Design, synthesis, and structure-activity correlations of novel dibenzo[b,d furan, dibenzo[b,d]thiophene, and N-methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of mycobacterium tuberculosis

Article abstract of DOI:10.1021/jm300125e

A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-bas

Full text of DOI:10.1021/jm300125e

Article
pubs.acs.org/jmc
Design, Synthesis, and Structure−Activity Correlations of Novel
Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole
Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium
tuberculosis
Santhosh Reddy Patpi,† Lokesh Pulipati,† Perumal Yogeeswari,‡ Dharmarajan Sriram,‡ Nishant Jain,§
Balasubramanian Sridhar,∥ Ramalinga Murthy,§ Anjana Devi T,§ Shasi Vardhan Kalivendi,§
and Srinivas Kantevari*,†
†Organic Chemistry (CPC) Division-II, Indian Institute of Chemical Technology, Hyderabad-500607, India
‡Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani,
Hyderabad Campus, Jawahar Nagar, Hyderabad-500078, India
§Chemical Biology Division, and ∥Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad-500607,
India
S
* Supporting Information
ABSTRACT: A molecular hybridization approach is an
emerging structural modification tool to design new molecules
with improved pharmacophoric properties. In this study, 1,2,3-
triazole-based Mycobacterium tuberculosis inhibitors and
synthetic and natural product-based tricyclic (carbazole,
dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobac-
terial agents were integrated in one molecular platform to
prepare various novel clubbed 1,2,3-triazole hybrids using click
chemistry. Structure−activity correlations and in vitro activity
against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-
methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 μg/mL (∼1.9 μM)
displayed a low cytotoxicity and high selectivity index (50−255) against four different human cancer cell lines. These results
together provided the potential importance of molecular hybridization and the development of triazole clubbed
dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.
antimycobacterial entities with novel mechanisms of action to
achieve effective TB control even against the resistant forms of
TB.4−6
INTRODUCTION
■
Tuberculosis (TB) is an ancient, contagious disease caused by
infection with Mycobacterium tuberculosis and characterized by
tubercle lesions in the lungs.1 It may also affect the skin, lymph
nodes, brain, and almost every other organ. According to the
latest WHO report,2 TB has become a more prevalent chronic
disease in the world today with millions of new cases of infected
individuals and millions of deaths being notified each year
globally. It is anticipated that by 2020, one billion people will be
newly infected, over 125 million people will get sick, and over
30 million will die of TB if control is not further
strengthened.2,3 TB is also declared to be a global health
emergency because of the increase in secondary infections and/
or coinfection in immunocompromised patients [such as those
infected with human immunodeficiency virus (HIV)] and the
emergence of resistant strains of M. tuberculosis [multidrug-
resistant (MDR) and extensively drug resistant (XDR) TB
strains].4 The long and complex TB regimen and lack of
appropriate treatments are also increasing the burden of TB.5
Therefore, the current situation necessitates the re-engineering
and repositioning of old drug families for developing new
The natural products are essential sources for new
antimicrobial agents.7 They are generally derived from plants
or microbes. They offer promising and amazing chemical
diversity, thereby inspiring the development of structurally
diverse new molecules to play a major role in drug discovery.8
The promising natural antimycobacterials include carbazole
alkaloids,9 such as Clausine (1) and Micromeline (2), isolated
independently from several sources, and dibenzofuran based on
the secondary metabolite of lichen usnic acid (3) (Figure 1),
isolated from Cladonia substellata,10 and were shown to have
moderate antitubercular activity. Modified natural products like
synthetic analogues 4, 5a, and 5b of dibenzofuran and carbazole
exhibited significantly improved in vitro as well as in vivo
antitubercular activity against M. tuberculosis H37Rv.11
Structure−activity relationship (SAR) studies direct that the
Received: January 28, 2012
Published: March 26, 2012
© 2012 American Chemical Society
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Figure 1. Antitubercular dibenzofuran and carbazole analogues of (A) natural and (B) synthetic origin.
Figure 2. Heterocyclic hybrids of [1,2,3]triazole with antitubercular activity.
presence of dibenzo[b,d]furan or a carbazole moiety plays a
vital role on their pharmacological properties.10,11 On the other
hand, 1,2,3-triazoles conjugated with a wide range of
heterocyclic moieties were reported12 to exhibit potent
antitubercular activity (Figure 2). Among them, benzofuran
saliccyclic acid derivative 6 (I-A09, Figure 2) is a lead
antitubercular agent currently in clinical evalautaions.13
cular compounds were also evaluated for their in vitro
cytotoxicity.
RESULTS AND DISCUSSION
■
Chemistry. The design strategy adopted here is based on
the most recent molecular hybridization approach.15 Molecular
hybridization is a strategy of rational design of new ligands or
prototypes based on the recognition of pharmacophoric
subunits in the molecular structure of two or more known
bioactive derivatives.18 The adequate fusion of these subunits
leads to the design of a new hybrid architecture that maintains
preselected characteristics of the original template. Here, a
triazole ligand of 613 and a core structure of natural alkaloids
1−39,10 were hybridized in one molecular platform for
optimized affinity and better pharmacological properties
associated with the target diseases, TB. The designed scaffold
(Figure 3) has three parts: 1,2,3-triazole as a central backbone,
attachment of dibenzo[b,d]furan or dibenzothiophene or 9-
methyl-9H-carbazole to a triazole unit to enhance desired
pharmacophoric behavior with druglike properties, and
aliphatic or aromatic groups to the other side of the triazole
core for lipophilicity. The method adopted for the synthesis of
1,2,3-triazole conjugates was based on a Huisgen 1,3-dipolar
cycloaddition reaction (click reaction) of alkynes and azides.
The azide precursors 9a, 9b, and 9c required for the
preparation of triazole conjugates were synthesized starting
Our continued interest in developing new antimycobacterial
agents14 led to molecular hybridization15 of dibenzo[b,d]furan
or 9-methyl-9H-carbazole and 1,2,3-triazole to integrate them
in one molecular platform to generate a new scaffold for
biological evaluation. Considering the fact that 1,2,3-triazoles
were efficiently made through Cu(I)-catalyzed click chem-
istry,16 we present here an efficient synthesis of novel 9-methyl-
9H-carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene
conjugated 1,2,3-triazole hybrids 11a−h, 12a−h, and 13a−t.
The inclusion of dibenzo[b,d]thiophene in this series is due to
structural similarity with dibenzo[b,d]furan and recent findings
of potential pharmacophoric properties (NU7441 as DNA-
dependent protein kinase inhibitor).17 All of the hybrid
heterocycles 11a−h, 12a−h, and 13a−t were evaluated for
their in vitro antimycobacterial activity against M. tuberculosis
H37Rv (ATCC 27294 strain). Structure−antitubercular activity
relationship of all of the new compounds were correlated with
respect to dibenzo[b,d]furan, dibenzo[b,d]thiophene, and 9-
methyl-9H-carbazole skeleton. The most promising antituber-
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0.5−6.0 h to give products in excellent yields. All of the
compounds were purified through silica gel column chromatog-
raphy (HPLC purity >95%) and were fully characterized by IR,
1H nuclear magnetic resonance (NMR), 13C NMR, electro-
spray ionization (ESI), and high-resolution mass spectral
(HRMS) analysis (Supporting Information). The single-crystal
X-ray diffraction studies of 13h unambiguously confirmed the
structure (Figure 5).
Biological Evaluation and Structure−Activity Correla-
tions. A total of 36 new 1,2,3-triazole hybrids 11a−h, 12a−h,
and 13a−t were screened for in vitro activity against M.
tuberculosis H37Rv (ATCC 27294 strain) using the agar
dilution method. The MIC (minimum inhibitory concen-
tration) is defined as the minimum concentration of the
compound required to completely inhibit bacterial growth. The
MIC values (μg/mL and μM) of all of the synthesized
compounds and three standard antitubercular drugs deter-
mined in triplicate at pH 7.40 are presented in Tables 1 and 2.
Several derivatives displayed MIC values below 6.25 μg/mL, a
value postulated by the global program for the discovery of new
antituberculosis drugs as an upper threshold for the evaluation
of new M. tuberculosis therapies.12d Twenty-seven compounds
from all three series 11a−h, 12a−h, and 13a−t have MIC
values in the micromolar range, varying from 1.89 to 41.0 μM.
In series 11a−h containing 9-methyl-9H-carbazole unit, two
compounds 11g and 11h; in series 12a−h containing
dibenzo[b,d]furan unit, six compounds 12a−d,g,h; and in
series 13a−h containing dibenzo [b,d]thiophene unit, almost all
of the compounds except 13n are more active than the first-line
antitubercular drug pyrazinamide (MIC = 50.8 μM). Ten
compounds, 13a, 13c,d, 13g,h, 13k, and 13p−s, are more
active, and one compound 13f is equipotent to another first-
line antitubercular drug ethambutol (MIC = 7.6 μM).
Incidentally, almost all of the compounds from dibenzo[b,d]-
thiophene series are more active than ethambutol. Out of all of
the library of compounds tested, two compounds 13h and 13q
possess the maximum M. tuberculosis inhibitory activity with
MIC = 1.9 μM (0.78 μg/mL) and are 26 times more active
than pyrazinamide and four times more active than ethambutol.
However, all of the compounds were less active than isoniazid
(INH), the most active first-line anti-TB drug. Figure 6 allows a
visual comparison of the structure−activity correlations for an
uniform series of 9-methyl-9H-carbazole, dibenzo[b,d]furan,
and dibenzo[b,d]thiophene clubbed 1,2,3-triazoles 11a−h,
12a−h, and 13a−h with respect to their M. tuberculosis
inhibitory activity and to that of three standard drugs. From the
point of view of the establishment of structure−M. tuberculosis
inhibitory activity relationships, the data in Table 1 and 2 and
Figure 6 disclose that (i) in general, compounds of series 13a−
h have higher activity by several fold than those in series 12a−
h, which, in turn, are more potent than the corresponding
compounds in series 11a−h; that is, structure−activity
correlation of uniform series of compounds is in the order
series 13 > series 12 > series 11. (ii) In the series 13a−h, most
of the compounds have low MIC values and are very useful for
further evaluation as potential candidates; (iii) in the extended
series 13i−t, introduction of more variations in the liphophilic
handle attached to 1,2,3-triazole unit did not show any
significant changes in M. tuberculosis inhibitory activity as
compared to 13a−h, except in one case, that is, 13n. The
higher M. tuberculosis inhibitory activity for dibenzothiophene
series suggests a blend of electronic factors underlying the
activity due to the presence of sulfur atom. These observations
Figure 3. Illustration of the design strategy for library generation.
from 9-methylcarbazole, dibenzo[b,d]furan, and dibenzo[b,d]-
thiophene, respectively (Scheme 1). Compounds 7a, 7b, and
Scheme 1. Synthesis of Azides 9a−c
7c, prepared by acylation of 9-methylcarbazole, dibenzo[b,d]-
furan, and dibenzo[b,d]thiophene, respectively, were reduced to
alcohol derivatives 8a−c using NaBH4. The azide building
blocks 9a−c were accomplished in excellent yields (96−98%)
from alcohols 8a−c at 60 °C by a direct InCl3-catalyzed
protocol using trimethylsilyl azide (TMSN3).
Initially, to assess the structure−activity correlations with
respect to M. tuberculosis inhibitory activity, a uniform series of
9-methyl-9H-carbazole, dibenzo[b,d]furan, and dibenzo[b,d]-
thiophene clubbed 1,2,3-triazoles 11a−h, 12a−h, and 13a−h
were synthesized through 1,3-dipolar cycloaddition reaction
(Scheme 2) between azides 9a−c and alkynes 10a−h (Figure
Scheme 2. Synthesis of 1,2,3-Triazole Hybrid Heterocycles
through Click Reaction
4) using copper sulfate and sodium ascorbate at RT in aqueous
tert-butanol (Table 1) with the addition of 0.5 mol % 4-
nitrobenzoic acid.19 Furthermore, to expand the series,
dibenzo[b,d]thiophene conjugated triazole analogues 13i−t
were prepared by a cycloaddition reaction between azide
building block 9c and alkynes 10i−t (Table 2) as described in
the Experimental Section. All of the reactions proceeded well in
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Figure 4. Alkynes 10a−t used in the present study.
Table 1. Synthesis and in Vitro Activity Evaluation (against M. tuberculosis H37Rv) of 11a−h, 12a−h, and 13a−h Using Copper-
Catalyzed Click Chemistry
a
b
entry
azide
alkyne
reaction time (h)
product
yield (%)
CLog P
MIC (μg/mL)
MIC (μM)
1
2
9a
9a
9a
9a
9a
9a
9a
9a
9b
9b
9b
9b
9b
9b
9b
9b
9c
9c
9c
9c
9c
9c
9c
9c
10a
10b
10c
10d
10e
10f
0.5
1.0
1.5
1.5
1.0
1.5
0.5
1.0
1.0
2.0
3.0
5.0
2.0
2.5
4.0
2.5
1.0
3.0
4.5
6.0
3.0
3.0
4.5
6.0
11a
11b
11c
11d
11e
11f
96
90
98
93
87
82
94
92
91
84
93
88
90
93
88
94
85
84
88
78
95
97
89
85
5.48
4.71
5.24
6.30
2.34
4.54
5.30
7.31
5.59
4.81
5.34
6.40
2.45
4.64
5.41
7.41
6.05
5.51
6.04
7.10
2.92
5.11
5.88
7.88
25
71
25
78
3
25
75.3
70
4
25
5
25
81.7
63.1
31.5
30.6
18.4
41
6
25
7
10g
10h
10a
10b
10c
10d
10e
10f
11g
11h
12a
12b
12c
12d
12e
12f
12.5
12.5
6.25
12.5
12.5
6.25
25
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
39.2
18.0
85.3
65.2
16.3
15.8
4.4
25
10g
10h
10a
10b
10c
10d
10e
10f
12g
12h
13a
13b
13c
13d
13e
13f
6.25
6.25
1.56
3.13
1.56
1.56
6.25
3.13
1.56
0.78
0.05
1.56
6.25
9.75
4.66
4.3
20.2
7.84
3.9
10g
10h
13g
13h
1.89
0.37
7.6
INH
ethambutol
pyrazinamide
50.08
a
b
Isolated yield. CLog P calculated using Chemdraw Ultra 12.0 software by Cambridge Soft.
have close relevance to previously reported sulfur-containing
nitrofuranyl amides as antituberculosis agents.20
Compounds that exhibited SI values greater than 10 in all four
cell lines were considered nontoxic.21 When comparing the
toxicity exhibited by the potent antitubercular dibenzo[b,d]-
thiophene-1,2,3-triazole hybrids 13a−c, 13f−k, and 13p−t
using the four cell lines, five compounds 13b, 13i,j, 13s,t
exhibited lower SI values (<10) in one or more examined cell
lines. The remaining compounds showed low toxicity, that is,
higher SI values (Figure 7). The results demonstrated that the
compounds 13h and 13q with high inhibitory activity against
M. tuberculosis also exhibited lowest toxicity, that is, high SI
(55−255) against all four cell lines examined.
Cytotoxicity Evaluation. The cytotoxicity of 14 most
potent antitubercular dibenzo[b,d]thiophene-1,2,3-triazole hy-
brids 13a−c, 13f−k, and 13p−t with MIC ≤ 3.13 μg/mL was
assessed by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide assay (MTT) assay against A549 (human lung
carcinoma epithelial), SK-N-SH (human neuroblastoma), HeLa
(human epithelial cervical cancer), and DU145 (human
prostate cancer) cell lines. The inhibitory activities (IC50) in
μM are summarized in Table 3. The ratios between cytotoxicity
(IC50 in μM) and antimycobacterial activity (MIC in μM) in
vitro enabled the determination of selectivity index (SI).
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Table 2. Synthesis and in Vitro Activity Evaluation (MICs) of 13i−t against M. tuberculosis H37Rv (ATCC 27294 Strain)
a
b
entry
azide
alkyne
reaction time (h)
product
yield (%)
CLog P
MIC (μg/mL)
MIC (μM)
1
2
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
9c
10i
2.5
3.0
4.0
5.0
3.5
3.5
3.0
6.0
6.0
6.0
6.0
6.0
13i
82
93
89
89
94
96
92
83
85
85
87
84
6.55
6.40
5.88
5.75
7.15
8.40
7.94
7.27
6.70
7.10
6.38
6.85
3.13
3.13
1.56
12.5
12.5
25
8.48
8.17
3.9
10j
13j
3
10k
10l
13k
13l
4
34.6
28.7
54.9
14.5
3.68
1.91
3.45
3.98
12.5
5
10m
10n
10o
10p
10q
10r
10s
10t
13m
13n
13o
13p
13q
13r
13s
13t
6
7
6.25
1.56
0.78
1.56
1.56
3.13
8
9
10
11
12
9c
a
b
Isolated yield. CLog P calculated using Chemdraw Ultra 12.0 software by Cambridge Soft.
Table 3. Cytotoxicity (IC50 in μM) of Triazole Hybrids 13a−
c, 13f−k, and 13p−t against HeLa, A549, DU145, and SK-N-
a
SH Cell Lines
T
compd
HeLa
A549
DU145
SK-N-SH
1
13a
13b
13c
13f
13g
13h
13i
329 5.1
87 3.9
62 3.3
438 4.3
136 3.8
444 5.2
68 1.8
90 3.5
96 3.6
291 5.9
93 4.5
101 4.9
103 5.2
386 6.8
260 5.5
32 2.9
ND
2
3
80 2.2
107 3.9
225 4.8
126 4.5
105 3.7
174 5.1
100 4.2
138 5.2
150 5.5
147 6.1
222 6.5
767 7.2
120 4.5
4
189 3.8
190 4.2
482 6.6
108 4.2
78 3.5
5
Figure 5. ORTEP representation of compound 13h with thermal
displacement ellipsoids drawn at the 30% probability.
6
191
4
7
164 3.9
79 2.5
8
13j
9
13k
13p
13q
13r
13s
13t
210 4.2
162 3.8
155 3.7
457 4.6
96 4.4
852 7.2
400 5.5
249 5.2
219 3.8
272 4.7
507 6.5
30 2.8
477 6.3
342 5.9
76 3.2
21 1.9
46 2.2
CONCLUSIONS
■
10
11
12
13
14
In summary, the new 1,2,3-triazole derivatives 11a−h, 12a−h,
and 13a−t, successfully designed through molecular hybrid-
ization approach, exhibited potent in vitro antimycobacterial
activity against M. tuberculosis H37Rv (ATCC 27294 strain)
with low toxicity. The synthesis of the 9-methyl-9H-carbazole,
dibenzo[b,d]furan, and dibenzo[b ,d]thiophene clubbed 1,2,3-
triazoles 11a−h, 12a−h, and 13a−t took advantage of azide
and alkyne reactivity in the Huisgen cycloaddition (click
116 4.1
a
ND, not determined; IC50 values are indicated as means SD of
three independent experiments.
Figure 6. Comparative analysis of triazole analogues 11a−h, 12a−h, and 13a−h with respect to their in vitro activity against M. tuberculosis H37Rv
(ATCC 27294 strain) expressed by MIC in μM (controls: A, INH; B, ethambutol; and C, pyrazinamide).
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Figure 7. SI for triazole hybrids 13a−c, 13f−k, and 13p−t against HeLa, A549, DU145, and SK-N-SH cell lines. SI is the ratio of cytotoxicity (IC50
in μM) to in vitro activity against M. tuberculosis H37Rv (ATCC 27294 strain) expressed as MIC in μM.
unresolved lines), etc. 13C NMR spectra were recorded on 75 MHz
chemistry) using CuSO4 and sodium ascorbate with the
spectrometer. HRMS were obtained by using ESI-QTOF mass
spectrometry.
General Procedure for the Preparation of 7a−c. Anhydrous AlCl3
(13.09 mmol) in chloroform (10 mL) was added to acetyl chloride
(13.09 mmol) and then dibenzo[b,d]furan (11.9 mmol) in chloroform
(20 mL) slowly and left at RT for 0.75 h. After the reaction (TLC) was
addition of a small amount (0.5 mol %) of 4-nitrobenzoic
acid. Several derivatives displayed MIC values below 6.25 μg/
mL, a value postulated by the global program for the discovery
of new antituberculosis drugs as an upper threshold for the
evaluation of new M. tuberculosis therapies. From the point of
view of the establishment of SAR, the order of the M.
tuberculosis inhibitory activity of the compounds is dibenzo-
[b,d]thiophene series 13 > dibenzo[b,d]furan series 12 > 9-
methyl-9H-carbazole series 11. Out of the library of all
compounds tested, two compounds, 13h and 13q, possess
the maximum M. tuberculosis inhibitory activity with MIC = 1.9
μM (0.78 μg/mL) and is 26 times more active than
pyrazinamide and four times more active than ethambutol
and has low toxicity profile (SI in the range of 55−255 for four
different cell lines). We believe that the observed results should
be useful in guiding future global efforts to discover new
compounds with improved antitubercular activity.
completed, the reaction mixture was quenched with 1 N HCl and
extracted with chloroform (2 × 25 mL). The combined organic
extracts were washed with H2O, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuum. The crude product obtained was
purified over silica gel column chromatography using hexane/ethyl
acetate (94:6) to obtain the pure product 7b as a white solid.
1-(9-Methyl-9H-carbazol-3-yl)ethanone (7a). Yield = 64%, mp =
90−92 °C. IR νmax (cm−1): 2924, 1657, 1593, 1475, 1364, 1252, 1132,
1
1018, 817, 748. H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.13−
8.03 (m, 2H), 7.52−7.41 (m, 1H), 7.40−7.21 (m, 3H), 3.86 (s, 3H),
2.68 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 196.9, 143.4, 141.5,
128.7, 126.3, 123.0, 122.4, 121.6, 120.4, 119.9, 108.8, 107.8, 29.1, 26.5.
MS (ESI) m/z 224 [M + H]+. HR-MS (ESI) calcd for C15H14NO [M
+ H]+, 224.1075; found, 224.1085.
1-(Dibenzo[b,d]furan-2-yl)ethanone (7b). Yield = 95%, mp = 58−
60 °C. IR νmax (cm−1): 2989, 1673, 1582, 1252, 1198, 1020, 819, 749.
1H NMR (300 MHz, CDCl3): δ 8.58 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H),
8.01 (d, J = 7.6 Hz, 1H), 7.66−7.56 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H),
7.39 (t, J = 7.6 Hz, 1H), 2.72 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
197.2, 158.8, 156.8, 132.4, 128.5, 127.9, 124.5, 123.3, 121.5, 120.8,
120.3, 111.8, 111.5, 26.7. MS (ESI) m/z 211 [M + H]+. HR-MS (ESI)
calcd for C14H11O2 [M + H]+, 211.0759; found, 211.0769.
EXPERIMENTAL SECTION
■
Chemistry. Reagents and all solvents were analytically pure and
were used without further purification. All reactions were carried out in
oven-dried flasks with magnetic stirring. All of the experiments were
monitored by analytical thin-layer chromatography (TLC) performed
on silica gel GF254 precoated plates. After elution, the plate was
visualized under UV illumination at 254 nm for UV active materials.
Staining with PMA and charring on a hot plate achieved further
visualization. Solvents were removed in vacuo and heated on a water
bath at 35 °C. Silica gel finer than 200 mesh was used for column
chromatography. Columns were packed as a slurry of silica gel in
hexane and equilibrated with the appropriate solvent/solvent mixture
prior to use. The compounds were loaded neat or as a concentrated
solution using the appropriate solvent system. Applying pressure with
an air pump assisted the elution. Yields refer to chromatographically
and spectroscopically homogeneous materials unless otherwise stated.
Appropriate names for all of the new compounds were given with the
help of ChemBioOffice 2010. Melting points were measured with a
Fischer−Johns melting point apparatus and are uncorrected. The
purities of all of the compounds (>95%) used for biological screening
were determined by analytical HPLC (SPD-M20A, make: Shimadzu)
using an ODS column eluted with a gradient mixture of acetonitrile−
water. IR spectra were recorded as neat liquids or KBr pellets, and
absorptions are reported in cm−1. NMR spectra were recorded on 300
(Bruker) and 500 MHz (Varian) spectrometers in appropriate solvents
using tetramethylsilane (TMS) as an internal standard or the solvent
signals as secondary standards, and the chemical shifts are shown in δ
scales. Multiplicities of NMR signals are designated as s (singlet), d
(doublet), t (triplet), q (quartet), br (broad), m (multiplet, for
1-(Dibenzo[b,d]thiophen-2-yl)ethanone (7c). Yield = 70%, mp =
110−112 °C. IR νmax (cm−1): 3049, 2921, 1675, 1585, 1415, 1354,
1
1236, 1019, 808, 761, 736. H NMR (300 MHz, CDCl3): δ 8.70 (s,
1H), 8.26−8.11 (m, 1H), 8.07−7.96 (m, 1H), 7.95−7.80 (m, 2H),
7.52−7.43 (m, 2H), 2.71 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
197.5, 144.4, 139.5, 133.5, 127.3, 126.1, 124.8, 122.8, 122.5, 121.7,
121.5, 26.7. MS (ESI) m/z 227 [M + H]+. HR-MS (ESI) calcd for
C14H11OS [M + H]+, 227.0530; found, 227.0527.
General Procedure for the Preparation of 8a−c. To the solution
of 1-(dibenzo[b,d]furan-2-yl)ethanone 7b (9.5 mmol) in dichloro-
methane/methanol (1:1, 20 mL), sodium borohydride (9.5 mmol)
was added at 0 °C and stirred at RT for 1 h. The crude reaction
mixture was evaporated under vacuum, water (15 mL) and
dichloromethane (2 × 25 mL) were added, and the organic layer
was separated, washed with H2O, dried over anhydrous Na2SO4, and
filtered. The residue thus obtained after rotary evaporation was
chromatographed over silica gel column and eluted with hexane/ethyl
acetate (90:10) to give 8b.
1-(9-Methyl-9H-carbazol-3-yl)ethanol (8a). Syrup, yield = 94%. IR
νmax (cm−1): 3325, 2967, 2922, 1598, 1482, 1330, 1246, 1070, 806,
737. 1H NMR (300 MHz, CDCl3): δ 8.07−7.93 (m, 2H), 7.39 (d, J =
6.9 Hz, 2H), 7.33−7.10 (m, 3H), 5.00 (q, J = 6.4 Hz, 1H), 3.78 (s,
3916
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3H), 1.56 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 141.2,
140.5, 134.7, 125.6, 125.3, 124.2, 122.8, 120.3, 118.8, 118.6, 118.4,
108.3, 75.5, 44.7, 25.3. MS (ESI) m/z 226 [M + H]+. HR-MS (ESI)
calcd for C15H15NONa [M + Na]+, 248.1051; found, 248.1063.
1-(Dibenzo[b,d]furan-2-yl)ethanol (8b). Yield = 96%, mp = 62−64
(ESI) m/z 353 [M + H]+. HR-MS (ESI) calcd for C23H21N4 [M +
H]+, 353.1766; found, 353.1760.
9-Methyl-3-(1-(4-propyl-1H-1,2,3-triazol-1-yl)ethyl)-9H-carbazole
(11b). mp = 120−122 °C. IR νmax (cm−1): 3113, 3060, 2958, 2926,
1598, 1489, 1330, 1249, 1126, 1043, 742. 1H NMR (300 MHz,
CDCl3): δ 8.07−7.97 (m, 2H), 7.50−7.39 (m, 1H), 7.40−7.28 (m,
3H), 7.24−7.15 (m, 1H), 7.03 (s, 1H), 5.91 (q, J = 7.5 Hz, 1H), 3.85
(s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 2.09 (d, J = 7.5 Hz, 3H), 1.63 (sex, J
= 7.5 Hz, 2H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ 148.0, 141.3, 140.6, 130.4, 126.1, 124.4, 122.8, 122.3, 120.2, 119.3,
119.1, 118.4, 108.8, 108.6, 60.3, 29.1, 27.7, 22.6, 21.6, 13.7. MS (ESI)
m/z 319 [M + H]+. HR-MS (ESI) calcd for C20H23N4 [M + H]+,
319.1922; found, 319.1924.
1
°C. IR νmax (cm−1): 3366, 2971, 2923, 1449, 1197, 1073, 748. H
NMR (300 MHz, CDCl3): δ 8.04−7.76 (m, 2H), 7.61−7.36 (m, 4H),
7.35−7.26 (m, 1H), 5.04 (q, J = 6.4 Hz, 1H), 1.57 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 156.5, 140.5, 127.1, 124.7, 124.2,
124.1, 122.6, 120.6, 120.1, 117.4, 111.6, 111.4, 70.4, 25.6. MS (ESI)
m/z 235 [M + Na]+. HR-MS (ESI) calcd for C14H12O2Na [M + Na]+,
235.0734; found, 235.0730.
1-(Dibenzo[b,d]thiophen-2-yl)ethanol (8c). Yield = 95%, mp =
3-(1-(4-Butyl-1H-1,2,3-triazol-1-yl)ethyl)-9-methyl-9H-carbazole
1
61−62 °C. IR νmax (cm−1): 3280, 2956, 1490, 1229, 1085, 760. H
(11c). mp = 139−141 °C. IR νmax (cm−1): 3118, 3060, 2951, 2927,
NMR (300 MHz, CDCl3): δ 8.18−8.06 (m, 2H), 7.87−7.73 (m, 2H),
7.48−7.36 (m, 3H), 5.05 (q, J = 6.4 Hz, 1H), 1.57 (d, J = 6.4 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 142.3, 139.7, 138.4, 126.7, 124.3,
122.8, 122.7, 121.5, 118.2, 70.4, 25.5. MS (ESI) m/z 211 [M − OH]+.
HR-MS (ESI) calcd for C14H11S [M − OH]+, 211.0581; found,
211.0578. .
1
2861, 1599, 1489, 1332, 1250, 1126, 1042, 743. H NMR (300 MHz,
CDCl3): δ 8.08−7.97 (m, 2H), 7.50−7.40 (m, 1H), 7.39−7.29 (m,
3H), 7.24−7.16 (m, 1H), 7.02 (s, 1H), 5.92 (q, J = 6.9 Hz, 1H), 3.87
(s, 3H), 2.63 (t, J = 7.5 Hz, 2H), 2.09 (d, J = 6.9 Hz, 3H), 1.59 (qt, J =
7.5 Hz, 2H), 1.33 (sex, J = 7.5 Hz, 2H), 0.89 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 148.3, 141.3, 140.7, 130.7, 126.1, 124.5,
122.3, 120.3, 119.1, 118.4, 108.8, 108.6, 60.3, 31.5, 29.1, 25.4, 22.3,
21.6, 13.7. MS (ESI) m/z 355 [M + Na]+. HR-MS (ESI) calcd for
C21H25N4 [M + H]+, 333.2079; found, 333.2086.
3-(1-(4-Hexyl-1H-1,2,3-triazol-1-yl)ethyl)-9-methyl-9H-carbazole
(11d). mp = 130−132 °C. IR νmax (cm−1): 3115, 3060, 2925, 2855,
1599, 1489, 1332, 1250, 1126, 1044, 743. 1H NMR (400 MHz,
CDCl3): δ 8.07−7.97 (m, 2H), 7.49−7.41 (m, 1H), 7.40−7.30 (m,
3H), 7.20 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.92 (q, J = 6.8 Hz, 1H),
3.86 (s, 3H), 2.62 (t, J = 7.4 Hz, 2H), 2.09 (d, J = 6.8 Hz, 3H), 1.59
(qt, J = 7.4 Hz, 2H), 1.35−1.23 (m, 6H), 0.84 (t, J = 7.4 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 141.3, 140.7, 130.4, 126.1, 124.4, 122.8,
122.3, 120.3, 119.1, 118.4, 108.7, 108.6, 60.3, 31.4, 29.3, 29.1, 28.9,
25.7, 22.4, 21.6, 13.9. MS (ESI) m/z 383 [M + Na]+. HR-MS (ESI)
calcd for C23H29N4 [M + H]+, 361.2392; found, 361.2387.
General Procedure for the Preparation of 9a−c. To the mixture of
1-(dibenzo[b,d]furan-2-yl) ethanol 8b (9.4 mmol) and trimethylsillyl
azide (9.4 mmol) in nitromethane (12 mL), indium chloride (5 mol
%) was added and heated at 60 °C for 0.5 h. After completion of the
reaction, solvent was evaporated, and the crude residue was purified
over silica gel column using hexane/ethylacetate (97:3) to give as a
pale yellow syrup 8c.
3-(1-Azidoethyl)-9-methyl-9H-carbazole (9a). Syrup, yield = 96%.
1
IR νmax (cm−1): 2924, 2857, 2097, 1602, 1483, 1246, 741. H NMR
(300 MHz, CDCl3): δ 8.05 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 7.47−
7.29 (m, 4H), 7.23−7.18 (m, 1H), 4.78 (q, J = 6.7 Hz, 1H), 3.85 (s,
3H), 1.62 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 141.4,
140.7, 131.2, 126.0, 124.3, 122.8, 122.5, 120.3, 119.0, 118.3, 108.7,
108.6, 61.8, 29.1, 22.0. MS (ESI) m/z 208 [M − N3]+. HR-MS (ESI)
calcd for C15H14N [M − N3]+, 208.1126; found, 208.1118.
2-(1-Azidoethyl)dibenzo[b,d]furan (9b). Syrup, yield = 98%. IR
νmax (cm−1): 2978, 2102, 1479, 1449, 1198, 748. 1H NMR (300 MHz,
CDCl3): δ 7.99−7.82 (m, 2H), 7.60−7.48 (m, 2H), 7.47−7.19 (m,
3H), 4.75 (q, J = 6.7 Hz, 1H), 1.61 (d, J = 6.7 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 156.7, 155.9, 135.6, 127.4, 125.5, 124.7, 124.0, 122.8,
120.7, 118.5, 111.9, 111.8, 61.2, 22.4. MS (ESI) m/z 195 [M − N3]+.
HR-MS (ESI) calcd for C14H11O [M − N3]+, 195.0804; found,
195.0795.
1-(1-(9-Methyl-9H-carbazol-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)-
methanol (11e). mp = 109−111 °C. IR νmax (cm−1): 3282, 3123,
1
2919, 1599, 1490, 1331, 1246, 1143, 1015, 741, 712. H NMR (300
MHz, DMSO-d6): δ 8.13 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.83 (s,
1H), 7.52−7.41 (m, 4H), 7.18 (t, J = 6.7 Hz, 1H), 6.01 (q, J = 7.1 Hz,
1H), 4.52 (s, 2H), 3.85 (s, 3H), 2.05 (d, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, DMSO-d6): δ 148.0, 140.9, 140.2, 131.2, 125.9, 124.5,
121.8, 121.7, 121.1, 120.2, 118.8, 118.4, 109.2, 59.5, 55.0, 28.9, 21.3.
MS (ESI) m/z 307 [M + H]+. HR-MS (ESI) calcd for C18H19N4O [M
+ H]+, 307.1558; found, 307.1548.
3-(1-(4-(Benzyloxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)-9-methyl-
9H-carbazole (11f). mp = 117−119 °C. IR νmax (cm−1): 3127, 3063,
2922, 2854, 1598, 1490, 1251, 1121, 740. 1H NMR (300 MHz,
CDCl3): δ 8.08−7.97 (m, 2H), 7.51−7.29 (m, 5H), 7.28−7.14 (m,
6H), 5.95 (q, J = 7.1 Hz, 1H), 4.58 (s, 2H), 4.51 (s, 2H), 3.85 (s, 3H),
2.10 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 144.9, 141.3,
140.7, 137.7, 129.9, 128.3, 127.8, 127.6, 126.1, 124.5, 122.8, 122.3,
121.2, 120.3, 119.1, 118.5, 108.8, 108.6, 72.4, 63.7, 60.6, 29.1, 21.6. MS
(ESI) m/z 397 [M + H]+. HR-MS (ESI) calcd for C25H25N4O [M +
H]+, 397.2028; found, 397.2045.
2-(1-Azidoethyl)dibenzo[b,d]thiophene (9c). Syrup, yield = 98%.
1
IR νmax (cm−1): 3280, 2956, 1490, 1229, 1085, 760. H NMR (300
MHz, CDCl3): δ 8.21−8.03 (m, 2H), 7.88−7.77 (m, 2H), 7.49−7.34
(m, 3H), 4.78 (q, J = 6.7 Hz, 1H), 1.63 (d, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 140.0, 139.3, 137.5, 135.9, 135.3, 126.9, 125.0,
124.4, 123.1, 122.9, 121.7, 119.3, 61.2, 22.3. MS (ESI) m/z 211 [M −
N3]+. HR-MS (ESI) calcd for C14H11S [M − N3]+, 211.0581; found,
211.0578.
General Procedure for the Preparation of 11a−h, 12a−h, and
13a−t. A mixture of 2-(1-azidoethyl) dibenzo[b,d]thiophene (0.39
mmol), phenyl acetylene (0.39 mmol), CuSO4 pentahydrate (1.0 mol
%), and sodium ascorbate (2.0 mol %), 4-nitrobenzoic acid (0.5 mol
%) in tert-butanol (1 mL), and H2O (1 mL) was stirred at RT for an
appropriate time, monitored by TLC, and subsequently extracted with
chloroform (3 × 5 mL). The combined organic extracts were washed
with H2O, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The crude residue was purified over silica gel column using
hexane/ethyl acetate to obtain the pure product.
9-Methyl-3-(1-(4-(2-nitrophenyl)-1H-1,2,3-triazol-1-yl)ethyl)-9H-
carbazole (11g). mp = 126−128 °C. IR νmax (cm−1): 3137, 3078,
1
2926, 1604, 1524, 1352, 1248, 1154, 1035, 747. H NMR (300 MHz,
CDCl3): δ 8.11 (dd, J = 1.2 and 7.8 Hz, 1H), 8.07−8.02 (m, 2H), 7.72
(dd, J = 0.9 and 8.0 Hz, 1H), 7.63 (s, 1H), 7.62−7.55 (m, 1H), 7.46−
7.38 (m, 3H), 7.37−7.32 (m, 2H), 7.22−7.16 (m, 1H), 6.01 (q, J = 7.1
Hz, 1H), 3.86 (s, 3H), 2.16 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 148.0, 141.8, 141.3, 140.7, 132.3, 131.0, 129.8, 128.6, 126.1,
124.8, 124.2, 123.8, 122.9, 121.7, 120.3, 119.1, 118.4, 108.9, 108.6,
61.0, 29.0, 21.7.
9-Methyl-3-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)-9H-carba-
zole (11a). mp = 187−189 °C. IR νmax (cm−1): 3122, 2923, 1599,
1
1477, 1332, 1249, 1152, 1034, 763. H NMR (400 MHz, CDCl3): δ
3-(1-(4-(4-tert-Butylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)-9-methyl-
9H-carbazole (11h). mp = 164−166 °C. IR νmax (cm−1): 3121, 2960,
8.12−8.00 (m, 2H), 7.76−7.68 (dd, J = 1.1 and 8.2 Hz, 2H), 7.51−
7.28 (m, 7H), 7.24−7.17 (m, 2H), 6.02 (q, J = 7.0 Hz, 1H), 3.88 (s,
3H), 2.17 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 147.5,
141.4, 140.8, 130.7, 130.0, 128.6, 127.9, 126.1, 125.5, 124.5, 122.9,
122.5, 120.3, 119.2, 118.5, 118.4, 108.9, 108.6, 60.6, 29.1, 21.6. MS
1
2868, 1601, 1490, 1334, 1251, 1221, 1035, 828, 747. H NMR (300
MHz, CDCl3): δ 8.11−8.00 (m, 2H), 7.69−7.59 (m, 2H), 7.51−7.27
(m, 7H), 7.24−7.17 (m, 1H), 6.00 (q, J = 6.9 Hz, 1H), 3.87 (s, 3H),
2.15 (d, J = 6.9 Hz, 3H), 1.30 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
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13C NMR (75 MHz, CDCl3): δ 156.6, 155.9, 148.1, 142.0, 134.3,
152.3, 150.9, 140.7, 130.1, 127.9, 126.1, 125.5, 125.3, 124.5, 122.3,
120.3, 119.2, 118.5, 108.9, 108.6, 60.6, 34.5, 31.2, 29.1, 21.7. MS (ESI)
m/z 409 [M + H]+. HR-MS (ESI) calcd for C27H29N4 [M + H]+,
409.2392; found, 409.2380.
132.4, 131.0, 128.8, 127.6, 125.6, 124.7, 123.9, 123.6, 122.9, 121.8,
121.2, 120.8, 118.8, 112.2, 111.7, 60.6, 21.8. MS (ESI) m/z 385 [M +
H]+. HR-MS (ESI) calcd for C22H16N4O3 Na[M + Na]+, 407.1114;
found, 407.1105.
1-(1-(Dibenzo[b,d]furan-2-yl)ethyl)-4-phenyl-1H-1,2,3-triazole
(12a). mp = 169−170 °C. IR νmax (cm−1): 3079, 2988, 2927, 1591,
4-(4-tert-Butylphenyl)-1-(1-(dibenzo[b,d]furan-2-yl)ethyl)-1H-
1,2,3-triazole (12h). mp = 134−136 °C. IR νmax (cm−1): 3133, 2964,
1594, 1450, 1358, 1206, 1033, 828, 747. 1H NMR (300 MHz, CDCl3):
δ 7.95−7.83 (m, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.61−7.21 (m, 8H),
5.95 (q, J = 6.9 Hz, 1H), 2.12 (d, J = 6.9 Hz, 3H), 1.31 (s, 9H). 13C
NMR (75 MHz, CDCl3): δ 155.8, 151.1, 147.7, 134.6, 127.6, 125.68,
125.63, 125.3, 122.9, 121.3, 121.1, 120.7, 118.8, 118.1, 112.0, 111.7,
60.2, 34.5, 31.2, 21.6. MS (ESI) m/z 396 [M + H]+. HR-MS (ESI)
calcd for C26H26N3O [M + H]+, 396.2075; found, 396.2077.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-phenyl-1H-1,2,3-tria-
zole (13a). mp = 149−151 °C. IR νmax (cm−1): 3122, 2923, 2853,
1462, 1424, 1227, 1073, 1024, 764, 731. 1H NMR (300 MHz, CDCl3):
δ 8.17−8.07 (m, 2H), 7.88−7.79 (m, 2H), 7.78−7.72 (m, 2H), 7.59 (s,
1H), 7.48−7.20 (m, 6H), 6.00 (q, J = 7.55 Hz, 1H), 2.16 (d, J = 7.55
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 143.3, 136.2, 136.0, 134.9,
130.5, 128.7, 128.0, 127.1, 127.0, 125.6, 125.1, 124.5, 123.4, 122.8,
121.7, 120.6, 120.0, 119.6, 118.4, 60.3, 21.5. MS (ESI) m/z 356 [M +
H]+. HR-MS (ESI) calcd for C22H17N3SNa [M + Na]+, 378.1040;
found, 378.1050.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-propyl-1H-1,2,3-triazole
(13b). mp = 67−69 °C. IR νmax (cm−1): 3112, 3062, 2925, 2853,
1463,1426, 1128, 1023, 817, 761, 730. 1H NMR (300 MHz, CDCl3): δ
8.15−8.06 (m, 1H), 8.02 (s, 1H), 7.86−7.78 (m, 2H), 7.47−7.40 (m,
2H), 7.38−7.32 (dd, J = 1.9 and 9.8 Hz 1H), 7.11 (s, 1H), 5.90 (q, J =
6.8 Hz, 1H), 2.64 (t, J = 7.8 Hz, 2H), 2.09 (d, J = 6.8 Hz, 3H), 1.67
(sex, J = 7.8 Hz, 2H), 0.94 (t, J = 7.8 Hz, 3H) .13C NMR (75 MHz,
CDCl3): δ 148.3, 139.8, 139.4, 136.6, 135.9, 134.9, 127.0, 125.0, 124.5,
123.3, 122.8, 121.6, 119.5, 60.0, 27.6, 22.6, 21.4, 13.7. MS (ESI) m/z
322 [M + H]+. HR-MS (ESI) calcd for C19H20N3S [M + H]+,
322.1377; found, 322.1372.
1
1443, 1198, 1075, 1030, 758. H NMR (300 MHz, CDCl3): δ 7.98−
7.84 (m, 2H), 7.75 (d, J = 7.1 Hz, 2H), 7.61−7.50 (m, 2H), 7.50−7.19
(m, 7H), 5.98 (q, J = 6.9 Hz, 1H), 2.15 (d, J = 6.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 156.6, 155.9, 147.7, 134.4, 130.5, 128.7, 128.0,
127.6, 125.7, 125.6, 124.8, 123.6, 122.9, 120.7, 118.8, 118.3, 112.1,
11.7, 60.3, 21.6. MS (ESI) m/z 340 [M + H]+. HR-MS (ESI) calcd for
C22H18N3O [M + H]+, 340.1449; found, 340.1464.
1-(1-(Dibenzo[b,d]furan-2-yl)ethyl)-4-propyl-1H-1,2,3-triazole
(12b). mp = 67−69 °C. IR νm1ax (cm−1): 3115, 3064, 2956, 2926, 1550,
1445, 1201, 1045, 817, 747. H NMR (300 MHz, CDCl3): δ 7.97−
7.80 (m, 2H), 7.58−7.27 (m, 5H), 7.09 (s, 1H), 5.89 (q, J = 6.9 Hz,
1H), 2.64 (t, J = 7.3 Hz, 2H), 2.08 (d, J = 6.9 Hz, 3H), 1.66 (sex, J =
7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
156.5, 148.2, 134.8, 127.5, 125.5, 122.8, 121.2, 120.9, 120.6, 119.3,
118.7, 111.9, 111.6, 109.6, 59.8, 27.6, 22.5, 21.6, 13.7. MS (ESI) m/z
306 [M + H]+. HR-MS (ESI) calcd for C19H20N3O [M + H]+,
306.1606; found, 306.1618.
4-Butyl-1-(1-(dibenzo[b,d]furan-2-yl)ethyl)-1H-1,2,3-triazole
(12c). mp = 84−86 °C. IR νmax (cm−1): 3115, 3067, 2922, 2858, 1591,
1440, 1202, 1038, 743. 1H NMR (300 MHz, CDCl3): δ 7.96−7.79 (m,
2H), 7.60−7.19 (m, 6H), 5.88 (q, J = 6.9 Hz, 1H), 2.65 (t, J = 7.3 Hz,
2H), 2.07 (d, J = 6.9 Hz, 3H), 1.61 (qt, J = 7.3 Hz, 2H), 136 (sex, J =
7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
156.6, 155.8, 148.5, 134.8, 127.6, 125.6, 122.9, 120.7, 119.2, 118.77,
112.0, 111.7, 59.9, 31.4, 25.4, 22.3, 21.6, 13.7. MS (ESI) m/z 320 [M +
H]+. HR-MS (ESI) calcd for C20H22N3O [M + H]+, 320.1762; found,
320.1750.
1-(1-(Dibenzo[b,d]furan-2-yl)ethyl)-4-hexyl-1H-1,2,3-triazole
(12d). mp = 91−93 °C. IR νm1ax (cm−1): 3117, 3070, 2923, 2851, 1585,
1445, 1202, 1047, 818, 747. H NMR (300 MHz, CDCl3): δ 7.95−
7.79 (m, 2H), 7.59−7.49 (m, 2H), 7.48−7.39 (m, 1H), 7.38−7.21 (m,
2H), 7.09 (s, 1H), 5.89 (q, J = 6.9 Hz, 1H), 2.65 (t, J = 7.5 Hz, 2H),
2.07 (d, J = 6.9 Hz, 3H), 1.62 (sex, J = 7.5 Hz, 2H), 1.34−1.20 (m,
6H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 155.8,
148.5, 134.8, 127.5, 125.6, 124.6, 123.6, 122.9, 120.7, 119.2, 118.7,
111.9, 111.7, 109.6, 59.9, 31.4, 29.3, 28.8, 25.7, 22.4, 21.6, 13.9. MS
(ESI) m/z 348 [M + H]+. HR-MS (ESI) calcd for C22H26N3O [M +
H]+, 348.2075; found, 348.2085.
(1-(1-(Dibenzo[b,d]furan-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)-
methanol (12e). mp = 117−119 °C. IR νmax (cm−1): 3278, 3116,
3072, 2925, 1589, 1196, 1141, 1030, 750. 1H NMR (300 MHz,
DMSO-d6): δ 8.07−7.88 (m, 2H), 7.78−7.65 (m, 1H), 7.62−7.38 (m,
4H), 7.32 (t, J = 7.5 Hz, 1H), 5.98 (q, J = 6.9 Hz, 1H), 4.86 (s, br,
1H), 4.59 (s, 2H), 2.07 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
DMSO): δ 155.9, 148.1, 136.1, 128.0, 126.4, 123.8, 123.4, 121.5, 121.3,
111.9, 111.8, 109.8, 59.2, 55.1, 21.3. MS (ESI) m/z 294 [M + H]+.
HR-MS (ESI) calcd for C17H16N3O2 [M + H]+, 294.1242; found,
294.1248.
4-Butyl-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-1,2,3-triazole
(13c). mp = 84−86 °C. IR νmax (cm−1): 3111, 3061, 2926, 2859, 1546,
1
1458, 1425, 1220, 1131, 1034, 730. H NMR (300 MHz, CDCl3): δ
8.15−8.05 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.86−7.77 (m, 2H),
7.49−7.39 (m, 2H), 7.38−7.30 (dd, J = 1.5 and 8.3 Hz, 1H), 7.11 (s,
1H), 5.90 (q, J = 6.9 Hz, 1H), 2.66 (t, J = 7.5 Hz, 2H), 2.09 (d, J = 6.9
Hz, 3H), 1.62 (q, J = 7.3 Hz, 2H), 1.36 (sex, J = 7.3 Hz, 2H), 0.91 (t, J
= 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 139.8, 136.6, 135.9,
134.9, 127.0, 125.0, 124.4, 123.2, 122.8, 121.9, 121.6, 121.4, 120.5,
119.4, 119.3, 59.9, 31.4, 25.4, 22.2, 13.7. MS (ESI) m/z 336 [M + H]+.
HR-MS (ESI) calcd for C20H22N3S [M + H]+, 336.1534; found,
336.1543.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-hexyl-1H-1,2,3-triazole
(13d). mp = 71−73 °C. IR νmax (cm−1): 3112, 3061, 2924, 2854,
1
1461,1425, 1222, 1130, 1026, 729. H NMR (300 MHz, CDCl3): δ
8.15−8.05 (m, 1H), 8.01 (s, 1H), 7.88−7.86 (m, 2H), 7.49−7.39 (m,
2H), 7.38−7.29 (m, 1H), 7.11 (s, 1H), 5.90 (q, J = 6.9 Hz, 1H), 2.65
(t, J = 7.5 Hz, 2H), 2.08 (d, J = 6.9 Hz, 3H), 1.62 (q, J = 7.5 Hz, 2H),
1.34−1.22 (m, 6H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 148.6, 139.8, 139.4, 136.6, 135.8, 134.9, 127.0, 125.0, 124.4,
123.2, 122.8, 121.9, 121.6, 120.5, 119.4, 59.9, 31.4, 29.3, 28.8, 25.7,
22.4, 21.4, 13.9. MS (ESI) m/z 364 [M + H]+. HR-MS (ESI) calcd for
C22H26N3S [M + H]+, 364.1847; found, 364.1850.
4-(Benzyloxymethyl)-1-(1-(dibenzo[b,d]furan-2-yl)ethyl)-1H-
1,2,3-triazole (12f). mp = 82−83 °C. IR νmax (cm−1): 3137, 3061,
2926, 2858, 1451, 1199, 1094, 1043, 749. 1H NMR (300 MHz,
CDCl3): δ 7.95−7.83 (m, 2H), 7.59−7.19 (m, 11H), 5.93 (q, J = 7.1
Hz, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 2.10 (d, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 156.6, 145.2, 137.6, 134.3, 128.3, 127.9,
127.7, 127.6, 125.7, 124.7, 123.6, 122.6, 122.9, 121.2, 120.7, 118.9,
112.0, 111.7, 109.8, 72.6, 63.7, 60.2, 21.6. MS (ESI) m/z 384 [M +
H]+. HR-MS (ESI) calcd for C24H22N3O2 [M + H]+, 384.1712; found,
384.1719.
1-(1-(Dibenzo[b,d]furan-2-yl)ethyl)-4-(2-nitrophenyl)-1H-1,2,3-
triazole (12g). mp = 64−66 °C. IR νmax (cm−1): 3065, 2924, 2856,
1611, 1526, 1439, 1350, 1192, 1026, 743. 1H NMR (300 MHz,
CDCl3): δ 8.02 (d, J = 7.5 Hz, 1H), 7.90−7.79 (m, 2H), 7.75 (s, 1H),
7.69 (d, J = 7.3 Hz, 1H), 7.60−7.44 (m, 3H), 7.43−7.31 (m, 3H), 7.26
(t, J = 7.3 Hz, 1H), 5.94 (q, J = 6.9 Hz, 1H), 2.08 (d, J = 6.9 Hz, 3H).
(1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)-
methanol (13e). mp = 155−157 °C. IR νmax (cm−1): 3293, 3116,
1
3072, 2923, 2854, 1462, 1419, 1343, 1140, 1026, 732. H NMR (300
MHz, CDCl3): δ 8.14−8.09 (m, 1H), 8.05 (s, 1H), 7.87−7.79 (m,
2H), 7.48−7.42 (m, 2H), 7.41−7.32 (m, 2H), 5.94 (q, J = 7.1 Hz,
1H), 4.71 (s, 2H), 2.11 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 147.7, 139.8, 139.6, 136.0, 134.8, 127.1, 125.0, 124.5, 123.3,
122.8, 121.6, 120.5, 119.6, 60.3, 56.3, 21.4. MS (ESI) m/z 310 [M +
H]+. HR-MS (ESI) calcd for C17H15N3ONaS [M + Na]+, 332.0833;
found, 332.0833.
4-(Benzyloxymethyl)-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-
1,2,3-triazole (13f). Syrup. IR νmax (cm−1): 3139, 3060, 2925, 2857,
3918
dx.doi.org/10.1021/jm300125e | J. Med. Chem. 2012, 55, 3911−3922

Journal of Medicinal Chemistry
Article
1
1452, 1322, 1226, 1077, 1042, 764. H NMR (300 MHz, CDCl3): δ
(300 MHz, CDCl3): δ 8.75−8.54 (m, 1H), 8.48−8.10 (m, 3H), 8.07−
7.87 (m, 3H), 7.85−7.72 (m, 2H), 7.61−7.39 (m, 3H), 7.27−7.05 (m,
2H), 6.16 (q, J = 7.1 Hz, 1H), 3.89 (s, 3H), 2.13 (d, J = 7.1 Hz, 3H).
MS (ESI) m/z 436 [M + H]+. HR-MS (ESI) calcd for C27H22N3OS
[M + H]+, 436.1483; found, 436.1476.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(phenanthren-9-yl)-1H-
1,2,3-triazole (13n). mp = 149−151 °C. IR νmax (cm−1): 3074, 2982,
1430, 1231, 1051, 896, 763, 728. 1H NMR (300 MHz, CDCl3): δ 8.72
(d, J = 8.1 Hz, 1H), 8.66 (d, J = 8.1 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H),
8.40−8.09 (m, 3H), 7.95 (s, 1H), 7.91−7.75 (m, 3H), 7.71−7.50 (m,
5H), 7.50−7.35 (m, 2H), 6.16 (q, J = 7.1 Hz, 1H), 2.21 (d, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 145.6, 138.9, 138.3, 137.0, 135.1,
134.5, 130.6, 129.9, 129.4, 129.3, 128.2, 127.4, 126.7, 126.5, 126.4,
126.3, 126.1, 125.2, 124.2, 122.8, 122.6, 122.5, 122.4, 122.2, 121.6,
119.8, 59.5, 21.1. MS (ESI) m/z 456 [M + H]+. HR-MS (ESI) calcd
for C30H22N3S [M + H]+, 456.1534; found, 456.1525.
4-(Biphenyl-4-yl)-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-
1,2,3-triazole (13o). mp = 193−195 °C. IR νma1x (cm−1): 3099, 2923,
1595, 1482, 1232, 1024, 841, 818, 730, 693. H NMR (300 MHz,
CDCl3): δ 8.18−8.08 (m, 2H), 7.91−7.78 (m, 5H), 7.62 (s, 1H),
7.60−7.53 (m, 4H), 7.49−7.27 (m, 5H), 6.00 (q, J = 7.1 Hz, 1H), 2.17
(d, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 146.0, 139.4,
139.3, 138.9, 138.2, 137.5, 135.1, 134.6, 129.7, 128.8, 127.4, 127.2,
127.0, 126.4, 125.6, 125.4, 124.7, 123.3, 123.0, 122.0, 120.1, 120.0,
59.4, 21.1. MS (ESI) m/z 432 [M + H]+. HR-MS (ESI) calcd for
C28H22N3S [M + H]+, 432.1534; found, 432.1528.
8.15−8.07 (m, 1H), 8.04 (s, 1H), 7.89−7.77 (m, 2H), 7.49−7.33 (m,
4H), 7.30−7.18 (m, 5H), 5.94 (q, J = 6.9 Hz, 1H), 4.61 (s, 2H), 4.55
(s, 2H), 2.11 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
145.2, 139.8, 139.6, 137.6, 136.1, 135.9, 134.9, 128.3, 127.9, 127.7,
127.1, 125.1, 124.5, 123.3, 122.8, 121.6, 121.2, 119.6, 72.6, 63.7, 60.2,
21.4. MS (ESI) m/z 400 [M + H]+. HR-MS (ESI) calcd for
C24H21N3ONaS [M + Na]+, 422.1303; found, 422.1299.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(2-nitrophenyl)-1H-
1,2,3-triazole (13g). mp = 144−146 °C. IR νmax (cm−1): 3123, 2924,
1
2852, 1532, 1355, 1228, 764, 732. H NMR (300 MHz, CDCl3): δ
8.18−8.08 (m, 2H), 8.05 (s, 1H), 7.89−7.72 (m, 4H), 7.63 (t, J = 7.5
Hz, 1H), 7.51−7.36 (m, 4H), 6.00 (q, J = 6.9 Hz, 1H), 2.16 (d, J = 6.9
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 148.0, 139.7, 139.6, 136.1,
135.9, 134.8, 132.4, 131.0, 128.8, 127.0, 124.8, 124.6, 124.4, 123.9,
123.3, 122.7, 121.9, 121.7, 119.4, 60.6, 21.6. MS (ESI) m/z 401 [M +
H]+. HR-MS (ESI) calcd for C22H16N4O2NaS [M + Na]+, 423.0891;
found, 423.0895.
4-(4-tert-Butylphenyl)-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-
1,2,3-triazole (13h). mp = 131−133 °C. IR νmax (cm−1): 3091, 2959,
1
2925, 2861, 1452, 1421, 1269, 1225, 1080, 1028, 727. H NMR (300
MHz, CDCl3): δ 8.17−8.08 (m, 1H), 8.06 (s, 1H), 7.87−7.77 (m,
2H), 7.67 (t, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.49−7.32 (m, 5H), 5.99
(q, J = 6.9 Hz, 1H), 2.15 (d, J = 6.9 Hz, 3H), 1.32 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 151.1, 147.8, 139.8, 139.6, 136.4, 135.9, 134.9,
127.7, 127.1, 125.6, 125.3, 125.0, 124.5, 123.3, 122.8, 121.7, 119.5,
118.1, 60.2, 34.5, 31.2, 21.5. MS (ESI) m/z 412 [M + H]+. HR-MS
(ESI) calcd for C26H25N3NaS [M + Na]+, 434.1666; found, 434.1679.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-p-tolyl-1H-1,2,3-triazole
(13i). mp = 163−165 °C. IR νmax (cm−1): 3103, 2920, 1888, 1589,
1495, 1420, 1225, 1152, 1040, 761, 731. 1H NMR (300 MHz, CDCl3):
δ 8.16−8.03 (m, 2H), 7.88−7.75 (m, 2H), 7.63 (d, J = 7.9 Hz, 2H),
7.55(s, 1H), 7.50−7.32(m, 3H), 7.13 (d, J = 7.9 Hz, 2H), 5.97 (q, J =
7.1 Hz, 1H), 2.34 (s, 3H), 2.14 (d, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 147.8, 139.8, 137.8, 136.3, 134.9, 129.3, 127.7, 127.1,
125.5, 125.0, 124.5, 123.3, 122.8, 122.0, 121.6, 120.6, 119.5, 118.0,
60.2, 21.5, 21.2. MS (ESI) m/z 370 [M + H]+. HR-MS (ESI) calcd for
C23H20N3S [M + H]+, 370.1377; found, 370.1362.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(2,4-dichlorophenyl)-
1H-1,2,3-triazole (13p). mp = 124−126 °C. IR νmax (cm−1): 2924,
1
1549, 1465, 1342, 1229, 1103, 1051, 861, 821, 762, 731. H NMR
(300 MHz, CDCl3): δ 8.26 (d, J = 8.4 Hz, 1H), 8.16−8.05 (m, 3H),
7.89−7.76 (m, 2H), 7.49−7.37 (m, 4H), 7.33 (dd, J = 2.0 and 8.4 Hz,
1H), 6.01 (q, J = 7.1 Hz, 1H), 2.17 (d, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 143.1, 139.8, 139.6, 136.1, 135.9, 134.8, 133.9, 131.4,
130.4, 129.7, 127.8, 127.4, 127.0, 124.8, 124.4, 123.3, 122.8, 122.0,
121.6, 119.4, 60.5, 21.6. MS (ESI) m/z 424 [M + H]+. HR-MS (ESI)
calcd for C22H16N3SCl2 [M + H]+, 424.0441; found, 424.0440.
4-(2-Chloro-4-fluorophenyl)-1-(1-(dibenzo[b,d]thiophen-2-yl)-
ethyl)-1H-1,2,3-triazole (13q). mp = 147−149 °C. IR νmax (cm−1):
1
3127, 2926, 1604, 1478, 1260, 1226, 1045, 895, 814, 731. H NMR
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-phenethyl-1H-1,2,3-tri-
azole (13j). mp = 94−96 °C. IR νmax (cm−1): 3109, 3024, 2924, 1544,
(300 MHz, CDCl3): δ 8.51−8.32 (m, 1H), 8.31−8.09 (m, 3H), 7.95−
7.77 (m, 2H), 7.56−7.39 (m, 3H), 7.33−7.01 (m, 2H), 6.13 (q, J = 7.1
Hz, 1H), 2.15 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
162.6, 138.9, 138.3, 136.8, 135.1, 134.5, 130.7, 130.5, 126.6, 124.9,
124.1, 122.7, 122.4, 122.1, 121.5, 119.5, 116.8, 116.4, 114.3, 114.0,
59.4, 21.0. MS (ESI) m/z 408 [M + H]+. HR-MS (ESI) calcd for
C22H16N3FSCl [M + H]+, 408.0737; found, 408.0730.
1
1469, 1451, 1422, 1212, 1024, 818, 761, 695. H NMR (300 MHz,
CDCl3): δ 8.19−8.04 (m, 1H), 7.97 (s, 1H), 7.89−7.75 (m, 2H),
7.52−7.39 (m, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.21−6.93 (m, 6H), 5.88
(q, J = 6.6 Hz, 1H), 2.97 (s, br, 4H), 2.06 (d, J = 6.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 140.9, 139.8, 139.4, 136.5, 135.9, 134.9,
128.3, 128.1, 127.0, 125.8, 124.9, 124.3, 123.1, 122.7, 121.7, 119.4,
60.2, 35.3, 27.5, 21.5. MS (ESI) m/z 384 [M + H]+. HR-MS (ESI)
calcd for C24H22N3S [M + H]+, 384.1534; found, 384.1537.
4-(4-Bromo-2-fluorophenyl)-1-(1-(dibenzo[b,d]thiophen-2-yl)-
ethyl)-1H-1,2,3-triazole (13r). mp = 115−117 °C. IR νmax (cm−1):
1
3075, 2924, 1614, 1570, 1549, 1472, 1339, 1224, 1153, 1062, 730. H
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(4-nitrophenyl)-1H-
1,2,3-triazole (13k). mp = 185−187 °C. IR νmax (cm−1): 3097, 2924,
NMR (300 MHz, CDCl3): δ 8.21 (t, J = 8.1 Hz, 1H), 8.16−8.01 (m,
2H), 7.89−7.72 (m, 3H), 7.53−7.32 (m, 4H), 7.30−7.18 (m, 1H),
6.00 (q, J = 7.1 Hz, 1H), 2.16 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 160.4, 157.0, 139.9, 136.2, 136.1, 134.9, 128.8, 128.0, 127.1,
124.9, 124.5, 123.4, 122.8, 122.1, 121.1, 120.6, 119.5, 119.3, 119.0,
60.5, 21.7. MS (ESI) m/z 452 [M + H]+. HR-MS (ESI) calcd for
C22H16N3FSBr [M + H]+, 452.0232; found, 452.0230.
1
1606, 1509, 1384, 1341, 1235, 1108, 850, 758. H NMR (300 MHz,
CDCl3): δ 8.97 (s, 1H), 8.42 (s, 1H), 8.38−8.23 (m, 3H), 8.12 (d, J =
8.6 Hz, 2H), 8.01−7.88 (m, 2H), 7.60−7.44 (m, 3H), 6.20 (q, J = 6.9
Hz, 1H), 2.11 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
146.2, 144.3, 138.8, 138.3, 137.0, 136.8, 135.1, 134.5, 126.8, 125.6,
125.1, 124.2, 123.7, 122.9, 122.5, 121.8, 121.7, 119.7, 59.5, 21.0. MS
(ESI) m/z 401 [M + H]+. HR-MS (ESI) calcd for C22H17N4O2S [M +
H]+, 401.1072; found, 401.1065.
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(thiophen-3-yl)-1H-
1,2,3-triazole (13l). mp = 124−126 °C. IR νma1x (cm−1): 3124, 2924,
1604, 1421, 1232, 1070, 853, 780, 732, 619. H NMR (300 MHz,
CDCl3): δ 8.15−8.05 (m, 2H), 7.88−7.74 (m, 2H), 7.65−7.58 (m,
1H), 7.52 (s, 1H), 7.48−7.33 (m, 4H), 7.32−7.26 (m, 1H), 5.98 (q, J
= 7.1 Hz, 1H), 2.13 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ 143.8, 139.6, 136.0, 132.7, 131.4, 127.1, 126.2, 125.7, 125.0, 124.5,
123.4, 122.8, 121.6, 121.2, 119.5, 118.3, 115.3, 115.6, 60.4, 21.4. MS
(ESI) m/z 362 [M + H]+. HR-MS (ESI) calcd for C20H16N3S2 [M +
H]+, 362.0785; found, 362.0770. .
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(2, 5-difluorophenyl)-
1H-1,2,3-triazole (13s). mp = 133−135 °C. IR νmax (cm−1): 3136,
1
2937, 1591, 1496, 1232, 1066, 885, 817, 762, 731. H NMR (300
MHz, CDCl3): δ 8.25−8.10 (m, 2H), 8.05 (d, J = 3.5 Hz, 1H), 8.02−
7.90 (m, 1H), 7.89−7.76 (m, 2H), 7.52−7.38 (m, 3H), 7.17−6.86 (m,
2H), 6.08 (q, J = 7.1 Hz, 1H), 2.16 (d, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 159.8, 156.7, 152.8, 138.9, 138.2, 137.3, 135.1, 134.5,
127.2, 125.5, 124.6, 123.3, 123.0, 122.0, 120.0, 117.7, 117.4, 115.7,
113.2, 112.8, 59.6, 20.8. MS (ESI) m/z 392 [M + H]+. HR-MS (ESI)
calcd for C22H16N3F2S [M + H]+, 392.1033; found, 392.1030.
4-(2-Chloro-3,5-difluorophenyl)-1-(1-(dibenzo[b,d]thiophen-2-
yl)ethyl)-1H-1,2,3-triazole (13t). mp = 185−187 °C. IR νmax (cm−1):
1
3087, 2924, 1469, 1430, 1235, 924, 836, 814, 732. H NMR (300
1-(1-(Dibenzo[b,d]thiophen-2-yl)ethyl)-4-(6-methoxynaphtha-
len-2-yl)-1H-1,2,3-triazole (13m). mp = 195−197 °C. IR νma1x (cm−1):
3122, 2924, 1614, 1480, 1346, 1265, 1208, 1025, 854, 731. H NMR
MHz, CDCl3): δ 8.54 (s, 1H), 8.43−8.22 (m, 2H), 8.07−7.84 (m,
2H), 7.63−7.37 (m, 4H), 7.36−7.20 (m, 1H), 6.23 (q, J = 7.1 Hz,
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Article
1H), 2.13 (d, J = 7.1 Hz, 3H). MS (ESI) m/z 426 [M + H]+. HR-MS
(ESI) calcd for C22H15N3 F2SCl [M + H]+, 426.O643; found,
426.0666.
(4-tert-butylphenyl)-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-1,2,3-
triazole 13 h: C26H25N3S, M = 411.55, monoclinic, space group P21/c,
a = 7.9466(5) Å, b = 26.2967(16) Å, c = 10.7696(7) Å, β = 102.466(1)
°, V = 2197.5(2) Å3, Z = 4, Dcalcd = 1.244 mg m−3, T = 294(2) K, μ =
0.165 mm−1, F(000) = 872, λ = 0.71073 Å. Data collection yielded
21020 reflections resulting in 3875 unique, averaged reflections, 3353
with I > 2σ(I). Full-matrix least-squares refinement led to a final R =
0.0571, wR = 0.1336, and GOF = 1.142.
Mycobacterial Growth Assay. Two-fold serial dilutions of each
test compound/drug were prepared and incorporated into Middle-
brook 7H11 agar medium with oleic acid, albumin, dextrose, and
catalase (OADC) growth supplement to get final concentrations of 25,
12.5, 6.25, 3.13, 1.56, and 0.78 μg/mL. Inoculum of M. tuberculosis
H37Rv ATCC 27294 was prepared from fresh Middlebrook 7H11
agar slants with OADC (Difco) growth supplement adjusted to 1 mg/
mL (wet weight) in Tween 80 (0.05%) saline diluted to 10−2 to give a
concentration of ∼107 cfu/mL. Five microliters of this bacterial
suspension was spotted onto 7H11 agar tubes containing different
concentrations of the drug as discussed above. The tubes were
incubated at 37 °C, and final readings (as MIC in μg/mL) were
determined after 28 days. The MIC is defined as the minimum
concentration of compound required to give complete inhibition of
bacterial growth. This method is similar to that recommended by the
National Committee for Clinical Laboratory Standards for the
determination of MIC in triplicate.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR, and mass (HRMS) of all of the
compounds, 7a−c, 8a−c, 9a−c, 11a−h, 12a−h, and 13a−t;
single-crystal X-ray diffraction data (cif file) for 13h. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +91-4027191437. Fax: +91-4027198933. E-mail:
kantevari@yahoo.com or kantevari@gmail.com.
■
Cell Cultures, Maintenance, and Cytotoxicity Evaluation. All
cell lines used in this study were purchased from the American Type
Culture Collection (ATCC, United States). A549, SK-N-SH, and
HeLa were grown in Dulbecco's modified Eagle's medium (containing
10% FBS in a humidified atmosphere of 5% CO2 at 37 °C). DU145
cells were cultured in Eagle's minimal essential medium (MEM)
containing nonessential amino acids, 1 mM sodium pyruvate, 10 mg/
mL bovine insulin, and 10% FBS. Cells were trypsinized when
subconfluent from T25 flasks/60 mm dishes and seeded in 96-well
plates. The synthesized 1,2,3-triazole hybrids 13a−c, 13f−k, and 13p−
t were evaluated for their in vitro cytotoxicity in four different human
cancer cell lines. A protocol of 48 h continuous drug exposure was
used, and a MTT cell proliferation assay was used to estimate cell
viability or growth. The cell lines were grown in their respective media
containing 10% fetal bovine serum and were inoculated into 96-well
microtiter plates in 200 μL aliquots at plating densities depending on
the doubling time of individual cell lines. The microtiter plates were
incubated at 37 °C, 5% CO2, 95% air, and 100% relative humidity for
24 h prior to addition of experimental drugs. Aliquots of 2 μL of the
test compounds were added to the wells already containing 198 μL of
cells, resulting in the required final drug concentrations. For each
compound, four concentrations (1, 10, 100, and 1000 μM) were
evaluated, and each was done in triplicate wells. Plates were incubated
further for 48 h, and the assay was terminated by the addition of 10 μL
of 5% MTT and incubated for 60 min at 37 °C. Later, the plates were
air-dried. Bound stain was subsequently eluted with 100 μL of DMSO,
and the absorbance was read on an ELISA plate reader at a wavelength
of 560 nm. Percent growth was calculated on a plate by plate basis for
test wells relative to control wells. The above determinations were
repeated thrice. The growth inhibitory effects of the compounds were
analyzed by generating dose−response curves as a plot of the
percentage surviving cells versus compound concentration. The
sensitivity of the cancer cells to the test compound was expressed in
terms of IC50, a value defined as the concentration of compound that
produced 50% reduction as compared to the control absorbance. IC50
values are indicated as means SD of three independent experiments.
X-ray Data. X-ray data for the compounds were collected at room
temperature using a Bruker Smart Apex CCD diffractometer with
graphite monochromated Mo Kα radiation (λ = 0.71073 Å) with the
ω-scan method.22 Preliminary lattice parameters and orientation
matrices were obtained from four sets of frames. Integration and
scaling of intensity data were accomplished using SAINT program [1].
The structure was solved by direct methods using SHELXS97, and
refinement was carried out by full-matrix least-squares technique using
SHELXL97.22 Anisotropic displacement parameters were included for
all nonhydrogen atoms. All H atoms attached to C and N were located
in different Fourier maps and subsequently geometrically optimized
and allowed for as riding atoms, with C−H = 0.93−0.97 Å, N−H =
0.86 Å, with Uiso(H) = 1.5Ueq(C) for methyl H or 1.2Ueq(C,N). The
methyl groups were allowed to rotate but not to tip. Crystal data for 4-
Author Contributions
S.K., S.R.P., and L.P. conceived, performed the experiments,
and characterized the compounds with spectral data. B.S.
performed single-crystal X-ray analysis. P.Y. and D.S. evaluated
compounds for antitubercular activity. R.M., N.J., and S.V.K.
performed cytotoxicity evaluations. S.K., T.A.D., and S.R.P.
analyzed the data and cowrote the manuscript and Supporting
Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to Dr. J. S. Yadav, Director, IICT, and Dr. B. B.
Gawali, Head, and Dr. V. J. Rao, Chief Scientist, Organic
Chemistry Division-II (Crop Protection Chemicals Division),
IICT, Hyderabad, for their constant support, encouragement,
and financial assistance from MLP projects. S.R.P. (SRF) and
L.P. (JRF) are thankful to CSIR for fellowships.
ABBREVIATIONS USED
■
TB, tuberculosis; HIV, human immunodeficiency virus; MDR-
TB, multiple drug-resistant M. tuberculosis; XDR-TB, extremely
drug-resistant M. tuberculosis; INH, isoniazid; MIC, minimum
inhibitory concentration; NMR, nuclear magnetic resonance;
FTIR, infrared spectroscopy; HRMS, high-resolution mass
spectrometry; OADC, oleic acid, albumin, dextrose, and
catalase; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-
zolium bromide assay; SI, selectivity index; TLC, thin-layer
chromatography; TMS, tetramethylsilane; IC50, minimum
inhibitory concentartion for 50% of the cells; A549, human
lung carcinoma epithelial; SK-N-SH, human neuroblastoma;
HeLa, human epithelial cervical cancer; DU145, human
prostate cancer
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