Design and synthesis of 1,2,3-triazole-etodolac hybrids as potent anticancer molecules

Article abstract of DOI:10.1039/c6ra28525b

A series of novel 1,2,3-triazole-etodolac hybrids (6a-l) were designed and synthesized as potent anti-cancer molecules. The synthesis strongly relied on Huisgen's 1,3-dipolar cycloaddition between etodolac azide 3 and substituted terminal alkynes 5a-l. Th

Full text of DOI:10.1039/c6ra28525b

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Design and synthesis of 1,2,3-triazole–etodolac
hybrids as potent anticancer molecules†
Cite this: RSC Adv., 2017, 7, 23680
a
a
b
c
Bhaskar Kummari,
Naveen Polkam, Perla Ramesh,
Hasithashilpa Anantaraju,
c
a
d
Perumal Yogeeswari, Jaya Shree Anireddy,* Sravanthi Devi Guggilapu
d
and Bathini Nagendra Babu
A series of novel 1,2,3-triazole–etodolac hybrids (6a–l) were designed and synthesized as potent anti-
cancer molecules. The synthesis strongly relied on Huisgen's 1,3-dipolar cycloaddition between etodolac
2 2 2
azide 3 and substituted terminal alkynes 5a–l. The use of CH Cl as a co-solvent with H O increased the
Received 21st December 2016
Accepted 12th April 2017
reaction rate and provided the corresponding 1,2,3-triazole–etodolac hybrids (6a–l) in excellent yields
compared to other organic co-solvent systems. All the compounds were screened for their in vitro
anticancer activity against human A549 cell lines and compounds 6e, 6f, 6h, 6j, and 6l were found to be
the best anti-cancer molecules as compared to the marketed drug doxorubicin.
DOI: 10.1039/c6ra28525b
rsc.li/rsc-advances
6
Cancer is a multi-factorial and dreadful disease characterized manner. 1,2,3-Triazoles conjugated with other pharmaco-
by uncontrolled growth of cells and spread of abnormal cells in phores (triazole-hybrids) known to possess potent anti-cancer
1
the body. It is the most common disease in the modern era and activities. In this context, Kamal et al. described a new class of
causes the most deaths (one in eight deaths) worldwide. triazole chalcone-pyrrolo[1,4]benzodiazepine (PBD) hybrids as
Because of enduring concern across the globe, there is an ever- inhibitors of cyclin D1 and NF-kB protein (Fig. 1) which showed
3
increasing requirement for safe and effective anti-tumour signicant G1 cell cycle arrest.
agents to ght against cancer.
2a–h
Liu et al. identied promising candidates with a broad spec-
1,2,3-Triazole is one of the extensively used scaffolds in trum of anti-cancer activities and low cytotoxicity against the
pharmaceuticals and exhibits a wide range of biological activi- normal cell lines HEK-293 by the synthesis of novel 1,2,3-triazole–
ties including signicant anti-cancer proles against many dithiocarbamate hybrids and some of them were more potent than
3
,4a–c,5a–f
4a–c
human cancer cell lines.
These heterocycles are the well-known anti-cancer drug 5-uorouracil (Fig. 2).
On the other hand nonsteroidal anti-inammatory drugs
bestowed with special properties like moderate dipole char-
acter, hydrogen bonding capability, rigidity, stability and can be (NSAIDs) are the cyclooxygenase (COX) inhibitors, and recent
7a–f
constructed through click chemistry approach in a facile ndings advocate that they possess anti-cancer effects through
7d
a COX-2-independent mechanism. Etodolac is a COX-2 inhibitor
with analgesic and antipyretic properties and is approved by US
7f
FDA. In recent years the antitumor activity of etodolac analogues
against many types of cancer, such as urogenital system cancers,
Burkitt's lymphoma, multiple myeloma, chronic lymphocytic
7e
leukemia, and prostate cancer has been described. In view of the
pharmacological signicance of etodolac and triazole derivatives
with reference to anticancer activity, we have attempted the
synthesis of a new series of 1,2,3-triazole–etodolac hybrids and
evaluated their anti-cancer properties (Fig. 3).
Fig. 1 Few hybrid triazoles.
a
Centre for Chemical Sciences and Technology, Institute of Science and Technology,
Jawaharlal
Nehru
Technological
University
Hyderabad,
Kukatpally,
Hyderabad-500085, TS, India. E-mail: jayashree_avc@yahoo.co.in
b
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Uppal
Road, Hyderabad-500007, India
c
Department of Pharmacy, Birla Institute of Technology and Science, Pilani,
Hyderabad Campus, Jawahar Nagar-500078, TS, India
d
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
Research (NIPER), Hyderabad, TS, India
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c6ra28525b
1
Fig. 2 Hybrid anti-cancer molecules with triazole skeleton.
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Fig. 3 Synthetic strategy.
Results and discussions
Scheme 2 Synthesis of 1,2,3-triazole–etodolac hybrids 6a–l.
Chemistry
Aer optimizing the reaction conditions, we have preceded
to synthesis the library of triazole–etodolac hybrids (6a–l) to
prove the generality of the adopted synthetic procedure. For the
The synthesis of a series of 1,2,3-triazole–etodolac hybrids (6a–l)
carried out by using the Cu(I)-catalyzed Huisgen's 1,3-dipolar
cycloaddition reaction is presented in Scheme 1.
The synthetic strategy to achieve the novel hybrid template
was initiated from the reduction of acid functionality of Table 2 Yields for the Cu-catalyzed synthesis of 1,2,3-triazole–eto-
commercially available etodolac 1 by using LAH (lithium dolac derivatives (6a–l)
8
aluminum hydride) to give the primary alcohol 2 in 92% yield.
S. No. 1-Alkynes (5a–l) Product (6a–l)
Time Yield (%)
The newly formed hydroxyl was transformed into azide 3 using
DPPA (diphenylphosphoryl azide), TPP (triphenylphosphine)
and DIAD (diisopropyl azodicarboxylate) in THF. The reaction
mixture was stirred for 12 h at room temperature. The whole
reaction mixture was concentrated to get the residue, which was
extracted with EtOAc. The organic layer dried over anhydrous
Na SO ltered and evaporated. The crude reaction mixture was
1
8 h
6 h
8 h
86
92
87
2
3
2
4
puried by silica gel column chromatography using EtOAc/
hexane (10%) as an eluent to provide the corresponding azide
9
3
in 86% yield. Finally, the synthesis of triazole–etodolac
hybrid 6a was attempted by treating the azide 3 with the
terminal alkyne 5a in the presence of CuSO $5H O and L-
O (1 : 1) at room temperature
4
2
4
6 h
92
t
sodium ascorbate in BuOH : H
2
and the desired compound 6a was formed in trace amount. The
prolonged reaction time and high temperature also did not
improve the outcome of the reaction. Later the reaction was
performed in various organic co-solvents to improve the reac-
5
6
7
8
9
6 h
6 h
8 h
6 h
89
93
92
93
14
tion outcome and the synthesis of 6a was successfully
10
accomplished in 1 : 1 DCM : H
lent yield (86%) and the results are summarized in Table 1
Scheme 2).
2
O solvent system with excel-
(
Scheme 1 Proposed Cu(I)-catalyzed Huisgen's 1,3-dipolar cycload-
dition reaction.
6 h
6 h
7 h
90
94
92
Table 1 Identification of co-solvent for the system of 6a
1
0
Entry Substrate Product Solvent Co-solvent Yield (%) Time (h)
1
2
3
4
5
6
5a
5a
5a
5a
5a
5a
6a
6a
6a
6a
6a
6a
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
CH
DMSO
THF
t-BuOH
DMF
DCM
3
CN
46
43
54
42
58
86
12
9
10
8
12
8
11
12
7 h
94
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purpose, we have synthesized desired alkynes (5a–l) by treating
It is apparent from the results that compounds 6e, 6f, 6h, 6j,
the commercially available phenols (4a–l) with propargyl 6l are found to be potent on lung cancer cell lines than the other
1
1
bromide and K CO (Scheme 2) in good yields. Finally, the (Fig. 4, Table 3)
2
3
5c,12
Huisgen's 1,3-dipolar cycloaddition
reaction was employed
The test compounds with >70% inhibition on cancer cell
to react the azide 3 and the alkynes 5a–l to furnish the hybrid lines were chosen for the IC50 prediction on lung cancers. It was
molecules 6a–l in excellent yields and the results were interesting to note that compounds 6e, 6f, 6h, 6j and 6l found to
summarized in Table 2.
possess more effect at the same dose compared to doxorubicin
against A549 (lung) cancer cell line. Next, dose–response studies
of active compounds were performed to calculate IC50 value
against the same cell lines. Among the whole series of title
compounds (6a–l), compound 6l was found to be the most
active compound with an IC50 value of 3.29 ꢃ 0.7 mM on lung
cancer cell line (A549). The second-best compound identied in
the series was 6f with IC50 3.65 ꢃ 0.4 value. The IC50 values of
active compounds are summarized in Table 2.
Biology
Cytotoxicity was measured using the MTT [3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay,
against A549 lung cancer cell lines which is a colorimetric
13a
assay.
MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazo-
lium bromide) is a water-soluble yellow color tetrazolium salt
and is converted to an insoluble purple formazan by cleavage of
the tetrazolium ring by succinate dehydrogenase which is
present in the mitochondria. The formazan product is imper-
meable to the cell membranes and therefore it accumulates in
healthy cells. Since the reduction of MTT can only occur in
metabolically active cells, the intensity of the purple color is
a measure of the viability of the cells. The intensity can be
measured by spectrophotometer aer dissolving formazan
Similar scaffolds have been reported earlier for their potent
14a–c
anticancer activities.
This prompted us to investigate the
possible mechanism of the synthesized compounds by per-
forming the molecular docking studies into the binding pocket
of the human topoisomerase-II ATPase co-crystallized with
15
AMP–PNP complex (TPII) [PDB:1ZXM]. The water molecules,
substrate cofactors were removed from the PDB le and the
missing hydrogen atoms were added to the system followed by
energy minimization using OPLS 2005 force eld with Polak–
Ribiere Conjugate Gradient (PRCG) algorithm. The ligands were
built using the builder feature in Maestro and each structure
was prepared for docking using Ligprep 2.7 followed by
molecular mechanics energy minimization using Macromodel
13b
crystal in DMSO.
3
The cells (5 ꢀ 10 ) were seeded in each well containing 0.1
mL of medium in 96 well plates. Aer overnight incubation at
ꢁ
3
7 C in 5% CO , the cells were treated with 100 mL of different
2
test concentrations of test compounds at identical conditions
with three replicates each. The cytotoxic effect of all the
synthesized molecules was evaluated using doxorubicin
a widely used anthracycline antibiotic and with IC50 values of
10.1. These geometrically optimized structures were used for
Glide (grid-based ligand docking with energetics) docking using
14
the “Extra Precision” (XP) mode of Glide 6.0. As depicted in
3.3 mM on A549 as the standard reference at 25 mM doses. The
(
Fig. 5b), compound 6l showed hydrophobic interactions with
active site residues Tyr 64, Ile 109, Pro 111, Val 236, Ala 237, Val
40, Pro 263, Leu 257 and interaction with other active site
cell viability was assessed aer 48 h, by adding 10 mL of MTT
ꢂ1
ꢁ
(
5 mg mL ) per well. The plates were incubated at 37 C for
2
additional 2–4 hours. The medium was discarded and the for-
mazan violet crystals, which were coloured for the viable cells,
were dissolved in 100 mL of DMSO. The rate of color formation
was measured at 570 nm in a spectrophotometer (Spectra MAX
Plus; Molecular Devices; supported by SOFT max PRO-5.4). The
percent inhibition of cell viability was determined with refer-
ence to the control values (without test compound). The data
were normalised with the lowest and highest values and sub-
jected to non-linear regression analysis to obtain log (concen-
tration) vs. normalised expression (variable slope) using graph
pad prism 6. The IC50 (inhibition of cell growth) concentrations
were further obtained using the graph pad prism 6.
residues such as Asp 65, Glu 66, Asp 67, Lys 233, Lys 261 were
also observed. Additionally, hydrogen bonding interactions
with Tyr 244 and Asn 258 were noticed (Fig. 5c). These results
also indicate that the compound 6l is bound well within the
binding site pocket of doxorubicin and almost similar binding
pattern was identied. The hydrogen bonding interaction with
active site residues Tyr 244 and Asn 258 was in common
(Fig. 5d).
Fig.
4 Log concentration–response curve of the most active
compounds on A549 cancer cell lines.
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a
Table 3 Determination of IC50 of selected compounds against cancer cell lines
b
IC50 (mM)
Compound
6e
6f
6h
6j
6l
A549
4.50 ꢃ 0.5
3.65 ꢃ 0.4
5.38 ꢃ 0.4
10.71 ꢃ 0.3
3.29 ꢃ 0.7
a
b
Standard drug used for in vitro activity studies is doxorubicin and its IC50 3.3 mM. IC50 (mM) is 50% inhibitory concentration and values are the
means of three experiments each done in duplicate.
d (doublet), t (triplet), q (quartet), dd (double doublet) and m
(multiplet). IR spectra were recorded on Perkin Elmer spectro-
photometer by using KBr pellets. Melting points were deter-
mined in open capillary tubes. Reactions were monitored by
thin-layer chromatographic (TLC) technique using silica gel
plates. Phosphate-buffered saline (PBS), antibiotic mixture,
Roswell Park Memorial Institute (RPMI) 1640 medium, F-12K
medium and new born calf serum (NBCS) were obtained from
Hi Media Laboratories Pvt. Ltd. MTT (3-(4,5-dimethylthiazole-2-
yl)-2,5-diphenyl tetrazolium bromide) was procured from
Sigma-Aldrich (Bangalore, India). Cell line that was used for
testing in vitro cytotoxicity included A549 derived from human
lung epithelial cells (ATCC No. CCL-185), which was procured
from American Type Culture Collection, Manassas, VA, USA.
Fig. 5 (a) Three-dimensional diagram displays the binding poses for
compound 6l interactions at the active site of TP II. (b) Key residues 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)
within a 4.5 A˚ sphere of 6l in the binding pocket are shown. (c) ethanol (2)
Hydrogen bonding of 6l with Tyr 244 and Asn 258 in the active site. (d)
Compound 6l overlaid with doxorubicin (orange). Yellow dotted lines
A stirred solution of LiAlH (0.38 g, 9.93 mmol) in dry THF (35
4
represent H-bonding with amino acid backbone respectively.
mL), was added to a solution of 2-(1,8-diethyl-1,3,4,9-tetrahy-
dropyrano[3,4-b]indol-1-yl)acetic acid 1 (1.42 g, 4.96 mmol) in
ꢁ
dry THF (14 mL) at 0 C. The mixture was stirred overnight at
Conclusion
room temperature. Then reaction mixture was quenched with
ꢁ
saturated Na
2
SO
4
solution at 0 C, the mixture was ltered
A series of 1,2,3-triazole–etodolac hybrids (6a–l) have been
designed and synthesized by employing Cu(I)-catalyzed Huisgen
through Celite, and washed with ethyl acetate. The solvent was
removed to yield pure product 2 (0.33 g, 92%).
1,3-dipolar cycloaddition reaction. The in vitro anti-cancer
activity of all the synthesized compounds against human A549
cancer cell lines was evaluated and it is found that the
compounds 6e, 6f, 6h, 6j, and 6l have shown promising results
in comparison with the marketed drug doxorubicin. In the
series, 6l has shown very good anticancer activity with an IC50
value of 3.29 ꢃ 0.7 mM and second-best compound was 6f with
an IC50 value of 3.65 ꢃ 0.4 mM. Therefore, these compounds can
serve as a promising lead candidate for further study.
1
-(2-Azidoethyl)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]
indole (3)
To a stirred solution of 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano
[3,4-b]indol-1-yl)ethanol 2 (0.5 g, 1.75 mmol) in THF (10 mL),
were DPPA (diphenylphosphoryl azide) (3.50 mmol), DIAD (di
isopropyl azodicarboxylate) (5.26 mmol) and triphenylphos-
phine (5.26 mmol) added at 0 C. The reaction mixture was
ꢁ
stirred overnight under nitrogen saturated atmosphere. Aer
completion of reaction. The reaction mixture was poured in 100
mL water and thoroughly extracted with ethyl acetate (3 ꢀ 50
Experimental
General information
2 4
mL). The organic layer was dried over Na SO , ltered and
evaporation under reduced pressure. The resulting residue was
puried by ash chromatography using petroleum ether : ethyl
acetate (90 : 10) as the eluent, to afford the 1-(2-azidoethyl)-1,8-
diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole 3 (0.45 g, 86%) as
The reagents and materials including etodolac were of the
highest commercially available purity grade and were used
without any further purication. Flash column chromatography
was performed on Merck silica gel 60–120 mesh. Compounds
1
a white solid. Chemical formula: C17
H N O.
22 4
were visualized with UV light. H NMR spectra were recorded on
1
3
Bruker Avance 400 MHz spectrometer and C NMR spectra
were recorded on Bruker Avance 100 MHz spectrometer in
1,4-Dimethyl-2-(prop-2-yn-1-yloxy)benzene (5a)
CDCl
3
as a solvent, with TMS as an internal standard. Multi- A mixture of 2,5-dimethylphenol (0.5 g, 4.09 mmol), propargyl
CO (0.84 g, 6.13 mmol)
plicities were denoted by s (singlet), brs (broad singlet), bromide (0.44 mL, 4.91 mmol) and K
2
3
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was stirred in dimethylformamide (20 mL) at room tempera- 3H), 1.3 (t, J ¼ 7.3, 3H), 1.75–1.9 (m, 1H), 1.95–2.15 (m, 1H),
ture. Aer completion of the reaction (TLC monitoring), the 2.45–2.68 (m, 2H), 2.75–2.85 (m, 3H), 2.87–3.02 (m, 1H), 3.95–
reaction mixture was diluted with EtOAc (100 mL) and washed 4.05 (m, 1H), 3.95–4.15 (m, 2H), 4.25–4.35 (m, 1H), 4.44–4.55
with water (3 ꢀ 50 mL) times. The organic phase was dried over (m, 1H), 4.85 (d, J ¼ 12.22 Hz, 1H), 5.15 (d, J ¼ 11.98 Hz, 1H),
1
3
with anhydrous Na
The obtained crude crystalline was puried by column chro- (100 MHz, CDCl
matography to obtain a pure white solid 5a. 46.25, 60.48, 67.72, 75.40, 108.99, 115.90, 117.26, 119.88,
20.52, 121.17, 124.80, 126.22, 126.60, 127.29, 134.98, 135.25,
2 4
SO and concentrated to dryness in vacuo. 7.08–7.15 (m, 2H), 7.25–7.4 (m, 2H), 7.75–7.95 (m, 2H); C NMR
3
): d 7.88, 13.25, 21.96, 23.87, 31.55, 38.11,
1
+
1
-(2-(4-((2,5-Dimethylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)
ethyl)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (6a)
To solution of 1,4-dimethyl-2-(prop-2-yn-1-yloxy)benzene
54 mg, 0.33 mmol) 5a and 1-(2-azidoethyl)-1,8-diethyl-1,3,4,9-
tetrahydropyrano[3,4-b]indole 3 (100 mg, 0.33 mmol) in CH Cl
140.21, 141.98, 145.61, 148.22; HRMS: m/z [M + H] calcd for
C
ꢂ1
H28Br
N
O
5
632.0508, found: 632.0508; IR (KBr, cm ): 3249,
26
2
4
3
8
073, 2964, 2920, 1692, 1528, 1445, 1352, 1254, 1139, 1045, 969,
70, 810, 744, 728.
a
(
2
2
1
,8-Diethyl-1-(2-(4-((naphthalen-1-yloxy)methyl)-1H-1,2,3-
(
0
0.7 mL) and H O (0.7 mL) were added CuSO $5H O (0.08 mg,
.0033 mmol) and sodium ascorbate (6.6 mg, 0.033 mmol). The
2 4 2
triazol-1-yl)ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6d)
ꢁ
resulting solution was stirred for 8 h at room temperature. The Pale yellow solid; yield 92%; mp 161 C; chemical formula:
1
reaction mixture was diluted with CH
mL). The organic layer was separated, dried over Na
2
Cl
2
(5 mL) and H
SO
2
O (5
C
30
H
32
N
4
O
2
; H NMR (400 MHz, CDCl
3
): d 0.96 (t, J ¼ 7.09, 3H),
2
4
, and 1.3 (t, J ¼ 7.3, 3H), 1.80–1.90 (m, 1H), 1.91–2.15 (m, 1H), 2.45–
concentrated. The residue was puried by ash column chro- 2.58 (m, 1H), 2.59–2.68 (m, 1H), 2.71–2.86 (m, 3H), 2.87–3.01
matography (hexane/EtOAc, 2 : 1) to give 1,2,3-triazole 6a as (m, 1H), 3.9–4.15 (m, 2H), 4.25–4.35 (m, 1H), 4.45–4.6 (m, 1H),
ꢁ
a pale green solid. Yield 86%; mp 140 C; chemical formula: 4.85 (d, J ¼ 12.22 Hz, 1H), 5.2 (d, J ¼ 11.98 Hz, 1H), 6.84–6.95 (m,
1
C H N O ; H NMR (400 MHz, CDCl ): d 0.92 (t, J ¼ 7.09, 3H), 1H), 7.15–7.20 (m, 2H), 7.3–7.6 (m, 6H), 7.82 (m, 1H), 8.2 (s, 2H);
2
8
34
4
2
3
1
3
1
3
.25 (t, J ¼ 7.3, 3H), 1.76–1.86 (m, 1H), 1.92–2.04 (m, 1H), 2.07 (s,
C NMR (100 MHz, CDCl ): d 7.8, 13.62, 21.90, 23.85, 31.49,
3
H), 2.26 (s, 3H), 2.45–255 (m, 1H), 2.56–2.65 (m, 1H), 2.74–2.88 37.99, 46.12, 60.40, 61.85, 70.02, 105.13, 108.87, 115.86, 119.89,
(m, 4H), 3.95–4.05 (m, 1H), 4.08–4.20 (m, 1H), 4.20–4.35 (m, 120.49, 120.68, 121.95, 123.47, 125.15, 125.54, 125.72, 126.16,
1
1
H), 4.43–4.52 (m, 1H), 4.72 (d, J ¼ 12.22 Hz, 1H), 4.88 (d, J ¼ 126.38, 126.57, 127.40, 134.45, 134.95, 135.24, 153.84; HRMS: m/
+
1.98 Hz, 1H), 6.61–6.74 (m, 2H), 6.88–7.18 (m, 2H), 7.22–7.40 z [M + H] calcd for C30
H
33
N
4
O
2
481.2603, found: 481.2600; IR
): d 7.85, 13.68, (KBr, cm ): 3276, 2953, 2898, 2870, 1741, 1681, 1577, 1456,
5.83, 21.41, 21.96, 23.91, 31.53, 38.04, 46.17, 60.47, 61.82, 1259, 1095, 788, 771.
1
3
ꢂ1
(m, 3H), 8.22 (s, 1H); C NMR (125 MHz, CDCl
3
1
7
1
1
5.44, 108.88, 112.44, 115.89, 119.91, 120.57, 121.41, 123.74,
26.21, 126.66, 129.79, 130.46, 135.00, 135.30, 136.57, 144.35, 1-(2-(4-((4-Bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)-
+
56.23; HRMS: m/z [M + H] calcd for C28
H
35
N
4
O
2
459.2760, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (6e)
ꢂ1
found: 459.2786; IR (KBr, cm ): 3243, 2958, 2914, 2870, 1714,
1
ꢁ
Off white solid; yield 89%; mp 132 C; chemical formula:
593, 1451, 1259, 1128, 1051, 958, 810, 739.
1
C H BrN O ; H NMR (400 MHz, CDCl ): d 0.95 (t, J ¼ 7.09,
2
6
29
4
2
3
3
2
3
H), 1.3 (t, J ¼ 7.3, 3H), 1.74–1.89 (m, 1H), 1.91–2.15 (m, 1H),
.40–2.15 (m, 1H), 2.52–2.67 (m, 1H), 2.70–2.85 (m, 3H), 2.85–
.01 (m, 1H), 3.95–4.15 (m, 2H), 4.3–4.45 (m, 2H), 4.55 (d, J ¼
1
,8-Diethyl-1-(2-(4-((naphthalen-2-yloxy)methyl)-1H-1,2,3-
triazol-1-yl)ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6b)
ꢁ
Pale brown solid; yield 92%; mp 190 C; chemical formula: 12.22 Hz, 1H), 4.85 (d, J ¼ 11.98 Hz, 1H), 6.78 (m, 2H), 7.0–7.2
1
13
C
1
30
H
32
N
4
O
2
; H NMR (400 MHz, CDCl
3
): d 0.96 (t, J ¼ 7.09, 3H), (m, 1H), 7.25–7.45 (m, 5H), 8.3 (s, 1H); C NMR (100 MHz,
.3 (t, J ¼ 7.3, 3H), 1.82–1.89 (m, 1H), 1.9–2.1 (m, 1H), 2.45–2.68 CDCl
3
): d 7.89, 13.19, 20.92, 23.53, 31.42, 37.55, 46.26, 61.36,
(m, 2H), 2.75–3.0 (m, 4H), 3.9–4.15 (m, 2H), 4.3–4.45 (m, 2H), 62.67, 75.34, 108.95, 113.63, 116.65, 117.82, 120.02, 121.93,
4
1
.85 (d, J ¼ 12.22 Hz, 1H), 5.2 (d, J ¼ 11.98 Hz, 1H), 6.84–7.15 (m, 123.20, 125.63, 126.67, 130.05, 133.13, 135.27, 135.83, 157.62;
+
H), 7.18–7.29 (m, 2H), 7.3–7.6 (m, 6H), 7.75–7.95 (m, 2H), 8.2 HRMS: m/z [M + H] calcd for C H BrN O 509.1552, found:
2
6
30
4 2
1
3
ꢂ1
(s, 1H); C NMR (100 MHz, CDCl
3
): d 7.79, 13.64, 22.40, 23.85, 509.1553; IR (KBr, cm ): 3276, 2953, 2931, 2892, 1709, 1593,
ꢂ1
3
1
1
1
1.43, 37.96, 46.11, 60.38, 61.43, 75.34, 107.06, 108.81, 115.84, 1489, 1456, 1237, 1193, 963, 826, 782, 689, 585 cm
.
18.72, 119.84, 120.46, 123.58, 123.78, 126.14, 126.37, 126.62,
26.81, 127.56, 129.05, 129.41, 129.75, 134.32, 134.95, 135.27, 1,8-Diethyl-1-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)
+
56.01; HRMS: m/z [M + H] calcd for C30
H
33
N
4
O
2
481.2603, ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6f)
ꢂ1
found: 481.2604; IR (KBr, cm ): 3254, 2958, 2898, 2870, 1709,
1
ꢁ
Pale yellow solid. Yield 93%; mp 84 C; chemical formula:
632, 1511, 1462, 1259, 1215, 1177, 1078, 1051, 832, 744.
1
C
1
2
26
H
30
N
4
O
2
, H NMR (400 MHz, CDCl
3
): d 0.93 (t, J ¼ 7.3, 3H),
.36 (t, J ¼ 7.3, 3H), 1.83–1.95 (m, 1H), 1.99–2.13 (m, 1H), 2.38–
1
-(2-(4-((2,4-Dibromo-6-nitrophenoxy)methyl)-1H-1,2,3-
.94 (m, 1H), 2.61–2.68 (m, 1H), 2.72–2.91 (m, 3H), 2.89–2.99
triazol-1-yl)ethyl)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]
indole (6c)
(m, 1H), 3.98–4.05 (m, 1H), 4.06–4.14 (m, 1H), 4.15–4.26 (m,
1H), 4.35–4.42 (m, 1H) 4.61 (d, J ¼ 12.22 Hz, 1H), 4.93 (d, J ¼
ꢁ
Brown colour solid; yield 87%; mp 141 C; chemical formula: 11.98 Hz, 1H), 6.85–7.05 (m, 2H), 7.12–7.34 (m, 2H), 7.32–7.41
C
1
13
26
H27Br
2
N
5
O
4
; H NMR (400 MHz, CDCl
3
): d 0.95 (t, J ¼ 7.09, (m, 5H), 8.52 (s, 1H); C NMR (100 MHz, CDCl
3
): d 7.83, 13.70,
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+
2
1
1
2.50, 23.88, 29.73, 31.42, 37.87, 46.17, 60.47, 61.29, 75.41, 135.30, 143.75, 155.96; HRMS: m/z [M + H] calcd for
ꢂ1
08.61, 114.70, 115.82, 119.81, 120.41, 121.60, 123.72, 126.18, C H N O 445.2603, found: 445.2605; IR (KBr, cm ): 3254,
29.82, 135.06, 135.49, 143.62, 150.08, 158.16; HRMS: m/z [M + 2953, 2909, 1722, 1596, 1503, 1312, 1225, 1055, 951, 825, 787,
2
7
33 4 2
+
H] calcd for C H N O 431.2447, found: 431.2446; IR (KBr, 749, 650, 508.
cm ): 3248, 2953, 2925, 1711, 1586, 1493, 1460, 1186, 968, 754,
2
6
31 4 2
ꢂ1
694.
1,8-Diethyl-1-(2-(4-((4-iodophenoxy)methyl)-1H-1,2,3-triazol-1-
yl)ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6j)
1
,8-Diethyl-1-(2-(4-((m-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
ꢁ
Yellow solid; yield 94%; mp 119 C; chemical formula:
ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6g)
1
C
26
H29IN
4
O
2
; H NMR (400 MHz, CDCl
3
): d 0.95 (t, J ¼ 7.09 Hz,
ꢁ
Yellow solid; yield 92%; mp 129 C; chemical formula: 3H), 1.30 (t, J ¼ 7.2 Hz, 3H), 1.76–1.85 (m, 1H), 1.93–2.01 (m,
1
C
27
H
32
N
4
O
2
: H NMR (400 MHz, CDCl
3
): d 0.96 (t, J ¼ 7.08, 3H), 1H), 2.43–2.50 (m, 1H), 2.55–2.63 (m, 1H), 2.72–2.79 (m, 3H),
1
.36 (t, J ¼ 7.32, 3H), 1.81–1.90 (m, 1H), 1.97–2.07 (m, 1H), 2.18 2.87–2.94 (m, 1H), 3.94–4.00 (m, 1H), 4.07–4.11 (m, 1H), 4.20–
(
2
4
s, 3H), 2.46–2.52 (m, 1H), 2.62–2.69 (m, 1H), 2.75–2.82 (m, 3H), 4.27 (m, 1H), 4.37–4.44 (m, 1H), 4.64 (d, J ¼ 12.22 Hz, 1H), 4.95
.89–2.96 (m, 1H), 3.98–4.04 (m, 1H), 4.09–4.12 (m, 1H), 4.22– (d, J ¼ 12.22 Hz, 1H), 6.64 (d, J ¼ 8.8 Hz, 2H), 7.01 (d, J ¼ 7.0 Hz,
.29 (m, 1H), 4.39–4.46 (m, 1H), 4.79 (d, J ¼ 12.22 Hz, 1H), 5.01 1H), 7.07 (t, J ¼ 7.5 Hz, 1H), 7.1 (s, 1H), 7.35 (d, J ¼ 7.5 Hz, 1H),
1
3
(
7
d, J ¼ 12.22 Hz, 1H), 6.80 (d, J ¼ 8.07 Hz, 1H), 6.86–6.90 (m, 1H), 7.5 (d, J ¼ 8.80 Hz, 2H), 8.03 (s, 1H); C NMR (100 MHz, CDCl
3
):
1
3
.01–7.35 (m, 4H), 7.36–7.45 (m, 2H), 8.56 (s, 1H); C NMR (100 d 7.78, 13.57, 21.89, 23.78, 31.49, 37.91, 46.03, 60.37, 61.37,
): d 7.73, 13.61, 16.14, 21.85, 23.82, 31.33, 37.93, 75.26, 108.83, 115.84, 117.07, 119.88, 120.47, 123.59, 126.09,
6.13, 60.38, 61.68, 75.40, 108.64, 111.25, 115.72, 119.74, 126.52, 134.90, 135.19, 138.17, 143.09, 157.94; HRMS: m/z [M +
MHz, CDCl
3
4
1
1
+
4 2
20.36, 120.76, 123.27, 126.12, 126.64, 126.69, 126.82, 130.65, H] calcd for C26H30IN O 547.1413, found: 547.1415; IR (KBr,
+
ꢂ1
34.94, 135.31, 144.05, 156.24; HRMS: m/z [M + H] calcd for cm ): 3271, 2958, 2926, 2893, 1736, 1687, 1583, 1523, 1484,
ꢂ1
C H N O 445.2603, found: 445.2603; IR (KBr, cm ): 3215, 1369, 1249, 1227, 1106, 1046, 805, 745, 635, 580.
2
7
33 4 2
2
1
958, 2920, 2893, 2871, 1739, 1689, 1591, 1498, 1460, 1378,
241, 1050, 858, 793, 742.
4-((1-(2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)
ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde
(6k)
1
,8-Diethyl-1-(2-(4-((o-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6h)
ꢁ
Pale yellow solid. Yield 92%; mp 193 C; chemical formula:
ꢁ
1
Yellow solid; yield 93%; mp 130 C; chemical formula:
C
28
H
32
N
4
O
4
; H NMR (400 MHz, CDCl
3
): d 0.96 (t, J ¼ 7.07 Hz,
1
C
27
H
32
N
4
O
2
: H NMR (400 MHz, CDCl
3
): d 0.95 (t, J ¼ 7.08, 3H), 3H), 1.32 (t, J ¼ 7.3 Hz, 3H), 1.77–1.82 (m, 1H), 1.92–1.99 (m,
1
3
2
4
.29 (t, J ¼ 7.3, 3H), 1.79–1.88 (m, 1H), 1.95–2.03 (m, 1H), 2.18 (s, 1H), 2.44–2.58 (m, 2H), 2.75–2.80 (m, 3H), 2.86–2.96 (m, 1H),
H), 2.44–2.52 (m, 1H), 2.60–2.68 (m, 1H), 2.74–2.82 (m, 3H), 3.88 (s, 3H), 3.42–4.05 (m, 1H), 4.06–4.18 (m, 1H), 4.21–4.33 (m,
.88–2.96 (m, 1H), 3.97–4.03 (m, 1H), 4.08–4.12 (m, 1H), 4.21– 1H), 4.37–4.48 (m, 1H), 4.75 (d, J ¼ 12.42 Hz, 1H), 5.08 (d, J ¼
.28 (m, 1H), 4.38–4.45 (m, 1H), 4.75 (d, J ¼ 12.22 Hz, 1H), 4.98 12.71 Hz, 1H), 7.01–7.12 (m, 3H), 7.20 (s, 1H), 7.34–7.47 (m, 3H),
1
3
(
d, J ¼ 12.22 Hz, 1H), 6.81 (d, J ¼ 7.82 Hz, 1H), 6.86–6.90 (m, 1H), 7.55 (brs, 1H), 9.83 (s, 1H); C NMR (100 MHz, CDCl ): d 7.83,
3
7
8
2
1
1
.01–7.09 (m, 2H), 7.13 (d, J ¼ 7.33 Hz, 2H), 7.26–7.37 (m, 2H), 13.54, 22.39, 23.79, 31.66, 37.93, 46.00, 55.95, 60.36, 62.26,
13
.42 (s, 1H); C NMR (125 MHz, CDCl
3
): d 7.76, 13.60, 16.16, 75.17, 109.09, 109.13, 112.32, 115.99, 120.05, 120.60, 124.01,
1.87, 23.83, 31.39, 37.93, 46.12, 60.39, 61.70, 75.39, 108.71, 126.12, 126.37, 126.68, 130.42, 134.90, 135.09, 142.69, 149.82,
11.29, 115.76, 119.79, 120.40, 120.77, 123.28, 126.13, 126.62, 153.01, 190.88; HRMS: m/z [M + H] calcd for C28
26.71, 126.84, 130.66, 134.95, 135.29, 144.09, 156.26; HRMS: m/ 489.2501, found: 489.2502; IR (KBr, cm ): 3271, 2958, 2909,
z [M + H] calcd for C27
+
H
33
N
4
O
4
ꢂ1
+
H
33
N
4
O
2
445.2603, found: 445.2602; IR 2904, 2854, 1687, 1583, 1512, 1463, 1265, 1172, 1128, 1013, 854,
ꢂ1
(
KBr, cm ): 3248, 2964, 2925, 2871, 1744, 1684, 1591, 1493, 810, 750.
1454, 1372, 1236, 1055, 858, 787, 738.
4-((1-(2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)
1,8-Diethyl-1-(2-(4-((p-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
ethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (6l)
ethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (6i)
ꢁ
Brown solid; yield 94%; mp 123 C; chemical formula:
ꢁ
1
Pale yellow solid; yield 90%; mp 140 C; chemical formula: C H N O : H NMR (400 MHz, CDCl ): d 0.95 (t, J ¼ 7.06 Hz,
2
7
30
4
3
3
1
C
27
H
32
N
4
O
2
; H NMR (400 MHz, CDCl
3
): d 0.95 (t, J ¼ 7.08, 3H), 3H), 1.30 (t, J ¼ 7.2 Hz, 3H), 1.78–1.90 (m, 1H), 1.95–2.09 (m,
1
3
2
4
(
7
.35 (t, J ¼ 7.3, 3H), 1.77–1.86 (m, 1H), 1.94–2.01 (m, 1H), 2.28 (s, 1H), 2.44–2.55 (m, 1H), 2.56–2.67 (m, 1H), 2.70–2.85 (m, 3H),
H), 2.42–2.48 (m, 1H), 2.56–2.64 (m, 1H), 2.74–2.80 (m, 3H), 2.86–3.01 (m, 1H), 3.92–4.04 (m, 1H), 4.05–4.19 (m, 1H), 4.20–
.88–2.95 (m, 1H), 3.96–4.02 (m, 1H), 4.07–4.13 (m, 1H), 4.16– 4.34 (m, 1H), 4.37–4.49 (m, 1H), 4.70 (d, J ¼ 12.22 Hz, 1H), 4.95
.27 (m, 1H), 4.36–4.45 (m, 1H), 4.72 (d, J ¼ 12.22 Hz, 1H), 4.91 (d, J ¼ 12.22 Hz, 1H), 6.95–7.09 (m, 4H), 7.16 (s, 1H), 7.36 (d, J ¼
d, J ¼ 12.22 Hz, 1H), 6.78 (d, J ¼ 8.3 Hz, 2H), 7.01–7.10 (m, 3H), 7.33 Hz, 1H), 7.80 (d, J ¼ 8.80 Hz, 2H), 8.24 (brs, 1H), 9.86 (s,
1
3
13
.26–7.33 (m, 2H), 7.35 (d, J ¼ 7.82 Hz, 1H), 8.35 (s, 1H);
C
1H); C NMR (100 MHz, CDCl ): d 7.78, 13.58, 22.39, 23.78,
3
NMR (100 MHz, CDCl ): d 7.75, 13.60, 20.39, 22.39, 23.80, 31.37, 31.44, 37.85, 46.06, 60.35, 61.47, 75.21, 108.80, 114.92 (2C),
3
3
1
7.89, 46.07, 60.37, 61.45, 75.34, 108.68, 114.48 (2C), 115.75, 115.86, 119.87, 120.47, 123.77, 126.09, 126.50, 130.12, 131.92
19.77, 120.38, 126.64, 129.71, 129.83 (2C), 130.31, 134.94, (2C), 134.90, 135.25, 142.50, 163.07, 190.82; HRMS: m/z [M + H]
+
This journal is © The Royal Society of Chemistry 2017
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Paper
ꢂ1
calcd for C27
3
1
H
31
N
4
O
3
459.2396, found: 459.2395; IR (KBr, cm ):
Bioorg. Med. Chem. Lett., 2014, 24, 325–327; (e)
S. R. Mandha, S. Siliveri, M. Alla, V. R. Bommena,
M. R. Bommineni and S. Balasubramanian, Bioorg. Med.
Chem. Lett., 2012, 22, 5272–5278; (f) P. Jangili, C. G. Kumar,
Y. Poornachandra and B. Das, Synthesis, 2015, 47, 653–658.
J.-M. Xu, E. Zhang, X.-J. Shi, Y.-C. Wang, B. Yu, W.-W. Jiao,
Y.-Z. Guo and H. M. Liu, Eur. J. Med. Chem., 2014, 80, 593–
604.
183, 2953, 2926, 2854, 1698, 1600, 1512, 1463, 1315, 1260,
167, 1073, 1013, 865, 827, 750.
Acknowledgements
6
Bhaskar Kummari thankful to CSIR for awarding Senior
Research Fellowship. Thankful to TEQIP II for laboratory
development and PS3 LABORATORIES LLP for HPLC analysis.
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W. Huihui, X. Shuhua and S. Guifan, Toxicol. Res., 2015, 4,
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23686 | RSC Adv., 2017, 7, 23680–23686
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