Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their anti-mycobacterial properties

Article abstract of DOI:10.1039/c0ob00445f

Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 μg mL^-1 and 0.78 μg mL^-1, respectively)¹⁴ with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c]quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 μg mL^-1. The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 μg mL^-1 (0.89 μM and 1 μM, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB.

Full text of DOI:10.1039/c0ob00445f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their
anti-mycobacterial properties†
Ram Shankar Upadhayaya,a Popat D. Shinde,a Aftab Y. Sayyed,a Sandip A. Kadam,a Amit N. Bawane,a
Avijit Poddar,b Oleksandr Plashkevych,c Andras Fo¨ldesic and Jyoti Chattopadhyaya*c
Received 19th July 2010, Accepted 27th August 2010
DOI: 10.1039/c0ob00445f
Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as
anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 mg mL-1 and 0.78 mg mL-1,
respectively)14 with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of
pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the
C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused
azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was
simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target
receptor. Out of 22 different azole-fused indeno[2,1-c]quinoline derivatives, seven structurally distinct
compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79–99% growth inhibition of Mycobacterium
tuberculosis H37Rv at a fixed dose of 6.25 mg mL-1. The efficacies of these compounds were evaluated in
vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose
on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at
MIC < 0.39 mg mL-1 (0.89 mM and 1 mM, respectively). These active compounds 9, 15, 17, 25, 27, 28
and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937),
which showed that the human cell survival is almost unperturbed (100% survival), except for compound
25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials,
virtually with no toxicity. Thus these “hit” molecules constitute our important “leads” for further
optimization by structure–activity relationship against TB.
whole cell assay. We assumed that by covalently restricting the
Introduction
rotation of the C2-imidazolo moiety in 2a and 3a, by fusing to
Many natural and synthetic biologically active compounds are
the adjacent quinoline-nitrogen in the form of pentacyclic azole-
found to be nitrogen containing heterocycles and they constitute
an important class of pharmacophores in medicinal chemistry.1–4
fused quinoline derivatives 4 and 5, we might be able to reduce the
entropy of the system without imposing enthalpy penalty, hence
Within this group of heterocycles, quinoline derivatives have
directly contributing to the reduction of the overall free-energy of
been well known in medicinal chemistry as anti-malarials,5
binding to the target receptor. We also argued that this would give
anti-bacterials,6 anti-cancer7 as well as anti-mycobacterials.8–10
us scope to explore the pharmacological role of the free-rotating
Quinoline-based anti-TB compound TMC20711 (Fig. 1) bearing a
C2-imidazolo substituent in compounds 2a and 3a for the anti-
bulky biaryl side chain at position C3, is a highly potent anti-TB
tuberculotic activity (Fig. 1).
agent, has novel mode of action and is currently in phase II clinical
trials with very promising activity against MDR-TB.12
Based on molecular dissection of TMC207, we have recently
Literature survey revealed that the tetrazolo-, 1,2,4-triazole-
and dihydroimidazole-fused quinolines were found to posses
important biological activities. Tetrazolo-fused quinolines have
anti-inflammatory, anti-bacterial properties15 and platinum(II)
complexes of tetrazolo-quinolones were found to possess anti-
tumor properties,16,17 whereas condensed 1,2,4-traizoles are found
to be excellent anti-depressants.18a–g Synthesis of azole-fused
quinolines19 and isoquinolines20 is reported in literature and these
compounds have been studied for the spectral characteristics like
proton-magnetic resonance19 and photochemical properties,21 but
no conclusive NMR data that unambiguously substantiates the
ring-closure to the fused heterocycles has been presented so far.22–26
Inspired by the interesting biological activities of fused quino-
lines and the potent anti-TB activity displayed by our confor-
mationally locked indeno[2,1-c] quinolines 2a and 3a, in which
the imidazolo group at the C2 position of the quinoline ring is
important for biological activity. In order to examine the role of the
reported the design, synthesis and biological activity of relatively
less complex molecules possessing potent anti-TB activity,13,14
among which conformationally-locked indeno[2,1-c]quinolines14
2a and 3a showed effective inhibition of Mycobacterium tuber-
culosis H37Rv with MIC99 < 0.39 mg mL-1 (1 mM) for the
former and MIC99 < 0.78 mg mL-1 (2 mM) for the latter in the
aInstitute of Molecular Medicine, Pune, 411 057, India
bInstitute of Molecular Medicine, Calcutta, 700 091, India
cBioorganic Chemistry, Department of Cell and Molecular Biology, Biomed-
ical Centre, Uppsala University, SE-75123, Uppsala, Sweden. E-mail: jy-
oti@boc.uu.se; Fax: +46-18-554495; Tel: +46-18-4714577
† Electronic supplementary information (ESI) available: Spectral data (1D-
NMR, 2D-NMR, LCMS, Mass, HPLC and IR) for all new compounds is
included. See DOI: 10.1039/c0ob00445f
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5661
©

View Article Online
Fig. 1 Structures of conformationally-locked indeno[2,1-c]quinoline 2a, 3a, 4, 5 and TMC207.11 The left-half of TMC207 (1) (shown in a dotted box)
is conformationally-locked at C4 of the quinoline system to C2¢ of the phenyl ring to give relatively simple molecules 2a and 3a, which have been shown
to successfully inhibit the growth of Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) of <0.39 mg mL-1 and 0.78 mg
mL-1.14 In order to examine the role of the free-rotating imidazolo ring at C2, we have conformationally-locked the C2-imidazolo ring by heteroannulation
with the quinoline-nitrogen to give the double-locked indeno[2,1-c]quinoline derivatives with general formulae 4 and 5.
free-rotating imidazolo group at C2, we have conformationally-
locked the C2-imidazolo ring by heteroannulation with the quino-
line nitrogen to give the pentacyclic double-locked indeno[2,1-c]
quinoline derivatives 4 and 5.
We herein report the design, synthesis and anti-mycobacterial
activity of the fused tetrazole-, triazole- and dihydroimidazole-
indeno[2,1-c]quinolines 7–29 with detailed spectroscopic analysis
of the ring closure reaction involving the C2 substituent and
quinoline nitrogen.
pot reaction to give the fused tetrazolo indeno[2,1-c]quinoline 7
(88%) in a single step. Subsequently, the oxime derivative 8 was
prepared in 95% yield from compound 7 by heating the latter with
NH2OH·HCl in DMF at 120 ◦C. Compound 8 was then converted
to N,N-dimethylcarbamyl oxime 9 (51%) by treatment with N,N-
dimethylcarbamyl chloride and NaH in DMF. Compound 7 was
also converted to the racemic C-methyl alcohol 10 (41%) by
a Grignard reaction with CH3MgI under standard conditions.
Compound 10 was subsequently transformed to various ester
derivatives 11–13 (16–55%) by treating with corresponding acid
chlorides in N,N-dimethylformamide in the presence of NaH.
Results
1.0 Synthesis of tetrazole-fused indeno[2,1-c]quinolines (9–13)
2.0 Synthesis of triazole-fused indeno[2,1-c]quinolines (15 and
16)
Synthesis of the title compounds 9–13 was started from an easily
accessible compound 614 (Scheme 1), which upon treatment with
NaN3 resulted in nucleophilic displacement of the C2-chloro
to C2-azido in situ, which concomitantly cyclized in a one-
These compounds were prepared from chloroketone 614
(Scheme 2). Treatment of compound 6 with NH2NH2·H2O in
ethanol at reflux temperature gave compound 14 (73%), which
Scheme 1 Synthesis of tetrazole-fused indeno[2,1-c]quinolines (7–13): Reagents and Conditions: (i) NaN3, DMF, 80 ◦C, 5 h; (ii) NH2OH·HCl, DMF,
120 ◦C, 5 h; (iii) NaH, RCOCl, DMF; (iv) CH3MgI, THF, rt, 12 h.
5662 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Scheme 2 Synthesis of triazole-fused indeno[2,1-c]quinolines (15 and 16): Reagents and Conditions: (i) NH2NH2·H2O, C2H5OH, reflux, 48 h; (ii)
HCOOH, reflux; 24 h; (iii) CH3MgI, THF, 0 ◦C–rt.
upon treatment with HCOOH under reflux gave compound 15
(56%). Compound 15 was converted to the racemic C-methyl
alcohol 16 (19%) by the Grignard reaction with CH3MgI under
standard conditions.
the corresponding C2-hydroxyethylamino derivative 24 (79%)
(Scheme 4), which was cyclized in phosphrous oxychloride to give
dihydroimidazole fused quinoline 25 (82%). Grignard reaction of
CH3MgI of compound 25 gave the alcohol 26 (35%), which was
further treated with N,N-dimethylcarbamyl chloride and NaH
in DMF to give compound 27 (46%). The oxime derivative of
compound 25 was prepared by treating it with NH2OH·HCl and
aq. NaOH in ethanol to give compound 28 (63%). Oxime 28 upon
treatment with N,N-dimethylcarbamyl chloride and NaH in DMF
afforded derivative 29 (69%).
3.0 Synthesis of substituted triazolo-fused
indeno[2,1-c]quinolines (17–23)
Treatment of hydrazino compound 14, with various aliphatic acids
at 140 ◦C resulted in the alkyl substituted fused triazoles 17–21
(4–54%) as shown in Scheme 3. Phenyl substituted triazole 22 was
prepared in 56% yield by the treatment of C2-hydrazino compound
14 with benzoyl chloride at reflux temperature, whereas mercapto-
triazole 23 was prepared in 12% yield by heating compound 14
and CS2 in pyridine for 20 h (Scheme 3).
5.0 Spectroscopic evidence of the ring-closure reaction to give the
azole-fused indeno[2,1-c]quinoline systems
Formation of ring fused indeno[2,1-c]quinolines, tetrazole 7,
triazole 15 and dihydroimidazole 25, was proved by extensive
1D and 2D NMR studies (see ESI† and Experimental section).
The observed chemical shifts of precursor chloroketone 6 and the
ring fused tetrazole (compound 7), triazole (compound 15) and
dihydroimidazole (compound 25) are given in Table S1 in ESI†.
The proton chemical shifts of the quinoline protons in the N1 and
4.0 Synthesis of fused-dihydroimidazole indeno[2,1-c]quinolines
(25–29)
These compounds were prepared by nucleophilic substitution
of C2-chloro of compound 614 with 2-aminoethanol to give
Scheme 3 Synthesis of alkyl/aryl substituted fused triazoloindeno[2,1-c]quinolines (17–23): Reagents and Conditions: (i) RCOOH, 135–140 ◦C, 20 h;
(ii) PhCOCl, 140 ◦C, reflux, 3 h; (iii) CS2, pyridine, reflux, 20 h.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5663
©

View Article Online
Scheme 4 Synthesis of dihydroimidazole-fused indeno[2,1-c]quinolines (25–29): Reagents and Conditions: (i) NH2CH2CH2OH, C2H5OH, reflux, 48 h;
(ii) POCl3, reflux, 3 h; (iii) CH3MgI, THF, 0 ◦C–rt; (iv) RCOCl, NaH, DMF; (v) NH2OH.HCl, NaOH, EtOH, H2O, reflux.
C2 fused quinoline system clearly shows the electronic influence of
the [2,1-c] fused heterocyclic ring. The key structural evidence for
the formation of tetrazolo compound 7 came from the comparison
of its 1H-NMR spectrum with the precursor chloroketone 6:
Compound 7 showed the expected downfield shift of quinoline
ring protons H8 (d 8.85), H7 (d 8.48) and H5 (d 9.15) due to
the tetrazole ring-current as compared to that of compound 6 in
which protons H8, H7 and H5 appeared at d 8.12, 8.27 and 9.00
respectively (Table S1 ESI†). The IR spectrum of compound 7
also showed clearly the absence of the azide band27 at nmax 2100–
2270 cm-1.
shifts of the protons in the dihydroimidazolo system and the fused
quinoline protons, upon addition of a drop of CF3COOH (TFA),
in compound 25 showed the expected downfield shift of all ring
protons (See Table S1 ESI†). When TFA was added in a similar
way to the NMR sample of the C2 imidazolo compound 2d (Table
1
Sl ESI†), the H chemical shifts of the quinoline protons moved
downfield by ~0.1 ppm, whereas a much larger downfield shift was
observed for the imidazole protons (1.41–0.46 ppm, Table S1 and
Fig S2 ESI†).
Detailed NMR characterization by 1D and 2D NMR spectra,
such as COSY to show proton–proton connectivity, HSQC to
show proton–carbon connectivity and finally HMBC to establish
long-range proton–carbon proved the structures of the azole-fused
indeno[2,1-c] quinolines (see ESI† and experimental section).
A plot of experimental 1H NMR chemicals shifts versus
aromatic proton positions is shown in Fig. S1 (ESI†). It clearly
shows that the quinoline ring protons H5, H7 and H8 have a
dramatic change in chemical shifts after formation of ring fused
compounds as compared to precursor compound 6.
The 1H-NMR spectrum of compound 15, showed the expected
downfield shift of H8 (d 8.65) and H7 (d 8.31) protons due to
the triazole ring-current as compared to compound 6, in which
protons H8 and H7 appeared at d 8.12 and 8.27 respectively (Table
S1 ESI† and Experimental section). The isolated signal at d 10.17
was unambiguously assigned to the triazole ring proton (H9),
since it disappears upon substitution at that position (see NMR
data of compounds 17–22 in Experimental section). The 1H-NMR
spectrum of compound 23 showed a downfield singlet at d 14.93
which was assigned to –SH protons as it is D2O exchangeable. The
downfield doublet at d 10.98 was assigned to the H8 proton of the
quinoline ring which may be due to the local anisotropy of C S.
In COSY the proton–proton coupling of H8 proton at d 10.98
with the H7 proton at 8.23 also proves the assignment of the H8
proton. Our ab initio studies and comparison of theoretical proton
chemical shifts of compound 23 with that of experimental showed
that the thione tautomeric form of compound 23 is more stable
than the thiol form (Table S2 in ESI†).
6.0 Anti-mycobacterial activity
Compounds 7–13, 15–29 and standard drug isoniazid28 were
tested against M. tuberculosis H37Rv (ATCC 27294) at a fixed
concentration of 6.25 mg mL-1 by the BACTEC 460 radiometric
method29,30 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. Compounds 9, 15, 17, 25, 27, 28
and 29 were found to inhibit the M. tb H37Rv growth successfully
by 97%, 99%, 99%, 81%, 79%, 97% and 99% respectively. Fig. 2
shows the bar graph of % TB growth for the compounds 9, 15, 17,
25, 27, 28 and 29 along with isoniazid28 for the comparison under
identical experimental conditions.
The 1H-NMR spectrum of dihyroimidazole compound 25
showed the expected upfield shift of the quinoline ring protons H8,
H7 and H5 which appeared at d 6.68, 7.57 and 8.19 respectively
1
as compared with compound 6 (Table S1 ESI†). The H NMR
5664 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 1 % Growth 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
Comp. No. Structure
% Growth Inhibitionb clogP Comp. No. Structure
% Growth Inhibitionb clogP
7
46
43
97
4.35
4.52
4.13
20
21
22
55
47
15
6.26
6.79
5.97
8
9
10
51
3.49
23
55
4.82
11
12
13
29
45
39
4.59
4.35
6.99
24
25
26
25
81
52
4.45
3.82
4.12
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5665
©

View Article Online
Table 1 (Contd.)
Comp. No.
Structure
% Growth Inhibitionb clogP Comp. No.
Structure
% Growth Inhibitionb clogP
15
99
66
99
3.87
3.02
4.14
27
28
29
79
97
99
5.31
3.87
5.34
16
17
18
19
72
5.20
99
0.67c
69
5.73
a Values are means of triplicate measurement of % growth inhibition (GI). Assays are performed by the BACTEC 460 radiometric method.29,30 b Estimated
with reference to Growth Inhibition of the first front-line inhibitor, Isoniazid. c From PubChem (http://pubchem.ncbi.nlm.nih.gov).
Fig. 2 % TB growth inhibition for compounds 9, 15, 17, 25, 27, 28 and 29 along with standard drug Isoniazid and untreated control.
5666 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
7.0 MIC and Cytotoxicity
81% growth inhibition respectively. This shows that triazole-fused
indeno[2,1-c]quinolines have great potential to develop as effective
anti-mycobacterial agents.
The MIC of the most active compounds 9, 15, 17, 25, 27, 28, and
29 are given in Table 2. These seven compounds have an MIC in
the range of 0.89–17.86 mM. Compounds 9 and 28 inhibited the
mycobacterial growth very effectively compared to others in the
series, with minimum inhibitory concentrations (MIC) of 0.39 mg
mL-1 (0.89 mM) and 0.39 mg mL-1 (1.0 mM) respectively.
Certain therapeutic properties are required to identify if an anti-
mycobacterial compound has the potential to be a drug. Toxicity
is one of those important criteria. Hence, we have investigated the
potential toxicity of our fused quinolines towards mammalian cells
(human monocytic cell line U937). Compounds 9, 15, 17, 25, 27,
28 and 29 were screened for cytotoxicity against human monocytic
cell line U937 (Mossman’s MTT assay).31–33 This preliminary
evaluation of cytotoxicity revealed that compounds 9, 15, 17 and
28 were non cytotoxic to host cells (human monocytic cells) at
given concentration (Table 2), while compounds 25, 27 and 29 are
least safe at a higher concentration (10 mg mL-1).
Compounds 9 and 28 inhibited growth of M. tuberculosis very
effectively at MIC < 0.39 mg mL-1 (0.89 mM and 1 mM, respec-
tively). These active compounds were screened for cytotoxic effect
on mammalian cells (human monocytic cell line U937), which
showed that the human cell survival is almost unperturbed (97–
99% survival, Table 2) when they were treated with compounds
9, 15, 17 or 28, hence identified as potent anti-mycobacterials,
virtually with no toxicity.
Conclusion
We have designed and synthesized a novel class of tetrazole-
, triazole- and dihydroimidazole-fused indeno[2,1-c]quinoline
molecules as anti-mycobacterial agents. Molecules 9, 15, 17, 25, 27,
28 and 29 inhibited the growth of M. tb effectively at the concentra-
tion of 6.25 mg mL-1. Compound 9 and 28 inhibited growth of M.
tuberculosis very effectively at minimum inhibitory concentration
(MIC) < 0.39 mg mL-1 (0.89 mM) and (1 mM) respectively, which
is comparable to that of the existing front-line drug isonaizid
(MIC 0.25 mg mL-1). Thus these “hit” molecules constitute our
important “leads” for further optimization by structure–activity
relationship to develop as effective anti-mycobacterial agents
which can help to shorten the duration of current anti-TB therapy.
8.0 Discussion
Most of the synthesized compounds were found to have good anti-
mycobacterial activity. Seven molecules of three different classes,
i.e. tetrazolo-, triazolo-, and dihydroimidazolo-fused indeno[2,1-
c]quinolines (compounds 9, 15, 17, 25, 27, 28 and 29) showed good
to excellent anti-TB activity (Table 1).
Compounds 9, 15, 17, 28 and 29 of three different series showed
most impressive TB growth inhibition in the range of 97–99%. Two
compounds, compound 9 (97% GI, Table 1; MIC (0.39 mg mL-1,
0.89 mM)) and compound 28 (97% GI, Table 1; MIC (0.39 mg
mL-1, 1.0 mM)) were found to have excellent anti-mycobacterial
activity against H37Rv. Compound 28, the oxime derivative of
a fused dihydroimidazole, and compound 2a, having a freely
rotating imidazolo substituent at C2, have comparable TB growth
inhibition and MIC values, whereas compound 9 (0.39 mg mL-1,
0.89 mM), a carbamoyl ester of a fused tetrazole, is having slightly
better MIC than compound 2a (0.39 mg mL-1, 1.0 mM).
The oxime carbamoyl esters, compound 9 (97% GI) and
fused dihydroimidazole compound 29 (99% GI), were found to
have excellent percentage growth inhibition whereas their parent
oximes, compound 8 (43% GI) and compound 25 (81% GI), were
found to be relatively less active. The Grignard reaction generated
alcohols of three different series, i.e. molecules 10, 16 and 26 have
been found to inhibit the M. tb growth by 51%, 66% and 52%
respectively. In general, derivatives carrying a tertiary hydroxyl
group were found to have moderated anti-mycobacterial activity.
Ester derivatives of tertiary alcohol 10 (51% GI), compounds 11,
12 and 13, were found to be less active, which suggests that increase
in steric bulk at the tertiary position shows gradual decrease in
activity.
Experimental section
Chemistry – General experimental methods
Purification and drying of reagents and solvents were carried out
according to literature procedure.34
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. H NMR and 13C
1
NMR spectra were recorded on Bruker Biospin 400 MHz, Bruker
Avance DRX500 and DRX600 spectrometers with TMS as an
internal standard. The values of chemical shifts are expressed in
ppm and the coupling constants (J) in Hertz (Hz). Mass spectra
were recorded on API 2000 LC/MS/MS system spectrometer up
to 2 decimal places. IR spectra were recorded on Perkin–Elmer
Spectrum RX1.
Preparation
a]quinolin-13-one (7).
of
7-bromo-13H-indeno[2,1-c]tetrazolo[1,5-
mixture of 2-bromo-6-chloro-
A
indeno[2,1-c]quinolin-7-one 614 (5.0 g, 14.53 mmol), sodium
azide (1.88 g, 29.06 mmol) in N,N-dimethyformamide (100 mL)
was heated at 80 ◦C under nitrogen atmosphere for 5 h. The
reaction mixture was cooled and then quenched with water, light
green solid obtained was filtered. The solid was washed with
water (3 ¥ 200 mL) and further purified by giving ethyl acetate
washings, dried under reduced pressure to obtain 7-bromo-13H-
indeno[2,1-c]tetrazolo[1,5-a]quinolin-13-one 7 (4.5 g, 88%) as a
light green solid. mp 300–301 ◦C; IR nmax(KBr, cm-1) 1713.77;
1H-NMR (600 MHz, DMSO-d6): d 7.76 (t, J = 7.2 Hz, 1 H, Hc),
7.85–7.90 (m, 1 H, Hb), 7.92 (d, J = 7.2 Hz, 1 H, Hd), 8.48 (d,
J = 8.7 Hz, 1 H, H7), 8.66 (d, J = 7.6 Hz, 1 H, Ha), 8.85 (d, J =
Ketones 15 (99% GI) and 17 (99% GI) from the triazolo series
have comparable steric bulk at the C9 position and were found to
show excellent growth inhibition of M. tb. While increasing the
chain length or steric bulk on the triazole ring, as in compounds
18 (72% GI), 19 (69% GI), and 22 (15% GI), showed the gradual
decrease in their M. tb growth inhibition.
The parent keto-compounds from tetrazole, triazole and dihy-
droimidazole, i.e. compounds 7, 15 and 25, showed 46%, 99% and
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5667
©

View Article Online
Table 2 MICa of compounds 9, 15, 17, 25, 27, 28 and 29 against M. tuberculosis H37Rv and cytotoxic effects on human monocytic cell line U937 after
72 h
% Cell Viability after 72 h
Compd. No.
Structure
MIC (mg mL-1
<0.39
MIC99/mM
Conc. (1 mg mL-1)
Conc. (10 mg mL-1)
9
0.89
100
100
15
17
6.25
6.25
17.86
17.17
100
100
100
100
25
3.125
6.25
8.90
14.27
1.06
3.56
1.86
38
39
10
76
8
27
96
28
<0.39
100
29
1.56
79
Isoniazid
0.256
a MIC determined by BACTEC 460 radiometric method.29,30 MIC was the lowest concentration inhibiting 99% of growth.
5668 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
8.7 Hz, 1 H, H8), 9.15 (s, 1 H, H5). ESI-MS m/z of 350.90, 352.90
J = 7.6 Hz, 1H, Hc), 7.76 (t, J = 7.6 Hz, 1 H, Hb), 8.27 (dd, J =
1.9, 9.1 Hz, 1 H, H7), 8.40 (d, J = 7.6 Hz, 1 H, Hd), 8.61 (d, J =
7.6 Hz, 1 H, Ha), 8.73 (d, J = 9.1 Hz, 1 H, H8), 9.01 (d, J = 1.9 Hz,
1 H, H5). ESI-MS m/z of 436.70, 438.80 [M+H]+ was obtained
for a calculated mass of 437.03, 439.03.
[M+H]+ was obtained for a calculated mass of 350.98, 352.98.
Preparation
of
7-bromo-13H-indeno[2,1-c]tetrazolo[1,5-
a]quinolin-13-one oxime (8). A mixture of compound 7 (5.00 g,
14.24 mmol), hydroxylamine hydrochloride (6.92 g, 99.71 mmol)
and anhydrous DMF (200 mL) was heated at 120 ◦C for 5 h.
The reaction mixture was poured into water and filtered; crude
product was washed with ethyl acetate, methanol and hexane,
dried under reduced pressure to get desired product 8 (5.0 g, 95%)
as yellow solid; mp 295–296 ◦C. IR nmax (KBr, cm-1) 3148.25;
1H NMR (600 MHz, DMSO-d6): d 7.72–7.77 (m, 1 H, Hc),
7.78–7.84 (m, 1 H, Hb), 8.65 (d, J = 6.4 Hz, 1 H, Hd), 8.65–8.70
(m, 1 H, Ha), 8.33 (d, J = 8.7 Hz, 1 H, H7), 8.82 (d, J = 8.4 Hz, 1
H, H8), 9.11 (s, 1 H, H5), 13.82 (brs, 1 H, N–OH). 13C NMR
(150.9 MHz, DMSO-d6): d 120.1 (C8), 122.2, 124.6 (Ca), 128.2
(Ar–C), 128.5 (Cd), 130.6 (Cc), 130.9, 131.7, 131.9 (Cb), 134.1,
134.6 (C7), 137.5, 138.7 (Ar–C). ESI-MS m/z of 365.80, 367.60
[M+H]+ was obtained for a calculated mass of 365.99, 367.99.
7-Bromo-13-methyl-13H-indeno[2,1-c]tetrazolo[1,5-a]quinolin-
13-ol (10). Procedure B. The crude product was purified by
column chromatography eluting with 2–5% methanol and DCM
to get the desired product 10 (41%) as off-white solid; mp 254–255
◦C. IRnmax (KBr, cm-1) 3432.59; 1H NMR (400 MHz, DMSO-d6):
d 1.86 (s, 3 H, CH3), 5.99 (s, 1 H, D2O exchangeable, CHOH),
7.57–7.62 (m, 2 H, Ar–H), 7.76–7.82 (m, 1 H, Ar–H), 8.22 (dd,
J = 1.84, 8.88 Hz, 1 H, H7), 8.45–8.48 (m, 1 H, Ar–H), 8.73 (d,
J = 8.96 Hz, 1 H, H8), 9.02 (d, J = 1.88 Hz, 1 H, H5). 13C NMR
(100.6 MHz, DMSO-d6) d 24.0 (CH3), 77.8 (OH–C), 118.9 (Ar–
C), 121.2 (Ar–C), 121.3 (Ar–C), 122.8 (Ar–C), 123.5 (Ar–C), 127.3
(Ar–C), 128.6 (Ar–C), 129.0 (Ar–C), 133.5 (Ar–C), 134.00 (Ar–C),
134.9 (Ar–C), 136.3 (Ar–C), 143.6 (Ar–C), 152.3 (Ar–C). ESI-MS
m/z of 366.90, 369.10 [M+H]+ was obtained for a calculated mass
of 367.01, 369.01.
General procedure A: Preparation of compounds 9, 11, 27 and
29. The appropriate oximes or alcohols 8, 10, 26 and 28 (1 eq)
and sodium hydride (3 eq) in anhydrous DMF at 0 ◦C were stirred
for 15–30 min, to this reaction mixture N,N-dimethylcarbamyl
chloride (3 eq) was added dropwise, and stirred for 3 h at
room temperature. The reaction mixture was poured into water,
extracted with DCM or ethyl acetate. The organic extract was
dried over anhydrous sodium sulfate, filtered and solvents were
evaporated under reduced pressure to obtain the corresponding
acylated crude products 9, 11, 27 and 29.
7-Bromo-13-methyl-13H-indeno[2,1-c]tetrazolo[1,5-a]quinolin-
13-yl dimethylcarbamate (11). Procedure A. The crude product
was purified by column chromatography eluting with 2% methanol
and DCM to get the desired product 11 (55%) as off-white solid;
mp 256–257 ◦C. IRnmax (KBr, cm-1) 1705.86; 1H NMR (400 MHz,
CDCl3): d 2.0 (s, 3 H, CH3), 2.62 (s, 3 H, NCH3), 3.11 (s, 3 H,
NCH3), 7.54–7.58 (m, 2 H, Ar–H), 7.65 (d, J = 7.12 Hz, 1 H,
Ar–H), 7.98 (dd, J = 1.92, 8.72 Hz, 1 H, H7), 8.22 (d, J = 7.6 Hz,
1 H, Ar–H), 8.70 (d, J = 8.88 Hz, 1 H, H8), 8.89 (d, J = 1.92 Hz,
1 H, H5). 13C NMR (100.6 MHz, CDCl3): d 24.3 (CH3), 36.2
(NCH3), 36.5 (NCH3), 83.2 (–O–C–CH3), 119.4 (Ar–C), 121.9
(Ar–C), 122.4 (Ar–C), 123.8 (Ar–C), 128.4 (Ar–C), 129.3 (Ar–C),
129.7 (Ar–C), 130.1 (Ar–C), 132.3 (Ar–C), 133.6 (Ar–C), 136.6
(Ar–C), 137.7 (Ar–C), 143.8 (Ar–C), 149.7 (Ar–C), 153.9 (N–
CO). ESI-MS m/z of 437.90, 440.00 [M+H]+ was obtained for a
calculated mass of 438.05, 440.05.
General procedure B: Preparation of compounds 10, 16, and
26. A freshly prepared solution of methyl magnesium iodide
(3 M solution in dry diethyl ether, 6 eq) was added to ketones
7, 15 and 25 (1 eq) in dry THF at 0 ◦C, and stirred for
1–5 h at room temperature. The reaction was quenched with
saturated ammonium chloride solution and extracted with ethyl
acetate, organic layer washed with brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to
obtain the crude product. Crude product was purified by column
chromatography eluting with 2–5% methanol and DCM.
7-Bromo-13-methyl-13H-indeno[2,1-c]tetrazolo[1,5-a]quinolin-
13-yl acetate (12). Procedure C. The crude product was purified
by column chromatography eluting with 5–10% ethyl acetate in
hexane to get the desired product 12 (16%) as off-white solid; mp
General procedure C: Preparation of compounds 12 and 13.
Sodium hydride (3 eq) was added to compound 10 (1 eq) in dry
DMF at 0 ◦C (ice bath) under nitrogen atmosphere. The reaction
mixture was stirred at 0 ◦C for 30 min. The appropriate acid
chloride (3 eq) was added to the reaction mixture and stirred for
3 h at room temperature. The reaction mixture was quenched
with ice and extracted with DCM. The organic layer was washed
with brine, dried over anhydrous sodium sulfate, filtered, and
evaporated under reduced pressure to obtain crude product. This
crude product was purified by column chromatography (silica gel
100–200 mesh, gradual elution with ethyl acetate–hexane in 5–
10%) to get the corresponding derivatives 12 and 13.
266–268 ◦C. IRnmax (KBr, cm-1) 1740.94; H NMR (400 MHz,
1
CDCl3): d 1.99 (s, 3 H, CH3), 2.02 (s, 3 H, COCH3), 7.46–7.62 (m,
2 H, Ar–H), 7.64 (d, J = 8.04 Hz, 1 H, H8), 8.01 (dd, J = 1.96,
8.88 Hz, 1 H, H7), 8.24 (d, J = 7.52 Hz, 1 H, Ar–H), 8.71 (d, J =
8.84 Hz, 1 H, Ar–H), 8.90 (d, J = 1.92 Hz, 1 H, H5). 13C NMR
(100.6 MHz, CDCl3): d 21.2 (CH3), 24.6 (COCH3), 83.3 (–O–C–
CH3), 119.4 (Ar–C), 122.1 (Ar–C), 122.4 (Ar–C), 123.8 (Ar–C),
128.4 (Ar–C), 129.5 (Ar–C), 129.8 (Ar–C), 130.1 (Ar–C), 131.3
(Ar–C), 133.8 (Ar–C), 136.7 (Ar–C), 137.9 (Ar–C), 143.6 (Ar–C),
148.8 (Ar–C), 169.1 (CO). ESI-MS m/z of 409.00, 411.10 [M+H]+
was obtained for a calculated mass of 409.03, 411.02.
7-Bromo-13H-indeno[2,1-c]tetrazolo[1,5-a]quinolin-13-one-O-
dimethylcarbamoyl oxime (9). Procedure A. The crude product
was purified by column chromatography eluting with 5% methanol
and DCM to get the desired product 9 (51%) as yellow solid; mp
7-Bromo-13-methyl-13H-indeno[2,1-c]tetrazolo[1,5-a]quinolin-
13-ylheptanoate (13). Procedure C. The crude product was
purified by column chromatography eluting with 5–10% ethyl
acetate in hexane to get the desired product 13 (19%) as off-
white solid; mp 159–161 ◦C. IRnmax (KBr, cm-1) 1733.97; 1H NMR
(500 MHz, DMSO-d6): d 0.90 (t, J = 7.1 Hz, 3 H, CH2CH3),
227–228 ◦C. IR nmax (KBr, cm-1) 1756.85; H NMR (600 MHz,
1
DMSO-d6): d 3.07 (s, 3 H, NCH3), 3.22 (s, 3 H, NCH3), 7.70 (d,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5669
©

View Article Online
1.18–1.35 (m, 6 H,–CH2–(CH2)3CH3), 1.49 (quint, J = 6.9 Hz,
2 H, CH2– (CH2)3 CH3), 2.04 (s, 3 H, CH3), 2.39 (t, 2 H, J =
7.3 Hz, COCH2), 7.69–7.76 (m, 2 H, Hb, Hc), 7.87 (m, 1 H,
Hd), 8.38 (dd, J = 2, 9.1 Hz, 1 H, H7), 8.68 (d, J = 7.6 Hz, 1
H, Ha), 8.86 (d, J = 9.1 Hz, 1 H, H8), 9.18 (d, J = 2.0 Hz, 1H,
H5). 13C-NMR (125.8 MHz, DMSO-d6): d 13.9 (CH3CH2), 21.9
(CH3CH2), 24.3 (O–C–CH3), 24.4 (–CH2–), 27.9 (–CH2–), 30.8
(–CH2–), 33.7 (COCH2–), 82.9 (C–O), 119.6 (C8), 121.8 (Ar–C),
122.0 (Ar–C), 122.4 (Ar–C), 124.6 (Ar–C), 128.0 (C5), 129.7 (Cb),
129.73 (Ar–C), 129.8 (Cc), 131.0 (C3), 134.4 (C7), 136.3 (Ar–C),
137.6 (C4), 143.5 (C2), 148.4 (Ar–C), 171.2 (C O). ESI-MS m/z
of 478.70, 481.00 [M+H]+ was obtained for a calculated mass of
479.10, 481.10.
8.59 (d, J = 8.8 Hz, 1 H, Ar–H), 8.84 (s, 1 H, Ar–H), 10.13 (s,
1 H, Ar–H). 13C NMR (100.6 MHz, DMSO-d6): d 24.7 (CH3),
78.4 (C–OH), 119.5 (Ar–C), 119.7 (Ar–C), 121.7 (Ar–C), 123.1
(Ar–C), 123.3 (Ar–C), 127.5 (Ar–C), 128.5 (Ar–C), 128.9 (Ar–C),
130.0 (Ar–C), 132.0 (Ar–C), 132.4 (Ar–C), 136.1 (Ar–C), 136.3
(Ar–C), 136.8 (Ar–C), 144.2 (Ar–C), 152.5 (Ar–C). ESI-MS m/z
of 365.80, 367.80 [M+H]+ was obtained for a calculated mass of
366.02, 368.02.
7-Bromo-3-methyl-13H -indeno[2,1-c][1,2,4]triazolo[4,3-a]qui-
nolin-13-one (17). A mixture of compound 14 (2.0 g, 5.89 mmol)
and acetic acid (15 ml) was refluxed at 135 ◦C for 20 h. The reaction
mixture was cooled to room temperature and then poured on
sodium bicarbonate solution. It was then extracted with DCM.
The organic layer was dried over anhydrous sodium sulfate and
filtered, evaporated under reduced pressure to obtain a crude solid.
The crude product was purified by column chromatography (silica
100–200 mesh) eluting with 1.5% methanol and DCM to give 17
(0.10 g, 5%) as red solid; mp >300 ◦C. IRnmax (KBr, cm-1) 1717.29;
1H NMR (500 MHz, DMSO-d6): d 3.06 (s, 3 H, CH3), 7.52 (t, J =
7.3 Hz, 1H, Hc), 7.64 (d, J = 7.3 Hz, 1 H, Hd), 7.65 (t, J = 7.6 Hz,
1 H, Hb), 8.08 (dd, J = 2.1, 9.1 Hz, 1 H, H7), 8.22 (d, J = 7.6 Hz,
1 H, Ha), 8.37 (d, J = 9.1 Hz, 1 H, H8), 8.68 (d, J = 2.1 Hz, 1 H,
H5). 13C NMR (125.8 MHz, DMSO-d6): d 15.3 (CH3), 118.0 (C3),
119.2 (C6), 119.6 (C8), 121.3 (Ar–C), 123.6 (Cd), 124.4 (Ca), 128.4
(C5), 130.5 (Cc), 132.1 (Ar–C), 133.3 (Ar–C), 134.8 (Cb), 134.9
(C7), 140.1 (Ar–C), 143.5 (C2), 145.0 (C4), 146.6 (Ar–C), 189.1
(C O). ESI-MS m/z of 364.00, 365.90 [M+H]+ was obtained for
a calculated mass of 364.00, 366.00.
2-Bromo-6-hydrazinyl-7H-indeno[2,1-c]quinolin-7-one (14).
A
mixture of 2-bromo-6-chloro-indeno[2,1-c]quinolin-7-one14 (2.0 g,
5.8 mmol), hydrazine hydrate (1.45 g, 29.06 mmol) in ethanol (20
mL) was refluxed under nitrogen atmosphere for 24 h. The solvents
were removed under reduced pressure; the red solid obtained was
quenched in water (500 mL) and filtered. The solid was washed
with water (3 ¥ 200 mL) and dried under reduced pressure to
obtain 2-bromo-6-hydrazinyl-7H-indeno[2,1-c]quinolin-7-one 14
as a red solid. The red solid obtained was heated with conc. HCl
at 60 ◦C for 24 h. The reaction mixture cooled, diluted with water
and filtered to get the red solid as pure compound 14 (1.2 g, 73%).
mp decomposes at 250 ◦C. IRnmax (KBr, cm-1); 1702, 3273, 3314, 1H
NMR (400 MHz, DMSO-d6): d 4.19 (s, 2 H, D2O exchangable),
7.43–7.8 (m, 1 H, Ar–H), 7.54–7.74 (m, 3 H, Ar–H and 1 H, D2O
exchangable), 7.92–7.96 (m, 1 H, Ar–H), 7.99 (d, J = 7.76 Hz, 1
H, Ar–H), 8.37 (s, 1 H, Ar–H). ESI-MS m/z of 339.80, 341.80
[M+H]+ was obtained for a calculated mass of 340.00, 342.00.
7-Bromo-3-propyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quino-
lin-13-one (18). A mixture of compound 14 (0.3 g, 0.88 mmol)
and butyric acid (10 ml) was refluxed at 140 ◦C for 20 h.
The reaction mixture was cooled and then poured on sodium
bicarbonate solution. It was then extracted with DCM. The
organic layer was dried over anhydrous sodium sulfate and filtered,
evaporated under reduced pressure to obtain a crude solid. The
crude product was purified by column chromatography (silica
230–400 mesh) eluting with 5% methanol and DCM to give
7-Bromo-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quinolin-13-one
(15).
A
mixture of 2-bromo-6-hydrazinyl-7H-indeno[2,1-
c]quinolin-7-one 14 (4.0 g, 11.79 mmol) in formic acid (50 mL)
was refluxed under nitrogen atmosphere for 24 h. The reaction
was quenched with aqueous sodium bicarbonate (500 mL) and
filtered. The solid obtained was washed with water (3 ¥ 200
mL) and dried under reduced pressure to obtain 7-bromo-13H-
indeno[2,1-c][1,2,4]triazolo[4,3-a]quinolin-13-one 15 (2.3 g, 56%)
as a brown solid. mp >300 ◦C. IRnmax (KBr, cm-1) 1724.27;
1H-NMR (600 MHz, DMSO-d6): d 7.64 (t, J = 7.2 Hz, 1 H, Hc),
7.77 (t, J = 7.6 Hz, 1 H, Hb), 7.78 (d, J = 7.6 Hz, 1 H, Hd), 8.31
(d, J = 9.1 Hz, 1 H, H7), 8.39 (d, J = 7.6 Hz, 1 H, Ha), 8.65 (d, J =
9.1 Hz, 1 H, H8), 8.84 (d, J = 1.2 Hz, 1 H, H5), 10.17 (s, 1 H, H9).
13C-NMR (150.9 MHz, DMSO-d6): d 118.4 (C3), 120.3 (C8 &
C6), 120.9 (Ar–C), 124.1 (Cd), 125.1 (Ca), 129.1 (C5), 131.1 (Cc),
132.4 (Ar–C), 132.5(Ar–C), 135.4 (Cb), 136.0 (C7), 137.1 (Ar–C),
140.8 (Ar–C), 142.5 (C2), 146.3 (C4), 189.8 (C O). ESI-MS m/z
of 349.90, 351.70 [M+H]+ was obtained for a calculated mass of
349.99, 351.99.
◦
1
compound 18 (0.1 g; 29%) as brown solid; mp 225–226 C. H
NMR (400 MHz, CDCl3): d 1.16 (t, J = 7.4 Hz, 3 H, CH3), 1.99–
2.15 (m, 2 H, CH2CH3), 3.43 (t, J = 7.56 Hz, 2 H, –CCH2), 7.47
(t, J = 7.48 Hz, 1 H, Ar–H), 7.61 (t, J = 7.6 Hz, 1 H, Ar–H), 7.80
(d, J = 7.2 Hz, 1 H, Ar–H), 7.94–7.98 (m, 2 H, Ar–H), 8.15 (d,
J = 9.12 Hz, 1 H, Ar–H), 8.71 (d, J = 2.12 Hz, 1 H, Ar–H). 13C
NMR (100.6 MHz, CDCl3): d 13.9 (CH3CH2), 20.1 (CH3CH2),
31.3 (CH3CH2CH2), 118.6 (Ar–C), 119.2 (Ar–C), 119.9 (Ar–C),
122.4 (Ar–C), 123.4 (Ar–C), 124.8 (Ar–C), 129.5 (Ar–C), 130.7
(Ar–C), 133.0 (Ar–C), 133.5 (Ar–C), 134.3 (Ar–C), 134.7 (Ar–C),
140.8 (Ar–C), 144.5 (Ar–C), 145.1 (Ar–C), 149.9 (Ar–C), 189.3
(C O). ESI-MS m/z of 392.00, 394.00 [M+H]+ was obtained for
a calculated mass of 392.03, 394.03.
7-Bromo-13-methyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]qui-
nolin-13-ol (16). Procedure B. The crude product was purified by
column chromatography eluting with 2–5% methanol and DCM
to get the desired product 16 (19%) as a pale yellow solid; mp
7-Bromo-3-butyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quino-
lin-13-one (19). A mixture of compound 14 (0.2 g, 0.58 mmol)
and pentanoic acid (8 ml) was refluxed at 140 ◦C for 20 h. Reaction
mixture was cooled and then poured on sodium bicarbonate
solution. It was then extracted with DCM, the organic layer
was dried over anhydrous sodium sulfate and filtered, evaporated
under reduced pressure to obtain a crude solid. Crude product
262–263 ◦C. IRnmax (KBr, cm-1) 3246.08; H NMR (400 MHz,
1
DMSO-d6): d 1.90 (s, 3 H, CH3), 5.85 (s, 1 H, D2O exchangeable,
CHOH), 7.49–7.57 (m, 2 H, Ar–H), 7.70–7.76 (m, 1 H, Ar–H),
8.09 (d, J = 8.88 Hz, 1 H, Ar–H), 8.33 (d, J = 7.2 Hz, 1 H, Ar–H),
5670 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
was purified by column chromatography (silica 230–400 mesh)
eluting with 5% methanol and DCM to give 19 (0.13 g; 54%) as
brown solid; mp 281–282 ◦C. IRnmax (KBr, cm-1) 1719.31; 1H NMR
(400 MHz, CDCl3): d 1.02 (t, J = 7.4 Hz, 3 H, CH3), 1.54–1.65
(m, 2 H, CH2CH3), 1.94–2.20 (m, 2 H, CH2CH2CH3), 3.45 (t, J =
9.52 Hz, 2 H, –CCH2CH2), 7.43–7.50 (m, 1 H, Ar–H), 7.60 (t, J =
8.28 Hz, 1 H, Ar–H), 7.80 (d, J = 8.32 Hz, 1 H, Ar–H), 7.93–7.99
(m, 2 H, Ar–H), 8.15 (d, J = 8.32 Hz, 1 H, Ar–H), 8.71 (d, J =
1.8 Hz, 1 H, Ar–H). 13C NMR (100.6 MHz, CDCl3 + DMSO-d6):
d 13.8 (CH3CH2), 22.4 (CH3CH2), 28.6 (CH3CH2CH2CH2), 29.0
(CH3CH2CH2CH2), 118.6 (Ar–C), 119.0 (Ar–C), 119.9 (Ar–C),
122.3 (Ar–C), 123.4 (Ar–C), 124.7 (Ar–C), 129.4 (Ar–C), 130.7
(Ar–C), 132.9 (Ar–C), 133.4 (Ar–C), 134.3 (Ar–C), 134.7 (Ar–C),
140.7 (Ar–C), 144.4 (Ar–C), 145.1 (Ar–C), 150.1 (Ar–C), 189.2
(C O). ESI-MS m/z of 405.80, 407.90 [M+H]+ was obtained for
a calculated mass of 406.05, 408.05.
(–CH2-), 31.4 (–CH2-), 118.6 (Ar–C), 118.7 (Ar–C), 119.8 (Ar–C),
121.9 (Ar–C), 123.2 (Ar–C), 124.4 (Ar–C), 129.0 (Ar–C), 130.6
(Ar–C), 132.6 (Ar–C), 133.1 (Ar–C), 134.2 (Ar–C), 134.7 (Ar–C),
140.4 (Ar–C), 144.0 (Ar–C), 144.6 (Ar–C), 150.0 (Ar–C), 188.8
(C O). ESI-MS m/z of 433.50, 435.70 [M+H]+ was obtained for
a calculated mass of 434.08, 436.08.
7-Bromo-3-phenyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quino-
lin-13-one (22). A mixture of compound 14 (1.0 g, 2.94 mmol)
and benzoyl chloride (15 ml) was refluxed at 140 ◦C for 24
h. Reaction mixture was cooled and then poured on sodium
bicarbonate solution. It was then extracted with DCM, the
organic layer was dried over anhydrous sodium sulfate and filtered,
evaporated under reduced pressure to obtain an oily residue, which
upon trituration with n-hexane gave a solid. The solid was filtered,
washed with n-hexane to give 22 (0.7 g; 56%) as red solid; mp >300
◦C. IRnmax (KBr, cm-1) 1716.45; 1H NMR (400 MHz, DMSO-d6):
d 7.47 (d, J = 9.08 Hz, 1 H), 7.58 (t, J = 7.36 Hz, 1 H, Ar–H),
7.64–7.76 (m, 6 H, Ar–H), 7.84 (d, J = 7.72, 1 H, Ar–H), 7.91
(d, J = 9.04 Hz, 1 H, Ar–H), 8.35 (d, J = 7.52 Hz, 1 H, Ar–H),
8.78 (s, 1 H, Ar–H). 13C NMR (100.6 MHz, CF3COOD): d 114.6
(Ar–C), 122.1 (Ar–C), 124.6 (Ar–C), 125.3 (Ar–C), 127.0 (Ar–C),
128.6 (Ar–C), 128.8 (Ar–C), 130.2 (Ar–C), 131.6 (Ar–C), 132.2
(Ar–C), 133.0 (Ar–C), 134.7 (Ar–C), 134.8 (Ar–C), 135.7 (Ar–C),
136.2 (Ar–C), 138.9 (Ar–C), 140.9 (Ar–C), 141.6 (Ar–C), 142.0
(Ar–C), 151.8 (Ar–C), 158.8 (Ar–C), 192.5 (C O). ESI-MS m/z
of 426.00, 428.00 [M+H]+ was obtained for a calculated mass of
426.02, 428.02.
7-Bromo-3-pentyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quino-
lin-13-one (20). A mixture of compound 14 (1.5 g, 5.89 mmol)
and hexanoic acid (15 ml) was refluxed at 135 ◦C for 20 h.
The reaction mixture was cooled and then poured on sodium
bicarbonate solution. It was then extracted with DCM, the
organic layer was dried over anhydrous sodium sulfate and filtered,
evaporated under reduced pressure to obtain a crude solid. The
crude product was purified by column chromatography (silica
230–400 mesh) eluting with 5% methanol and DCM to give 20
(0.10 g, 4%) as red solid; mp 272–273 ◦C. IRnmax (KBr, cm-1)
1
1720.31; H NMR (400 MHz, CDCl3): d 0.93 (t, J = 7.28 Hz,
3 H, CH3), 1.37–1.44 (m, 2 H, CH2CH2CH3), 1.48–1.55 (m, 2
H, CH2CH2CH3), 1.97–2.03 (m, 2 H, –CCH2CH2) 3.40 (m, 2
H, –CCH2CH2), 7.48 (t, J = 7.32 Hz, 1 H, Ar–H), 7.60 (t, J =
7.56 Hz, 1 H, Ar–H), 7.80 (d, J = 7.12 Hz, 1 H, Ar–H), 7.93–7.99
(m, 2 H, Ar–H), 8.14 (d, J = 9.16 Hz, 1 H, Ar–H), 8.70 (d, J =
2.0 Hz, 1 H, Ar–H). 13C NMR (100.6 MHz, CF3COOD): d 14.4
(CH2CH3), 24.0 (CH2CH2CH3), 27.4 (CH2CH2CH2CH2CH3),
31.4 (CH2CH2CH2CH3), 33.0 (CH2CH2CH2CH2CH3), 115.0 (Ar–
C), 122.1 (Ar–C), 124.7 (Ar–C), 126.9 (Ar–C), 128.7 (Ar–C), 128.9
(Ar–C), 134.4 (Ar–C), 134.9 (Ar–C), 135.2 (Ar–C), 136.3 (Ar–C),
139.0 (Ar–C), 141.6 (Ar–C), 142.2 (Ar–C), 154.2 (Ar–C), 158.5
(Ar–C), 192.8 (C O). ESI-MS m/z of 420.00, 422.20 [M+H]+
was obtained for a calculated mass of 420.07, 422.06.
7-Bromo-3-mercapto-13H -indeno[2,1-c][1,2,4]triazolo[4,3-a]-
quinolin-13-one (23). To a solution of compound 14 (0.3 g,
0.884 mmol) in pyridine (6 ml) was added carbon disulfide (0.8
ml) and heated to 40 ◦C for 1 h. It was then refluxed at 115
◦C for 20 h. The reaction mixture was cooled and poured in
water, solid separated was filtered and washed with water. This
crude product was dried under reduced pressure and purified by
column chromatography (silica gel 100–200 mesh, gradual elution
with 1–3% of methanol, DCM mixture) to get the correspond◦ing
compound 23 (40.0 mg; 12%) as dark violet solid; mp >300 C.
1
IRnmax (KBr, cm-1) 1715.55; H-NMR (500 MHz, DMSO-d6): d
7.67 (t, J = 7.5 Hz, 1 H, Hc), 7.78 (d, J = 6.6, 1 H, Hd), 7.80 (t,
J = 7.6 Hz, 1 H, Hb), 8.23 (d, J = 9.1 Hz, 1 H, H7), 8.39 (d, J =
7.6 Hz, 1 H, Ha), 8.76 (s, 1 H, H5), 10.98 (d, J = 9.1 Hz, 1 H, H8),
14.93 (s, 1H, SH). 13C-NMR (125.8 MHz, DMSO-d6): d 117.8
(C3), 118.6 (C8), 119.9 (C6), 122.0 (Ar–C), 123.9 (Cd), 124.9 (Ca),
128.3 (C5), 131.2 (Cc), 132.1 (Ar–C), 134.4 (C7), 135.1 (Cb), 135.9
(Ar–C), 139.8 (Ar–C), 140.8 (C2), 148.4 (C4), 161.9 (C-SH), 188.6
(C O). ESI-MS m/z of 381.70, 383.80 [M+H]+ was obtained for
a calculated mass of 381.96, 383.96.
7-Bromo-3-hexyl-13H-indeno[2,1-c][1,2,4]triazolo[4,3-a]quino-
lin-13-one (21). A mixture of compound 14 (2.0 g, 5.89 mmol)
and heptanoic acid (15 ml) was refluxed at 135 ◦C for 20 h.
The reaction mixture was cooled and then poured on sodium
bicarbonate solution. It was then extracted with DCM, the
organic layer was dried over anhydrous sodium sulfate and filtered,
evaporated under reduced pressure to obtain a crude solid. The
crude product was purified by column chromatography (silica
230–400 mesh) eluting with 5% methanol◦and DCM to give 21
(0.3 g, 12%) as brown solid; mp 279–280 C. IRnmax (KBr, cm-1)
2-Bromo-6-(2-hydroxyethylamino)-7H-indeno[2,1-c]quinolin-7-
one (24). A mixture of 2-bromo-6-chloro-indeno[2,1-c]quinolin-
7-one 614 (1.0 g, 2.90 mmol) and 2-aminoethanol (4.2 mL,
69.7 mmol) in ethanol (40 mL) was refluxed for 24 h. The reaction
was quenched with water. The red solid obtained was filtered. The
solid was washed with water (2 ¥ 100 mL), and further purified
by giving methanol and ethyl acetate washings, dried under
reduced pressure to obtain 2-bromo-6-(2-hydroxyethylamino)-
7H-indeno[2,1-c]quinolin-7-one 24 (0.850 g, 79%) as a red solid.
1
1720.12; H NMR (400 MHz, CDCl3): d 0.90 (t, J = 6.88 Hz,
3 H, CH3), 1.1.34–1.37 (m, 4 H, CH2CH2CH3), 1.50–1.54 (m, 2
H, CH2CH2CH2CH3), 1.95–2.02 (m, 2 H, –CCH2CH2) 3.45 (t,
J = 9.52 Hz, 2 H, –CCH2CH2), 7.43–7.50 (m, 1 H, Ar–H), 7.61
(t, J = 8.44 Hz, 1 H, Ar–H), 7.81 (d, J = 7.0 Hz, 1 H, Ar–H),
7.95–7.99 (m, 2 H, Ar–H), 8.16 (d, J = 8.76 Hz, 1 H, Ar–H), 8.72
(d, J = 2.12 Hz, 1 H, Ar–H). 13C NMR (100.6 MHz, CDCl3): d
14.0 (–CH2CH3), 22.5 (–CH2-), 26.4 (–CH2-), 29.0 (–CH2-), 29.37
◦
1
mp 226–228 C. IRnmax (KBr, cm-1) 3362.16, 1697.53; H NMR
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5671
©

View Article Online
(400 MHz, CDCl3): d 3.75–3.84 (m, 2 H, –NHCH2), 3.86–3.94
(m, 2 H, CH2OH), 5.29 (s, 1 H, D2O exchangeable, NH or OH)
7.35–7.42 (m, 1 H, D2O exchangeable, NH or OH), 7.45 (dd, J =
7.36, 7.20 Hz, 1 H, Ar–H), 7.53 (d, J = 9.04 Hz, 1 H, Ar–H),
7.56–7.63 (m, 1 H, Ar–H), 7.65–7.73 (m, 2 H, Ar–H), 7.97 (d,
J = 7.48 Hz, 1 H, Ar–H), 8.32 (d, J = 2.08 Hz, 1 H, Ar–H).13C
NMR (100.6 MHz, DMSO-d6): d 41.9 (NCH2), 59.0 (OCH2),
110.9 (Ar–C), 115.3 (Ar–C), 118.2 (Ar–C), 119.1 (Ar–C), 131.1
(Ar–C), 132.3 (Ar–C), 139.8 (Ar–C), 151.2 (Ar–C), 151.4 (Ar–
C), 152.6 (Ar–C), 192.5 (C O). ESI-MS m/z of 369.00, 370.80
[M+H]+ was obtained for a calculated mass of 369.02, 371.02.
Ar–H), 8.28 (d, J = 2.04 Hz, 1 H, Ar–H). 13C NMR (100.6 MHz,
CDCl3): d 23.3 (CH3), 36.2 (NCH3), 36.5 (NCH3), 45.7 (CH2),
53.8 (CH2), 83.6 (CH3–C–O), 112.0 (Ar–C), 113.6 (Ar–C), 120.0
(Ar–C), 121.6 (Ar–C), 123.4 (Ar–C), 127.5 (Ar–C), 128.6 (Ar–C),
128.7 (Ar–C), 132.4 (Ar–C), 134.5 (Ar–C), 137.2 (Ar–C), 138.9
(Ar–C), 139.7 (Ar–C), 149.8 (Ar–C), 152.1 (Ar–C), 154.3 (Ar–
C). ESI-MS m/z of 438.00, 440.00 [M+H]+ was obtained for a
calculated mass of 438.08, 440.07.
7-Bromo-2H -imidazo[1,2-a]indeno[2,1-c]quinolin-13(3H)-one
oxime (28). To a cooled (0 ◦C) suspension of the compound 26
(1.0 g, 2.85mmol) inethanol(30 ml), hydroxylamine hydrochloride
(0.59 g, 8.54 mmol) and sodium hydroxide (0.45 g, 11.39 mmol)
in water (10 ml) was added. The reaction mixture was stirred for
15 min, and further refluxed for 20 h. The reaction mixture was
cooled to room temperature and poured into water. The precipitate
obtained was filtered, washed with water, ethyl acetate and hexane,
and dried under reduced pressure to obtain the oxime 28 (63%) as
7-Bromo-2H -imidazo[1,2-a]indeno[2,1-c]quinolin-13(3H)-one
(25). 2-Bromo-6-(2-hydroxyethylamino)-7H-indeno[2,1-c] qui-
nolin-7-one 24 (4.0 g, 10.83 mmol) in phosphorusoxychloride (50
mL) was refluxed for 7 h. The reaction was quenched with ice,
the reaction mixture was neutralized with 10% NaOH solution,
extracted with dichloromethane (500 mL) and washed with water
(2 ¥ 200 mL) and brine (100 mL). The organic extract was
dried over anhydrous sodium sulfate, the solvents were evaporated
under reduced pressure to obtain blue solid. The solid was
further purified by giving ethyl acetate and hexane washings,
dried under reduced pressure to obtain 7-bromo-2H-imidazo[1,2-
a]indeno[2,1-c]quinolin-13(3H)-one 25 (3.1 g, 82%) as a blue solid.
mp 276–279 ◦C. IRnmax (KBr, cm-1) 1716.68; 1H NMR (600 MHz,
CDCl3): d 3.92 (t, J = 10.2 Hz, 2 H, CH2–N), 4.25 (t, J = 10.2 Hz,
2 H, CH2–N ), 6.68 (d, J = 9.1 Hz, 1 H, H8), 7.48 (t, J = 7.6 Hz,
1 H, Hc), 7.58–7.56 (m, 2 H, H7&Hb), 7.73 (d, J = 7.2 Hz, 1
H, Hd), 7.89 (d, J = 7.6 Hz, 1 H, Ha), 8.17 (d, J = 1.9 Hz, 1
H, H5).13C NMR (150.9 MHz, CDCl3): d 45.7 (–CH2–), 54.3 (–
CH2–), 112.8 (C6), 114.7 (C8), 118.4 (Ar–C), 118.8 (C3), 123.7
(Ca), 123.9 (Cd), 128.9 (C5), 131.1 (Cc), 133.2 (Ar–C), 133.6 (Ar–
C), 136.5 (Ar–C), 139.9 (Ar–C), 141.3 (Ar–C), 150.4 (C2), 154.3
(C4), 190.2 (C O). ESI-MS m/z of 350.80, 352.90 [M+H]+ was
obtained for a calculated mass of 351.01, 353.01.
◦
red solid; mp 273–275 C. IRnmax (KBr, cm-1) 1621.97, 3421.82;
1H NMR (400 MHz, CF3COOD): d 4.32 (t, J = 10.08 Hz, 2 H,
–NCH2), 4.77 (t, J = 10.0 Hz, 2 H, NCH2), 7.37 (d, J = 9.08 Hz,
1 H, Ar–H), 7.59–7.60 (m, 2 H, Ar–H), 7.94 (d, J = 8.68 Hz, 1 H,
Ar–H), 8.14–8.20 (m, 1 H, Ar–H), 8.41 (d, J = 3.08, 1 H, Ar–H),
8.67 (s, 1 H, Ar–H). 13C NMR (100.6 MHz, CF3COOD): d 43.3
(–NCH2), 47.0 ( NCH2), 116.7 (Ar–C), 119.9 (Ar–C), 124.5 (Ar–
C), 128.8 (Ar–C), 128.9 (Ar–C), 129.5 (Ar–C), 131.6 (Ar–C), 132.6
(Ar–C), 134.6 (Ar–C), 135.7 (Ar–C), 136.9 (Ar–C), 149.3 (Ar–C),
149.9 (C N–OH). ESI-MS m/z of 365.80, 367.90 [M+H]+ was
obtained for a calculated mass of 366.02, 368.02
7-Bromo-2H -imidazo[1,2-a]indeno[2,1-c]quinolin-13(3H)-one
O-dimethylcarbamoyl oxime (29). Procedure A. The crude prod-
uct was purified by washing with n-hexane to get desired product
29 (69%) as violet solid; mp 160–162 ◦C. IRnmax (KBr, cm-1)
1
1640.53, 1735.80; H NMR (400 MHz, CDCl3): d 3.10 (s, 3 H,
NCH3), 3.18 (s, 3 H, NCH3), 3.99 (t, J = 10 Hz, 2 H, NCH2),
4.25 (t, J = 10 Hz, 2 H, –NCH2), 6.72 (d, J = 8.76 Hz, 1 H, Ar–H),
7.42–7.58 (m, 3 H, Ar–H), 7.99 (d, J = 7.68 Hz, 1 H, Ar–H), 8.18
(d, J = 2.04 Hz, 1 H, Ar–H), 8.26 (d, J = 7.48 Hz, 1 H, Ar–H).
13C NMR (100.6 MHz, CDCl3 + DMSO-d6): d 36.7 (CONCH3),
37.5 (CONCH3), 46.0 (CH2CH2 N), 53.3 (CH2CH2 N), 112.5
(Ar–C), 114.4 (Ar–C), 118.4 (Ar–C), 123.6 (Ar–C), 127.5 (Ar–C),
128.6 (Ar–C), 129.6 (Ar–C), 129.8 (Ar–C), 131.3 (Ar–C), 131.6
(Ar–C), 134.4 (Ar–C), 138.6 (Ar–C), 139.3 (Ar–C), 145.3 (Ar–C),
150.3 (Ar–C), 154.5 (Ar–C), 155.7 (OCON(CH3)2). ESI-MS m/z
of 437.00, 439.20 [M+H]+ was obtained for a calculated mass of
437.06, 439.05.
7-Bromo-13-methyl-3,13-dihydro-2H-imidazo[1,2-a]indeno[2,1-
c]quinolin-13-ol (26). Procedure B. The crude product was puri-
fied by column chromatography eluting with 5–10% methanol and
DCM to get desired product 26 (35%) as green solid; mp 146–148
◦C. IRnmax (KBr, cm-1) 3438.40; 1H NMR (400 MHz, CDCl3): d 1.8
(s, 3 H, CH3), 3.47 (s, 1 H, D2O exchangeable, CHOH), 3.86–4.16
(m, 4 H, CH2CH2), 6.66 (d, J = 8.68 Hz, 1 H, Ar–H), 7.42–7.49
(m, 3 H, Ar–H), 7.65–7.67 (m, 1 H, Ar–H), 7.97–7.99 (m, 1 H,
Ar–H), 8.24 (d, J = 2.04 Hz, 1 H, Ar–H). 13C NMR (100.6 MHz,
CDCl3): d 24.5 (CH3), 45.7 (NCH2CH2), 53.3 (NCH2CH2 N),
79.2 (C–OH), 112.4 (Ar–C), 113.7 (Ar–C), 119.8 (Ar–C), 123.1
(Ar–C), 127.4 (Ar–C), 128.6 (Ar–C), 128.8 (Ar–C), 132.6 (Ar–C),
136.0 (Ar–C), 136.7 (Ar–C), 138.5 (Ar–C), 139.4 (Ar–C), 151.7
(Ar–C), 153.0 (Ar–C). ESI-MS m/z of 366.90, 368.90 [M+H]+
was obtained for a calculated mass of 367.04, 369.04.
Biological Activity – Methods
Anti-mycobacterial activity. Compounds 7–13, 15–29 and the
first front-line drug isoniazid28 (employed as a reference) were
dissolved in DMSO at a concentration of 6.25 mg mL-1 and stored
at ~4 ◦C until used.
7-Bromo-13-methyl-3,13-dihydro-2H-imidazo[1,2-a]indeno[2,1-
c]quinolin-13-yl dimethylcarbamate (27). Procedure A. The crude
product was purified by washing with n-hexane to get the desired
product 27 (46%) as green solid; mp 179–181 ◦C. IRnmax (KBr,
cm-1) 1630.99, 1706.17; 1H NMR (400 MHz, CDCl3): d 1.82 (s, 3
H, CH3), 2.70 (s, 3 H, NCH3), 2.94 (s, 3 H, NCH3), 3.92–398 (m,
2 H, NCH2), 4.15–4.21 (m, 2 H, –NCH2), 6.66 (d, J = 8.72 Hz,
1 H, Ar–H) 7.38–7.49 (m, 4 H, Ar-H),, 8.04 (d, J = 7.6 Hz, 1 H,
Cytotoxicity
Cell viability in the presence and absence of test compounds was
determined by Mosmans’s MTT assay31–33 for the most active
compounds (9, 15, 17, 25, 27, 28, and 29) from our data set.
The cells (human monocytic cell line U937) were plated in flat-
5672 | Org. Biomol. Chem., 2010, 8, 5661–5673
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
bottomed 96 well plates (1 ¥ 105 cells ml-1), cultured for 1 h in
controlled atmosphere (5% CO2 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 2). After completion of the experiment protocol 10 mL of
MTT solution (5 mg mL-1 solution in Phosphate Buffer Saline)
was added to each well. Plates were incubated for three hours in a
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 2).
9 V. Monga, A. Nayyar, B. Vaitilingam, P. B. Palde, S. Jhamb, S. Kaur, P.
Singh and R. Jain, Bioorg. Med. Chem., 2004, 12, 6465–6472.
10 K. Balamurugan, V. Jeyachandran, S. Perumal, T. H. Manjashetty, P.
Yogeeswari and D. Sriram, Eur. J. Med. Chem., 2010, 45, 682–688.
11 K. Andries, et al., Science, 2005, 307, 223–227.
12 R. Rustomjee, A. H. Diacon, J. Allen, A. Venter, C. Reddy, R. F.
Patientia, T. C. P. Mthiyane, T. DE Marez, R. Van Heeswijk, R.
Kerstens, A. Koul, K. De Beule, P. R. Donald and D. F. McNeeley,
Antimicrob. Agents Chemother., 2008, 52, 2831–2835.
13 (a) R. S. Upadhayaya, V. Jaya Kishore, V. Nageswara Rao, V. Sharma,
S. S. Dixit and J. Chattopadhaya, Bioorg. Med. Chem., 2009, 17,
2830–2841; (b) 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; (c) R. S. Upadhayaya, V.
Jaya Kishore, R. A. Kardile, S. V. Lahore, S. S. Dixit, H. S. Deokar,
P. D. Shinde and J. Chattopadhaya, Eur. J. Med. Chem., 2010, 45,
1854–1867.
14 R. S. Upadhayaya, S. V. Lahore, A. Y. Sayyed, S. S. Dixit, P. D. Shinde
and J. Chattopadhyaya, Org. Biomol. Chem., 2010, 8, 2180–2197.
15 A. A. Bekhit, O. A. El-Sayed, E. Aboulmagd and J. Y. Park, Eur. J.
Med. Chem., 2004, 39, 249–255.
Abbreviations
16 A. A. Bekhit, O. A. El-Sayed, T. A. K. Al-Allaf, H. Y. Aboul-Enein,
M. Kunhi, S. M. Pulicat, K. Al-Hussain, F. Al-Khodairy and J. Arif,
Eur. J. Med. Chem., 2004, 39, 499–505.
17 N. Balasubramanian, P. I. Brown, R. A. Parker and J. J. Wright, Bioorg.
Med. Chem. Lett., 1992, 2, 99–104.
DCM
DMF
dichloromethane
N,N-dimethylformamide
DMSO dimethyl sulfoxide
18 (a) T. Akbarzadeh, S. A. Tabatabai, M. J. Khoshnoud and B. Shafaghi,
Bioorg. Med. Chem., 2003, 11, 769–773; (b) J. D. Albright, D. B. Moran,
W. B. Wright, J. B. Collins, B. Beer, A. S. Lippa and E. N. Greenblatt,
J. Med. Chem., 1981, 24, 592–600; (c) G. Grandolini, M. C. Tiratti,
C. Rossi, V. Ambrogi, G. Orazalesi and M. Derigis, Farmaco Ed. Sci.,
1987, 42, 43–60; (d) D. Catarzi, D. Cecchi and L. Colotta, Farmaco,
1993, 48, 1065–1078; (e) J. B. Hester, A. D. Allan and F. Philip, J. Med.
Chem., 1980, 23, 392–402; (f) A. Foroumadi, S. A. Tabatabai and G.
Gitinezhad, Pharmacol. Commun., 2000, 6, 1–5; (g) A. Almasirad, S.
A. Tabatabai, M. Faizi, A. Kebriaeezadeh, N. Mehrabi, A. Dalvandi
and A. Shafiee, Bioorg. Med. Chem. Lett., 2004, 14, 6057–6059.
19 K. T. Potts and J. Bhattacharyya, J. Org. Chem., 1972, 37, 4410–4415.
20 G. A. Reynolds and J. A. VanAllan, J. Org. Chem., 1959, 24, 1478–
1486.
GI
growth index
MDR
MIC
mp
multi-drug resistance
minimum inhibitory concentration
melting point
MeOH
NMR
SAR
NaH
TB
methanol
nuclear magnetic resonance
structure–activity relationship
sodium hydride
tuberculosis
TLC
THF
thin layer chromatography
tetrahydrofuran
21 K. T. Potts, W. C. Dunlap and F. S. Apple, Tetrahedron, 1977, 33,
1263–1271.
22 (a) S. Naqui and V. R. Srinivasan, Tetrahedron Lett., 1962, 3, 1193–
1198; (b) K. T. Potts and H. R. Burton, J. Org. Chem., 1966, 31, 251;
(c) K. T. Potts, Burton, H. R. Burton and J. Bhattacharayya, J. Org.
Chem., 1966, 31, 260.
Acknowledgements
We thank Uppsala University, Sweden for valuable scientific sup-
port through Professor Jyoti Chattopadhyaya. 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 greatly acknowledged.
23 R. M. Shaker, ARKIVOC, 2006, ix, 59–112.
24 A. Cappelli, G. Giuliani, M. Anzini, D. Riitano, G. Giorgi and S.
Vomero, Bioorg. Med. Chem., 2008, 16, 6850–6859.
25 (a) G. Roma, G. C. Grossi, M. Di Braccio, D. Piras, V. Ballabeni,
M. Tognolini, S. Bertoni and E. Barocelli, Eur. J. Med. Chem., 2008,
43, 1665–1680; (b) G. Roma, M. Di Braccio, G. Grossi, D. Piras, V.
Ballabeni, M. Tognolini, S. Bertoni and E. Barocelli, Eur. J. Med.
Chem., 2010, 45, 352–366; (c) S. V. Gupta, K. Baheti, R. Bora, D.
Dekhane, M. Chhabria, M. Shingare, S. Pawar, C. J. Shishoo and S. N.
Thore, Eur. J. Med. Chem., 2009, 44, 4721–4725.
References
26 Q. Cai, Z. Li, J. Wei, L. Fu, C. Ha, D. Pei and K. Ding, Org. Lett.,
2010, 12, 1500–1503.
1 A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic Chemistry,
Pergamon Press: New York, 1984.
2 M. A. Koch, A. Schuffenhauer, M. Scheck, S. Wetzel, M. Casaulta, A.
Odermatt, P. Ertl and H. Waldman, Proc. Natl. Acad. Sci. U. S. A.,
2005, 102, 17272–17277.
27 E. Liber, Anal. Chem., 1957, 29, 916–918.
28 B. R. Bloom and C. J. L. Murray, Science, 1992, 257, 1055–1064.
29 J. D. Vanitha and C. N. Paramasivan, Mycobacteriology, 2004, 49,
179–182.
30 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.
31 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.
32 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.
33 M. V. Carvalho, C. Penido, A. C. Siani, L. M. M. Valente and
M. G. M. O. Henriques, Inflammopharmacology, 2006, 14, 48–
56.
3 M. Stark, X. F. Lin and L. A. Flippin, J. Org. Chem., 2000, 65, 3227–
3230.
4 S. D. Phillips and R. N. Castle, J. Heterocycl. Chem., 1981, 18, 223–232.
5 (a) H. Ginsburg and M. Krugliak, Biochem. Pharmacol., 1992, 43, 63–
70; (b) E. Milner, W. McCalmont, J. Bhonsle, D. Caridha, D. Carroll,
S. Gardner, L. Gerena, M. Gettayacamin, C. Lanteri, T. Luong, V.
Melendez, J. Moon, N. Roncal, J. Sousa, A. Tungtaeng, P. Wipf and G.
Dow, Bioorg. Med. Chem. Lett., 2010, 20, 1347–1351.
6 M. Wainwright and J. E. Kristiansen, Int. J. Antimicrob. Agents, 2003,
22, 479–486.
7 C. H. Tseng, Y. L. Chen, P. J. Lu, C. N. Yang and C. C. Tzeng, Bioorg.
Med. Chem., 2008, 16, 3153–3162.
8 A. Nayyar, A. Malde, R. Jain and E. Coutinho, Bioorg. Med. Chem.,
2006, 14, 847–856.
34 W. L. F. Armarego and C. L. L. Chai, Purification of Labo-
ratory Chemicals, 5th edn., Butterworth Heinemann Publishing,
2003.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5661–5673 | 5673
©