Microwave-induced synthesis and anti-microbial activities of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives

Article abstract of DOI:10.1016/j.ejmech.2008.07.004

Some new substituted tetrahydroacridin-8-ones and diverse derivatives were synthesized by uncatalysed multi-component reaction of dimedone or cyclohexan-1,3-dione, α-naphthylamine and various (o,p,m)-substituted benzaldehydes. The in vitro anti-microbial

Full text of DOI:10.1016/j.ejmech.2008.07.004

European Journal of Medicinal Chemistry 44 (2009) 976–980
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Microwave-induced synthesis and anti-microbial activities of
7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives
,
b
Vetrivel Nadaraj a, Senniappan Thamarai Selvi a , Sellappan Mohan
*
a Department of Chemistry (PG and Research), Kongunadu Arts and Science College, G.N. Mills Post, Coimbatore 641 029, India
b Department of Pharmaceutical Biotechnology, KMCH College of Pharmacy, Coimbatore 641 035, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Some new substituted tetrahydroacridin-8-ones and diverse derivatives were synthesized by uncata-
Received 10 October 2007
Received in revised form 5 July 2008
Accepted 5 July 2008
lysed multi-component reaction of dimedone or cyclohexan-1,3-dione,
a-naphthylamine and various
(o,p,m)-substituted benzaldehydes. The in vitro anti-microbial activities of the prepared compounds
were evaluated against some bacteria and fungi strains. The results suggested that, the products 2a–g
and 4a–g exhibited good inhibitory effect against most of the tested organisms. Especially, 2f, 2g, 4f and
4g were shown to be most effective against Rhodotorula rubra and Aspergillus parasiticus and compounds
Available online 12 July 2008
Keywords:
Dimedone
Acridine
2a, 2c, 2g, 4f and 4g proved to be effective with MIC values in the range of 3.9–7.8 mg/ml.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Multi-component reaction
Microwaves
Anti-microbial activity
1. Introduction
Recently, synthesis of organic compounds assisted by
microwaves [21] under solvent free conditions [22,23], is an
improved technique. Due to greater selectivity, rapid transfer of
energy, significant practical simplicity and pure products,
microwave-assisted reactions have greater advantages over
conventional homogeneous methods. The coupling of micro-
wave technology with one-pot multi-component condensation
reactions has received significant attention [24] since two or
more steps in the synthetic sequence can be carried out
without the isolation of intermediates. This leads to reduction
of time and energy and constitutes overall an economical way
of developing new pharmaceutically important compounds
[25].
Acridine derivatives have been known since the 19th century
where they were first used as pigments and dyes [1]. Their anti-
septic activity has been discovered in the early 1900s and some
derivatives were extensively used during First World War for their
antibacterial and anti-malarial activities. In the 1920s, their
potential in the fight against cancer was first noted. The synthetic
research on acridine derived antimalarial experienced a renais-
sance during the middle of 1960s. Wide ranges of acridines were
tested for anti-malarial activities [2] and among them the intro-
duction of benzo analogue is one of the types of nuclei variation,
that has received a considerable attention [3,4].
1,4-Dihydropyridines (DHPs) are well known compounds
because of their pharmacological profile as calcium channel
modulations [5,6]. In fact, it is well established that slight structural
modification on the DHP ring may bring significant change in
pharmacological activities [7–9]. With an 1,4-DHPs parent nucleus,
acridines are well known therapeutic agent [10,11]. The use of
acridine derivatives as therapeutic agent has been the subject of
numerous studies [12–14]. Therefore, the synthesis of new tetra-
cyclic acridine compounds has increased rapidly in last few years
[15–20].
Some methods are available in the literature for the synthesis
of acridine compounds containing 1,4-dihydropyridines, from
dimedone, aldehyde and different anilines or ammonium acetate
via traditional heating in organic solvents [26], in water catalyzed
by TEBAC [27], under microwave irradiation [28] and using ionic
liquids [29]. Nowadays, to avoid the use of toxic organic solvents,
ionic liquids are emerging as effective solvents for green
processes. However, the high cost of most conventional ionic
liquids and their toxicity prompted us to explore other clean
method. Hence, we now report an efficient, solvent free, no
catalyst, microwave-assisted multi-component synthesis of some
substituted 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one deriv-
atives and evaluation of anti-microbial activities of the prepared
compounds.
* Corresponding author. Tel.: þ91 422 2642095; fax: þ91 422 2644452.
E-mail address: thamaraimohan@yahoo.co.in (S. Thamarai Selvi).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.07.004

V. Nadaraj et al. / European Journal of Medicinal Chemistry 44 (2009) 976–980
977
2. Results and discussion
2.1. Chemistry
anti-microbial tests were carried out by disc-diffusion method [33].
One hundred microlitres of suspension containing 108 CFU/ml of
bacteria, 106 CFU/ml of fungi were spread on Mueller–Hinton agar
medium (MHA) and Sabouraud’s dextrose agar (SDA) medium,
Irradiation of a mixture of dimedone (1),
a
-naphthylamine and
respectively. The discs (6 mm in diameter), impregnated with 10
ml
salicylaldehyde (Scheme 1) containing no catalyst or solvent, under
microwaves at 160 W gave a yellow solid (91.9%) within 3 min time.
The product was identified as 10,10-dimethyl-7-(o-hydrox-
yphenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one (2a). IR
spectrum of 2a showed a strong band at 1587 cmꢀ1 for carbonyl
group and broadband in the region 3100–3500 cmꢀ1 for NH and OH
of the test compounds (500 g/disc and 1000 g/disc) at the
concentration of 50 and 100 mg/ml were placed on the inoculated
agar. Negative controls were prepared using the same solvent
m
m
(DMSO) employed to dissolve the test compounds. Ofloxacin (5
mg/
disc) and Clotrimazole (10 g/disc) were used as positive reference
m
standard to determine the sensitivity of each microbial species
tested. The inoculated plates were incubated at 37 ꢂC for 24 h and
27 ꢂC for 72 h for bacteria and fungi strains, respectively. Anti-
microbial activity was evaluated by measuring the diameter of zone
of inhibition against test organisms.
groups. The 1H NMR spectrum revealed two singlets at
1.09 for gem dimethyl protons, two fine doublets at 2.06–2.29 and
2.61–2.71 for C9–H and C11–H, singlet at 5.87 for C7–H, multiplet
in the region 6.99–7.73 for aromatic protons, doublet at 8.18 for
C6–H, a singlet at 8.93 for NH proton and broad singlet at 13.03 for
d 1.03 and
d
d
d
d
d
The results of the anti-microbial screening are given in Tables 2
and 3. From the results obtained, it is obvious that most of the
compounds showed promising activity against bacteria and fungi.
The compounds 2a–g showed significant inhibition effect on the
growth of bacteria like Escherichia coli, Klebsiella aerogenes,
Salmonella typhimurium, Bacillus subtilis and Bacillus cereus (Table
2) and moderate activity against Pseudomonas aeruginosa, Vibrio
fischeri, Corynebacterium rubrum, Staphylococcus albus and Proteus
vulgaris. Among the compounds 2a–g, 2c, 2f and 2g showed activity
against all the bacteria, which might be due to the presence of
chlorine and hydroxyl groups in p-position and nitro group in o-
position in phenyl ring. These compounds also showed very good
anti-fungal activity. For instance, the growth of fungi like Asper-
gillus flavus, Rhodotorula rubra, Aspergillus parasiticus and Tricho-
derma viridie was very much affected by 2a–g and 2f indicated
OH proton. The mass spectrum of 2a exhibited a molecular ion peak
ꢁ
at m/z 369 (Mþ ) and its base peak at m/z 276, similar to known 7-
phenyltetarahydrobenzo[c]acridin-8(9H)-ones [30].
Extension of this technique to different aldehydes provided some
known and new benzo[c]acridin-8(9H)-one derivatives (Scheme 1).
The known compounds 2b, 2c, 2e, 2f and 2g were identical in all
respects (mp, mmp, IR, 1H NMR and Mass) with authentic samples
prepared [30,31] and new compounds 2a and 2d were completely
characterized by IR,1H NMR, Mass spectral data and elemental analysis.
In order to apply this reaction to a library synthesis, cyclohexan-
1,3-dione (3) was treated with
a-naphthylamine and various
aldehydes which successfully yielded the corresponding 7-
(substituted phenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-
ones 4a–g (Scheme 2). The expected products were formed in
quantitative yields and purity (Table 1). The IR spectra of
compounds (4a–g) showed intense bands in the region 1587–
1591 cmꢀ1 due to carbonyl stretching and broad bands in the
region 3100–3300 cmꢀ1 due to NH stretching.
maximum activity of 21 and 23 mm at 500 and 1000 mg/disc,
respectively, against Rhodotorula rubra which is greater than the
standard inhibition value (Table 2). These compounds (2a–g)
showed moderate activity against other fungi (Table 2).
The 1H NMR spectra were recorded in DMSO-d6 support the
proposed structure of the compounds. The CH2 protons (C9, C10 and
The anti-microbial activity of compounds 4a–g is similar to 2a–g
(Table 3). Among them, 4c, 4f and 4g showed activity against all
bacteria and fungi, whereas compounds 4a, 4b, 4d and 4e showed
activity only against Escherichia coli, Bacillus subtilis and Bacillus
cereus. The compounds 4a–g have a pronounced effect on the
growth of fungi like Aspergillus flavus, Rhodotorula rubra, Aspergillus
parasiticus and Trichoderma viridie and moderate activity against
other fungi (Table 3).
Minimum inhibitory concentration (MIC) of the compounds was
also estimated by broth dilution assay [34] for the microorganisms,
which were determined as sensitive to the compounds in disc-
diffusion assay. Nutrient broth (NB) and Sabouraud’s dextrose broth
(SDB) were used to estimate the MIC values of the test compounds
against bacteria and fungi, respectively. Two fold serial dilutions of
test compounds were followed with 1 ml of sterile broth in test
tubes to provide various concentration range from 3.9 to 1000
C11) of 4a–g appeared as a multiplet at
proton (C7) appeared as a singlet at
aromatic protons showed multiplet at
d
1.81–2.85 ppm and the CH
5.64–5.86 ppm. The entire
d
d
6.78–8.47 ppm. The NH
proton resonance at 9.20–9.35 was disappeared after addition of
D2O. The mass spectra of all compounds (4a–g) showed molecular
ion peaks confirming their molecular weight; moreover their
fragmentation pathways are similar to 2a–g. The known compound
4e was identical in all respects (mp, mmp, IR, 1H NMR and Mass)
with authentic sample prepared [32].
2.2. Anti-microbial activity
All the synthesized compounds were screened for their anti-
bacterial and anti-fungal activities. For preliminary screening, the
R
R
O
O
MWI
6
7
8
5
CHO
+
Neat condition
9
4
10
N
H
H2N
O
12
11
1
3
1
2a-g
2
2a
o
o
p
m
: R = -OH, 2b: R = -Cl, 2c: R = -Cl, 2d: R = -Cl,
2g
2e: R = H, 2f: R = p-OH, : R = m-NO2
Scheme 1.

978
V. Nadaraj et al. / European Journal of Medicinal Chemistry 44 (2009) 976–980
R
R
O
O
MWI
CHO
+
Neat condition
N
H
H2N
O
3
4a-g
4a
: R = o-OH, 4b: R = o-Cl, 4c: R = p-Cl, 4d: R = m-Cl,
4g
4e: R = H, 4f: R = p-OH, : R = m-NO2
Scheme 2.
m
g/ml of the test compounds. Ten microlitres of the test organism
(3) (0.1121 g, 1 mmol), and respective aldehydes (1 mmol) was
taken in a 100 ml beaker and the mixture was placed inside the
microwave oven and irradiated at an output of 160 W under neat
condition for the specified times (Table 1). After completion of
reaction, the mixture was poured into ice; the precipitate formed
was filtered and purified by column chromatography using petro-
leum ether and ethyl acetate as an eluant.
were added to each tube and incubated at 37 ꢂC for 24 h and 27 ꢂC
for 72 h for bacteria and fungi strains, respectively. The highest
dilution of the test compound completely inhibiting the test
organism was considered as MIC value of the test compound,
respectively. The results of the MIC values of the compounds have
been listed in Table 4. The MIC values of the compounds 2a–g and
4a–g range between 3.9 and 125
the compounds 2a–g, 2a, 2c and 2f showed MIC values as 3.9 and
7.8 g/ml against Aspergillus parasiticus, whereas 2g showed 3.9, 7.8
and 15.6 g/ml against Escherichia coli, Aspergillus parasiticus, Rho-
dotorula rubra and Bacillus cereus. The compounds 4b, 4c, 4f and 4g
also showed 3.9 g/ml as MIC value against some bacteria and fungi.
mg/ml, in most of the cases. Among
3.1.1. 10,10-Dimethyl-7-(o-hydroxyphenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2a
m
IR (nmax): 1587 (C]O), 3100–3500 (NH and OH); 1H NMR
(DMSO-d6): 1.03 (s, 3H, CH3), 1.09 (s, 3H, CH3), 2.06–2.29 (dd, 2H,
C9–H), 2.61–2.71 (dd, 2H, C11–H), 5.87 (s, 1H, C7–H), 6.99–7.73 (m,
9H, Ar–H), 8.18 (d, 1H, C6–H), 8.93 (s, 1H, NH), 13.03 (s, 1H, OH); Ms
(m/z): 369; Anal. Calc. (C25H23NO2): C, 81.27, H, 6.27, N, 3.79; found:
C, 81.25, H, 6.27, N, 3.77.
m
m
3. Experimental
All reagents used were AR grade. Melting points (mp) were
determined using Boetius microheating table and are uncorrected.
Infrared spectra (cmꢀ1) were recorded on Shimadzu-8201 spec-
trophotometer as pallets on KBr discs. The 1H NMR (400 MHz)
spectra were recorded on Bruker AMX-400 spectrometer in DMSO-
3.1.2. 10,10-Dimethyl-7-(o-chlorophenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2b
IR (nmax): 1587 (C]O), 3300 (NH); 1H NMR (DMSO-d6): 1.00 (s,
3H, CH3), 1.06 (s, 3H, CH3), 2.03–2.24 (dd, 2H, C9–H), 2.52–2.71 (dd,
2H, C11–H), 6.04 (s, 1H, C7–H), 6.87–7.82 (m, 9H, Ar–H), 8.42 (d, 1H,
C6–H), 9.23 (s, 1H, NH); Ms (m/z): 387; Anal. Calc. (C25H22NOCl): C,
77.41, H, 5.72, N, 3.61; found: C, 77.50, H, 5.74, N, 3.60.
d6 using TMS as an internal reference (Chemical shifts in d, ppm)
unless otherwise stated. The splitting patterns are designated as
follows: s, singlet, d, doublet, t, triplet, m, multiplet, dd, doublet
of doublet. Elemental analyses were performed on Perkin Elmer
CHN-analyzer. Mass spectra were recorded on Shimadzu GCMS-
QP5050A (70 eV) mass spectrometer. The reactions were moni-
tored by thin layer chromatography (TLC) using glass plates coated
with Silica gel-G containing 13% calcium sulphate as binder.
Column chromatography was performed on silica gel (60–120
mesh). For microwave irradiation a Kenstar (OM-20ESP, 2450 MHz)
domestic microwave oven was used.
3.1.3. 10,10-Dimethyl-7-(p-chlorophenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2c
IR (nmax): 1589 (C]O), 3307 (NH); 1H NMR (DMSO-d6): 0.98
(s, 3H, CH3), 1.08 (s, 3H, CH3), 2.04–2.28 (dd, 2H, C9–H), 2.58–2.70
(dd, 2H, C11–H), 5.43 (s, 1H, C7–H), 7.18–7.83 (m, 9H, Ar–H), 8.46
(d, 1H, C6–H), 9.35 (s, 1H, NH); Ms (m/z): 387; Anal. Calc.
(C25H22NOCl): C, 77.41, H, 5.72, N, 3.61; found: C, 77.49, H, 5.71, N,
3.58.
3.1. Synthesis of 10,10-dimethyl-7-(substituted phenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-ones (2a–g) and 7-(substituted
phenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-ones (4a–g)
3.1.4. 10,10-Dimethyl-7-(m-chlorophenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2d
IR (nmax): 1591 (C]O), 3340 (NH); 1H NMR (DMSO-d6): 1.05 (s,
3H, CH3), 1.10 (s, 3H, CH3), 2.03–2.29 (dd, 2H, C9–H), 2.60–2.71 (dd,
2H, C11–H), 5.80 (s, 1H, C7–H), 6.68–7.48 (m, 9H, Ar–H), 8.40 (d, 1H,
C6–H), 9.25 (s, 1H, NH); Ms (m/z): 387; Anal. Calc. (C25H22NOCl): C,
77.41, H, 5.72, N, 3.61; found: C, 77.49, H, 5.72, N, 3.60.
General procedure: a mixture of
a-naphthylamine (0.1432 g,
1 mmol), dimedone (0.1402 g, 1 mmol) (or) cyclohexan-1,3-dione
Table 1
Microwave synthesis of 2a–g and 4a–g at 160 W under microwave irradiation
Compound Time
(min)
Yield
(%)
mp (ꢂC) Compound Time
(min)
Yield
(%)
mp (ꢂC)
3.1.5. 10,10-Dimethyl-7-phenyl-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2e
2a
2b
2c
2d
2e
2f
3
4
3
3
2
4
2
91.9
95.8
98.1
96.8
93.5
93.5
92.9
220–222 4a
265–266 4b
290–292 4c
270–272 4d
258–259 4e
280–282 4f
238–240 4g
5
4
3
3
3
4
4
93.8
92.4
96.0
94.6
95.4
94.1
92.4
1196–198
256–258
205–206
240–241
246–248
228–230
202–203
IR (nmax): 1599 (C]O), 3309 (NH); 1H NMR (DMSO-d6): 0.99 (s,
3H, CH3), 1.05 (s, 3H, CH3), 2.02–2.22 (dd, 2H, C9–H), 2.59–2.75 (dd,
2H, C11–H), 6.04 (s, 1H, C7–H), 6.85–7.52 (m, 9H, Ar–H), 7.77 (d, 1H,
C5–H), 8.41 (d, 1H, C6–H), 9.23 (s, 1H, NH); Ms (m/z): 353; Anal. Calc.
(C25H23NO): C, 84.95, H, 6.56, N, 3.96; found: C, 84.95, H, 6.56, N,
3.98.
2g

V. Nadaraj et al. / European Journal of Medicinal Chemistry 44 (2009) 976–980
979
Table 2
In vitro anti-microbial activity of 2a–g (
m
g/disc) by disc-diffusion assay
Diameter of zone of inhibition in mm
2a ( g/disc) 2b ( g/disc) 2c ( g/disc)
500 1000 500 1000 500 1000 500 1000 500 1000 500 1000 500 1000
Microorganisms
m
m
m
2d (m
g/disc) 2e (
m
g/disc)
2f (
mg/disc)
2g (m
g/disc) A (
m
g/disc) B (
10
mg/disc)
5
Escherichia coli (NCIM 2065)a
–
–
7
10
–
7
–
–
–
–
–
9
10
–
10
–
8
–
7
–
–
10
7
8
7
–
–
–
–
8
10
–
8
–
7
7
8
–
7
7
8
9
8
10
7
7
7
9
–
7
9
–
12
–
–
9
9
7
–
–
8
–
9
7
7
–
–
–
9
7
–
11
7
–
8
–
7
–
–
9
8
9
–
–
–
–
–
9
10
–
7
–
10
–
–
10
11
12
8
–
–
–
–
10
12
10
10
–
7
7
9
9
7
9
7
7
7
7
8
9
21
–
12
–
7
12
9
10
7
8
10
9
10
7
8
7
7
–
9
10
8
10
8
8
15
8
23
22
24
21
24
19
27
25
21
19
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
16
16
17
Pseudomonas aeruginosa (NCIM 2200)a
Klebsiella aerogenes (NCIM 2239)a
Salmonella typhimurium (NCIM 2501)a
Bacillus subtilis (NCIM 2063)a
10
11
9
10
8
–
–
–
–
10
14
–
16
–
9
13
8
11
9
–
–
–
–
10
13
8
10
–
11
11
10
13
9
10
9
10
–
8
13
8
17
–
–
9
10
9
10
9
8
–
–
–
10
9
9
12
10
8
12
11
10
11
9
10
8
9
10
12
23
–
14
9
11
13
11
13
10
9
9
9
–
13
15
10
16
11
11
12
Bacillus cereus (NCIM 2155)a
Vibrio fischeri (NCIM 2154)a
Corynebacterium rubrum (NCIM 2252)a
Staphylococcus albus (NCIM 2178)a
Proteus vulgaris (NCIM 2027)a
Aspergillus niger (NCIM 1196)b
Aspergillus flavus (NCIM 535)b
Rhodotorula rubra (NCIM 3174)b
Aspergillus fumigatus (NCIM 902)b
Aspergillus parasiticus (NCIM 904)b
Penicillium chrysogenum (NCIM 707)b
Lipomyces lipofera (NCIM 3252)b
Trichoderma viridie (NCIM 1195)b
18
18
21
18
19
–
10
–
12
10
8
–
9
–
12
10
12
7
9
10
13
10
10
A ¼ Ofloxacin, B ¼ Clotrimazole, –, no inhibition, NT – not tested.
a
Bacteria.
Fungi.
b
3.1.6. 10,10-Dimethyl-7-(p-hydroxyphenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2f
3.1.8. 7-(o-Hydroxyphenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-
8(9H)-one 4a
IR (nmax): 1590 (C]O), 3290–3400 (NH and OH); 1H NMR
(DMSO-d6): 1.02 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.04–2.24 (dd, 2H,
C9–H), 2.50–2.73 (dd, 2H, C11–H), 5.82 (s, 1H, C7–H), 6.94–7.80 (m,
9H, Ar–H), 8.44 (d, 1H, C6–H), 9.08 (s, 1H, NH), 12.93 (s, 1H, OH); Ms
(m/z): 369; Anal. Calc. (C25H23NO2): C, 81.27, H, 6.27, N, 3.79; found:
C, 81.28, H, 6.25, N, 3.76.
IR (nmax): 1591 (C]O), 3100–3300 (NH and OH); 1H NMR
(DMSO-d6): 1.90–2.85 (m, 6H, C9–H, C10-H and C11–H), 5.74 (s,
1H, C7–H), 7.03–7.80 (m, 9H, Ar–H), 8.47 (d, 1H, C6–H), 9.20 (s,
1H, NH), 10.36 (s, 1H, OH); Ms (m/z): 341; Anal. Calc.
(C23H19NO2): C, 80.91, H, 5.61, N, 4.10; found: C, 80.90, H, 5.59,
N, 4.10.
3.1.7. 10,10-Dimethyl-7-(m-nitrophenyl)-7,10,11,12-
tetrahydrobenzo[c]acridin-8(9H)-one 2g
3.1.9. 7-(o-Chlorophenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-
8(9H)-one 4b
IR (nmax): 1590 (C]O), 3310 (NH); 1H NMR (DMSO-d6): 1.03 (s,
3H, CH3), 1.14 (s, 3H, CH3), 2.04–2.25 (dd, 2H, C9–H), 2.58–2.71 (dd,
2H, C11–H), 5.65 (s, 1H, C7–H), 7.00–8.14 (m, 9H, Ar–H), 8.44 (d, 1H,
C6–H), 9.17 (s, 1H, NH); Ms (m/z): 398; Anal. Calc. (C25H22N2O3): C,
75.36, H, 5.57, N, 7.03; found: C, 75.36, H, 5.55, N, 7.00.
IR (nmax): 1590 (C]O), 3270 (NH); 1H NMR (DMSO-d6): 1.82–
2.50 (m, 6H, C9–H, C10–H and C11–H), 5.86 (s, 1H, C7–H), 6.92–7.32
(m, 10H, Ar–H), 9.35 (s, 1H, NH); Ms (m/z): 359; Anal. Calc.
(C23H18NOCl): C, 76.77, H, 5.04, N, 3.89; found: C, 76.87, H, 5.02, N,
3.88.
Table 3
In vitro anti-microbial activity of 4a–g (
m
g/disc) by disc-diffusion assay
Microorganisms
Diameter of zone of inhibition in mm
4a (
m
g/disc) 4b (
m
g/disc) 4c (
m
g/disc)
4d (
m
g/disc) 4e (
m
g/disc)
4f (
m
g/disc)
4g (
m
g/disc) A (
m
g/disc) B (
10
mg/disc)
500 1000 500 1000 500 1000 500 1000 500 1000 500 1000 500 1000
5
Escherichia coli (NCIM 2065)a
8
–
–
–
8
7
–
–
–
–
–
8
11
–
9
–
9
–
–
–
10
8
–
–
–
–
–
–
–
7
–
7
7
–
–
–
7
13
–
8
–
8
–
–
–
10
–
9
8
–
–
–
9
16
9
10
–
–
7
7
–
9
8
10
8
7
8
7
8
7
12
8
10
7
–
8
10
9
11
12
13
9
8
10
9
10
10
16
10
12
8
7
–
–
–
8
–
9
7
–
–
–
9
8
8
12
–
9
–
9
–
11
–
10
9
–
–
8
–
–
–
8
8
–
–
–
–
–
9
8
–
7
–
–
11
9
–
–
–
10
9
–
–
–
–
–
10
12
11
9
–
–
12
7
7
7
7
9
–
7
7
8
7
9
7
12
–
12
9
10
10
9
9
10
9
11
–
9
9
10
9
10
8
14
–
9
–
7
7
10
7
7
7
8
7
7
8
10
–
11
–
12
–
9
10
12
10
9
8
11
9
23
22
24
21
24
19
27
25
21
19
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
16
16
17
Pseudomonas aeruginosa (NCIM 2200)a
Klebsiella aerogenes (NCIM 2239)a
Salmonella typhimurium (NCIM 2501)a
Bacillus subtilis (NCIM 2063)a
Bacillus cereus (NCIM 2155)a
Vibrio fischeri (NCIM 2154)a
Corynebacterium rubrum (NCIM 2252)a
Staphylococcus albus (NCIM 2178)a
Proteus vulgaris (NCIM 2027)a
–
9
Aspergillus niger (NCIM 1196)b
Aspergillus flavus (NCIM 535)b
Rhodotorula rubra (NCIM 3174)b
Aspergillus fumigatus (NCIM 902)b
Aspergillus parasiticus (NCIM 904)b
Penicillium chrysogenum (NCIM 707)b
Lipomyces lipofera (NCIM 3252)b
Trichoderma viridie (NCIM 1195)b
–
9
11
13
12
10
9
11
10
12
13
–
12
14
9
13
–
18
18
21
18
19
13
10
11
11
–
9
–
10
–
9
9
8
–
8
–
10
8
9
10
10
10
–
A ¼ Ofloxacin, B ¼ Clotrimazole, –, no inhibition, NT – not tested.
a
Bacteria.
Fungi.
b

980
V. Nadaraj et al. / European Journal of Medicinal Chemistry 44 (2009) 976–980
Table 4
Minimum inhibitory concentration values of 2a–g and 4a–g (mg/ml) against the microorganisms tested in broth dilution assay
Microorganisms
Escherichia coli (NCIM 2065)a
2a
2b
2c
62.5
2d
2e
62.5
–
–
62.5
31.2
31.2
2f
31.2
62.5
31.2
31.2
62.5
31.2
125
62.5
125
125
62.5
2g
3.9
125
31.2
15.6
31.2
15.6
62.5
4a
4b
4c
62.5
62.5
125
62.5
31.2
15.6
62.5
125
62.5
125
62.5
62.5
3.9
4d
62.5
–
125
–
31.2
–
62.5
4e
4f
4g
31.2
–
125
62.5
31.2
62.5
125
125
62.5
125
125
31.2
3.9
125
15.6
–
62.5
62.5
125
–
62.5
31.2
62.5
62.5
125
–
125
125
–
125
62.5
62.5
62.5
125
125
–
–
–
125
–
–
–
62.5
125
–
–
–
–
125
31.2
15.6
62.5
62.5
125
–
62.5
125
–
–
–
62.5
125
–
–
–
62.5
125
–
–
–
–
–
62.5
31.2
62.5
62.5
–
–
31.2
125
125
62.5
125
31.2
–
125
125
62.5
125
62.5
125
7.8
Pseudomonas aeruginosa (NCIM 2200)a
Klebsiella aerogenes (NCIM 2239)a
Salmonella typhimurium (NCIM 2501)a
Bacillus subtilis (NCIM 2063)a
62.5
62.5
31.2
31.2
15.6
62.5
62.5
125
62.5
–
125
15.6
125
3.9
–
–
31.2
62.5
31.2
62.5
Bacillus cereus (NCIM 2155)a
–
Vibrio fischeri (NCIM 2154)a
125
125
125
125
–
–
–
Corynebacterium rubrum (NCIM 2252)a
Staphylococcus albus (NCIM 2178)a
Proteus vulgaris (NCIM 2027)a
–
–
–
–
62.5
7.8
–
–
–
–
–
125
125
–
–
–
–
125
125
–
Aspergillus niger (NCIM 1196)b
Aspergillus flavus (NCIM 535)b
Rhodotorula rubra (NCIM 3174)b
Aspergillus fumigatus (NCIM 902)b
Aspergillus parasiticus (NCIM 904)b
Penicillium chrysogenum (NCIM 707)b
Lipomyces lipofera (NCIM 3252)b
Trichoderma viridie (NCIM 1195)b
–
62.5
62.5
31.2
15.6
–
–
125
62.5
15.6
125
62.5
–
125
125
62.5
62.5
31.2
3.9
15.6
62.5
62.5
62.5
31.2
62.5
125
15.6
31.2
62.5
62.5
–
–
7.8
62.5
3.9
62.5
62.5
31.2
3.9
62.5
62.5
–
–
–
–
62.5
31.2
125
125
125
–
3.9
7.8
15.6
125
62.5
31.2
–
–
125
62.5
31.2
31.2
62.5
31.2
62.5
– Not tested.
a
Bacteria.
Fungi.
b
3.1.10. 7-(p-Chlorophenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-
References
8(9H)-one 4c
IR (nmax): 1588 (C]O), 3280 (NH); 1H NMR (DMSO-d6): 1.85–
2.53 (m, 6H, C9–H, C10–H and C11–H), 5.80 (s, 1H, C7–H), 6.86–7.19
(m, 10H, Ar–H), 9.22 (s, 1H, NH); Ms (m/z): 359; Anal. Calc.
(C23H18NOCl): C, 76.77, H, 5.04, N, 3.89; found: C, 76.88, H, 5.04, N,
3.86.
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14 (2006) 3896–3903.
3.1.11. 7-(m-Chlorophenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-
8(9H)-one 4d
IR (nmax): 1590 (C]O), 3220 (NH); 1H NMR (DMSO-d6): 1.82–
2.55 (m, 6H, C9–H, C10–H and C11–H) 5.64 (s, 1H, C7–H), 6.96–7.40
(m, 10H, Ar–H), 9.32 (s, 1H, NH); Ms (m/z): 359; Anal. Calc.
(C23H18NOCl): C, 76.77, H, 5.04, N, 3.89; found: C, 76.88, H, 5.02, N,
3.88.
3.1.12. 7-Phenyl-7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one
4e
IR (nmax): 1587 (C]O), 3280 (NH); 1H NMR (DMSO-d6): 1.81–2.45
(m, 6H, C9–H, C10–H and C11–H), 5.84 (s,1H, C7–H), 6.78–7.19 (m,11H,
Ar–H), 9.24 (s, 1H, NH); Ms (m/z): 325; Anal. Calc. (C23H19NO): C,
84.89, H, 5.89, N, 4.31; found: C, 84.95, H, 5.85, N, 4.28.
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3.1.13. 7-(p-Hydroxy)-7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-
one 4f
IR (nmax): 1591 (C]O), 3100–3300 (NH and OH); 1H NMR
(DMSO-d6): 1.98–2.55 (m, 6H, C9–H, C10–H and C11–H), 5.64 (s, 1H,
C7–H), 6.92–7.11 (m, 10H, Ar–H), 9.20 (s, 1H, NH), 10.32 (s, 1H, OH);
Ms (m/z): 341; Anal. Calc. (C23H19NO2): C, 80.91, H, 5.61, N, 4.10;
found: C, 80.90, H, 5.60, N, 4.08.
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3.1.14. 7-(m-Nitrophenyl)-7,10,11,12-tetrahydrobenzo[c]acridin-
8(9H)-one 4g
IR (nmax): 1587 (C]O), 3200 (NH); 1H NMR (DMSO-d6): 1.86–2.46
(m, 6H, C9–H, C10–H and C11–H), 5.80 (s, 1H, C7–H), 6.89–7.80 (m,
10H, Ar–H), 9.33 (s,1H, NH); Ms (m/z): 370; Anal. Calc. (C23H18N2O3):
C, 74.58, H, 4.90, N, 7.56; found: C, 74.58, H, 4.90, N, 7.55.