Conformationally-constrained indeno[2,1-c]quinolines - A new class of anti-mycobacterial agents

Article abstract of DOI:10.1039/b924102g

The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new conformationally-constrained indeno[2,1-c]quinoline analogs (Fig. 1), by retaining the biologically significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class of conformationally-constrained compounds has been designed such that their conformational flexibility across C4-C2′ is diminished to nil by covalently locking the C4 center of the quinoline moiety in the SW hemisphere with the C2′ center of the phenyl ring in the NW hemisphere, thereby decreasing the entropic penalty for their complex formation within the target protein, which will in turn give improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of 0.39 μg mL^-1 (1 μM) and 0.78 μg mL^-1 (2 μM) respectively.

Full text of DOI:10.1039/b924102g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Conformationally-constrained indeno[2,1-c]quinolines – a new class of
anti-mycobacterial agents†
Ram Shankar Upadhayaya,a Santosh V. Lahore,a Aftab Y. Sayyed,a Shailesh S. Dixit,a Popat D. Shindea and
Jyoti Chattopadhyaya*b
Received 18th November 2009, Accepted 9th February 2010
First published as an Advance Article on the web 15th March 2010
DOI: 10.1039/b924102g
The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained
indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural
comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new
conformationally-constrained indeno[2,1-c]quinoline analogs (Fig. 1), by retaining the biologically
significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class
of conformationally-constrained compounds has been designed such that their conformational
flexibility across C4-C2¢ is diminished to nil by covalently locking the C4 center of the quinoline moiety
in the SW hemisphere with the C2¢ center of the phenyl ring in the NW hemisphere, thereby decreasing
the entropic penalty for their complex formation within the target protein, which will in turn give
improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were
evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration
of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition
of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial
growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of
0.39 mg mL-1 (1 mM) and 0.78 mg mL-1 (2 mM) respectively.
develop new and effective anti-TB drugs to treat this deadly
Introduction
disease. Focusing on the existing drugs and drug targets for anti-
TB drug development8 may have limitations because of potential
cross-resistance of M. tuberculosis.9
Tuberculosis (TB) is a contagious, deadly disease that spreads
through air and has become a serious worldwide health problem.1
It is the greatest cause of mortality and morbidity worldwide.2
The WHO has reported that 1/3 (nearly 2 billion) of the world’s
population is already infected with TB bacilli and every second
a new case of TB infection is reported.3 The WHO report also
reveals that 22 countries have the highest TB burden, among them
India, China, Indonesia, South Africa and Nigeria rank 1st to 5th
respectively in terms of absolute number of TB cases.4 In 2004, 14.6
million chronic active cases, 8.9 million new cases, and 1.6 million
deaths were reported worldwide.3,4 According to the WHO, the
increase in the cases of TB during recent years was largely due
to the pathogenic synergy with HIV infection.3,4 The situation
has worsened very seriously with the spread of HIV-1, which
allows the latent TB to become active and makes the patient more
susceptible to re-infection with either drug-susceptible or drug-
resistant strains. Moreover, the increasing emergence of drug-
resistant TB, particularly multi-drug resistant TB (MDR-TB),5
extensive-drug resistant TB (XDR-TB)6 and the latent form of
TB is a great threat to mankind and has already caused several
fatal outbreaks.7 This justifies an urgent need to discover and
Among the new anti-TB drugs,10 the quinoline class of
compounds11,12 has shown promising activity against resistant
TB. Amongst these, diarylquinoline based molecule R207910
(TMC207) inhibits TB with very high potency.13 The MIC
of TMC207 against M. tuberculosis H37Rv is 0.060 mg mL-1,
(0.1 mM).13 Insights from both experimental and theoretical
investigations13 reveal that ATP synthase subunit C is the target
of this drug and a mode of action has been discussed.14,15
In order to elaborate on the SAR and to develop synthetically
more accessible analogs of TMC207, we have systematically
altered the functional groups in the four hemispheres of the
TMC207 molecule: North-East (NE),16,17 North-West (NW),17
South-East (SE)16,17 and South-West (SW)17,18 (Fig. 1). One of our
primary aims is to develop highly potent molecules with minimal
structural complexity, in high yield and through easier routes
leading to their chemical synthesis. We have reported the func-
tional importance of the phenyl, naphthyl and bromine moieties of
TMC207, based on ATP synthase-ligand docking calculations.16-18
These studies also revealed the critical role of electrostatic inter-
actions, van der Waals interactions in determining the biological
activity.16-18
aInstitute of Molecular Medicine, Pune 411 057, India
bProgram of Bioorganic Chemistry, Institute of Cell and Molecular Biol-
ogy, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden.
E-mail: jyoti@boc.uu.se; Fax: +46-18-554495; Tel: +46-18-4714577
Herein we have explored
a novel class of 23 new
conformationally-constrained indeno[2,1-c]quinolines by cova-
lently locking the C4 center of the quinoline moiety in the SW
hemisphere with the C2¢ center of the phenyl ring in the NW
hemisphere (shown in green dotted line in Fig. 1(A)) based on
† Electronic supplementary information (ESI) available: Spectral data (1H,
13C NMR, DEPT, LCMS, Mass, HPLC and IR) for all new compounds.
See DOI: 10.1039/b924102g
2180 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Fig. 1 Four structural hemispheres of R207910 (TMC207). The variable part is shown in red. C4-C2¢ bond is shown with a green dotted line in the
conformationally-constrained core (A). General formulae (B) and (C) represent the series of compounds synthesized.
following considerations: (1) As TMC207 is a unique molecule
with a novel mode of action in term of its anti-mycobacterial
activity, which has two chiral centres, i.e. four diastereomers,
out of which only R/S diastereomer is active, we saw the need
to work around this molecule in order to find a less complex
molecule ideally without any chiral centers, which should be cost
effective/affordable and accessible. (2) Dissection of the TMC207
molecule (Fig. 1) into four hemispheres shows that the phenyl ring
is located at the NW hemisphere, and this phenyl has a free rotation
(Fig. 1) with respect to quinoline skeleton. The free rotation of
this phenyl ring should potentially increase the entropy during the
ligand-protein complex formation, which we wanted to minimize
by locking the C2¢ phenyl at the C4 position of quinoline, thereby
increasing the free-energy of stabilization of the ligand-protein
complex.
We anticipated that the entropic penalty for complex formation
with the target protein would be reduced upon restricting the con-
formational flexibility, which might enhance the binding affinity.
Based on a simple two-dimensional comparison of the TMC207
with our conformationally-constrained molecules (Fig. 1), we have
attempted to explore the biological significance of the quinoline
moiety and the phenyl ring in the SW and NW hemispheres of
TMC207, respectively. This was achieved by constructing the
indeno[2,1-c]quinoline core system as shown in A→ B/C in
Fig. 1. At the same time, the functionally important groups of the
NE hemisphere were replaced with different polar groups, which
would retain the equivalent polar interactions with the binding
site.
We herein report that the new indeno[2,1-c]quinoline based
molecules exhibited very good activity toward M. tuberculosis
H37Rv, showing up to 99% inhibition in vitro by BACTEC 460
radiometric assay19,20 at MIC of <0.39-6.25 mg mL-1 (<0.99-
14.63 mM mL-1).
Results
Synthesis
Synthesis of the conformationally-constrained indeno[2,1-
c]quinoline molecules started with 2-amino-5-bromo-
benzophenone21 (1, Scheme 1). Treatment of benzophenone
121 with malonic acid in POCl3 gave quinoline 2 (<20%) and
unreacted benzophenone 1. Optimization of reaction conditions
however improved the yield of quinoline 2 (53%) along with
the desired conformationally-locked indeno[2,1-c]quinoline 3
(16%) as a result of Friedel-Crafts cyclization of 2. The yield
of indeno[2,1-c]quinoline 3 (84%) was however improved by
intramolecular Friedel-Crafts acylation (AlCl3)21 of quinoline
2. Nucleophilic displacement at the C2 center of 2-chloro-
indeno[2,1-c]quinoline 3 by an appropriate nucleophile furnished
2-substituted indeno[2,1-c]quinolines 4-9 (71-97%) (Scheme 1
and experimental section).
The indeno[2,1-c]quinoline-7-oximes 10-14 (72-96%) were syn-
thesized by heating NH2OH·HCl and NaOH with the appro-
priate indeno[2,1-c]quinoline-7-ketones (4, 6-9, respectively) in
an ethanol-water (2 : 1, v/v) mixture. The oximes 10-12 were
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2181
©

View Article Online
Scheme 1 Synthesis of conformationally-constrained indeno[2,1-c]quinolines (3-20). Reagents and conditions: (i) malonic acid (1.5 eq), POCl3, 105 ◦C,
3 h; 53%; (ii) AlCl3 (2.5 eq), DCM, rt, 3 h; 84%; (iii) NaOMe (10 eq), dry THF : dry MeOH (2 : 1), reflux, 3 h; 4 (97%); (iv) R1H (5 eq), pyridine, 105 ◦C,
12 h; 5 (90%), 6 (92%), 7 (71%), 8 (87%), 9 (76%); (v) NH2OH·HCl (3 eq), NaOH (5 eq), EtOH-water (2 : 1), 0 ◦C, 15 min followed by 80-90 ◦C, 3-8 h;
10 (91%), 11 (96%), 12 (95%), 13 (72%), 14 (94%); (vi) NaH (1.1 eq), N,N-dimethylcarbamyl chloride (2 eq), dry DMF, rt, 12 h; 15 (66%), 16 (63%), 17
(62%); (vii) NaH (1.1 eq), 1-chloromethyl naphthalene (1.5 eq), dry DMF, rt, 3-12 h; 18 (48%), 19 (54%), 20 (50%).
subsequently acylated with N,N-dimethylcarbamoyl chloride
and NaH in dry DMF to give the corresponding N,N-
dimethylcarbamoyl oximes 15-17 (62-66%). The second set of
molecules was prepared from indeno[2,1-c]quinoline-7-oximes 10-
12 to give O-naphthalene-1-yl methyl-oximes 18-20 (48-54%) by
alkylation with 1-chloromethyl-naphthalene using NaH (Scheme 1
and experimental section).
The third set of molecules (Scheme 2) were based on the
conversion of 2-methoxyindeno[2,1-c]quinoline-7-ketone 4 to
the corresponding 7-methyl-7-ol 21 (77%) as an inseparable
enantiomeric mixture by Grignard reagent (MeMgI). The key
intermediate oxirane 22 (69%) was then synthesized by treatment
of alcohol 21 with epi-chlorohydrin and NaH. Oxirane 22 was
subsequently reacted with appropriate amines (R2H) and K2CO3
to give 23-31 (40-77%, respectively) as a diastereomeric mixture.
From these, only the diastereomeric mixture of compounds 23 and
24 could be separated as pure 23 and 24 (compound 23 is relatively
less polar then 24) by flash column chromatography. Compound 32
was synthesized by acylation of the alcohol 21 with N,N-dimethyl
carbamoyl chloride in dry DMF using NaH. Grignard reaction of
MeMgI on ketones 5 and 8 gave target compounds 33 (82%) and
34 (56%) respectively.
2182 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Scheme 2 Synthesis of compounds 21-34. Reagents and conditions: (i) MeMgI (1.2-6 eq), dry THF, 21, 15 ◦C-rt, 6 h, (77%); 33, rt, 6 h, (82%); 34, 0 ◦C,
15 min (56%); (ii) NaH (2.1 eq), epi-chlorohydrin (2.1 eq), dry DMF, rt, 48 h; 69%; (iii) K2CO3 (5 eq), R2H (1-5 eq), dry DMF, 65-70 ◦C, 15 h; 23 (22%),
24 (28%), 25 (50%), 26 (70%), 27 (40%), 28 (77%), 29 (77%), 30 (70%), 31 (41%); (iv) dry DMF, N,N-dimethylcarbamoyl chloride (2.5 eq), NaH (2.1 eq),
rt, 15 h; 32 (25%).
Anti-mycobacterial activity
of growth index (GI) and growth inhibition (%) (Figure S1,
Supplementary information), seven compounds 11, 13, 16, 24, 30,
32 and 34 were found to show excellent anti-mycobacterial activity.
Fig. 2 shows the bar graph of % TB growth inhibition for the
compounds 11, 13, 16, 24, 30, 32 and 34 along with Isoniazid22 for
the sake of comparison under identical experimental conditions.
Fig. 2 shows comparison of the inhibition ability of compounds
11, 13, 16, 24, 30, 32 and 34 with respect to Isoniazid, and suggests
Compounds 10-34 and standard drug Isoniazid22 were tested
against M. tuberculosis H37Rv (ATCC 27294) at a fixed concen-
tration of 6.25 mg mL-1 by BACTEC 460 radiometric method19,20
upon administration of a single-dose on day-one and then the
TB growth was monitored for 8/9 consecutive days. The results
are summarized in Table 1. On the basis of the calculated values
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2183
©

View Article Online
Table 1 % GI inhibition of M. tuberculosis H37Rv at a fixed dose 6.25 mg mL-1, administered on day-one, and effect observed for 8/9 consecutive days
and clogP valuesa
Compd. no.
R1
R2
% GI Inhibitionb
clogP
10
11
-OCH3
-OH
-OH
22
90
5.67
5.95
12
13
14
-OH
-OH
-OH
16
99
29
7.22
4.90
5.29
15
16
17
18
-OCH3
58
85
50
13
5.18
5.45
6.71
9.36
-OCH3
19
20
29
8
9.66
10.92
23
24
25
-OCH3
-OCH3
-OCH3
43
88
77
8.11
8.11
7.70
2184 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 1 (Contd.)
Compd. no.
R1
R2
% GI Inhibitionb
66
clogP
6.75
26
-OCH3
27
28
29
-OCH3
-OCH3
-OCH3
40
77
79
7.51
4.68
3.68
30
31
32
-OCH3
-OCH3
-OCH3
98
68
92
4.27
4.71
5.65
33
34
-OH
-OH
34
6.94
91
99
3.77
Isoniazid
-0.8c
a Values are means of triplicate measurement of % GI inhibition. Assays are performed by BACTEC 460 radiometric method.19,20 b Estimated with
reference to Growth Inhibition of the first front-line inhibitor, Isoniazid. c From PubChem (http://pubchem.ncbi.nlm.nih.gov).
that these compounds can successfully inhibit the M. tuberculosis
H37Rv growth by 90% ( 4.54), 99% ( 0.29), 85% ( 3.54), 88%
( 3.11), 98% ( 0.98), 92% ( 0.96) and 91% ( 3.15), respectively
under identical experimental condition. These compounds are
comparable to Isoniazid (Table 1, Figure S1). Based on the GI
plots, it was observed that Isoniazid did not show zero growth of
M. tuberculosis (Figure S1), which was not the case with the highly
active compound 13. The anti-mycobacterial activity profiles of
compounds 13 and 30 suggest that they may have a bactericidal
effect, as there was no growth in the treated control over 8/9
consecutive days. MIC of the most active compounds 11, 13, 16,
24, 30, 32 and 34 are given in Table 2.
Diastereomers 23 and 24 displayed different biological activities.
We found that more the polar diastereomer 24 is more active (88%
inhibition) than the relatively less polar diastereomer 23 (43%
inhibition). The high-inhibition capacity of compound 30 (98%
inhibition) is likely because of its relatively smaller size, hence
better induced fitting in the binding site (lower van der Waals
energy as described by docking and scoring calculations, Table S3
in SI).
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2185
©

View Article Online
Table 2 MIC aof compounds against M. tuberculosis H37Rv
Compd. no.
Structure
MIC/mg mL-1
6.25
MIC/mM
12.8
11
13
16
< 0.39
< 0.99
1.56
2.79
24
30
32
34
3.125
3.125
6.25
5.0
6.51
14.63
1.98
0.78
Isoniazid
0.256
1.86
a MIC determined by BACTEC 460 radiometric method.19,20
2186 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Fig. 2 % TB growth inhibition shown for compounds 11, 13, 16, 24, 30, 32 and 34 along with standard drug Isoniazid. Negative control is shown in
error bar graph (A). MIC99 in mM of individual compounds is represented on the top of bar in (B). The daywise %GI curve upon single dose at day one
is given in supporting information Figure S1.
Cytotoxicity
the proton-transfer of ATP-synthase, when bound to its sub-
unit C.12,13
Cytotoxicity results of 11, 13, 16, 24, 32 and 34 (Table 3) suggest
that these compounds are not cytotoxic to host cells at the given
concentrations, except compound 30, which is the least safe (cell
viability 65%) to human monocytic cells.
Compound 13 showed most impressive TB inhibition (99%,
Table 1) and lowest MIC (<0.39 mg mL-1, 0.99 mM, Table 2)
amongst all the compounds tested. Compound 13 has an imida-
zole ring at C2 which besides being a good protonable group at
physiological pH, could also act as a binding region by proton
bridge, and at the same time may be helping in enhancing
membrane permeability.23,24 It is likely that the highly polar oxime
group of compound 13 can act as a main binding motif to
the protein. The relatively smaller size of compound 13 could
potentially improve induced fitting in the binding site (low van der
Waals energy, Table S3), as was observed with docking calculations
(Table S3). Compound 13 has a smaller imidazole group at
the C2 position (99% GI), relative to compound 11 with a 2-
pyridyl piperazine group (90% GI), and inhibits Mycobacterium
TB effectively. Apparently, the oxime analogue; compound 13
with an imidazole group (MIC <0.39 mg mL-1) is likely to be
the reason for its enhanced potency compared to compound
34 (MIC 0.78 mg mL-1), which possesses a relatively less polar
hydroxyl group. However, both compounds 34 (91% GI) and
13 (99% GI) have a smaller and similar imidazole moiety at
the C2 position and they showed very similar and effective TB
inhibition, suggesting a critical role for the imidazole ring, as
discussed above. A slight change of the aromatic character of
the nitrogen i.e. from imidazole in 13 (99% GI) to pyrazole in 14
(29% GI) resulted in a drastic reduction in biological activity for
the latter. A possible reason could be a difference in pKa values of
imidazole and pyrazole. The pKa of the imidazole group is ~6.3
and the pKa of the pyrazole group is ~2.1, and hence there is
a considerable concentration (~10%) of protonated 13 at neutral
pH compared to that of 14. Perhaps, this charged species of 13
is the active form and makes compound 13 highly active against
M. tuberculosis. Similarly activity of compound 28 and compound
30 can be compared. Compound 30 (98% GI) is also an imidazole
Discussion
The bulky naphthalene group of the SE hemisphere of TMC207
was replaced by a methyl group in compounds 33 and 34 while the
tertiary hydroxyl group of the NE hemisphere was retained, which
would enable polar interactions with the binding site and maintain
both polar and non-polar interactions with the target protein.
Compound 34 displayed good biological activity; presumably
the imidazole ring enhanced the cell-membrane permeability23,24
while the hydroxyl group may form polar interactions with
the target site. The low biological activity of compound 33 as
compared to 34 may be due to steric hindrance caused by the
bulky trifluoromethyl-phenyl-piperazine group at the C2 position.
Also docking calculations (SI) with putative target ATP-synthase
subunit C (since these compounds are derivatives of DARQ12,13
reveal that compound 33 had high van der Waals docking energies
(Table S3).
)
In general, derivatives carrying a tertiary hydroxyl group
(compound 34) or an oxime group (compound 11 and 13) along
with imidazole (compound 34 and 13) or 2-pyridyl-piperizine
groups (compound 11 and 16) at the C2 position showed
good anti-mycobacterial activity (Table 1). Replacing the tertiary
hydroxyl group with an oxime resulted in more polar compounds
(10-14), which we assumed would bind relatively more tightly
with the target binding site. In addition, loss of the methyl group
would allow less hindered interactions of the hydroxyl group with
the binding site. Both imidazole and 2-pyridyl piperazine are
potential proton-acceptors as with DARQ, which could block
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2187
©

View Article Online
Table 3 Cytotoxic effects of tested compounds on human monocytic cell line U937 at 24 h and 72 h after the treatment (See experimental section for
cytotoxicity protocol)
Human monocytic U937 cell viability (%)
Conc./
Conc./
Conc./
Conc./
Compd. No.
Structure
24 h
100
mg mL-1 72 h
mg mL-1 24 h
mg mL-1 72 h
mg mL-1
11
4
100
4
100
1
100
1
13
89
3
91
3
100
1
100
1
16
100
5
100
5
100
1
100
1
24
30
32
34
79
80
90
48
5
10
10
5
82
68
74
64
5
10
10
5
100
1
1
1
1
100
1
1
1
1
78
65
100
100
85
93
2188 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
containing analogue with a similar pKa and displays excellent
activity as compared to pyrazole containing compound 28 (77%
GI). Comparison of compound 13 (imidazole at C2) (99% GI) and
30 (imidazole at side chain) (98% GI), both displaying the highest
TB inhibition, allows us to conclude that besides the common
core (conformationally constrained system), the imidazole ring
may have a crucial functional role in modulating the binding to
the target protein. We suggest that the polar groups on these two
compounds could form stabilizing interactions with the putative
target receptor ATP-synthase.
Comparison of compound 16 (85% GI) and compound 11 (90%
GI) suggest that the 2-pyridyl-piperizine moiety at the C2 position
is critical, and presumably the adverse bulkiness of the functional
2-pyridyl-piperizine group is compensated by the high proton-
affinity or hydrogen-bonding capability of the pyridyl-piperazine
group. Compounds 10 (22% GI), 15 (58% GI) and 18 (13% GI)
were found to be less active as compared to the compounds 11
(90% GI), 13 (99% GI), 16 (85% GI) and 34 (91% GI) (Table 1),
which suggests that the C2 position should not have electron
donating group like methoxy group. Compounds 18-20 showed
very low (<29% GI) anti-mycobacterial activities, possibly due to
the bulky naphthalene group, making it hydrophobic (clogP values
for compound 18, 19 and 20 are 9.36, 9.66 and 10.92 respectively)
which may be preventing the interaction of the oxime group with
the target protein.
Our preliminary docking studies for compounds 10-20 (data set
I in Table S3) have been analyzed by AutoDock scoring, potential
of mean force (PMF) scoring, X-scoring and by electrostatic
energies in comparison with their respective biological activity
data (Table S3). It has been found that biologically active molecules
show lower docking scores (Table S3).
The compounds presented here possess a conformationally
constrained indeno[2,1-c]quinoline core, which has analogy to the
well-known TMC207.12,13 Besides, the replacement of polar groups
of the NE hemisphere of TMC207 with oxime and hydroxyl, we
foresee that further SAR studies with more analogs might shed
more light to further explore and modulate the synergistic effects
of both the indeno[2,1-c]quinoline core as well as the substituents
at C2 position of the ring, as observed for compounds 11, 13
and 34.
Experimental section
Chemistry – general experimental methods
2-Amino-5-bromo-benzophenone (1) was prepared according to
the literature procedure.21 Purification and drying of reagents and
solvents were carried out according to literature procedures.25 Thin
layer chromatographic analysis was performed on E-Merck 60 F
254 precoated aluminium thin layer chromatographic plates. All
air-sensitive reactions were carried out under nitrogen atmosphere.
Melting points were determined on a Bu¨chi melting point B-540
instrument and are uncorrected. 1H-NMR, 13C NMR spectra were
recorded on a Bruker Biospin 400 MHz spectrometer with TMS as
an internal standard. The values of chemical shifts are expressed in
d ppm and the coupling constants (J) in Hertz (Hz). Mass spectra
were recorded on an API 2000 LC/MS/MS system spectrometer
up to 2 decimal places. IR spectra were recorded on a Perkin-Elmer
Spectrum RX1.
6-Bromo-2-chloro-4-phenyl-quinoline-3-carbonyl chloride (2)
2-Amino-5-bromo-benzophenone21 (1, 10.0 g, 36.23 mmol) and
malonic acid (5.65 g, 54.30 mmol) were mixed, dried under reduced
pressure, dissolved in freshly distilled POCl3 (200 mL) and heated
at 105 ◦C for 3 h. The reaction mixture was cooled, poured in
crushed ice in portions with constant stirring and extracted with
DCM (2 ¥ 500 mL). A DCM insoluble yellow solid was formed.
The DCM extract was washed with water until the aqueous washes
became neutral to pH paper, followed by brine (1 ¥ 100 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure to obtain a brown gum.
This crude gum was purified by column chromatography (silica gel
100-200 mesh, eluent: gradient elution with n-hexane to 3% ethyl
acetate in n-hexane) to give compound 2 (7.33 g, 53%) as a yellow
solid; mp 166-170 ◦C. nmax (KBr, cm-1): 1773. 1H NMR (400 MHz,
CDCl3): d 7.34-7.40 (m, 2 H, Ar-H), 7.53-7.61 (m, 3 H, Ar-H),
7.74 (d, J = 2.0 Hz, 1 H, Ar-H), 7.88 (dd, J = 9.0, 2.0 Hz, 1 H,
Ar-H), 7.96 (d, J = 9.0 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz,
CDCl3): d 122.5 (Ar-C), 126.6 (Ar-C), 129.0 (Ar-C), 129.1 (Ar-C),
129.4 (Ar-C), 130.1 (Ar-C), 130.5 (Ar-C), 131.9 (Ar-C), 132.1 (Ar-
C), 135.7 (Ar-C), 143.4 (Ar-C), 146.3 (Ar-C), 146.8 (Ar-C), 165.9
+
=
(C O). ESI-MS m/z of 380.00, 381.90 [M+H] was obtained for
a calculated mass of 379.92, 381.92.
The yellow solid obtained was washed with DCM, dried and
characterized by mp and H-NMR, which matched with com-
Conclusion
1
In conclusion, we have designed and synthesized a novel class
of conformationally constrained anti-mycobacterial molecules
based on the combination of the indeno[2,1-c]quinoline backbone
with various polar groups. The effects of various substituents
on the indeno[2,1-c]quinoline skeleton on the relative activity of
the molecules synthesized are described. The activity of seven
molecules, 11 (MIC 6.25 mg mL-1), 13 (MIC 0.39 mg mL-1), 16
(MIC 1.56 mg mL-1), 24 (MIC 3.125 mg mL-1), 30 (MIC 3.125 mg
mL-1), 32 (MIC 6.25 mg mL-1) and 34 (MIC 0.78 mg mL-1) were
comparable to that of the existing front-line drug, Isoniazid (MIC
0.25 mg mL-1) under identical conditions. This is the first report
on indeno[2,1-c]quinoline derivatives as active anti-mycobacterial
agents. This class of molecules has shown a great potential to
develop as effective, easily accessible anti-mycobacterial agents,
which can help to shorten the duration of anti-TB therapy.
pound 3 (2.0 g, 16%) [See below for the spectroscopic properties
of compound 3].
2-Bromo-6-chloro-indeno[2,1-c]quinolin-7-one (3)
To a cooled (0 ◦C) solution of compound 2 (8.15 g, 21.39 mmol)
in DCM (150 mL), aluminium chloride (7.11 g, 53.5 mmol) was
added portion wise and then the mixture was stirred at room
temperature for 3 h. The color of the reaction turned brown. The
reaction mixture was again cooled to 0 ◦C, quenched by adding ice
and stirred vigorously for 1 h. The desired product precipitated as
a yellow solid which was extracted with DCM (4 ¥ 500 mL). The
organic layer was evaporated under reduced pressure to obtain a
yellow solid which was washed with methanol (3 ¥ 100 mL), ethyl
acetate (2 ¥ 50 mL), n-hexane (2 ¥ 50 mL) and dried under reduced
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2189
©

View Article Online
pressure to obtain pure compound 3 (6.20 g, 84%); mp 304-306 ◦C.
nmax (KBr, cm-1): 1714. 1H NMR (400 MHz, CF3COOD): d 8.06-
8.13 (m, 1 H, Ar-H), 8.14-8.20 (m, 1 H, Ar-H), 8.26 (d, J = 7.2 Hz,
1 H, Ar-H), 8.35 (d, J = 9.0 Hz, 1 H, Ar-H), 8.60 (d, J = 9.0 Hz,
1 H, Ar-H), 8.72 (d, J = 7.5 Hz, 1 H, Ar-H), 9.33 (s, 1 H, Ar-H).
13C NMR (100.6 MHz, CF3COOD): d 124.8 (Ar-C), 125.8 (Ar-
C), 126.5 (Ar-C), 129.4 (Ar-C), 129.8 (Ar-C), 130.8 (Ar-C), 131.8
(Ar-C), 137.5 (Ar-C), 139.1 (Ar-C), 140.1 (Ar-C), 140.8 (Ar-C),
(Ar-C), 158.5 (Ar-C), 191.9 (C O). ESI-MS m/z of 538.00, 539.90
=
[M+H]+ was obtained for a calculated mass of 538.07, 540.07.
2-Bromo-6-(4-pyridin-2-yl-piperazin-1-yl)-indeno[2,1-c]quinolin-7-
one (6)
Procedure A, yield 92%. Red solid; mp 186-188 ◦C. nmax
1
(KBr, cm-1): 1699. H NMR (400 MHz, CDCl3): d 3.79 (s, 8 H,
piperazine-CH2), 6.65 (dd, J = 7.0, 5.1 Hz, 1 H, Ar-H), 6.71 (d,
J = 8.5 Hz, 1 H, Ar-H), 7.43-7.54 (m, 2 H, Ar-H), 7.58 (td, J = 7.5,
1.1 Hz, 1 H, Ar-H), 7.63-7.76 (m, 3 H, Ar-H), 8.01 (d, J = 7.5 Hz,
1 H, Ar-H), 8.18-8.25 (m, 1 H, Ar-H), 8.45 (d, J = 2.0 Hz, 1 H, Ar-
H). 13C NMR (100.6 MHz, CDCl3): d 45.3 (Ar-N-CH2-CH2), 48.7
(Ar-N-CH2-CH2), 107.1 (Ar-C), 113.4 (Ar-C), 115.8 (Ar-C), 117.8
(Ar-C), 121.1 (Ar-C), 123.77 (Ar-C), 123.81 (Ar-C), 126.7 (Ar-C),
130.0 (Ar-C), 130.8 (Ar-C), 133.4 (Ar-C), 133.9 (Ar-C), 135.5 (Ar-
C), 137.5 (Ar-C), 140.9 (Ar-C), 147.9 (Ar-C), 150.8 (Ar-C), 154.4
=
144.1 (Ar-C), 145.7 (Ar-C), 146.2 (Ar-C), 190.2 (C O). ESI-MS
m/z of 344.00, 345.90 [M+H]+ was obtained for a calculated mass
of 343.95, 345.95.
2-Bromo-6-methoxy-indeno[2,1-c]quinolin-7-one (4)
To a suspension of compound 3 (5.00 g, 14.51 mmol) in dry
THF : dry MeOH (2 : 1, 450 mL), sodium methoxide (30% w/v
in MeOH, 26.1 mL, 145.1 mmol) was added and refluxed
under nitrogen atmosphere for 3 h. The reaction mixture was
concentrated under reduced pressure to obtain a brown solid. The
brown solid obtained was extracted with DCM (500 mL), washed
with water (3 ¥ 200 mL) and brine (1 ¥ 100 mL). The organic layer
was dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure to obtain compound 4 (4.80 g, 97%) as
=
(Ar-C), 155.4 (Ar-C), 159.6 (Ar-C), 191.6 (C O). ESI-MS m/z
of 471.00, 473.10 [M+H]+ was obtained for a calculated mass of
471.08, 473.08.
2-Bromo-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-indeno[2,1-
c]quinolin-7-one (7)
◦
a yellow solid; mp 208-210 C. nmax (KBr, cm-1): 1719. H NMR
(400 MHz, CDCl3): d 4.19 (s, 3 H, OCH3), 7.44-7.52 (m, 1 H, Ar-
H), 7.60 (td, J = 7.6, 1.2 Hz, 1 H, Ar-H), 7.74 (d, J = 8.8 Hz, 2 H,
Ar-H), 7.79 (dd, J = 9.0, 2.0 Hz, 1 H, Ar-H), 8.01 (d, J = 7.6 Hz, 1
H, Ar-H), 8.50 (d, J = 2.0 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz,
CDCl3): d 54.0 (OCH3), 114.9 (Ar-C), 118.9 (Ar-C), 122.1 (Ar-
C), 123.9 (Ar-C), 124.2 (Ar-C), 126.9 (Ar-C), 130.1 (Ar-C), 131.2
(Ar-C), 133.4 (Ar-C), 134.1 (Ar-C), 135.5 (Ar-C), 140.7 (Ar-C),
1
Procedure A, yield 71%. Red solid; mp 192-194 ◦C. nmax
(KBr, cm-1): 1703. 1H NMR (400 MHz, CDCl3): d 3.22-3.46 (m,
4 H, Ar-N-CH2-CH2), 3.72-3.90 (m, 4 H, Ar-N-CH2-CH2), 6.94-
7.02 (m, 4 H, Ar-H), 7.46 (t, J = 7.4 Hz, 1 H, Ar-H), 7.59 (t,
J = 7.5 Hz, 1 H, Ar-H), 7.64-7.76 (m, 3 H, Ar-H), 8.01 (d, J =
7.5 Hz, 1 H, Ar-H), 8.46 (d, J = 1.8 Hz, 1 H, Ar-H). 13C NMR
(100.6 MHz, CDCl3): d 49.0 (Ar-N-CH2-CH2), 50.4 (Ar-N-CH2-
CH2), 115.5 (Ar-C), 115.7 (Ar-C), 116.0 (Ar-C), 117.98 (Ar-C),
118.03 (Ar-C), 118.11 (Ar-C), 121.3 (Ar-C), 123.9 (Ar-C), 124.0
(Ar-C), 127.0 (Ar-C), 130.2 (Ar-C), 131.0 (Ar-C), 133.5 (Ar-C),
134.1 (Ar-C), 135.7 (Ar-C), 141.1 (Ar-C), 148.1 (Ar-C), 151.0 (Ar-
=
150.0 (Ar-C), 154.2 (Ar-C), 158.6 (Ar-C), 190.7 (C O). ESI-MS
m/z of 340.10, 342.10 [M+H]+ was obtained for a calculated mass
of 340.00, 342.00.
C), 154.7 (Ar-C), 155.5 (Ar-C), 156.1 (Ar-C), 158.5 (Ar-C), 191.9
General procedure A for 5-9: 6-amino-2-bromo-
indeno[2,1-c]quinolin-7-ones
+
=
(C O). ESI-MS m/z of 488.00, 490.10 [M+H] was obtained for
a calculated mass of 488.08, 490.08.
A mixture of compound 3 (1 eq) and the appropriate amine (R1H,
5 eq) was heated in dry pyridine at 105 ◦C for 12 h. The reaction
mixture was cooled to room temperature and poured into water.
The precipitate obtained was filtered, washed with water and dried
under reduced pressure to obtain the corresponding 2-bromo-
indeno[2,1-c]quinolin-7-ones 5-9 in good yield (71-92%).
2-Bromo-6-imidazol-1-yl-indeno[2,1-c]quinolin-7-one (8)
Procedure A, yield 87%. Red solid; mp 284-286 ◦C. nmax
1
(KBr, cm-1): 1712. H NMR (400 MHz, DMSO-d6): d 7.13 (s,
1 H, Ar-H), 7.65 (t, J = 7.2 Hz, 1 H, Ar-H), 7.73-7.82 (m, 2 H,
Ar-H), 7.88 (s, 1 H, Ar-H), 7.98 (d, J = 9.0 Hz, 1 H, Ar-H), 8.12
(d, J = 9.0 Hz, 1 H, Ar-H), 8.43 (s, 1 H, Ar-H), 8.54 (d, J =
7.5 Hz, 1 H, Ar-H), 8.87 (s, 1 H, Ar-H). 13C NMR (100.6 MHz,
CF3COOD): d 120.1 (Ar-C), 121.9 (Ar-C), 124.3 (Ar-C), 127.4
(Ar-C), 128.35 (Ar-C), 128.37 (Ar-C), 128.5 (Ar-C), 130.0 (Ar-C),
132.6 (Ar-C), 135.2 (Ar-C), 136.0 (Ar-C), 138.9 (Ar-C), 139.4 (Ar-
2-Bromo-6-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-
indeno[2,1-c]quinolin-7-one (5)
Procedure A, yield 90%. Red solid; mp 177-179 ◦C. nmax
(KBr, cm-1): 1702. 1H NMR (400 MHz, CDCl3): d 3.31-3.38 (m,
4 H, Ar-N-CH2-CH2), 3.79-3.86 (m, 4 H, Ar-N-CH2-CH2), 6.94-
7.02 (m, 4 H, Ar-H), 7.42-7.50 (m, 1 H, Ar-H), 7.55-7.62 (m, 1 H,
Ar-H), 7.63-7.70 (m, 2 H, Ar-H), 7.73 (dd, J = 9.0, 2.0 Hz, 1 H,
Ar-H), 8.03 (d, J = 7.5 Hz, 1 H, Ar-H), 8.47 (d, J = 2.0 Hz, 1 H,
Ar-H). 13C NMR (100.6 MHz, CDCl3): d 49.0 (Ar-N-CH2-CH2),
50.4 (Ar-N-CH2-CH2), 115.5 (Ar-C), 115.7 (Ar-C), 116.0 (Ar-C),
117.99 (Ar-C), 118.0 (Ar-C), 118.1 (Ar-C), 121.3 (Ar-C), 123.9
(Ar-C), 124.0 (Ar-C), 126.9 (Ar-C), 130.2 (Ar-C), 131.0 (Ar-C),
133.5 (Ar-C), 134.1 (Ar-C), 135.7 (Ar-C), 141.1 (Ar-C), 148.0 (Ar-
C), 149.8 (Ar-C), 151.0 (Ar-C), 154.7 (Ar-C), 155.5 (Ar-C), 156.1
C), 141.9 (Ar-C), 142.7 (Ar-C), 143.0 (Ar-C), 151.3 (Ar-C), 160.0
+
=
(Ar-C), 194.0 (C O). ESI-MS m/z of 376.03, 378.05 [M+H] was
obtained for a calculated mass of 376.01, 378.01.
2-Bromo-6-pyrazol-1-yl-indeno[2,1-c]quinolin-7-one (9)
Procedure A, yield 76%. Red solid; mp 289-290 ◦C. nmax
(KBr, cm-1): 1711. 1H NMR (400 MHz, DMSO-d6): d 6.56-
6.60 (m, 1 H, Pyrazole-CH), 7.59 (t, J = 7.2 Hz, 1 H, Ar-H),
7.66 (d, J = 7.0 Hz, 1 H, Ar-H), 7.69-7.76 (m, 1 H, Ar-H),
2190 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
7.85 (d, J = 1.0 Hz, 1 H, Ar-H), 7.92 (d, J = 9.0 Hz, 1 H, Ar-H),
8.05 (d, J = 8.7 Hz, 1 H, Ar-H), 8.41 (d, J = 2.4 Hz, 1 H, Ar-H),
8.43 (d, J = 7.6 Hz, 1 H, Ar-H), 8.77 (s, 1 H, Ar-H). 13C NMR
(100.6 MHz, CDCl3): d 107.6 (Ar-C), 117.3 (Ar-C), 122.2 (Ar-
C), 123.6 (Ar-C), 124.2 (Ar-C), 124.7 (Ar-C), 126.7 (Ar-C), 131.4
(Ar-C), 131.75 (Ar-C), 131.79 (Ar-C), 133.0 (Ar-C), 134.7 (Ar-C),
136.4 (Ar-C), 140.1 (Ar-C), 142.6 (Ar-C), 146.6 (Ar-C), 149.6 (Ar-
2-Bromo-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-indeno[2,1-
c]quinolin-7-one oxime (12)
Procedure B, yield 95%. Yellow solid; mp 241-243 ◦C. nmax
(KBr, cm-1): 3167, 1699. 1H NMR (400 MHz, DMSO-d6): d 3.10-
3.38 (m, 4 H, Ar-N-CH2-CH2), 3.50-3.74 (m, 4 H, Ar-N-CH2-
CH2), 6.95-7.14 (m, 4 H, Ar-H), 7.54-7.70 (m, 2 H, Ar-H), 7.76
(d, J = 7.0 Hz, 1 H, Ar-H), 7.81 (d, J = 9.5 Hz, 1 H, Ar-H),
8.47 (d, J = 7.2 Hz, 1 H, Ar-H), 8.57 (d, J = 7.2 Hz, 1 H, Ar-H),
=
C), 154.4 (Ar-C), 188.9 (C O). ESI-MS m/z of 375.90, 377.70
[M+H]+ was obtained for a calculated mass of 376.01, 378.01.
=
8.71 (s, 1 H, Ar-H), 13.21 (s, 1 H, D2O exchangeable, C N-OH).
13C NMR (100.6 MHz, DMSO-d6): d 48.9 (Ar-N-CH2-CH2), 49.1
(Ar-N-CH2-CH2), 115.2 (Ar-C), 115.5 (Ar-C), 117.2 (Ar-C), 117.3
(Ar-C), 117.5 (Ar-C), 119.9 (Ar-C), 121.8 (Ar-C), 124.1 (Ar-C),
125.8 (Ar-C), 128.6 (Ar-C), 129.4 (Ar-C), 130.17 (Ar-C), 130.23
(Ar-C), 130.8 (Ar-C), 133.0 (Ar-C), 137.4 (Ar-C), 144.4 (Ar-C),
146.4 (Ar-C), 148.2 (Ar-C), 150.8 (Ar-C), 154.9 (Ar-C), 155.8 (Ar-
C). ESI-MS m/z of 503.40, 505.40 [M+H]+ was obtained for a
calculated mass of 503.09, 505.09.
General procedure B for 10-14: 6-amino-2-bromo-
indeno[2,1-c]quinolin-7-one oximes
To a cooled (0 ◦C) suspension of the appropriate ketone 4, 6, 7, 8
and 9 (1 eq) and hydroxylamine hydrochloride (3 eq) in ethanol-
water (2 : 1) mixture, sodium hydroxide pellets (5 eq) were added
in portions. The reaction was stirred at 0 ◦C for 15 min and then
heated up to 80-90 ◦C for 3-8 h. The reaction mixture was cooled
to room temperature and poured into 15% aq. hydrochloric acid.
The precipitate obtained was filtered, washed with water and dried
under reduced pressure to obtain the corresponding oximes 10-14
in good yield (72-96%).
2-Bromo-6-imidazol-1-yl-indeno[2,1-c]quinolin-7-one oxime (13)
Procedure B, yield 72%. Brown solid; mp 268-271 ◦C. nmax
(KBr, cm-1): 3402, 1710. 1H NMR (400 MHz, DMSO-d6): d 7.68-
7.84 (m, 2 H, Ar-H), 7.96 (s, 1 H, Ar-H), 8.13 (s, 2 H, Ar-H),
8.28 (s, 1 H, Ar-H), 8.55 (d, J = 7.1 Hz, 1 H, Ar-H), 8.73 (d, J =
7.1 Hz, 1 H, Ar-H), 9.0 (s, 1 H, Ar-H), 9.79 (s, 1 H, Ar-H), 13.44
2-Bromo-6-methoxy-indeno[2,1-c]quinolin-7-one oxime (10)
(s, 1 H, D2O exchangeable, C N-OH). 13C NMR (100.6 MHz,
Procedure B, yield 91%. Yellow solid; mp 270-275 ◦C. nmax
(KBr, cm-1): 3176, 1640. 1H NMR (400 MHz, DMSO-d6): d 4.08
(s, 3 H, OCH3), 7.54-7.69 (m, 2 H, Ar-H), 7.77 (d, J = 9.0 Hz, 1
H, Ar-H), 7.83 (d, J = 8.6 Hz, 1 H, Ar-H), 8.41 (d, J = 6.8 Hz,
1 H, Ar-H), 8.51 (d, J = 7.3 Hz, 1 H, Ar-H), 8.67 (s, 1 H, Ar-
=
DMSO-d6): d 119.7 (Ar-C), 122.60 (Ar-C), 122.64 (Ar-C), 123.4
(Ar-C), 124.7 (Ar-C), 125.3 (Ar-C), 126.4 (Ar-C), 128.9 (Ar-C),
129.6 (Ar-C), 131.7 (Ar-C), 131.8 (Ar-C), 132.0 (Ar-C), 134.9 (Ar-
C), 136.2 (Ar-C), 137.0 (Ar-C), 141.6 (Ar-C), 145.4 (Ar-C), 146.0
(Ar-C), 149.0 (Ar-C). ESI-MS m/z of 390.90, 393.00 [M+H]+ was
obtained for a calculated mass of 391.02, 393.02.
H), 13.38 (s, 1 H, C N-OH). 13C NMR (100.6 MHz, DMSO-d6):
=
d 53.4 (OCH3), 117.8 (Ar-C), 118.0 (Ar-C), 122.2 (Ar-C), 124.2
(Ar-C), 125.9 (Ar-C), 128.5 (Ar-C), 129.4 (Ar-C), 129.9 (Ar-C),
130.4 (Ar-C), 130.8 (Ar-C), 133.0 (Ar-C), 137.0 (Ar-C), 144.7 (Ar-
2-Bromo-6-pyarazol-1-yl-indeno[2,1-c]quinolin-7-one oxime (14)
=
C), 145.7 (Ar-C), 150.1 (Ar-C), 157.9 (C N-OH). ESI-MS m/z
of 355.10, 357.00 [M+H]+ was obtained for a calculated mass of
355.01, 357.01.
◦
Procedure B, yield 94%. Light brown solid; mp 195-198 C. nmax
(KBr, cm-1): 3453, 1660. 1H NMR (400 MHz, CF3COOD): d 7.04-
7.12 (m, 1 H, Ar-H), 7.68-7.82 (m, 2 H, Ar-H), 8.01-8.11 (m, 2 H,
Ar-H), 8.29 (d, J = 7.2 Hz, 1 H, Ar-H), 8.44 (s, 1 H, Ar-H),
8.66 (d, J = 7.2 Hz, 1 H, Ar-H), 8.77 (s, 1 H, Ar-H), 9.34 (s, 1
H, Ar-H). 13C NMR (100.6 MHz, CF3COOD): d 110.0 (Ar-C),
115.6 (Ar-C), 123.7 (Ar-C), 124.8 (Ar-C), 125.1 (Ar-C), 126.2 (Ar-
C), 128.7 (Ar-C), 130.3 (Ar-C), 130.6 (Ar-C), 132.9 (Ar-C), 133.7
(Ar-C), 134.1 (Ar-C), 137.4 (Ar-C), 138.6 (Ar-C), 139.6 (Ar-C),
2-Bromo-6-(4-pyridin-2-yl-piperazin-1-yl)-indeno[2,1-c]quinolin-
7-one-oxime (11)
Procedure B, yield 96%. Greenish solid; mp 235-237 ◦C. nmax
(KBr, cm-1): 3014, 1603. 1H NMR (400 MHz, DMSO-d6): d 3.57-
3.70 (m, 4 H, Ar-N-CH2-CH2), 3.77-3.90 (m, 4 H, Ar-N-CH2-
CH2), 6.97 (t, J = 6.5 Hz, 1 H, Ar-H), 7.46 (d, J = 9.0 Hz, 1 H,
Ar-H), 7.53-7.69 (m, 2 H, Ar-H), 7.78 (d, J = 9.0 Hz, 1 H, Ar-H),
7.82 (dd, J = 9.0, 1.4 Hz, 1 H, Ar-H), 7.98-8.11 (m, 2 H, Ar-H),
8.45 (d, J = 7.5 Hz, 1 H, Ar-H), 8.56 (d, J = 7.0 Hz, 1 H, Ar-H),
8.70 (d, J = 1.0 Hz, 1 H, Ar-H), 13.30 (s, 1 H, D2O exchangeable,
=
=
145.0 (Ar-C), 150.2 (C N-OH), 150.7 (C N-OH). ESI-MS m/z
of 390.90, 392.90 [M+H]+ was obtained for a calculated mass of
391.02, 393.02.
General procedure C for 15-17: acylation of the oximes
C N-OH). 13C NMR (100.6 MHz, THF-d8): d 45.9 (Ar-N-CH2-
=
CH2), 50.49 (Ar-N-CH2-CH2), 107.6 (Ar-C), 113.4 (Ar-C), 118.1
(Ar-C), 122.6 (Ar-C), 123.7 (Ar-C), 124.0 (Ar-C), 126.7 (Ar-C),
128.5 (Ar-C), 129.3 (Ar-C), 130.1 (Ar-C), 130.6 (Ar-C), 131.1 (Ar-
C), 132.1 (Ar-C), 137.66 (Ar-C), 137.72 (Ar-C), 147.0 (Ar-C),
The appropriate oximes 10-12 (1 eq) and N,N-dimethylamine
carbamyl chloride (2 eq) were stirred at room temperature in
anhydrous DMF for 12 h in presence of sodium hydride (1.1
eq). The reaction mixture was poured into water; the precipitate
obtained was filtered, washed with cold water and dried under
reduced pressure to obtain the corresponding acylated products
15-17.
=
148.6 (Ar-C), 152.9 (Ar-C), 157.6 (Ar-C), 160.9 (C N-OH). ESI-
MS m/z of 486.40, 488.30 [M+H]+ was obtained for a calculated
mass of 486.09, 488.09.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2191
©

View Article Online
2-Bromo-6-methoxy-indeno[2,1-c]quinolin-7-one N,N-dimethyl
General procedure D for 18-20: 6-amino-2-bromo-indeno[2,1-
carbamoyl oxime (15)
c]quinolin-7-one-O-naphthalen-1-ylmethyl-oximes
Procedure C, yield 66%. Yellow solid; mp 238-240 ◦C. nmax
(KBr, cm-1): 1748. 1H NMR (400 MHz, CDCl3): d 3.13 (s,
3 H, -NCH3), 3.21 (s, 3 H, -NCH3), 4.23 (s, 3 H, OCH3), 7.49
(t, J = 7.6 Hz, 1 H, Ar-H), 7.56-7.64 (m, 1 H, Ar-H), 7.70-7.76
(m, 1 H, Ar-H), 7.78 (d, J = 8.9 Hz, 1 H, Ar-H), 8.18 (d, J =
7.7 Hz, 1 H, Ar-H), 8.35 (d, J = 7.6 Hz, 1 H, Ar-H), 8.54 (d, J =
1.8 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz, CF3COOD): d 38.1
(-NCH3), 39.2 (-NCH3), 61.0 (OCH3), 119.4 (Ar-C), 123.3 (Ar-C),
123.5 (Ar-C), 126.1 (Ar-C), 129.1 (Ar-C), 130.6 (Ar-C), 132.5 (Ar-
C), 132.9 (Ar-C), 136.3 (Ar-C), 136.6 (Ar-C), 138.6 (Ar-C), 139.1
Sodium hydride (1.1 eq) was added to the appropriate oxime
10-12 (1 eq) in dry DMF at 0 ◦C (ice bath) under nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 30 min. 1-Chloromethyl naphthalene (1.5 eq) was added to
the reaction mixture and stirred for 3-12 h. The reaction was
quenched with ice, diluted with ethyl acetate and washed with brine
several times. The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated under reduced pressure to obtain
a gum as a crude product. This crude product was purified by
column chromatography (silica gel 100-200 mesh, gradual elution
with ethyl acetate, n-hexane mixture) to give the corresponding
oximes 18-20.
(Ar-C), 141.5 (Ar-C), 157.1 (Ar-C), 158.9 (Ar-C), 159.4 (Ar-C),
+
=
159.9 (C N-OH). ESI-MS m/z of 426.00, 428.10 [M+H] was
obtained for a calculated mass of 426.05, 428.04.
2-Bromo-6-methoxy-indeno[2,1-c]quinolin-7-one-O-naphthalen-1-
ylmethyl-oxime (18)
2-Bromo-6-(4-pyridin-2-yl-piperazin-1-yl)-indeno[2,1-c]quinolin-7-
one N,N-dimethyl carbamoyl oxime (16)
◦
1
Procedure D, yield 48%. Pale-yellow solid; mp 188-192 C. H
◦
Procedure C, yield 63%. Brownish-yellow solid; mp 215-217 C.
NMR (400 MHz, CDCl3): d 4.24 (s, 3 H, OCH3), 6.01 (s, 2 H,
nmax (KBr, cm-1): 1752. 1H NMR (400 MHz, CDCl3): d 3.11 (s, 3
H, -NCH3), 3.20 (s, 3 H, -NCH3), 3.69-3.80 (m, 4 H, Ar-N-CH2-
CH2), 3.84-3.93 (m, 4 H, Ar-N-CH2-CH2), 6.56-6.66 (m, 1 H,
Ar-H), 6.74 (d, J = 8.5 Hz, 1 H, Ar-H), 7.43-7.56 (m, 2 H, Ar-H),
7.61 (t, J = 7.6 Hz, 1 H, Ar-H), 7.71 (dd, J = 9.0, 2.0 Hz, 1 H, Ar-
H), 7.78 (d, J = 9.0 Hz, 1 H, Ar-H), 8.17-8.28 (m, 2 H, Ar-H), 8.37
=
C NOCH2Ar), 7.29 (t, J = 7.6 Hz, 1 H, Ar-H), 7.45 (t, J = 7.6 Hz,
1 H, Ar-H), 7.50-7.60 (m, 3 H, Ar-H), 7.64-7.72 (m, 2 H, Ar-H),
7.76 (d, J = 9.0 Hz, 1 H, Ar-H), 7.86-7.96 (m, 2 H, Ar-H), 8.11
(d, J = 7.7 Hz, 1 H, Ar-H), 8.25-8.34 (m, 2 H, Ar-H), 8.54 (d, J =
2.0 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz, CDCl3+DMSO-d6):
=
d 53.7 (OCH3), 76.8 (C NOCH2Ar), 117.5 (Ar-C), 117.9 (Ar-C),
(d, J = 7.5 Hz, 1 H, Ar-H), 8.57 (d, J = 2.0 Hz, 1 H, Ar-H). 13
C
122.4 (Ar-C), 123.1 (Ar-C), 123.9 (Ar-C), 125.1 (Ar-C), 125.7 (Ar-
C), 125.8 (Ar-C), 126.2 (Ar-C), 127.6 (Ar-C), 128.3 (Ar-C), 129.1
(Ar-C), 129.3 (Ar-C), 129.7 (Ar-C), 129.8 (Ar-C), 130.0 (Ar-C),
130.5 (Ar-C), 131.7 (Ar-C), 132.0 (Ar-C), 132.7 (Ar-C), 133.5 (Ar-
NMR (100.6 MHz, CDCl3): d 36.7 (-NCH3), 37.5 (-NCH3), 45.1
(Ar-N-CH2-CH2), 49.5 (Ar-N-CH2-CH2), 107.3 (Ar-C), 112.9
(Ar-C), 118.2 (Ar-C), 119.4 (Ar-C), 121.9 (Ar-C), 124.1 (Ar-C),
126.0 (Ar-C), 129.0 (Ar-C), 129.9 (Ar-C), 130.0 (Ar-C), 130.5
(Ar-C), 131.9 (Ar-C), 133.7 (Ar-C), 137.3 (Ar-C), 140.0 (Ar-C),
147.1 (Ar-C), 147.8 (Ar-C), 148.2 (Ar-C), 154.4 (O-CO-N), 156.2
C), 138.2 (Ar-C), 145.6 (Ar-C), 146.4 (Ar-C), 151.5 (Ar-C), 158.0
+
=
(C N-OH). ESI-MS m/z of 494.90, 497.00 [M+H] was obtained
for a calculated mass of 495.07, 497.07.
=
(Ar-C), 156.6 (Ar-C), 159.7 (C N-OH). ESI-MS m/z of 557.40,
559.20 [M+H]+ was obtained for a calculated mass of 557.13,
559.13.
2-Bromo-6-(4-pyridin-2-yl-piperazin-1-yl)-indeno[2,1-c]quinolin-7-
one-O-naphthalen-1-ylmethyl-oxime (19)
2-Bromo-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-indeno[2,1-
c]quinolin-7-one N,N-dimethyl carbamoyl oxime (17)
Procedure D, yield 54%. Orange-red solid; mp 98-100 ◦C. 1H NMR
(400 MHz, CDCl3): d 3.58-3.67 (m, 8 H, Ar-N-CH2-CH2), 6.00
Procedure C, yield 62%. Yellow solid; mp 192-194 ◦C. nmax
(KBr, cm-1): 1752. 1H NMR (400 MHz, CDCl3): d 3.11 (s, 3 H, -
NCH3), 3.19 (s, 3 H, -NCH3), 3.40-3.49 (m, 4 H, Ar-N-CH2-CH2),
3.75-3.83 (m, 4 H, Ar-N-CH2-CH2), 6.97 (d, J = 6.4 Hz, 4 H, Ar-
H), 7.49 (t, J = 7.6 Hz, 1 H, Ar-H), 7.60 (t, J = 7.6 Hz, 1 H,
Ar-H), 7.72 (dd, J = 9.0, 2.0 Hz, 1 H, Ar-H), 7.78 (d, J = 9.0 Hz,
1 H, Ar-H), 8.22 (d, J = 7.8 Hz, 1 H, Ar-H), 8.37 (d, J = 7.4 Hz, 1
H, Ar-H), 8.57 (d, J = 1.7 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz,
CF3COOD): d 38.3 (-NCH3), 39.1 (-NCH3), 50.4 (Ar-N-CH2-
CH2), 58.1 (Ar-N-CH2-CH2), 120.4 (Ar-C), 120.6 (Ar-C), 121.5
(Ar-C), 123.3 (Ar-C), 123.4 (Ar-C), 125.0 (Ar-C), 125.1 (Ar-C),
126.0 (Ar-C), 129.1 (Ar-C), 130.5 (Ar-C), 132.4 (Ar-C), 132.6
(Ar-C), 136.4 (Ar-C), 136.6 (Ar-C), 138.1 (Ar-C), 139.3 (Ar-C),
139.7 (Ar-C), 141.9 (Ar-C), 152.7 (Ar-C), 157.8 (O-CO-N), 159.4
(s, 2 H, C NOCH2Ar), 6.36 (d, J = 8.5 Hz, 1 H, Ar-H), 6.61
=
(dd, J = 6.8, 1.6 Hz, 1 H, Ar-H), 7.36 (t, J = 7.5 Hz, 1 H, Ar-H),
7.40-7.47 (m, 1 H, Ar-H), 7.48-7.57 (m, 4 H, Ar-H), 7.65 (d, J =
7.0 Hz, 1 H, Ar-H), 7.69 (dd, J = 9.0, 1.8 Hz, 1 H, Ar-H), 7.78
(d, J = 8.9 Hz, 1 H, Ar-H), 7.89 (d, J = 8.2 Hz, 1 H, Ar-H),
7.91-7.96 (m, 1 H, Ar-H), 8.15-8.22 (m, 3 H, Ar-H), 8.40 (d, J =
7.6 Hz, 1 H, Ar-H), 8.60 (d, J = 1.7 Hz, 1 H, Ar-H).13C NMR
(100.6 MHz, CDCl3): d 45.2 (Ar-N-CH2-CH2), 49.2 (Ar-N-CH2-
CH2), 106.9 (Ar-C), 113.3 (Ar-C), 118.1 (Ar-C), 119.5 (Ar-C),
122.2 (Ar-C), 123.4 (Ar-C), 123.7 (Ar-C), 125.3 (Ar-C), 125.95
(Ar-C), 125.97 (Ar-C), 126.0 (Ar-C), 126.5 (Ar-C), 126.7 (Ar-C),
128.7 (Ar-C), 129.1 (Ar-C), 129.4 (Ar-C), 129.9 (Ar-C), 130.20
(Ar-C), 130.24 (Ar-C), 130.7 (Ar-C), 131.5 (Ar-C), 132.5 (Ar-C),
133.0 (Ar-C), 133.6 (Ar-C), 137.3 (Ar-C), 138.9 (Ar-C), 145.9 (Ar-
=
(Ar-C), 159.6 (Ar-C), 167.9 (C N-OH). ESI-MS m/z of 574.40,
C), 147.3 (Ar-C), 147.9 (Ar-C), 152.4 (Ar-C), 156.1 (Ar-C), 159.7
+
576.20 [M+H]+ was obtained for a calculated mass of 574.13,
576.12.
(C N-OH). ESI-MS m/z of 626.20, 628.10 [M+H] was obtained
=
for a calculated mass of 626.16, 628.15.
2192 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
2-Bromo-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-indeno[2,1-
c]quinolin-7-one-O-naphthalen-1-ylmethyl-oxime (20)
mixture and stirred for 48 h at room temperature and quenched
with ice. The reaction mixture was extracted with ethyl acetate
(150 mL), washed with brine (3 ¥ 50 mL), dried over anhydrous
sodium sulfate, filtered and the solvents were evaporated under
reduced pressure to obtain a gum as a crude product. The crude
product was purified by column chromatography (silica gel 100-
200 mesh, eluent: 8% ethyl acetate in n-hexane) to give 22 as (1 : 1
diastereomeric mixture) (1.60 g, 69%) a light yellowish green solid
◦
1
Procedure D, yield 50%. Brownish-red solid; mp 203-206 C. H
NMR (400 MHz, CDCl3): d 2.97-3.06 (m, 4 H, Ar-N-CH2-CH2),
=
3.57-3.64 (m, 4 H, Ar-N-CH2-CH2), 6.02 (s, 2 H, C NOCH2Ar),
6.48-6.58 (m, 2 H, Ar-H), 6.85 (t, J = 8.7 Hz, 2 H, Ar-H), 7.40-7.48
(m, 2 H, Ar-H), 7.53-7.61 (m, 3 H, Ar-H), 7.64 (d, J = 6.5 Hz,
1 H, Ar-H), 7.70 (dd, J = 9.0, 2.0 Hz, 1 H, Ar-H), 7.77 (d, J =
9.0 Hz, 1 H, Ar-H), 7.86 (d, J = 8.3 Hz, 1 H, Ar-H), 7.91-7.98 (m,
1 H, Ar-H), 8.12-8.18 (m, 1 H, Ar-H), 8.21 (d, J = 7.8 Hz, 1 H,
Ar-H), 8.49 (d, J = 7.3 Hz, 1 H, Ar-H), 8.60 (d, J = 2.0 Hz, 1 H,
Ar-H). 13C NMR (100.6 MHz, THF-d8): d 50.3 (Ar-N-CH2-CH2),
◦
1
along with starting alcohol (0.40 g, 20%); mp 159-160 C. H
NMR (400 MHz, CDCl3): d 1.83 (s, 1.5 H, CH3), 1.84 (s, 1.5 H,
CH3), 2.26 (dd, J = 5.0, 2.6 Hz, 0.5 H, Epoxy-CH2), 2.35 (dd,
J = 5.0, 2.3 Hz, 0.5 H, Epoxy-CH2), 2.62 (dd, J = 9.3, 5.3 Hz,
1 H, Epoxy-CH2), 2.79 (dd, J = 10.6, 5.7 Hz, 0.5 H, OCH2CH),
2.87 (dd, J = 11.6, 6.2 Hz, 0.5 H, OCH2CH), 2.90-3.04 (m, 2
H, OCH2CH), 4.18 (s, 3 H, OCH3), 7.45-7.56 (m, 2 H, Ar-H),
7.59-7.66 (m, 1 H, Ar-H), 7.73 (dd, J = 8.9, 1.6 Hz, 1 H, Ar-H),
7.82 (dd, J = 8.9, 1.6 Hz, 1 H, Ar-H), 8.17 (d, J = 7.0 Hz, 1 H,
Ar-H), 8.62 (s, 1 H, Ar-H).13C NMR (100.6 MHz, CDCl3): d 23.4
(CH3), 23.5 (CH3), 44.7 (OCH2), 44.9 (OCH2), 50.64 (OCH2CH),
50.68 (OCH2CH), 53.53 (OCH3), 53.56 (OCH3), 65.3 (Epoxy-
CH2), 65.9 (Epoxy-CH2), 84.48 (CHOH), 84.53 (CHOH), 117.93
(Ar-C), 117.97 (Ar-C), 123.09 (Ar-C), 123.10 (Ar-C), 123.65 (Ar-
C), 123.71 (Ar-C), 123.82 (Ar-C), 123.86 (Ar-C), 126.27 (Ar-C),
126.30 (Ar-C), 128.68 (Ar-C), 128.70 (Ar-C), 129.3 (Ar-C), 129.6
(Ar-C), 129.7 (Ar-C), 129.79 (Ar-C), 129.80 (Ar-C), 132.69 (Ar-
C), 132.72 (Ar-C), 137.7 (Ar-C), 137.8 (Ar-C), 145.6 (Ar-C), 145.7
(Ar-C), 147.03 (Ar-C), 147.05 (Ar-C), 148.8 (Ar-C), 148.9 (Ar-
C), 159.67 (Ar-C), 159.71 (Ar-C). ESI-MS m/z of 412.10, 414.10
[M+H]+ was obtained for a calculated mass of 412.05, 414.05.
=
50.8 (Ar-N-CH2-CH2), 77.3 (C NOCH2Ar), 115.7 (Ar-C), 116.0
(Ar-C), 118.3 (Ar-C), 118.4 (Ar-C), 118.7 (Ar-C), 120.6 (Ar-C),
123.1 (Ar-C), 124.6 (Ar-C), 124.8 (Ar-C), 126.2 (Ar-C), 126.9 (Ar-
C), 126.95 (Ar-C), 127.1 (Ar-C), 127.4 (Ar-C), 129.6 (Ar-C), 129.7
(Ar-C), 130.2 (Ar-C), 130.9 (Ar-C), 131.2 (Ar-C), 131.3 (Ar-C),
131.9 (Ar-C), 132.5 (Ar-C), 133.9 (Ar-C), 134.3 (Ar-C), 135.0 (Ar-
C), 140.0 (Ar-C), 146.7 (Ar-C), 148.6 (Ar-C), 149.5 (Ar-C), 153.1
(Ar-C), 156.7 (Ar-C), 157.1 (Ar-C), 159.0 (Ar-C). ESI-MS m/z
of 643.60, 645.50 [M+H]+ was obtained for a calculated mass of
643.15, 645.15.
2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-ol (21)
Compound 4 (2.0 g, 5.91 mmol) was dissolved in dry THF
(130 mL), to this freshly prepared methyl magnesium iodide
(1 M solution in diethyl ether, 7.1 mL, 7.1 mmol) was added
in one portion at 15 ◦C under nitrogen atmosphere. The reaction
was stirred for 3 h allowing it to gradually warm up to room
temperature during which the color of reaction mixture changed
from yellow to dark brown. Reaction was quenched by adding ice
and reaction mixture was extracted with ethyl acetate (150 mL),
washed with saturated ammonium chloride solution (60 mL),
water (100 mL) and brine (50 mL). The organic extract was
dried over anhydrous sodium sulfate, filtered and the solvents
were evaporated under reduced pressure to obtain a brown sticky
mass as a crude product. Crude product was purified by column
chromatography (silica gel 100-200 mesh, eluent: 7% ethyl acetate
in n-hexane) to give 21 (1.6 g, 77%) as an off white solid; mp 159-
General procedure E for 23-31: 1-(2-bromo-6-methoxy-7-methyl-
7H-indeno[2,1-c]quinolin-7-yloxy)-3-amino-propan-2-ol
derivatives
To a mixture of activated potassium carbonate (5 eq) and
compound 3 (1 eq) in dry DMF, the appropriate amine (R2H,
1~5 eq) was added under nitrogen atmosphere. The reaction was
◦
stirred at 65-70 C for 15 h and quenched with ice. The reaction
mixture was diluted with ethyl acetate and washed thrice with
brine. The organic extract was dried over anhydrous sodium
sulfate, filtered and the solvents were evaporated under reduced
pressure to obtain an oily compound as a crude product. The crude
product was purified by flash column chromatography (on silica
gel 230-400 mesh) to obtain the corresponding 3-amino-propan-
2-ol derivatives 23-31 in reasonable yields (22~77%). Compounds
23 and 24 were obtained in a 4 : 6 diastereomeric ratio and
were separated by column chromatography to give two pair of
diastereomers, as compound 23 and compound 24. Analytical
data of, compound 23 and compound 24 represent data of racemic
diastereomer respectively.
◦
1
160 C. nmax (KBr, cm-1): 3338. H NMR (400 MHz, CDCl3): d
1.80 (s, 3 H, CH3), 3.10 (s, 1 H, D2O exchangeable, CHOH), 4.19
(s, 3 H, OCH3), 7.45-7.53 (m, 3 H, Ar-H), 7.58 (d, J = 8.9 Hz, 1 H,
Ar-H), 7.62-7.70 (m, 1 H, Ar-H), 7.95-8.04 (m, 1 H, Ar-H), 8.46
(s, 1 H, Ar-H). 13C NMR (100.6 MHz, CDCl3): d 23.9 (CH3), 53.3
(OCH3), 78.5 (CHOH), 117.9 (Ar-C), 122.5 (Ar-C), 122.9 (Ar-C),
123.7 (Ar-C), 125.6 (Ar-C), 128.3 (Ar-C), 128.5 (Ar-C), 129.5 (Ar-
C), 130.6 (Ar-C), 131.5 (Ar-C), 135.6 (Ar-C), 143.9 (Ar-C), 145.3
(Ar-C), 151.8 (Ar-C), 159.3 (Ar-C). ESI-MS m/z of 355.80, 357.90
[M+H]+ was obtained for a calculated mass of 356.03, 358.03.
2-Bromo-6-methoxy-7-methyl-7-oxiranylmethoxy-7H-indeno[2,1-
c]quinoline (22)
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[3-(3,4-dichloro-phenyl)-pyrazol-1-yl]-propan-2-ol (23)
Compound 21 (2.◦0 g, 5.62 mmol) was dissolved in dry DMF (7 mL)
and cooled to 0 C, under nitrogen atmosphere. Sodium hydride
(0.28 g, 11.8 mmol) was added to it and stirred for 30 min. During
this period, the color of the reaction changed from yellow to dark
red. epi-Chlorohydrin (1.1 g, 11.8 mmol) was added to the reaction
Procedure E, Yield 22% as a racemic diastereomer. Sticky solid.
nmax (KBr, cm-1): 3391. 1H NMR (400 MHz, CDCl3): d 1.81 (s, 3
H, CH3), 2.44 (dd, J = 9.6, 7.5 Hz, 1 H, OCH2), 3.01 (dd, J = 9.7,
4.4 Hz, 1 H, OCH2), 3.50 (d, J = 2.4 Hz, 1 H, D2O exchangeable,
CHOH), 3.97 (dd, J = 13.5, 5.7 Hz, 1 H, NCH2CHOH), 4.01-4.09
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2193
©

View Article Online
(m, 1 H, CHOH), 4.10-4.13 (m, 1 H, NCH2CHOH), 4.14 (s, 3 H,
OCH3), 6.23 (d, J = 2.2 Hz, 1 H, Pyrazole-CH), 7.29 (dd, J = 8.3,
1.9 Hz, 1 H, Ar-H), 7.33-7.39 (m, 2 H, Ar-H), 7.46-7.58 (m, 3 H,
Ar-H), 7.61 (d, J = 1.8 Hz, 1 H, Ar-H), 7.70 (dd, J = 9.0, 2.0 Hz,
1 H, Ar-H), 7.76 (d, J = 8.9 Hz, 1 H, Ar-H), 8.10 (d, J = 7.2 Hz, 1
H, Ar-H), 8.49 (d, J = 1.9 Hz, 1 H, Ar-H).13C NMR (100.6 MHz,
CDCl3): d 23.3 (CH3), 53.5 (OCH3), 54.1 (NCH2CHOH), 65.3
(OCH2), 69.1 (CHOH), 84.7 (CH3CO-), 102.6 (Ar-C), 118.1 (Ar-
C), 123.0 (Ar-C), 123.5 (Ar-C), 124.1 (Ar-C), 124.5 (Ar-C), 126.2
(Ar-C), 127.0 (Ar-C), 128.1 (Ar-C), 129.5 (Ar-C), 129.6 (Ar-C),
129.7 (Ar-C), 130.4 (Ar-C), 131.2 (Ar-C), 132.4 (Ar-C), 132.5 (Ar-
C), 132.7 (Ar-C), 133.2 (Ar-C), 137.7 (Ar-C), 145.9 (Ar-C), 146.9
(Ar-C), 148.3 (Ar-C), 149.0 (Ar-C), 159.1 (Ar-C). ESI-MS m/z
of 624.10, 626.30 [M+H]+ was obtained for a calculated mass of
624.05, 626.04.
122.31 (Ar-C), 122.35 (Ar-C), 122.39 (Ar-C), 122.76 (Ar-C), 123.0
(Ar-C), 123.1 (Ar-C), 123.44 (Ar-C), 123.48 (Ar-C), 124.07 (Ar-C),
124.16 (Ar-C), 124.20 (Ar-C), 124.24 (Ar-C), 124.27 (Ar-C), 124.3
(Ar-C), 125.5 (Ar-C), 126.27 (Ar-C), 126.3 (Ar-C), 128.2 (Ar-C),
128.3 (Ar-C), 128.6 (Ar-C), 128.7 (Ar-C), 128.98 (Ar-C), 129.02
(Ar-C), 129.5 (Ar-C), 129.7 (Ar-C), 129.8 (Ar-C), 130.3 (Ar-C),
130.4 (Ar-C), 130.7 (Ar-C), 130.8 (Ar-C), 131.0 (Ar-C), 131.1 (Ar-
C), 131.3 (Ar-C), 131.4 (Ar-C), 132.2 (Ar-C), 132.4 (Ar-C), 132.83
(Ar-C), 132.88 (Ar-C), 133.6 (Ar-C), 133.7 (Ar-C), 137.61 (Ar-
C), 137.63 (Ar-C), 145.95 (Ar-C), 145.97 (Ar-C), 146.87 (Ar-C),
146.93 (Ar-C), 148.3 (Ar-C), 148.4 (Ar-C), 150.0 (Ar-C), 150.3
(Ar-C), 159.1 (Ar-C), 159.2 (Ar-C). ESI-MS m/z of 624.30, 626.30
[M+H]+ was obtained for a calculated mass of 624.11, 626.11.
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[3-(3-methoxy-phenyl)-pyrazol-1-yl]-propan-2-ol (26)
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[3-(3,4-dichloro-phenyl)-pyrazol-1-yl]-propan-2-ol (24)
Procedure E, Yield 70%. Reddish solid; mp 98-100 ◦C. nmax
1
(KBr, cm-1): 3370. H NMR (400 MHz, CDCl3): d 1.82 (s, 1.5
Procedure E, Yield 28% as a racemic diastereomer. Sticky solid.
nmax (KBr, cm-1): 3294. 1H NMR (400 MHz, CDCl3): d 1.83 (s, 3
H, CH3), 2.73 (dd, J = 9.6, 5.4 Hz, 1 H, OCH2), 2.92 (dd, J = 9.6,
4.2 Hz, 1 H, OCH2), 3.43 (br-s, 1 H, D2O exchangeable, CHOH),
3.88-3.98 (m, 1 H, CHOH), 4.10-4.16 (m, 1H, NCH2), 4.18 (s, 3 H,
OCH3), 4.29 (dd, J = 13.8, 4.4 Hz, 1 H, NCH2), 6.45 (d, J = 2.2 Hz,
1 H, Ar-H), 7.39 (d, J = 8.3 Hz, 1 H, Ar-H), 7.45 (d, J = 2.2 Hz, 1
H, Ar-H), 7.47-7.59 (m, 4 H, Ar-H), 7.73 (d, J = 8.9, 2.0 Hz, 1 H,
Ar-H), 7.77 (d, J = 2.0 Hz, 1 H, Ar-H), 7.81 (d, J = 8.9 Hz, 1 H,
Ar-H), 8.15 (d, J = 7.0 Hz, 1 H, Ar-H), 8.60 (d, J = 2.0 Hz, 1 H,
Ar-H). 13C NMR (100.6 MHz, CDCl3): d 23.5 (CH3), 53.6 (OCH3),
54.5 (NCH2), 64.7 (OCH2), 69.5 (CHOH), 84.5 (CH3CO-), 102.8
(Ar-C), 118.2 (Ar-C), 123.1 (Ar-C), 123.4 (Ar-C), 124.1 (Ar-C),
124.7 (Ar-C), 126.3 (Ar-C), 127.2 (Ar-C), 128.3 (Ar-C), 129.5 (Ar-
C), 129.7 (Ar-C), 129.9 (Ar-C), 130.5 (Ar-C), 131.3 (Ar-C), 132.1
(Ar-C), 132.6 (Ar-C), 132.9 (Ar-C), 133.3 (Ar-C), 137.7 (Ar-C),
145.9 (Ar-C), 147.0 (Ar-C), 148.4 (Ar-C), 149.4 (Ar-C), 159.3 (Ar-
C). ESI-MS m/z of 624.30, 626.40 [M+H]+ was obtained for a
calculated mass of 624.05, 626.04.
H, CH3), 1.83 (s, 1.5 H, CH3), 2.58 (dd, J = 9.5, 6.5 Hz, 0.6 H,
OCH2), 2.71 (dd, J = 9.4, 5.8 Hz, 0.4 H, OCH2), 2.85-3.04 (m,
1 H, OCH2), 3.60 (br-s, 1 H, D2O Exchangeable, CHOH), 3.81
(s, 1.5 H, Ph-OCH3), 3.82 (s, 1.5 H, Ph-OCH3), 3.91-4.0 (m, 0.5
H, CHOH), 4.01-4.15 (m, 2 H, CHOH and NCH2), 4.16 (s, 1.5
H, OCH3), 4.19 (s, 1.5 H, OCH3), 4.33 (dd, J = 13.7, 4.0 Hz,
0.5 H, - NCH2), 6.35 (d, J = 2.0 Hz, 0.5 H, Ar-H), 6.48 (d, J =
2.0 Hz, 0.5 H, Ar-H), 6.76-6.89 (m, 1 H, Ar-H), 7.12-7.19 (m, 1
H, Ar-H), 7.20-7.30 (m, 2 H, Ar-H), 7.36-7.46 (m, 1 H, Ar-H),
7.47-7.53 (m, 2 H, Ar-H), 7.54-7.61 (m, 1 H, Ar-H), 7.68-7.76 (m,
1 H, Ar-H), 7.77-7.86 (m, 1 H, Ar-H), 8.13 (dd, J = 11.5, 7.4 Hz,
1 H, Ar-H), 8.54 (d, J = 1.8 Hz, 0.5 H, Ar-H), 8.61 (d, J = 1.8 Hz,
0.5 H, Ar-H) total 28 H in diastereomeric ratio 1 : 1. 13C NMR
(100.6 MHz, CDCl3): d 23.4 (CH3), 23.5 (CH3), 53.5 (OCH3),
54.0 (NCH2), 54.3 (NCH2), 55.2 (Ph-OCH3), 64.7 (OCH2), 65.4
(OCH2), 69.5 (CHOH), 69.7 (CHOH), 84.5 (OCH3), 84.6 (OCH3),
102.7 (Ar-C), 102.8 (Ar-C), 110.6 (Ar-C), 110.7 (Ar-C), 113.62
(Ar-C), 113.65 (Ar-C), 118.1 (Ar-C), 118.15 (Ar-C), 123.1 (Ar-C),
123.16 (Ar-C), 123.5 (Ar-C), 124.03 (Ar-C), 124.09 (Ar-C), 126.3
(Ar-C), 128.3 (Ar-C), 128.4 (Ar-C), 129.4 (Ar-C), 129.51 (Ar-C),
129.56 (Ar-C), 129.59 (Ar-C), 129.65 (Ar-C), 129.8 (Ar-C), 129.85
(Ar-C), 131.9 (Ar-C), 132.0 (Ar-C), 132.76 (Ar-C), 132.79 (Ar-C),
134.21 (Ar-C), 134.25 (Ar-C), 137.66 (Ar-C), 137.68 (Ar-C), 145.9
(Ar-C), 146.98 (Ar-C), 147.0 (Ar-C), 148.4 (Ar-C), 148.5 (Ar-C),
151.3 (Ar-C), 151.5 (Ar-C), 159.2 (Ar-C), 159.3 (Ar-C), 159.7 (Ar-
C), 159.8 (Ar-C). ESI-MS m/z of 586.00, 588.00 [M+H]+ was
obtained for a calculated mass of 586.13, 588.13.
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[3-(3-trifluoromethyl-phenyl)-pyrazol-1-yl]-propan-2-ol
(25)
◦
1
Procedure E, Yield 50%. Off-white fluffy-solid; mp 75-76 C. H
NMR (400 MHz, CDCl3): d 1.82 (s, 1.5 H, CH3), 1.84 (s, 1.5 H,
CH3), 2.49 (dd, J = 9.6, 7.0 Hz, 0.5 H, OCH2), 2.75 (dd, J = 9.6,
5.3 Hz, 0.5 H, OCH2), 2.94 (dd, J = 11.4, 4.1 Hz, 0.5 H, OCH2),
3.02 (dd, J = 9.6, 4.2 Hz, 0.5 H, OCH2), 3.93-4.11 (m, 2 H, CHOH
and NCH2), 4.02-4.24 (m, 4 H, NCH2 and OCH3), 4.33 (dd, J =
13.9, 4.3 Hz, 0.5 H, NCH2), 4.62 (br-s, 1 H, D2O exchangeable,
CHOH), 6.36 (d, J = 2.4 Hz, 0.5 H, Ar-H), 6.53 (d, J = 2.4 Hz,
0.5 H, Ar-H), 7.38-7.59 (m, 6 H, Ar-H), 7.62-7.98 (m, 4 H, Ar-H),
8.07-8.19 (m, 1 H, Ar-H), 8.51 (d, J = 2.0 Hz, 0.5 H, Ar-H), 8.60 (d,
J = 2.0 Hz, 0.5 H, Ar-H) for total 25 H in diastereomeric ratio 1 : 1.
13C NMR (100.6 MHz, CDCl3): d 23.3 (CH3), 23.5 (CH3), 53.60
(OCH3), 53.63 (OCH3), 54.0 (NCH2), 54.5 (NCH2), 64.7 (OCH2),
65.3 (OCH2), 69.3 (CHOH), 69.6 (CHOH), 84.6 (CH3CO-), 84.7
(CH3CO-), 102.8 (Ar-C), 102.9 (Ar-C), 118.16 (Ar-C), 118.21 (Ar-
C), 122.13 (Ar-C), 122.17 (Ar-C), 122.21 (Ar-C), 122.28 (Ar-C),
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[3-(4-chloro-phenyl)-pyrazol-1-yl]-propan-2-ol (27)
Procedure E, Yield 40%. White fluffy-solid; mp 55-57 ◦C. nmax
1
(KBr, cm-1): 3419. H NMR (400 MHz, CDCl3): d 1.82 (s, 1.5
H, CH3), 1.83 (s, 1.5 H, CH3), 2.50 (dd, J = 9.5, 7.0 Hz, 0.5
H, OCH2), 2.72 (dd, J = 9.5, 5.6 Hz, 0.5 H, OCH2), 2.92 (dd,
J = 9.5, 4.2 Hz, 0.4 H, OCH2), 2.98 (dd, J = 9.6, 4.4 Hz, 0.5 H,
OCH2), 3.54 (br s, 1 H, D2O exchangeable, CHOH), 3.87-4.12 (m,
2.5 H, -NCH2 and CHOH), 4.14 (s, 1.5 H, OCH3), 4.18 (s, 1.5
H, OCH3), 4.30 (dd, J = 13.8, 4.1 Hz, 0.5 H, -NCH2), 6.27 (d,
J = 2.1 Hz, 0.5 H, Pyrazole-CH), 6.44 (d, J = 2.1 Hz, 0.5 H,
2194 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Pyrazole-CH), 7.27 (d, J = 8.5 Hz, 1 H, Ar-H), 7.30 (d, J = 8.5 Hz,
1 H, Ar-H), 7.35 (d, J = 2.2 Hz, 1 H, Ar-H), 7.44-7.51 (m, 3 H,
Ar-H), 7.52-7.57 (m, 1 H, Ar-H), 7.60 (d, J = 8.4 Hz, 1 H, Ar-H),
7.68-7.85 (m, 2 H, Ar-H), 8.10 (d, J = 7 Hz, 0.5 H, Ar-H), 8.14 (d,
J = 7.3 Hz, 0.5 H, Ar-H), 8.52 (d, J = 1.7 Hz, 0.5 H, Ar-H), 8.60
(d, J = 1.8 Hz, 0.5 H, Ar-H) total 25 H in diastereomeric ratio 1 : 1.
13C NMR (100.6 MHz, CDCl3): d 23.3 (CH3), 23.5 (CH3), 53.54
(OCH3), 53.57 (OCH3), 54.0 (NCH2), 54.4 (NCH2), 64.8 (OCH2),
65.4 (OCH2), 69.3 (CHOH), 69.6 (CHOH), 84.5 (CH3CO-), 84.7
(CH3CO-), 102.4 (Ar-C), 102.5 (Ar-C), 118.2 (Ar-C), 123.1 (Ar-
C), 123.2 (Ar-C), 123.46 (Ar-C), 123.48 (Ar-C), 124.06 (Ar-C),
124.1 (Ar-C), 126.26 (Ar-C), 126.31 (Ar-C), 126.6 (Ar-C), 126.7
(Ar-C), 128.2 (Ar-C), 128.4 (Ar-C), 128.6 (Ar-C), 128.7 (Ar-C),
128.8 (Ar-C), 129.4 (Ar-C), 129.62 (Ar-C), 129.64 (Ar-C), 129.8
(Ar-C), 129.9 (Ar-C), 131.6 (Ar-C), 131.7 (Ar-C), 131.9 (Ar-C),
132.1 (Ar-C), 132.79 (Ar-C), 132.84 (Ar-C), 133.2 (Ar-C), 133.3
(Ar-C), 137.7 (Ar-C), 145.9 (Ar-C), 147.0 (Ar-C), 147.03 (Ar-C),
148.4 (Ar-C), 148.46 (Ar-C), 150.3 (Ar-C), 150.6 (Ar-C), 159.2
(Ar-C), 159.3 (Ar-C). ESI-MS m/z of 589.80, 591.80 [M+H]+ was
obtained for a calculated mass of 590.08, 592.08.
0.5 H, -NCH2), 4.31 (dd, J = 13.8, 4.2 Hz, 0.6 H, -NCH2), 7.47-
7.58 (m, 3 H, Ar-H), 7.73-7.89 (m, 3 H, Ar-H), 8.07 (s, 0.5 H,
Ar-H), 8.15 (s, 0.5 H, Ar-H), 8.16-8.22 (m, 1 H, Ar-H), 8.61-8.66
(m, 1 H, Ar-H) total 21 H in diastereomeric ratio 1 : 1. 13C NMR
(100.6 MHz, CDCl3): d 23.4 (CH3), 23.5 (CH3) 51.9 (-NCH2),
52.4 (-NCH2), 53.53 (OCH3), 53.55 (OCH3), 64.7 (OCH2), 65.4
(OCH2), 68.63 (CHOH), 68.68 (CHOH), 84.5 (CH3CO-), 84.6
(CH3CO-), 118.14 (Ar-C), 118.15 (Ar-C), 123.03 (Ar-C), 123.06
(Ar-C), 123.3 (Ar-C), 123.4 (Ar-C), 124.1 (Ar-C), 126.2 (Ar-C),
128.1 (Ar-C), 129.4 (Ar-C), 129.7 (Ar-C), 129.8 (Ar-C), 132.8 (Ar-
C), 137.6 (Ar-C), 143.8 (Ar-C), 143.9 (Ar-C), 145.8 (Ar-C), 145.82
(Ar-C), 147.0 (Ar-C), 148.2 (Ar-C), 151.4 (Ar-C), 151.6 (Ar-C),
159.1 (Ar-C). ESI-MS m/z of 481.30, 483.20 [M+H]+ was obtained
for a calculated mass of 481.09, 483.09.
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-imidazol-1-yl-propan-2-ol (30)
Procedure E, Yield 70%. Off-white solid; mp 82-84 ◦C. nmax
1
(KBr, cm-1): 3113. H NMR (400 MHz, CDCl3): d 1.82 (s, 3 H,
CH3), 2.60-2.76 (m, 1 H, OCH2), 2.77-2.94 (m, 1 H, OCH2), 3.65-
3.85 (m, 2 H, NCH2), 3.92 (dd, J = 13.5, 2.8 Hz, 0.5 H, CHOH),
4.06 (dd, J = 13.9, 3.9 Hz, 0.5 H, CHOH), 4.13 (s, 1.5 H, OCH3),
4.14 (s, 1.5 H, OCH3), 4.90 (br-s, 1 H, D2O exchangeable, CHOH),
6.64-6.90 (m, 2 H, Ar-H), 7.12-7.29 (m, 1 H, Ar-H), 7.43-7.58
(m, 3 H, Ar-H), 7.68 (dd, J = 8.9, 1.3 Hz, 1 H, Ar-H), 7.78
(d, J = 8.9 Hz, 1 H, Ar-H), 8.07-8.21 (m, 1 H, Ar-H), 8.59 (s,
1 H, Ar-H). Total 22 H in diastereomeric ratio 1 : 1. 13C NMR
(100.6 MHz, CDCl3): d 23.3 (CH3), 23.4 (CH3), 49.9 (-NCH2),
50.1 (-NCH2), 53.42 (OCH3), 53.44 (OCH3), 64.9 (OCH2), 65.6
(OCH2), 69.16 (CHOH), 69.22 (CHOH), 84.37 (CH3CO-), 84.42
(CH3CO-), 118.0 (Ar-C), 119.5 (Ar-C), 123.0 (Ar-C), 123.3 (Ar-C),
123.4 (Ar-C), 123.9 (Ar-C), 126.2 (Ar-C), 128.17 (Ar-C), 128.21
(Ar-C), 128.25 (Ar-C), 129.3 (Ar-C), 129.6 (Ar-C), 129.7 (Ar-C),
132.7 (Ar-C), 137.3 (Ar-C), 137.55 (Ar-C), 137.58 (Ar-C), 145.68
(Ar-C), 145.71 (Ar-C), 146.9 (Ar-C), 148.36 (Ar-C), 148.41 (Ar-
C), 159.14 (Ar-C), 159.20 (Ar-C). ESI-MS m/z of 480.16, 482.18
[M+H]+ was obtained for a calculated mass of 480.09, 482.09.
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-pyrazol-1-yl-propan-2-ol (28)
Procedure E, Yield 77%. Off-white solid; mp 106-109 ◦C. nmax
1
(KBr, cm-1): 3436. H NMR (400 MHz, CDCl3): d 1.81 (s, 1.5
H, CH3), 1.82 (s, 1.5 H, CH3), 2.60 (dd, J = 9.5, 6.0 Hz, 0.5 H,
OCH2), 2.66 (dd, J = 9.4, 5.8 Hz, 0.5 H, OCH2), 2.84-2.94 (m, 1 H,
OCH2), 3.87-3.94 (m, 0.5 H, CHOH), 3.96-4.06 (m, 1 H, CHOH
and-NCH2), 4.08-4.16 (m, 1 H,-NCH2), 4.17-4.22 (m, 3 H, OCH3),
4.29 (dd, J = 13.8, 4.0 Hz, 0.6 H,-NCH2), 6.13 (t, J = 2.0 Hz, 0.5 H,
Pyrazole-CH), 6.19 (t, J = 2.0 Hz, 0.5 H, Pyrazole-CH), 6.35 (br-s,
0.5 H, Ar-H), 7.34-7.40 (m, 1 H, Ar-H), 7.41-7.45 (m, 1 H, Ar-H),
7.46-7.58 (m, 3 H, Ar-H), 7.61 (d, J = 1.7 Hz, 1 H, Ar-H), 7.72 (t,
J = 2.2 Hz, 0.5 H, Ar-H), 7.75 (t, J = 2.2 Hz, 0.5 H, Ar-H), 7.82
(dd, J = 9.0, 2.1 Hz, 1 H, Ar-H), 8.14-8.21 (m, 1 H, Ar-H), 8.62
(d, J = 1.5 Hz, 1 H, Ar-H) total 22 H in diastereomeric ratio 1 : 1.
13C NMR (100.6 MHz, CDCl3): d 23.31 (CH3), 23.35 (CH3), 53.4
(OCH3), 53.9 (OCH3), 54.3 (NCH2), 64.9 (OCH2), 65.4 (OCH2),
69.4 (CHOH), 84.3 (CH3CO-), 84.37 (CH3CO-), 105.1 (Ar-C),
117.9 (Ar-C), 122.96 (Ar-C), 122.98 (Ar-C), 123.32 (Ar-C), 123.36
(Ar-C), 123.9 (Ar-C), 126.1 (Ar-C), 128.23 (Ar-C), 128.25 (Ar-C),
129.2 (Ar-C), 129.5 (Ar-C), 129.7 (Ar-C), 130.17 (Ar-C), 130.19
(Ar-C), 132.6 (Ar-C), 133.3 (Ar-C), 137.5 (Ar-C), 139.1 (Ar-C),
139.2 (Ar-C), 145.6 (Ar-C), 146.8 (Ar-C), 148.32 (Ar-C), 148.37
(Ar-C), 159.1 (Ar-C). ESI-MS m/z of 480.10, 482.20 [M+H]+ was
obtained for a calculated mass of 480.09, 482.09.
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-morpholin-4-yl-propan-2-ol (31)
Procedure E, Yield 41%. Off-white solid; mp 189-195 ◦C. nmax
1
(KBr, cm-1): 3394. H NMR (400 MHz, CDCl3): d 1.67 (br-s, 1
H, D2O exchangeable, CHOH), 1.77 (s, 1.5 H, CH3), 1.79 (s, 1.5
H, CH3), 2.58-2.72 (m, 1 H, Ar-N-CH2-CH2), 2.82-3.10 (m, 4 H,
Ar-N-CH2-CH2), 3.25 (d, J = 13.2 Hz, 1 H, Ar-N-CH2-CH2),
3.31-3.74 (m, 2 H, Ar-N-CH2-CH2), 3.84-4.09 (m, 2 H, OCH2),
4.16 (s, 1.5 H, OCH3), 4.17 (s, 1.5 H, OCH3), 4.21-4.52 (m, 3
H, NCH2CHOH), 7.46-7.60 (m, 3 H, Ar-H), 7.74 (dd, J = 8.9,
2.0 Hz, 1 H, Ar-H), 7.81 (dd, J = 8.8, 1.4 Hz, 1 H, Ar-H), 8.17 (d,
J = 6.9 Hz, 1 H, Ar-H), 8.61 (d, J = 1.8 Hz, 1 H, Ar-H) total 27
H in diastereomeric ratio 1 : 1. 13C NMR (100.6 MHz, CDCl3):
d 23.3 (CH3), 23.4 (CH3), 53.50 (OCH3) 53.55 (OCH3), 61.4
(Ar-NCH2CH2), 62.7 (Ar-NCH2CH2), 63.7 (Ar-NCH2CH2), 64.4
(Ar-NCH2CH2), 64.8 (CHOH), 65.4 (OCH2), 65.7 (OCH2), 84.5
(CH3CO-), 84.6 (CH3CO-), 118.2 (Ar-C), 118.3 (Ar-C), 123.09
(Ar-C), 123.12 (Ar-C), 123.4 (Ar-C), 123.5 (Ar-C), 124.1 (Ar-C),
124.13 (Ar-C), 126.3 (Ar-C), 127.86 (Ar-C), 127.94 (Ar-C), 129.6
1-(2-Bromo-6-methoxy-7-methyl-7H-indeno[2,1-c]quinolin-7-
yloxy)-3-[1,2,4]triazol-1-yl-propan-2-ol (29)
Procedure E, Yield 77%. Off-white solid; mp 77-79 ◦C. nmax
1
(KBr, cm-1): 3385. H NMR (400 MHz, CDCl3): d 1.81 (s, 1.5
H, CH3), 1.82 (s, 1.5 H, CH3), 2.59 (dd, J = 9.5, 6.5 Hz, 0.6 H,
OCH2), 2.74 (dd, J = 9.8, 5.0 Hz, 0.6 H, OCH2), 2.87-2.96 (m, 1
H, OCH2), 2.99 (dd, J = 9.5, 3.6 Hz, 0.6 H, -NCH2), 3.16-3.23
(m, 1 H, D2O exchangeable, CHOH), 3.85-3.94 (m, 1 H, CHOH),
4.00-4.07 (m, 1 H, CHOH and -NCH2), 4.08-4.14 (m, 1 H, -
NCH2), 4.16 (s, 1.5 H, OCH3), 4.18 (s, 1.5 H, OCH3), 4.20-4.25 (m,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2195
©

View Article Online
(Ar-C), 129.8 (Ar-C), 129.9 (Ar-C), 132.92 (Ar-C), 132.94 (Ar-C),
137.58 (Ar-C), 137.62 (Ar-C), 145.9 (Ar-C), 146.0 (Ar-C), 147.02
(Ar-C), 147.03 (Ar-C), 148.1 (Ar-C), 159.0 (Ar-C), 159.2 (Ar-
C). ESI-MS m/z of 499.30, 501.30 [M+H]+ was obtained for a
calculated mass of 499.12, 501.12.
(m, 1 H, Ar-H), 7.74-7.83 (m, 2 H, Ar-H), 8.35 (d, J = 4.7 Hz, 1
H, Ar-H), 8.74 (s, 1 H, Ar-H). 13C NMR (100.6 MHz, DMSO-d6):
d 23.0 (CH3), 48.2 (-N-CH2CH2-N-), 49.5 (-N-CH2CH2-N-), 78.9
(CHOH), 111.3 (Ar-C), 115.1 (Ar-C), 117.7 (Ar-C), 119.2 (Ar-
C), 122.8 (Ar-C), 123.5 (Ar-C), 124.2 (Ar-C), 126.0 (Ar-C), 129.2
(Ar-C), 129.9 (Ar-C), 130.3 (Ar-C), 130.4 (Ar-C), 132.7 (Ar-C),
135.9 (Ar-C), 136.0 (Ar-C), 143.8 (Ar-C), 146.5 (Ar-C), 151.7 (Ar-
C), 153.0 (Ar-C), 158.6 (Ar-C). ESI-MS m/z of 554.10, 555.90
[M+H]+ was obtained for a calculated mass of 554.11, 556.10.
Dimethyl-carbamic acid 2-bromo-6-methoxy-7-methyl-7H-
indeno[2,1-c]quinolin-7-yl ester (32)
To a cooled (0 ◦C) solution of 21 (0.20 g, 0.56 mmol) in dry DMF
(4 mL) sodium hydride (0.030 g, 1.18 mmol) was added under
nitrogen atmosphere and stirred for 30 min. During this period,
the color of the reaction changed from yellow to dark red. N,N-
Dimethylcarbamyl chloride (0.15 g, 1.40 mmol) was added to the
reaction mixture and was stirred for 15 h at room temperature.
The reaction was quenched with ice. The reaction mixture was
diluted with ethyl acetate (20 mL), washed with brine (3 ¥ 50 mL)
and dried over anhydrous sodium sulfate. The organic layer was
filtered and solvents were evaporated under reduced pressure to
obtain a gum as a crude product. The crude product was purified
by column chromatography (silica gel 100-200 mesh, eluent: 10%
ethyl acetate in n-hexane) to give 32 (0.060 g; 25%) as a white
solid; mp 197-198 ◦C. nmax (KBr, cm-1): 1711. 1H NMR (400 MHz,
CDCl3): d 1.84 (s, 3 H, CH3), 2.69 (s, 3 H, -NCH3), 3.03 (s,
3 H, -NCH3), 4.14 (s, 3 H, OCH3), 7.40-7.54 (m, 2 H, Ar-H), 7.55-
7.61 (m, 1 H, Ar-H), 7.68 (dd, J = 8.9, 2.0 Hz, 1 H, Ar-H), 7.78 (d,
J = 8.9 Hz, 1 H, Ar-H), 8.18 (d, J = 7.3 Hz, 1 H, Ar-H), 8.62 (d, J =
2.0 Hz, 1 H, Ar-H). 13C NMR (100.6 MHz, CDCl3): d 23.7 (CH3),
36.1 (NCH3), 36.2 (NCH3), 53.3 (OCH3), 83.3 (CHOH), 117.6
(Ar-C), 122.2 (Ar-C), 123.4 (Ar-C), 123.9 (Ar-C), 126.4 (Ar-C),
128.8 (Ar-C), 129.2 (Ar-C), 129.7 (Ar-C), 130.0 (Ar-C), 132.1 (Ar-
C), 137.3 (Ar-C), 144.3 (Ar-C), 146.7 (Ar-C), 149.7 (Ar-C), 154.2
(Ar-C), 158.8 (Ar-C). ESI-MS m/z of 427.10, 429.20 [M+H]+ was
obtained for a calculated mass of 427.07, 429.06.
2-Bromo-6-imidazol-1-yl-7-methyl-7H-indeno[2,1-c]quinolin-
7-ol (34)
Procedure F. The crude reaction mixture was washed with DCM
to give desired product 34 (56%) as a pale-yellow solid; mp 175-
180 ◦C. nmax (KBr, cm-1): 3146. 1H NMR (400 MHz, DMSO-d6): d
1.41 (s, 3 H, CH3), 6.45 (s, 1 H, D2O exchangeable, CHOH), 7.18
(s, 1 H, Ar-H), 7.55-7.67 (m, 2 H, Ar-H), 7.70-7.78 (m, 1 H, Ar-H),
8.03 (s, 2 H, Ar-H), 8.19 (d, J = 1.2 Hz, 1 H, Ar-H), 8.51 (d, J =
7.0 Hz, 1 H, Ar-H), 8.68 (s, 1 H, Ar-H), 8.95 (s, 1 H, Ar-H). 13
C
NMR (100.6 MHz, DMSO-d6) d 22.6 (CH3), 78.1 (CHOH), 120.5
(Ar-C), 121.2 (Ar-C), 123.4 (Ar-C), 124.1 (Ar-C), 124.6 (Ar-C),
126.0 (Ar-C), 128.7 (Ar-C), 129.3 (Ar-C), 130.7 (Ar-C), 131.4 (Ar-
C), 133.9 (Ar-C), 134.8 (Ar-C), 135.0 (Ar-C), 138.2 (Ar-C), 145.9
(Ar-C), 146.2 (Ar-C), 152.5 (Ar-C). ESI-MS m/z of 392.00, 394.10
[M+H]+ was obtained for a calculated mass of 392.04, 394.04.
Biological activity – methods
Anti-mycobacterial activity
Compounds 10-34 and the first front-line drug Isoniazid22 (as a
reference) were dissolv◦ed in DMSO at a concentration of 6.25 mg
mL-1 and stored at ~4 C until used.
General procedure F for 33-34: 6-amino-2-bromo-7-methyl-
7H-indeno[2,1-c]quinolin-7-ols
Cytotoxicity
Cell viability in the presence and absence of test compounds was
determined by Mosmans’s MTT assay26-28 for the most active
compounds (11, 13, 16, 24, 30, 32 and 34) from our data set.
The cells (human monocytic cell line U937) were plated in flat-
bottomed 96 well plates (1 ¥ 105 cells ml-1), cultured for 1 h in
controlled atmosphere (CO2 5% at 37 ◦C), and non- adherent cells
were washed by gentle flushing with RPMI 1640. Adherent cells
were cultured in the presence of medium alone, Tween 20 (3%)
(live and dead controls, respectively) or different concentration of
compounds (depending upon the solubility) in a triplicate assay
(Table 3). After completion of the experiment protocol 10 mL of
MTT solution (5 mg mL-1 solution in Phosphate Buffer Saline)
was added in each well. Plates were incubated for three hours in
CO2 incubator at 37 ◦C. Then 100 mL solubilizing solution (0.4 M
HCl in isopropanol) was added to solubilize the formazan crystals
formed by the surviving cells. Finally the absorbance was read at
600 nm in a micro plate reader (Bio-Rad-i Mark) using acidified
isopropanol as blank. The results were presented as percentage
cell viability (Table 3).
A freshly prepared solution of methyl magnesium iodide (3 M
solution in dry diethyl ether, 6 eq) was added to the appropriate
ketone 5 or 8 (1 eq) in dry THF, at 0 ◦C, and stirred at 0 ◦C for 2 h
followed by 6 h at room temperature. The reaction was quenched
with ice-cold water, diluted with ethyl acetate and washed with
saturated ammonium chloride solution followed by brine. The
organic layer was dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure to obtain the product in
good yields.
2-Bromo-7-methyl-6-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-
7H-indeno[2,1-c]quinolin-7-ol (33)
Procedure F. Crude product was purified by column chromatogra-
phy (100-200 mesh silica gel, eluent: 15% ethyl acetate in hexa◦ne)
to give pure 33 (82%) as a yellow-orange solid; mp 145-148 C.
1
nmax (KBr, cm-1): 3441. H NMR (400 MHz, DMSO-d6): d 1.76
(s, 3 H, CH3), 3.30-3.40 (m, 1 H, -N-CH2CH2-N-), 3.46-3.60 (m,
4 H, -N-CH2CH2-N-), 4.27-4.36 (m, 2 H, -N-CH2CH2-N-), 6.07
(s, 1 H, D2O exchangeable, CHOH), 7.10 (d, J = 7.5 Hz, 1 H,
Ar-H), 7.28 (s, 1 H, Ar-H), 7.33 (d, J = 8.6 Hz, 1 H, Ar-H), 7.45
(t, J = 8.0 Hz, 1 H, Ar-H), 7.50-7.58 (m, 2 H, Ar-H), 7.66-7.72
NOTE: All amino acid numbering corresponds to Mycobac-
terium tuberculosis ATP synthase subunits A and C. Subunit type
shown in superscript.
2196 | Org. Biomol. Chem., 2010, 8, 2180–2197
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
D. Chaffoy, E. Huitric, S. Hoffner, E. Cambau, C. T. Pernot, N. Lounis
and V. Jarlier, Science, 2005, 307, 223–227; (b) WO Pat. 2006/125769,
2006.; (c) J. C. Sacchettini, E. J. Rubin and J. S. Freundlich, Nat. Rev.
Microbiol., 2008, 6, 41–52.
Acknowledgements
We thank Dr Avijit Poddar, Institute of Molecular Medicine,
for cytotoxicity study of compounds. We thank Uppsala Uni-
versity, Sweden for valuable scientific support through Prof.
Jyoti Chattopadhyaya. We thank M. P. Sarmah, A. M. Vibhute
and M. M. Shaikh for the preparation of some intermediates
in the early phase of this work. Generous financial support
from the European Union (Project No. 222965, Project name:
New approaches to target Tuberculosis, Call identifier: FP7-
Health-2007-B) and TCG Life Sciences, Kolkata for funding the
collaboration are also gratefully acknowledged.
14 (a) R. Jonge, H. M. Koymans, E. G. Guillemont, A. Koul and K.
Andries, Proteins: Struct., Funct., Bioinf., 2007, 67, 971–980; (b) WO
Pat. 2004011436 A1, 2004; (c) WO Pat. WO 2005070430 A1, 2005;
(d) WO Pat. WO 2005070924 A1, 2005; (e) WO Pat. WO 2005075428
A1, 2005; (f) WO Pat. WO 2007000434 A1, 2007; (g) WO Pat. WO
2007000435 A1, 2007; (h) WO Pat. WO 2007014940 A2, 2007; (i) WO
Pat. WO 2007000436 A1, 2007; (j) WO Pat. WO 2007071055 A1, 2007;
(k) US Pat. 20080182855 A1, 2008; (l) S. Gaurrand, S. Desjardins, C.
Meyer, P. Bonnet, J. Argoullon, H. Oulyadi and J. Guillemont, Chem.
Biol. Drug Des., 2006, 68, 77–84.
15 S. Petrella, E. Cambau, A. Chauffour, K. Andries, V. Jarlier and W.
Sougakoff, Antimicrob. Agents Chemother., 2006, 50, 2853–2856.
16 R. S. Upadhayaya, V. Jaya Kishore, V. Nageswara Rao, V. Sharma, S. S.
Dixit and J. Chattopadhaya, Bioorg. Med. Chem., 2009, 17, 2830–2841.
17 R. S. Upadhayaya, V. Jaya Kishore, R. A. Kardile, S. V. Lahore, S. S.
Dixit, H. S. Deokar, P. D. Shinde, M. P. Sarmah and J. Chattopadhaya,
Eur. J. Med. Chem., 2010, DOI: 10.1016/j.ejmech.2010.01.024.
18 R. S. Upadhayaya, G. M. Kulkarni, V. Jaya Kishore, V. Nageswara Rao,
V. Sharma, S. S. Dixit and J. Chattopadhaya, Bioorg. Med. Chem., 2009,
17, 4681–4692.
References
1 World Health Organization. http://www.who.int/tb/en/.
2 D. E. Snider, M. Raviglione and A. Kochi, Global Burden of Tubercu-
losis, Tuberculosis: Pathogenesis, Protection and Control, B. R. Bloom,
Ed., ASM, Washington, DC, 1994, 3–11.
3 ‘Tuberculosis’ WHO fact sheet No. 104 Health communications,
WHO, Geneva, Switzerland 2006, http://www.who.int/mediacentre/
factsheets/fs104/en/index.html.
4 WHO Report 2008, Global Tuberculosis Control, Surveillance, Plan-
ning and Financing.
5 M. A. Espinal, Tuberculosis, 2003, 83, 44–51.
19 J. D. Vanitha and C. N. Paramasivan, Diagn. Microbiol. Infect. Dis.,
2004, 49, 179–182.
20 R. S. Reis, I. Jr. Neves, S. L. S. Lourenco, L. S. Fonseca and M. C. S.
Lourenco, J. Clin. Microbiol., 2004, 42, 2247–2248.
21 A. Mamo, S. Nicoletti and N. C. Tat, Molecules, 2002, 7, 618–627.
22 B. R. Bloom and C. J. L. Murray, Science, 1992, 257, 1055–1064.
23 K. Iguchi, S. Usui, R. Ishida and K. Hirao, Apoptosis, 2002, 7, 519–525.
24 G. Simonetti, S. Baffa and N. Simonetti, Int. J. Antimicrob. Agents,
2001, 17, 389–393.
25 W. L. F. Armarego and C. L. L. Chai, Purification of Laboratory
Chemicals, Fifth Edition, Butterworth Heinemann Publishers, 2003.
26 M. C. S. Lourenc¸o, F. R. Vicente, M. G. M. O. Henriques, A. L. P.
Cande´a, R. S. B. Gonc¸alves, T. C. M. Nogueira, M. L. Ferreira and
M. V. N. Souza, Bioorg. Med. Chem. Lett., 2007, 17, 6895–6898.
27 M. C. Souza, A. C. Siani, M. F. S. Ramos, O. M. Jr. Limas and
M. G. M. O. Henrique, Pharmazie, 2003, 58, 582–586.
6 M. C. Raviglione and I. M. Smith, N. Engl. J. Med., 2007, 356, 656–659.
7 T. R. Frieden and S. S. Munsiff, Clin. Chest. Med., 2005, 26, 197–205.
8 I. Chopra, L. Hesse and A. J. O’Neill, J. Appl. Microbiol., 2002, 92,
4S–15S.
9 (a) L. Jugheli, N. Bzekalava, P. Rijk, K. Fissette, F. Portaels and L.
Rigouts, Antimicrob. Agents Chemother., 2009, 53, 5064–5068; (b) I.
Sugawara, J. Zhang and C. Li, Indian J. Exptl. Biol., 2009, 47, 520–522.
10 E. C. Rivers and R. L. Mancera, Drug Discovery Today, 2008, 13,
1090–1098.
11 H. Tomioka, Y. Tatano, K. Yasumoto and T. Shimizu, Curr. Pharm.
Des., 2006, 12, 4047–4070.
12 A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau and A. P.
Kozikowski, J. Med. Chem., 2009, 52, 2109–2118.
28 M. V. Carvalho, C. Penido, A. C. Siani, L. M. M. Valente and
M. G. M. O. Henriques, Gmelin Inflammopharmacol., 2006, 14, 48–
56.
13 (a) K. Andries, P. Verhasselt, J. Guillemont, W. H. Gohlmann, J. Neefs,
H. Winkler, J. V. Gestel, P. Timmerman, M. Zhu, E. Lee, P. Williams,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2180–2197 | 2197
©