7, 117.2, 115.2, 107.4, 49.9, 30.7, 20.4,
123

Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-a]acridines
637
11.1 ppm; IR (KBr): vꢀ = 3,415 (NH), 1,660 (C=O) cm-1
MS (70 eV): m/z = 327 (M ? 2).
;
121.5, 119.1, 111.7, 110.8, 52.5, 21.5, 10.2 ppm; MS
(70 eV): m/z = 332 (M ? 2).
3-Butyl-3H-imidazo[4,5-a]acridine (5e, C18H16ClN3)
Compound 5e was obtained as yellow crystals (CH3CN),
yield 75%, m.p.: 172–174 °C; 1H NMR (100 MHz,
CDCl3): d = 0.99 (t, J = 7.0 Hz, 3H), 1.26–1.61 (m, 2H),
1.88–2.16 (m, 2H), 4.35 (t, J = 7.0 Hz, 2H), 7.69–8.34 (m,
6H), 8.68 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H) ppm; 13C NMR
(125 MHz, CDCl3): d = 157.7, 156.5, 147.7, 141.9, 134.5,
131.6, 130.8, 130.3, 126.9, 125.6, 121.4, 118.7, 111.2,
110.1, 49.7, 30.8, 20.4, 11.1 ppm; MS (70 eV): m/z = 309
(M?).
General procedure for the synthesis of 5a–f from 4a–f
A mixture of 4a–f (4 mmol) and 6 cm3 POCl3 was refluxed
with stirring for 3 h. After cooling to rt, the reaction
mixture was poured onto crushed ice and neutralized with
ammonia solution. The product was extracted with
2 9 50 cm3 EtOAc. The extract was dried and evaporated
to give 5a–f.
3-Methyl-3H-imidazo[4,5-a]acridine (5a, C15H10ClN3)
Compound 5a was obtained as yellow crystals (CH3CN),
yield 75%, m.p.: 240–241 °C; 1H NMR (100 MHz,
CDCl3): d = 4.02 (s, 3H), 7.61 (d, J = 8.9 Hz, 1H),
7.65–8.05 (m, 5H), 8.65 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H)
ppm; 13C NMR (125 MHz, CDCl3): d = 157.9, 156.7,
150.3, 142.6, 134.6, 131.6, 131.3, 130.7, 127.4, 125.8,
122.0, 119.0, 111.7, 110.6, 33.2 ppm; MS (70 eV): m/
z = 267 (M?).
3-Butyl-8-chloro-3H-imidazo[4,5-a]acridine
(5f, C18H15Cl2N3)
Compound 5f was obtained as yellow crystals (CH3CN),
yield 82%, m.p.: 183–185 °C; 1H NMR (100 MHz,
CDCl3): d = 1.01 (t, J = 6.8 Hz, 3H), 1.25–1.60 (m, 2H),
1.73–2.01 (m, 2H), 4.38 (t, J = 6.8 Hz, 2H), 7.62 (dd,
J = 9.5 Hz, J = 2.1 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 8.11
(d, J = 9.4 Hz, 1H), 8.21 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H),
8.62 (d, J = 9.5 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 157.9, 156.7, 148.6, 142.6, 139.4, 133.9,
131.6, 130.9, 127.9, 125.7, 121.3, 119.0, 111.5, 110.2,
49.8, 30.8, 20.4, 11.1 ppm; MS (70 eV): m/z = 346
(M ? 2).
8-Chloro-3-methyl-3H-imidazo[4,5-a]acridine
(5b, C15H9Cl2N3)
Compound 5b was obtained as yellow crystals (CH3CN),
yield 80%, m.p.: 282–284 °C; 1H NMR (100 MHz,
CDCl3): d = 4.05 (s, 3H), 7.62 (dd, J = 9.5 Hz,
J = 2.1 Hz, 1H), 7.85 (d, J = 9.4 Hz, 1H), 8.03 (d,
J = 9.4 Hz, 1H), 8.13 (s, 1H), 8.30 (d, J = 2.1 Hz, 1H),
8.62 (d, J = 9.5 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 157.9, 157.0, 150.3, 142.6, 139.7, 134.6,
131.8, 130.9, 127.9, 125.9, 121.7, 119.1, 111.6, 110.9,
33.3 ppm; MS (70 eV): m/z = 304 (M ? 2).
Acknowledgments We are grateful to Mashhad University of
Medical Sciences for financial support of this work.
References
1. Tabarrini O, Cecchetti V, Fravolini A, Nocentini G, Barzi A,
Sabatini S, Miao H, Sissi C (1999) J Heterocycl Chem 42:2136
2. Denny WA (2002) Curr Med Chem 9:1655
3. Goodell JR, Madhok AA, Hiasa H, Ferguson DM (2006) Bioorg
Med Chem 14:5467
4. Tabarrini O, Manfroni G, Fravolini A, Cecchetti V, Sabatini S,
De Clercq E, Rozenski J, Canard B, Dutartre H, Paeshuyse J,
Neyts J (2006) J Med Chem 49:2621
5. Kukowska-Kaszuba M, Dzierzbicka K (2007) Curr Med Chem
14:3079
3-Propyl-3H-imidazo[4,5-a]acridine (5c, C17H14ClN3)
Compound 5c was obtained as yellow crystals (CH3CN),
yield 79%, m.p.: 185–187 °C; 1H NMR (100 MHz,
CDCl3): d = 1.01 (t, J = 7.2 Hz, 3H), 1.88–2.11 (m, 2H),
4.30 (t, J = 7.2 Hz, 2H), 7.68–8.32 (m, 6H), 8.67 (dd,
J = 9.0 Hz, J = 2.0 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): d = 157.7, 156.6, 148.3, 142.3, 134.6, 131.7,
130.8, 130.3, 127.0, 125.6, 121.5, 118.8, 111.5, 110.5,
52.3, 21.6, 10.1 ppm; MS (70 eV): m/z = 295 (M?).
6. Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D,
Riscoe MK (2008) Exp Parasitol 118:487
7. Joshi AA, Viswanathan CL (2006) Anti-Infect Agents Med Chem
5:105
8-Chloro-3-propyl-3H-imidazo[4,5-a]acridine
(5d, C17H13Cl2N3)
8. Dheyongera JP, Geldenhuys WJ, Dekker TG, Matsabisa MG,
Van Der Schyf CJ (2005) Bioorg Med Chem 13:1653
9. Kesten SJ, Degnan MJ, Hung J, Mc Namara DJ, Ortwine DF,
Uhlendorf SE, Werbel LM (1992) J Med Chem 35:3429
10. Raether W, Enders B, Hofmann J, Schwannecke U, Seidenath H,
Hanel H, Uphoff M (1989) Parasitol Res 75:619
11. Belmont P, Bosson J, Godet T, Tiano M (2007) Anti-Cancer
Agents Med Chem 7:139
Compound 5d was obtained as yellow crystals (CH3CN),
yield 80%, m.p.: 205–207 °C; 1H NMR (100 MHz,
CDCl3): d = 1.02 (t, J = 7.1 Hz, 3H), 1.81–207 (m, 2H),
4.32 (t, J = 7.1 Hz, 2H), 7.60 (dd, J = 9.5 Hz, J = 2.1 Hz,
1H), 7.90 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H),
8.25 (s, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 9.5 Hz,
1H) ppm; 13C NMR (125 MHz, CDCl3): d = 157.8, 156.9,
148.8, 142.5, 139.7, 134.1, 131.7, 130.9, 128.0, 125.7,
12. Kamal A, Srinivas O, Ramulu P, Ramesh G, Kumar PP (2004)
Bioorg Med Chem Lett 14:4107
13. Demeunynck M (2004) Expert Opin Ther Pat 14:55
123

638
M. Rahimizadeh et al.
14. Robertson IGC, Palmer BD, Officer M, Siegers DJ, Paxton JW,
Shaw GJ (1991) Biochem Pharmacol 42:1879
15. Smith JA, West RM, Allen M (2004) J Fluoresc 14:151
29. Bakavoli M, Nikpour M, Rahimizadeh M (2006) J Heterocycl
Chem 43:1327
30. Davoodnia A, Bakavoli M, Vahedinia A, Rahimizadeh M,
Roshani M (2006) Heterocycles 68:801
31. Bakavoli M, Davoodnia A, Rahimizadeh M, Heravi MM (2006)
Mendeleev Commun 16:29
32. Bakavoli M, Nikpour M, Rahimizadeh M, Saberi MR, Sadeghian
H (2007) Bioorg Med Chem 15:2120
33. Bakavoli M, Pordel M, Rahimizadeh M, Jahandari P, Seresht ER
(2008) Heterocycles 75:165
34. Davis RB, Pizzini LC (1960) J Org Chem 25:1884
35. Pechenina VM, Mukhina NA, Klimenko VG, Granik VG (1986)
Chem Heterocycl Compd 22:876
´
´
16. Blazquez MT, Mun˜iz FM, Saez S, Simon LM, Alonso A, Raposo
C, Lithgow A, Alcazar V, Moran JR (2006) Heterocycles 69:73
`
´
´
´
17. Bernthsen A (1878) Ann 1:192
18. Ullmann F (1907) Ber 40:2521
19. Meyer H, Hofmann A (1916) Monatsh 37:698
20. Koller G, Krakauer E (1928) Monatsh 50:51
21. Gorelik MV, Titova SP (2007) Russ Chem Bull 56:1679
22. Zhao J, Larock RC (2007) J Org Chem 72:583
23. Nishio R, Wessely S, Sugiura M, Kobayashi S (2006) J Comb
Chem 8:459
24. Herath HMTB, Mu¨ller K, Diyabalanage HVK (2004) J Hetero-
cycl Chem 41:23
36. Cruickshank R, Duguid JP, Marion BP, Swain RHA (1975)
Medicinal Microbiology, vol II, 12th edn. Churchil Livingstone,
London, p 196
37. Collins AH (1976) Microbiological methods, 2nd edn. Butter-
worth, London
´
´
25. Xuarez L, Pellon RF, Fascio M, Montesano V, D’Accorso N
(2004) Heterocycles 63:23
26. Galy J-P, Hanoun J-P, Pique V, Jagerovic N, Elguero J (1997)
J Heterocycl Chem 34:1781
27. Tanasescu I, Suciu M (1937) Bull Soc Chim France 4:245
28. Bakavoli M, Feizyzadeh B, Rahimizadeh M (2006) Tetrahedron
Lett 47:8965
38. Aliprandi B, Cacace F, Possagno E (1958) Ann Chim (Italy)
48:1349
123