New class of antitubercular compounds: Synthesis and anti-tubercular activity of 4-substituted pyrrolo[2,3-c]quinolines

Article abstract of DOI:10.1007/s00706-013-1141-1

Modified synthesis and antitubercular activity of 4-substituted pyrrolo[2,3-c]quinolines are reported. Some of the compounds showed significant antitubercular activity, when compared to some of the existing antitubercular drugs. A compound with an imidazole moiety at position 4 shows the highest activity and least toxicity. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1141-1

Monatsh Chem
DOI 10.1007/s00706-013-1141-1
ORIGINAL PAPER
New class of antitubercular compounds: synthesis
and anti-tubercular activity of 4-substituted
pyrrolo[2,3-c]quinolines
•
Mahesh Akula Jonnalagadda Padma Sridevi
•
•
P. Yogeeswari D. Sriram Anupam Bhattacharya
•
Received: 7 August 2013 / Accepted: 18 December 2013
Ó Springer-Verlag Wien 2014
Abstract Modified synthesis and antitubercular activity
of 4-substituted pyrrolo[2,3-c]quinolines are reported.
Some of the compounds showed significant antitubercular
activity, when compared to some of the existing antitu-
bercular drugs. A compound with an imidazole moiety at
position 4 shows the highest activity and least toxicity.
difficult. Thus molecules bearing some resemblance to
the existing drugs are a reasonable starting point for the
rational development of newer entities to combat
tuberculosis.
Isoniazid, the most well-known antitubercular drug, and
ethionamide, a drug used for treatment of MDR-TB, were
the starting points for our exploration in this area. Attempts
in our lab to synthesize 4-substituted pyrrolo[2,3-c]quino-
lines has been going on for some time. These molecules
have similar structures to isoniazid and ethionamide
(Fig. 1). The presence of a quinoline system is also an
important feature of 4-substituted pyrrolo[2,3-c]quinolines
because many antitubercular compounds possess this
skeleton [2–5]. Structural correlation also led us to another
interesting observation: pyrrolnitrin, a natural product
isolated form Pseudomonas species, shows moderate anti-
tubercular activity [6]. After comparing 4-substituted
pyrrolo[2,3-c]quinolines with respect to the pyrrolnitrin
skeleton, one can clearly see that pyrrolo[2,3-c]quinolines
can be treated as a modified pyrrolnitrin system having
substantial structural rigidity (Fig. 1).
Keywords Heterocycles Á Strained molecules Á
Aldehydes Á Mannich reaction Á Antitubercular
Introduction
Increasing drug resistance along with emergence of
multidrug-resistant tuberculosis (MDR-TB) has made TB
a global epidemic with 8.5 million new cases in 2011
[1]. Newer chemical entities are thus required to solve
this problem. Although new chemical entities far
removed structurally from the existing drugs might pro-
vide an answer to this problem, the inherent structural
difference means that the systematic study of a drug
candidate’s efficacy or mode of action is much more
Results and discussion
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1141-1) contains supplementary
material, which is available to authorized users.
Fused pyrroloquinolines exhibit numerous biological
activities [7–16]. Synthetic methods for these molecules
generally preclude any universal strategy, as pyrrole can be
linked to either the benzene or pyridine half of the quino-
line skeleton [17–25]. Only few reports pertaining to the
synthesis of 4-substituted pyrrolo[2,3-c]quinolines are
known in the literature [26–30]. These methods, though
successful in the synthesis of the desired molecules, are not
truly robust in allowing diverse substitutions at position 4
of pyrrolo[2,3-c]quinoline. There was therefore the need
M. Akula Á A. Bhattacharya (&)
Department of Chemistry, Birla Institute of Technology and
Science-Pilani Hyderabad Campus, Hyderabad 500078,
Andhra Pradesh, India
e-mail: anupam@hyderabad.bits-pilani.ac.in
J. P. Sridevi Á P. Yogeeswari Á D. Sriram
Department of Pharmacy, Birla Institute of Technology and
Science-Pilani Hyderabad Campus, Hyderabad 500078,
Andhra Pradesh, India
123

M. Akula et al.
for an improvised strategy to overcome the aforementioned
shortcoming.
generate the target molecule. The source of o-nitrophe-
nylpyrrole was envisioned to be the reaction between o-
nitrostyrene and TosMIC [33–37]. 2-(6-Amino-9H-purine-
9-yl)acetaldehyde was to be obtained from the reaction
between adenine and commercially available 2-bromo-1,1-
diethoxyethane, followed by acetal deprotection [38]. It is
important to note here that using other aliphatic or aromatic
aldehydes in place of 2-(6-amino-9H-purine-9-yl)acetal-
dehyde will give different 4-substituted[2,3-c]quinolines.
Synthesis of aplidiopsamine A started with the reaction
between TosMIC and o-nitrostyrene [39] in the presence of
potassium tert-butoxide to generate o-nitrophenylpyrrole
(2), followed by reduction in the presence of iron and
hydrochloric acid to o-aminophenylpyrrole 3 (Scheme 1).
2-(6-Amino-9H-purine-9-yl)acetaldehyde (4a) was
obtained in acetal protected form by reaction of adenine
with 2-bromo-1,1-diethoxyethane, followed by deprotec-
tion. After required amine 3 and aldehyde 4a were
prepared, reactions were carried out in DMF using various
acids in order to optimize the reaction conditions. Forma-
tion of 4-methyl-3H-pyrrolo[2,3-c]quinoline as a by-
product along with the desired compound was observed
when HCl, ZnCl2, and p-toluenesulfonic acid (PTSA) were
used as catalyst. No by-product formation happened while
using acetic acid and under neat reaction conditions. The
better yield (62 %) obtained while using acetic acid com-
pared to neat reaction (32 %) prompted us to use acetic
acid in DMF to carry out the final step for the synthesis of
aplidiopsamine A. Thus the successful synthesis of aplid-
iopsamine A was accomplished (Scheme 1) in 22.8 %
overall yield.
In our attempt to devise a general method for the syn-
thesis of 4-substituted pyrrolo[2,3-c]quinolines, we decided
to use the synthesis of aplidiopsamine A (9-[(3H-pyrrol-
o[2,3-c]quinolin-4-yl)methyl]-9H-purin-6-amine, 1a) as a
model reaction owing to its relative structural complexity;
it was felt that any method that can successfully synthesize
aplidiopsamine A can be used as a general method for the
synthesis of other 4-substituted pyrrolo[2,3-c]quinolines.
The synthetic route devised was partially based on the most
probable biochemical route for aplidiopsamine A, as sug-
gested by Carroll et al. [12]. It was planned in two parts,
first involving the synthesis of o-nitrophenylpyrrole and
2-(6-amino-9H-purine-9-yl)acetaldehyde and then cou-
pling the two units, first by reduction of o-
nitrophenylpyrrole to o-aminophenylpyrrole followed by a
Mannich-type reaction [31, 32] between o-aminophenyl-
pyrrole and 2-(6-amino-9H-purine-9-yl)acetaldehyde to
In order to establish the generality of the developed
procedure, reactions were carried out with aldehydes con-
taining natural bases like uracil, thymine, and cytosine, as
well as several aromatic and aliphatic aldehydes (Table 1).
Fig. 1 Structural similarities between isoniazid, 4-substituted pyrrol-
o[2,3-c]quinoline, pyrrolnitrin, and ethionamide
Scheme 1
123

New class of antitubercular compounds
Table 1 Yield, antitubercular activity, and cytotoxicity of 4-substituted pyrrolo[2,3-c]quinolines
NH
N
R
Compound
RCHO 4a-u
Yield/%
62
Antitubercular activity:
MIC/lM
Cytotoxicity: %
inhibitiona
1a
158.7
n.d.
N
N
N
CHO
H2N
N
1b
1c
82
63
12.9
12.2
22.1
22.6
CHO
CHO
1d
1e
1f
68
79
67
53
6.0
16.4
18
O2N
F3C
CHO
5.6
CHO
CHO
45.6
48.0
12.6
n.d.
H3CO
1g
OH
CHO
1h
1i
85
72
[160
n.d.
CHO
N
5.5
15.6
CHO
Cl
N
123

M. Akula et al.
Table 1 continued
Compound
RCHO 4a-u
Yield/%
78
Antitubercular activity:
MIC/lM
Cytotoxicity: %
inhibitiona
1j
176
n.d.
CHO
N
H
1k
61b
80.2
n.d.
O
CHO
N
H
1l
65
86
3.3
3.3
24.6
N
H
CHO
CHO
CHO
1m
8.6
N
N
H
1n
1o
72
74
44
18.4
n.d.
S
[160
CHO
N
Ph
N
N
1p
1q
69
52
32.8
81.6
30.4
CHO
Fe
O
n.d.
HN
N
CHO
O
123

New class of antitubercular compounds
Table 1 continued
Compound
RCHO 4a-u
Yield/%
32
Antitubercular activity:
MIC/lM
Cytotoxicity: %
inhibitiona
1r
85.9
n.d.
O
N
N
CHO
H2N
1s
49
21.4
21.2
O
HN
N
CHO
O
1t
(CH3)2CHCH2CHO
CH3CHO
57
48
–
6.9
137
0.7
4.7
7.6
17.6
n.d.
–
1u
Isoniazid
Ciprofloxacin
Ethambutol
–
–
–
–
n.d. not determined
a
Cytotoxicity at 50 lM; only for compounds with MIC values \48 lM
Solvent used for this reaction was ethanol instead of DMF
b
While choosing the aldehydes 4b–4u we have ensured that
some of the examples contain either a free amino group
(modified cytosine aldehyde) or nitrogen with a relatively
free lone pair of electrons (pyridine-2-carbaldehyde,
imidazole-2-carbaldehyde, and 2-phenyl-1,2,3-triazole-4-
carbaldehyde). The main motivation was to demonstrate
the advantage of aldehydes over acid chlorides in such
substrates with reactive nitrogen, which we suggest is a
major disadvantage in the existing methodology by Ni
et al. [26]. The yields obtained for the final step leading to
formation of various 4-substituted pyrrolo[2,3-c]quinolines
were between 32 and 86 % (Table 1).
activity of the molecule as the MIC values are comparable.
However with aliphatic substituents at position 4, increase
in the chain length in 1t compared to 1u does increase the
activity of the molecule as clearly indicated by the MIC
values. Isoniazid, however, showed better activity com-
pared to 4-substituted pyrrolo[2,3-c]quinolines.
Further cytotoxicity assays carried out in order to ascer-
tain the effect of compounds on healthy cells revealed that
compound 1m, which along with compound 1l shows the
highest activity, is least toxic to healthy cells. Other active
compounds (MIC values \10 lM) showed percentage
inhibition of RAW 264.7 cells in the range 15–24 %. Thus
compound 1m can be modified further in order to improve its
efficacy as well as to reduce its cytotoxicity.
1
The products were characterized by H and 13C NMR
and mass spectrometry and were assayed for antitubercular
activity [40]. The best results were obtained when the
substituents at position 4 of pyrrolo[2,3-c]quinoline skele-
ton were pyrrol-2-yl (1l), imidazol-2-yl (1m),
2-chloropyridin-3-yl (1i), isobutyl (1t), p-nitrophenyl (1d),
and p-(trifluoromethyl)phenyl (1e). The compounds
exhibited better minimum inhibitory concentration (MIC)
values than ethambutol and similar values to ciprofloxacin.
Comparison of the activity shown by compound 1b with
that of compounds 1d, 1e, 1f, and 1g clearly indicates that
the presence of an electron-withdrawing group increases
the antitubercular activity of pyrrolo[2,3-c]quinolines.
Introduction of an extra methylene group in compound 1c
with respect to that of compound 1b has no impact on the
Conclusions
We have described a general synthesis of 4-substituted
pyrrolo[2,3-c]quinolines showing antitubercular activity. To
the best of our knowledge this is the first report on antitu-
bercular activity exhibited by a fused pyrroloquinoline
system. The approach described herein gives a similar
overall yield for aplidiopsamine A as that reported by Ma-
hajan et al. and Panarese et al. it is also a more flexible
method as diverse aldehydes can be exploited to prepare
4-substituted pyrrolo[2,3-c]quinolines. The synthetic route
123

M. Akula et al.
30–40 % EtOAc/ n-hexane) to afford the desired compound
as a brown liquid. Yield: 0.780 g (71 %). The structure was
confirmed by IR, 1H, 13C NMR, and MS, which were
consistent with those described in the literature [Ref. 27].
utilized is shorter and more efficient compared to the existing
ones. By choosing aldehydes over acid chlorides [26] (as
reported previously) we have shown that the reaction is now
compatible with substrates containing reactive nitrogen, and
reactivity normally associated with acid chlorides does not
hamper the synthesis of diverse compounds. Work is cur-
rently underway to synthesize modified analogues of these
compounds to improve the antitubercular activity as well as
to carry out the enzyme binding studies.
General procedure for the preparation of 4-substituted
pyrrolo[2,3-c]quinolones 1a–1u
To a solution of aminophenylpyrrole (1.89 mmol) and
aldehyde (1.89 mmol) in 15 cm3 DMF was added acetic acid
(20 mol%). The solution was stirred for 12 h at 60 °C. After
completion of the reaction as indicated by TLC, the reaction
mixture was cooled to room temperature. Brine (10 cm3) and
5 cm3 NaHCO3 were added to the reaction mixture and it
was extracted with ethyl acetate (3 9 30 cm3). The com-
bined organic layer was washed with 30 cm3 brine and dried
over sodium sulfate. Removal of ethyl acetate under reduced
pressure gave the crude product, which was chromato-
graphed over silica gel to afford the desired compounds 1a–
1u in 32–86 % yields (Table 1).
Experimental
All starting materials were purchased from Aldrich, Spect-
rochem, SRL, and Sd Fine (India) and used directly without
further purification. Solvents were dried using standard
methods and distilled before use. Visualization of TLC
plates was achieved by use of UV light (254 nm) or iodine.
Melting points were recorded on a Stuart SMP 30 melting
point apparatus. 1H (300 and 400 MHz) and 13C NMR (75
and 100 MHz) spectra were recorded in CDCl3 and DMSO-
d6 solution with TMS as internal standard. IR spectra were
recorded as KBr plates on a Jasco FT/IR-4200 instrument.
High resolution mass spectra were recorded on a Bruker
microTOF QII instrument. Column chromatography was
performed on silica gel (100–200 mesh, SRL, India).
9-[(3H-Pyrrolo[2,3-c]quinolin-4-yl)methyl]-9H-purin-6-
amine (aplidiopsamine A, 1a)
Starting from aldehyde 4a, 473 mg 1a (62 %) was isolated
as a yellow oil, which solidifies under cooling. The
1
structure was confirmed by H, 13C NMR, and MS data,
which were consistent with those described in the literature
[Ref. 12].
3-(o-Nitrophenyl)pyrrole (2)
To a solution of 2.4 g o-nitrostyrene (16.09 mmol) in 30 cm3
DMSO 4 g TosMIC (20.5 mmol) and 3.611 g t-BuOK
(32.2 mmol) were added, and the reaction mixture was stirred
for4 hat100 °C. Aftercompletionofthereactionasindicated
by TLC, 30 cm3 brine solution was added and the reaction
mixture was extracted with ethyl acetate (3 9 50 cm3), and
the combined organic layer was dried over anhydrous
Na2SO4. Ethyl acetate was removed under vacuum. The
crude product was subjected to column chromatography
(silica gel, 8–10 % EtOAc/ n-hexane) to provide the pure
compound as a yellow oil. Yield: 1.52 g (51 %). The structure
4-Phenyl-3H-pyrrolo[2,3-c]quinoline (1b)
Starting from aldehyde 4b, 187 mg 1b (82 %) was isolated
as a yellow solid. M.p.: 209 °C ( [27] 212–214 °C). The
structure was confirmed by IR, 1H, 13C NMR, and MS data,
which were consistent with those described in the literature
[Ref. 27].
4-Benzyl-3H-pyrrolo[2,3-c]quinoline (1c)
Starting from aldehyde 4c, 91 mg 1c (63 %) was isolated
as a white solid. M.p.: 172–174 °C ([27] 179–181 °C). The
structure was confirmed by IR, 1H, 13C NMR, and MS data,
which were consistent with those described in the literature
[Ref. 27].
1
was confirmed by IR, H, 13C NMR, and MS, which were
consistent with those described in the literature [Ref. 27].
3-(o-Aminophenyl)pyrrole (3)
4-(4-Nitrophenyl)-3H-pyrrolo[2,3-c]quinoline (1d)
Starting from aldehyde 4d, 305 mg 1d (68 %) was isolated
as a light yellow solid. M.p.: 215 °C ([27] 220–221 °C).
The structure was confirmed by IR, 1H, 13C NMR, and MS
data, which were consistent with those described in the
literature [Ref. 27].
To a solution of 1.3 g o-nitrophenylpyrrole (6.91 mmol) in
20 cm3 ethanol 3.858 g Fe (69.08 mmol) and 1.5 cm3
0.6 N HCl were added and the reaction mixture was stirred
at 80 °C for 1.5 h. The reaction mixture was cooled to room
temperature and passed through a Celite pad and the solvent
was evaporated. HCl was neutralized with NaHCO3 and the
aqueous solution was extracted with EtOAc (3 9 50 cm3);
the combined organic layer was washed with brine
(2 9 20 cm3) and dried with Na2SO4. Ethyl acetate was
removed under vacuum. The crude product thus obtained
was subjected to column chromatography (silica gel,
4-[4-(Trifluoromethyl)phenyl]-3H-pyrrolo[2,3-c]quinoline
(1e, C18H11F3N2)
Starting from aldehyde 4e, 572 mg 1e (69 %) was isolated
as a white solid. M.p.: 165–167 °C; Rf = 0.65 (n-hexane/
ethyl acetate = 7:3); 1H NMR (400 MHz, CDCl3):
123

New class of antitubercular compounds
d = 7.12–7.16 (m, 1H), 7.44 (t, J = 2.8 Hz, 1H),
7.54–7.62 (m, 4H), 7.88 (d, J = 8.1 Hz, 2H), 8.14–8.19
(m, 1H), 8.21–8.26 (m, 1H), 9.66 (s, 1H) ppm; 13C NMR
(101 MHz, CDCl3): d = 102.33, 123.09, 123.36, 123.9
(CF3, J = 273 Hz), 125.85, 126.37, 126.57, 126.86,
127.19, 128.6, 129.55, 129.80, 130.50, 130.83, 131.15,
131.47, 141.70, 142.84, 145.16 ppm; IR (KBr): v = 3,092,
1,475, 1,323, 1,131, 1,012, 754 cm-1; HRMS: calcd for
C18H12F3N2 [M ? H?] 313.0947, found 313.0938.
10.31 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3):
d = 101.8, 122.9, 123.2, 123.6, 126.6, 126.6, 127.6,
127.7, 129.5, 129.6, 134.1, 140.9, 142.4, 143.0, 149.8,
149.9 ppm; IR (KBr): v = 3,082, 1,588, 1,480, 1,125,
1,027, 728 cm-1; HRMS: calcd for C16H11ClN3 [M ? H?]
280.0636, found 280.0651.
4-(1H-Indol-3-yl)-3H-pyrrolo[2,3-c]quinoline (1j)
Starting from aldehyde 4j, 115 mg 1j (78 %) was isolated as a
yellow solid. M.p.: 266–268 °C ([27] 264–266 °C). The
structure was confirmed by IR, 1H, 13C NMR, and MS data,
which were consistent with those described in the literature
[Ref. 27].
4-(4-Methoxyphenyl)-3H-pyrrolo[2,3-c]quinoline (1f)
Starting from aldehyde 4f, 104 mg 1f (67 %) was isolated
as
a
pale brown solid. M.p.: 168–170 °C ([13]
173–174 °C). The structure was confirmed by IR, H, 13C
NMR, and MS data, which were consistent with those
described in the literature [Ref. 27].
1
(1H-Indol-3-yl)(3H-pyrrolo[2,3-c]quinolin-4-yl)-
methanone (1k)
Starting from aldehyde 4k, 437 mg 1k (61 %) was isolated
as a yellow solid. M.p.: 201 °C. The structure was
2-(3H-Pyrrolo[2,3-c]quinolin-4-yl)phenol
1
confirmed by H, 13C NMR, and MS data, which were
(1g, C17H12N2O)
Starting from aldehyde 4g, 178 mg 1g (53 %) was isolated
as a yellow solid. M.p.: 208–210 °C; Rf = 0.4 (n-hexane/
ethyl acetate = 6:4); 1H NMR (400 MHz, DMSO-d6):
d = 7.00–7.14 (m, 2H), 7.32 (d, J = 2.9 Hz, 1H),
7.37–7.46 (m, 1H), 7.58–7.70 (m, 2H), 7.76 (d,
J = 2.9 Hz, 1H), 8.02–8.07 (m, 1H), 8.09 (dd, J = 8.1,
1.5 Hz, 1H), 8.33–8.45 (m, 1H), 12.11 (s, 1H), 14.05 (s,
1H) ppm; 13C NMR (101 MHz, DMSO-d6): d = 101.99,
117.93, 119.43, 120.45, 123.07, 123.64, 125.82, 126.52,
127.04, 127.86, 129.83, 130.04, 130.61, 131.67, 139.65,
146.48, 159.30 ppm; IR (KBr): v = 3,309, 3,051, 1,585,
consistent with those described in the literature [Ref. 13].
4-(1H-Pyrrol-2-yl)-3H-pyrrolo[2,3-c]quinoline
(1l, C15H11N3)
Starting from aldehyde 4l, 75 mg 1l (65 %) was isolated as
1
a brown oil. Rf = 0.5 (n-hexane/ethyl acetate = 7:3); H
NMR (400 MHz, CDCl3): d = 6.40 (t, 1H, J = 3.6 Hz),
6.91 (d, 1H, J = 4 Hz), 7.01 (t, 1H, J = 1.6 Hz), 7.06 (d,
1H, J = 3.2 Hz), 7.44 (d, 1H, J = 4 Hz), 7.48–7.56 (m,
2H), 8.09 (d, 1H, J = 8 Hz), 8.14 (d, 1H, J = 8 Hz), 9.53
(s, 1H) ppm; 13C NMR (101 MHz, CDCl3): d = 102.2,
109.6, 110.5, 111.4, 121.26, 122.7, 122.9, 125.3, 126.5,
126.7, 128.1, 129.6, 138.1, 142.0 ppm; IR (KBr):
v = 2,932, 1,662, 1,583, 1,483, 1,098, 757 cm-1; HRMS:
calcd for C15H12N3 [M ? H?] 234.1026, found 234.1016.
1,503, 1,378, 1,160, 737 cm-1
; HRMS: calcd for
C17H13N2O [M ? H?] 261.1022, found 261.1058.
4-(Pyridin-2-yl)-3H-pyrrolo[2,3-c]quinoline
(1h, C16H11N3)
Starting from aldehyde 4h, 78 mg 1h (85 %) was isolated
as yellow solid. M.p.: 155 °C; Rf = 0.5 (n-hexane/ethyl
acetate = 8:2); H NMR (400 MHz, CDCl3): d = 7.11 (s,
4-(1H-Imidazol-2-yl)-3H-pyrrolo[2,3-c]quinoline
(1m, C14H10N4)
1
Starting from aldehyde 4m, 58 mg1m (86 %) was isolated as a
yellow solid. M.p.: 173–176 °C; Rf = 0.5 (n-hexane/ethyl
acetate = 5:5); H NMR (400 MHz, CDCl3): d = 7.02 (s,
1H), 7.10 (d, 1H, J = 4 Hz), 7.31 (s, 1H), 7.50–7.58 (m, 3H),
8.10 (d, 1H, J = 8 Hz), 8.25 (d, 1H, J = 8 Hz), 11.44 (s, 1H,
NH) ppm; 13C NMR (101 MHz, CDCl3): d = 101.4, 118.3,
123.3, 123.9, 126.1, 126.4, 126.8, 127.6, 128.4, 129.6, 130.3,
135.7, 141.9, 146.0 ppm; IR (KBr): v = 3,380, 3,343, 3,048,
1,523, 1,384, 1,108, 751 cm-1; HRMS: calcd for C14H11N4
[M ? H?] 235.0978, found 235.1003.
1H), 7.35 (s, 1H), 7.49 (t, 1H, J = 8 Hz), 7.55–7.59 (m,
3H), 7.64 (d, 1H, J = 4 Hz), 8.00 (d, 1H, J = 8 Hz), 8.07
(d, 1H, J = 8 Hz), 8.22 (d, 1H, J = 8 Hz), 9.14 (s, 1H,
NH) ppm; 13C NMR (101 MHz, CDCl3): d = 102.2,
123.1, 123.4, 124.9, 126.5, 127.0, 127.5, 129.5, 129.9,
131.4, 132.7, 133.2, 142.5, 143.4, 149.0 ppm; IR (KBr):
v = 3,373, 3,061, 1,576, 1,156, 1,063, 743 cm-1; HRMS:
calcd for C16H12N3 [M ? H?] 246.1026, found 246.1045.
1
4-(2-Chloropyridin-3-yl)-3H-pyrrolo[2,3-c]quinoline
(1i, C16H10ClN3)
Starting from aldehyde 4i, 178 mg 1i (72 %) was isolated
as a brown solid. M.p.: 206–209 °C; Rf = 0.5 (n-hexane/
ethyl acetate = 5:5); 1H NMR (400 MHz, CDCl3):
d = 7.15 (d, 1H, J = 8 Hz), 7.27 (d, 1H, J = 8 Hz),
7.52–7.53 (t, 1H, J = 4 Hz), 7.61–7.64 (m, 2H), 7.97 (d,
1H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz), 8.26–8.29 (m, 1H),
4-(Thiophen-2-yl)-3H-pyrrolo[2,3-c]quinoline
(1n, C15H10N2S)
Starting from aldehyde 4n, 184 mg 1n (72 %) was isolated
as a yellow solid. M.p.: 162–165 °C; Rf = 0.45 (n- hexane/
ethyl acetate = 7:3); 1H NMR (400 MHz, CDCl3):
d = 7.10 (d, 1H, J = 4 Hz), 7.14 (t, 1H, J = 4 Hz), 7.43
123

M. Akula et al.
1
(t, 1H, J = 4 Hz), 7.47 (d, 1H, J = 8 Hz), 7.53–7.61 (m,
2H), 7.71 (d, 1H, J = 8 Hz), 8.19 (d, 2H, J = 8 Hz), 9.38
(s, 1H) ppm; 13C NMR (101 MHz, CDCl3): d = 102.4,
122.9, 123.2, 126.0, 126.4, 126.5, 126.7, 128.0, 128.1,
129.4, 129.8, 140.4, 142.2, 142.7 ppm; IR (KBr):
v = 3,103, 1,575, 1,528, 1,351, 1,126, 750 cm-1; HRMS:
calcd for C15H11N2S [M ? H?] 251.0637, found 251.0644.
determine the melting point. H NMR (400 MHz, DMSO-
d6): d = 5.42 (s, 2H, CH2), 5.83 (d, 1H, J = 6.8 Hz), 7.17
(s, 1H), 7.50–7.55 (m, 3H), 7.70 (t, 1H, J = 2.4 Hz), 7.83
(d, 1H, J = 8 Hz), 7.89 (d, 1H, J = 8 Hz), 8.27 (d, 1H,
J = 6.5 Hz), 12.18 (s, 1H, NH) ppm; 13C NMR (101 MHz,
DMSO-d6): d = 50.6 (CH2), 93.9, 101.5, 123.5, 125.9,
127.4, 128.0, 128.3, 129.4, 141.9, 144.9, 147.9, 156.2,
166.2 ppm; IR (KBr): v = 3,177, 1,663, 1,524, 1,390,
1,272, 1,189, 741 cm-1; HRMS: calcd for C16H14N5O
[M ? H?] 292.1193, found 292.1205.
4-(2-Phenyl-2H-1,2,3-triazol-4-yl)-3H-pyrrolo[2,3-c]-
quinoline (1o, C19H13N5)
Starting from aldehyde 4o, 109 mg 1o (74 %) was isolated
as yellow solid. M.p.: 199 °C; Rf = 0.5 (n-hexane/ethyl
acetate = 9:1); H NMR (400 MHz, CDCl3): d = 7.14 (t,
1-[(3H-Pyrrolo[2,3-c]quinolin-4-yl)methyl]pyrimidine-
2,4(1H,3H)-dione (1s, C16H12N4O2)
1
1H, J = 2.0 Hz), 7.43 (t, 1H, J = 7.6 Hz), 7.55–7.66 (m,
5H), 8.19 (d, 2H, J = 9.6 Hz), 8.24 (d, 2H, J = 9.6 Hz),
8.80 (s, 1H), 10.40 (s, 1H, NH) ppm; 13C NMR (101 MHz,
CDCl3): d = 101.8, 119.1, 123.0, 123.7, 126.4, 126.7,
126.8, 128.0, 129.0, 129.4, 129.5, 129.7, 129.9, 130.0,
132.2, 135.54, 136.0, 139.6, 142.5, 148.9 ppm; IR (KBr):
v = 3,226, 2,926, 1,592, 1,457, 1,080, 758 cm-1; HRMS:
calcd for C19H14N5 [M ? H?] 312.1244, found 312.1269.
Starting from aldehyde 4s, 145 mg 1s (49 %) was isolated
as a brown solid, which decomposed when attempting to
1
determine the melting point. H NMR (400 MHz, DMSO-
d6): d = 5.44 (s, 2H, CH2), 5.67 (d, 2H, J = 8 Hz), 7.18 (s,
1H), 7.47–7.86 (m, 2H), 7.71 (t, 1H, J = 2.7 Hz), 7.82 (d,
2H, J = 8 Hz), 8.25 (d, 1H, J = 7.2 Hz), 11.31 (s, 1H,
NH), 12.21 (s, 1H, NH) ppm; 13C NMR (101 MHz,
DMSO-d6): d = 49.1 (CH2), 100.8, 101.6, 123.5, 125.9,
126.9, 129.5, 141.8, 144.0, 147.9, 151.7, 164.5 ppm; IR
4-(Ferrocen-1-yl)-3H-pyrrolo[2,3-c]quinoline
(1p, C21H16FeN2)
(KBr): v = 3,280, 1,691, 1,464, 1,249, 804, 750 cm-1
;
HRMS: calcd for C16H13N4O2 [M ? H?] 293.1033, found
Starting from aldehyde 4p, 540 mg 1p (69 %) was isolated as a
brown solid. M.p.: 177–180 °C; Rf = 0.4 (n-hexane/ethyl
293.1023.
1
acetate = 8:2); H NMR (400 MHz, CDCl3): d = 4.12 (s,
4-Isobutyl-3H-pyrrolo[2,3-c]quinoline (1t)
Starting from aldehyde 4t, 54 mg 1t (57 %) was isolated as
a yellow solid. M.p.: 201 °C (27] 205–207 °C). The
5H), 4.49 (s, 2H), 5.08 (s, 2H), 7.09 (s, 1H), 7.55 (t, 2H,
J = 8 Hz), 7.47 (s, 1H), 8.16 (t, 2H, J = 8 Hz), 9.45 (s, 1H)
ppm; 13C NMR (101 MHz, CDCl3): d = 68.3, 69.4, 70.2, 82.8,
102.0, 122.8, 123.1, 125.4, 126.2, 128.4, 129.3, 130.1, 143.1,
148.1 ppm; IR (KBr): v = 3,386, 2,924, 1,524, 1,090, 880,
1
structure was confirmed by IR, H, 13C NMR, and MS
data, which were consistent with those described in the
literature [Ref. 27].
;
751 cm-1 HRMS: calcd for C21H17FeN2 [M ? H?]
4-Methyl-3H-pyrrolo[2,3-c]quinoline (1u)
353.0740, found 353.0777.
Starting from aldehyde 4u, 57.2 mg 1u (48 %) was isolated
as white solid compound. M.p.: 226 °C ([13] 236–237 °C).
The structure was confirmed by IR, 1H NMR, and MS data,
which were consistent with those described in the literature
[Ref. 13].
1-[(3H-Pyrrolo[2,3-c]quinolin-4-yl)methyl]-5-methylpyr-
imidine-2,4(1H,3H)-dione (1q, C17H14N4O2)
Starting from aldehyde 4q, 138 mg 1q (52 %) was isolated
as a brown solid, which decomposed when attempting to
1
determine the melting point. H NMR (400 MHz, DMSO-
d6): d = 1.83 (s, 3H, CH3), 5.41 (s, 2H, CH2), 7.18 (s, 1H),
7.48–7.57 (m, 2H), 7.72 (m, 2H), 7.87 (d, 1H, J = 8 Hz),
7.98 (s, 1H), 8.27 (d, 1H, J = 8 Hz), 11.35 (s, 1H, NH),
12.20 (s, 1H, NH) ppm; 13C NMR (101 MHz, DMSO-d6):
d = 12.5 (CH3), 48.6, 101.6, 108.2, 123.5, 125.9, 127.0,
128.0, 128.3, 129.5, 141.8, 143.5, 144.1, 151.7, 162.7,
165.1 ppm; IR (KBr): v = 3,170, 1,673, 1,473, 1,364,
1,250, 1,051, 759 cm-1; HRMS: calcd for C17H15N4O2
[M ? H?] 307.1190, found 307.1190.
Biological activity
The in vitro antimycobacterial activity of the compounds
against Mycobacterium tuberculosis H37Rv was carried
out by the microplate Alamar Blue assay method leading to
the determination of MIC values in duplicate. MICs of the
standard drugs and the synthesized compounds are reported
in Table 1 for comparison.
Compounds showing MIC values of less than 48 lM in
the antimycobacterial assay were chosen for cytotoxicity
determination. Cell line RAW 264.7 (mouse leukemic
monocyte macrophage) was used for this purpose and the
concentration used was 50 lM. Viability was assessed on
the basis of cellular conversion of MTT into a formazan
1-[(3H-Pyrrolo[2,3-c]quinolin-4-yl)methyl]-4-aminopyr-
imidin-2(1H)-one (1r, C16H13N5O)
Starting from aldehyde 4r, 203 mg 1r (32 %) was isolated
as a white solid, which decomposed when attempting to
123

New class of antitubercular compounds
16. Ishikawa H, Uno T, Miyamoto H, Ueda H, Tamaoka H, Tomi-
naga M, Nakagawa K (1990) Chem Pharm Bull 38:2459
17. Ramesh S, Nagarajan R (2012) Synlett 717
18. Benakki H, Colacino E, Andre C, Guenoun F, Martinez J, Lamaty
F (2008) Tetrahedron 64:5949
19. Reddy PVN, Banerjee B, Cushman M (2010) Org Lett 12:3112
20. Gee MB, Lee WJ, Yum EK (2003) Bull Korean Chem Soc
24:1193
product, after 72 h of exposure using the Promega Cell
Titer 96 non-radioactive cell proliferation assay.
Acknowledgments M.A. thanks the University Grants Commission
(India) for a junior research fellowship. A.B. thanks the Department
of Science and Technology, New Delhi, India for the fast-track grant.
21. Yamashkin SA, Yurovskaya MA (2001) Chem Heterocycl Comp
37:1439
References
22. Yamaskin SA, Kucherenko NY, Yurovskaya MA (1995) Chem
Heterocycl Comp 31:1299
23. Elouar M, Kuouzi N, El Kihel A, Essassi EM (1995) Synth
Commun 25:1601
24. Ferlin MG, Chiarelotto G, Baccichetti F, Carlossare F, Toniolo L,
Bordin F (1992) Farmaco 47:1513
25. Romeiro GA, Khan MA, Fereira VF (1991) J Braz Chem Soc 2:1
26. Ni L, Li Z, Wu F, Xu J, Wu X, Kong L, Yao H (2012) Tetra-
hedron Lett 53:1271
27. Schwalm CS, Correia CRD (2012) Tetrahedron Lett 53:4836
28. Mahajan JP, Suryawanshi YR, Mhaske SB (2012) Org Lett
14:5804
29. Panarese JD, Lindsley CW (2012) Org Lett 14:5808
30. Ma X, Vo Y, Banwell MG, Willis AC (2012) Asian J Org Chem
1:160
1. World Health Organization (2012) WHO: Global tuberculosis
report. World Health Organization, Geneva
2. Andries K, Verhasselt P, Guillemont J, Gohlmann HWH, Neefs
J-M, Winkler H, Gestel JV, Timmerman P, Zhu M, Lee E,
Williams P, Chaffoy D, Huitric E, Hoffner S, Cambau E, Truffot-
Pernot C, Lounis L, Jarlier V (2005) Science 307:223
3. de Souza MVN, Pais KC, Kaiser CR, Peralta MA, Ferreira M,
Lourenco MCS (2009) Bioorg Med Chem 17:1474
4. Nayyar A, Monga V, Malde A, Coutinho E, Jain R (2007) Bioorg
Med Chem 15:626
5. Eswaran S, Adhikari AV, Pal NK, Chowdhury IH (2010) Bioorg
Med Chem Lett 20:1040
6. Santo RD, Costi R, Artico M, Massa S, Lampis G, Deidda D,
Pompei R (1998) Bioorg Med Chem Lett 8:2931
7. Zhao R, Oreski B, Lown JW (1996) Bioorg Med Chem Lett
6:2169
31. Curti C, Battistini L, Ranieri B, Pelosi G, Rassu G, Casiraghi G,
Zanardi F (2011) J Org Chem 76:2248
32. Pacorel B, Leung SC, Stachulski AV, Davies J, Vivas L, Lander
H, Ward SA, Kaiser M, Brun R, O’Neill PM (2010) J Med Chem
53:633
33. Smith ND, Huang D, Cosford NDP (2002) Org Lett 4:3537
34. Moliner FD, Hulme C (2012) Org Lett 14:1354
35. Pavri NP, Trudell ML (1997) J Org Chem 62:2649
36. Sisko J, Kassick AJ, Mellinger M, Filan JJ, Allen A, Olsen MA
(2000) J Org Chem 65:1516
37. Mendiola J, Minguez JM, Alvarez-Builla J, Varquero JJ (2000)
Org Lett 2:3253
38. Xu ZQ, Qiu YL, Chokekijchai S, Mitsuya H, Zemlicka J (1995) J
Med Chem 38:875
8. Ferlin MG, Dalla Via L, Gia OM (2004) Bioorg Med Chem
12:771
9. Dalla Via L, Gia O, Gasparotto V, Ferlin MG (2008) Eur J Med
Chem 43:429
10. Wang W, Rayburn ER, Velu SE, Nadkarni DH, Murugesan S,
Zhang R (2009) Clin Cancer Res 15:3511
11. Legentil L, Lesur B, Delfourne E (2006) Bioorg Med Chem Lett
16:427
12. Carroll AR, Duffy S, Avery VM (2010) J Org Chem 75:8291
13. Okanya PW, Mohr PI, Gerth K, Jansen R, Muller R (2011) J Nat
Prod 74:603
14. Davis RA, Buchanan MS, Duffy S, Avery VM, Charman SA,
White KL, Shackleford DM, Edstein MD, Andrews KT, Camp D,
Quinn RJ (2008) J Med Chem 43:429
39. Xu W, Xu JH, Pan J, Gu Q, Wu XY (2006) Org Lett 8:1737
40. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G,
Hernandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson
RM, Gilman RH (1998) J Clin Microbiol 36:362
15. Sun HH, Sakemi S, Burres N, McCarthy P (1990) J Org Chem
55:4964
123