Synthesis and characterization of 2-(4-((1-alkyl or aryl-1H-1,2,3-triazol- 4-yl)methoxy)phenyl)naphtho[1,2-d]oxazoles for protein tyrosine phosphatase 1B inhibitory activity

Article abstract of DOI:10.1007/s00044-013-0784-0

2-(4-((1-Alkyl/aryl-1H-1,2,3-triazol-4-yl)methoxy) phenyl)naphtho[1,2-d] were prepared and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors. In this study, two new compounds with potent PTP1B inhibitory activity were identified. Springer Sc

Full text of DOI:10.1007/s00044-013-0784-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2062–2069
DOI 10.1007/s00044-013-0784-0
ORIGINAL RESEARCH
Synthesis and characterization of 2-(4-((1-alkyl or aryl-1H-1,2,3-
triazol-4-yl)methoxy)phenyl)naphtho[1,2-d]oxazoles for protein
tyrosine phosphatase 1B inhibitory activity
•
Sridhar Madabhushi Narsaiah Chinthala
•
•
Abhinav Kanwal Gagandeep Kaur
•
Sanjay K. Banerjee
Received: 4 April 2013 / Accepted: 7 September 2013 / Published online: 4 October 2013
Ó Springer Science+Business Media New York 2013
Abstract 2-(4-((1-Alkyl/aryl-1H-1,2,3-triazol-4-yl)methoxy)
phenyl)naphtho[1,2-d] were prepared and evaluated as protein
tyrosine phosphatase 1B (PTP1B) inhibitors. In this study, two
new compounds with potent PTP1B inhibitory activity were
identified.
Protein tyrosine phosphatase-1B (PTP1B), which is a
member of the PTP family, directly interacts with the
activated insulin receptor or insulin receptor substrate-1
(IRS-1) and dephosphorylate the phosphotyrosine residue.
Thus, PTP1B acts as a negative regulator of insulin sig-
naling pathway and leads to hyperglycemia by reducing the
metabolic action of insulin (Elchebly et al., 1999; Gold-
stein et al., 2000). Molecular modeling studies also proved
that treatment of type II diabetes is possible using potent
and orally active PTP1B inhibitors (Taha et al., 2007). In
recent years, studies have been extensively focused to
identify small molecules, which exhibit high PTP1B inhi-
bition and high in vivo efficacy with minimum side effects
(Bialy and Waldmann, 2005; Srinivasan et al., 2006; Shim
et al., 2003; Popov, 2011; Van Huijsduijnen et al., 2002;
Ibrahimi et al., 2000; Tjernberg et al., 2004; Adams et al.,
2007; Ye et al., 2010; Xie et al., 2011). In this communi-
cation, we report the synthesis and characterization of
2-(4-((1-alkyl/aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
naphtho[1,2-d]oxazoles 4a–l as new class of PTP1B
inhibitors.
Keywords Naphtho[1,2-d]oxazole derivatives ꢀ
PTP1B inhibitor ꢀ Antidiabetic activity
Introduction
Type II diabetes is a progressive disease caused by insulin
resistance in peripheral tissues and/or impaired insulin
secretion by the pancreas (King et al., 1998). At the
molecular level, the mechanism of insulin resistance in
type II diabetes is believed to be due to defects in post-
receptor signal transduction pathway (Montalibet and
Kennedy, 2005; Youngren and Goldfine, 1997; Vats et al.,
2005). Phosphorylation of protein tyrosyl residues is con-
sidered to be the controlling factor, which activates or
attenuates the intracellular signaling pathways involved in
cell proliferation, differentiation, and metabolism (Ken-
nedy and Ramachandran, 2000).
Chemistry
Earlier, Elchebly et al., (1999) showed that PTP1B
deficiency in mice results in enhanced insulin sensitivity.
In the present study, a small library of 2-(4-((1-alkyl/aryl-
1H-1,2,3-triazol-4-yl)methoxy)phenyl)naphtho[1,2-d]oxaz-
oles 4a–l was prepared using an efficient three-step method
as shown in Scheme 1. To obtain 4a–l, we first carried out
reaction of 2-(2-hydroxynaphthalen-1-yl) (4-hydroxy-
phenyl) methanone 1 and acetohydroxamic acid using
H2SO4 as the catalyst under microwave heating at 80 °C to
obtain 4-(naphtho[1,2-d]oxazol-2-yl)phenol 2 in 45 %
yield (Sridhar et al., 2011). In the next step, 2 was reacted
with propargyl bromide using K2CO3 as a base under reflux
S. Madabhushi (&) ꢀ N. Chinthala
Fluoroorganics Division, Indian Institute of Chemical
Technology, Hyderabad 500607, India
e-mail: smiict@gmail.com
A. Kanwal ꢀ G. Kaur ꢀ S. K. Banerjee (&)
Pharmacology Division, Indian Institute of Chemical
Technology, Hyderabad 500607, India
e-mail: skbanerjee@iict.res.in
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Med Chem Res (2014) 23:2062–2069
2063
R
N
E
N
N
OH
O
O
HO
D
O
N
N
N
C
O
OH
O
O
a
(b)
( )
(c)
B
A
a-
4
l
1
2
3
4a (R = Ph); 4b (R = 4-MeOPh); 4c (R = 3-CF3Ph) ;4d(R = 3-ClPh); 4e (R=3-Cl,4-FPh);
4f (R = 3,4-diFPh); 4g (R = n-Bu); 4h (R = n-hexyl); 4i (R = CF3(CF2)5CH2CH2);
4j (R = CF3(CF2)7CH2CH2); 4k (R = 4-Me Ph); 4l R = 4-CF3Ph).
Scheme 1 Synthesis of 2-(4-((1-alkyl/aryl-1H-1,2,3-triazol-4-yl)methoxy)-
phenyl)naphtho[1,2-d]oxazoles. Reagents and conditions: (a) acetohy-
droxamic acid, H2SO4 (catalyst), acetonitrile, MW, 80 °C, 10 min,
45 %; (b) K2CO3, propargyl bromide, acetone, reflux, 4 h, 98 %;
(c) CuI, R-N3, dry THF, 50 °C, 4–6 h, 87–98 %
in acetone and the corresponding O-propargyl ether 3 in
98 % yields was obtained . Next, Huisgen reaction of 3 and
alkyl or aryl azide under copper(I) iodide catalysis (Huis-
gen, 1984) gave the desired products 4a–l in high 87–98 %
yields as shown in Scheme 1.
Table 1 Study of PTP1B inhibitory activity of molecule 4a–l
Compounds
% Inhibition
4a
-29.21
-30.81
-31.54
-24.95
-21.34
-29.29
-17.25
-24.23
-12.68
-19.02
41.62
4b
4c
4d
Results and discussion
4e
4f
Initially, test systems were prepared by pre-incubating the
PTP-1B enzyme (3 lL) derived from rat liver homogenate
with compound 4a–l (10 lM, 5 lL) for 30 min. Next, we
estimated the residual PTPase activity in these test systems
by Goldstein method (Goldstein et al., 2000) using sodium
orthovanadate (10 lM, 5 lL), a non-selective PTP’s
inhibitor, as a standard. In this study, we observed PTP1B
inhibitory activity only with compounds 4k (41.62 %) and
4l (68.32 %) with respect to the standard sodium ortho-
vanadate, (60.63 %) as shown in Table 1. In this study,
compounds 4k and 4l gave IC50 of 20.43 and 8.61 lM,
respectively, as shown in Table 2. Both these compounds
also showed dose-dependent inhibitory activity as shown in
Figs. 1 and 2.
4g
4h
4i
4j
4k
4l
68.32
Sod. Vandate
60.68
Table 2 PTB1B inhibitor activity (IC50) of compounds 4k and 4l
Serial no.
Compound
IC50 (lM)
1
2
4k
4l
20.43
8.61
We also studied in vivo PTP-1B inhibitory activity of
compounds 4k and 4l in Sprague-Dawley (SD) rats, which
were treated with these compounds after oral glucose
challenge. In this study, compounds 4k and 4l reduced the
blood glucose level by 62.64 and 78.59 %, respectively,
while the standard drug, metformin, lowered the blood
glucose level by 57.10 % under similar experimental
conditions as shown Table 3. We also estimated the cyto-
toxicity of 4k and 4l against the standard doxorubicin on
two cell lines A549 (lung cancer cell line) and HEK-293
(human embryonic kidney cell line) and the results are
given in Table 4. The results obtained in this study suggest
that the compounds 4k and 4l are safer than doxorubicin.
The compounds 4a–l contain identical core structure,
which is designated as A, B, C, D, and E ring system and
they have different groups such as alkyl, aryl, or fluoroal-
kyl on their E ring (triazole ring). In our study, discour-
aging results were observed with compounds 4a–j, which
did not act as PTP1B inhibitors, while the compounds 4k
and 4l showed good PTP-1B inhibitory activity. The
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having 3-CF3Ph functionality on ring E, did not act as a
PTP1B inhibitor. This observation suggests that possibly
the orientation of CF3 group in 4l plays an important role in
binding with PTP1B enzyme effectively and thereby
inhibiting its activity.
Phosphatase-1B inhibitory assay protein tyrosine
Protein tyrosine phosphatase inhibitory activity was
determined according to the modified method of Goldstein
et al. (2000). As a rat liver is very rich in PTP-1B enzyme,
we used rat liver homogenate as a source of protein tyro-
sine phosphatase 1B. Initially to standardize this method,
we used a range of given homogenate (1–10 lL) to find the
PTP-1B activity. The test compounds (5–50 lM, 5 lL)
were pre-incubated with liver homogenate (3 lL) in 4-(2-
hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES)
buffer (total volume 50 lL) for 30 min. Drug assay was
performed in a final volume of 200 lL in a test mixture
containing 10 mM of p-nitro phenyl phosphate (p-NPP) in
50 mM HEPES buffer (pH 7.0) and 1 mM DTT. After
10 min of incubation at 37 °C, the reaction was stopped by
addition of 50 lL of 0.1 N NaOH and the absorbance was
determined at 410 nm. Sodium orthovanadate was taken as
a standard for this enzyme assay (Goldstein et al., 2000).
Fig. 1 Dose–response curve for 4k
Fig. 2 Dose–response curve for 4l
Table 3 Blood glucose level after 10 min of oral glucose challenge
in SD rats
In vivo glucose assay
Compound
Blood glucose level
10 min after oral
glucose (mg/dL)
% Inhibition
of blood glucose
from control
The method described by Goldstein et al., (2000) was used
for determination of in vivo glucose level after oral glucose
challenge in male albino rats of Sprague-Dawley strain,
which are having average body weight 250–300 g. The
blood glucose level of each animal was checked by glu-
cometer using glucostrips (one touch horizon) after 12 h
starvation. Animals of experimental group were adminis-
tered dimethylsulfoxide (DMSO) solution of the synthetic
compounds (50 mg/kg) and metformin (300 mg/kg) through
intraperitoneal (i.p.) route. Animal of a control group was
given an equal amount of DMSO and 10 min after the
administration of test compound, glucose (5 g/kg body wt.)
was administered orally to each animal. Blood glucose was
measured exactly after 10 min of post administration of the
glucose solution by glucometer. Percentage inhibition was
calculated from the blood glucose levels of both rats that
received 5 g/kg glucose orally in the presence and absence
of test compounds, respectively.
Control
Metformin
4k
257
110
96
–
57.10
62.64
78.59
4l
55
Table 4 Cytotoxicity (IC50) assay of4k and 4l
Compound
IC-50 values (lM)
A549- cells
IC-50 values
(lM) HEK293-cells
4k
[1,000
[1,000
3.98
[1,000
[1,000
1.006
4l
Doxorubicin
compounds 4k and 4l contain 4-CH3Ph and 4-CF3Ph as the
pendent groups on the E ring of their structures, respec-
tively, and CF3 and CH3 groups are known to be bioisos-
teres (Yamazaki et al., 2009). However, in this study, 4l
was found to be substantially more active than 4k and it
could be possibly because CF3 group is more lipophilic and
exhibits better metabolic stability than CH3 group. How-
ever, compound 4c, which is a structural isomer of 4l
Cytotoxicity assay cell line
A549-cells (Human Lung Adenocarcinoma Epithelial Cell
Line) and HEK293 cells (Human Embryonic Kidney Cell
Line) were purchased from National Centre for Cell Sci-
ence (NCCS), Pune. Both cell lines were maintained in
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Med Chem Res (2014) 23:2062–2069
2065
Typical procedure for the preparation of 2-aryl-naphtho
Dulbecco’s modified Eagle’s medium (DMEM, Sigma,
USA) containing 10 % heat-inactivated fetal bovine serum
(FBS, Lonza), 100 U/mL penicillin, 100 U/mL strepto-
mycin, and 2 mM L-glutamine at 37 °C in a humidified
atmosphere of 5 % CO2. Cells were passaged every
2–3 days to maintain exponential growth.
[1,2-d]oxazole 2
2-(2-Hydroxynaphthalen-1-yl)(4-hydroxyphenyl) 1 (1.0 g,
3.78 mmol), acetohydroxamic acid (0.45 g, 5.68 mmol),
acetonitrile (5 mL), and conc. H2SO4 (catalyst, 0.3 mL)
were taken into a 10 mL pressure tube and subjected to
microwave heating (CEM discover, 360 W, 80 °C, 25 psi)
for 10 min. Next, the reaction mixture was diluted with
ethyl acetate (5 mL) and to this saturated sodium bicar-
bonate solution (5 mL) was added dropwise. The mixture
was extracted with ethyl acetate (2 9 10 mL) and the
combined organic layer was washed with saturated NaCl
solution, dried over anhy. Na2SO4, and concentrated under
reduced pressure. Purification of the mixture was per-
formed by normal column chromatography (silica gel
60–120 mesh, ethyl acetate/hexane: 1:10) to obtain
4-(naphtho[1,2-d]oxazol-2-yl)phenol 2(0.43 g, 45 %, m.p.
275–278 °C) and it was characterized by the following
spectral data: EI (m/z) 261 (M)? IR (KBr, cm-1), 3450,
In vitro cytotoxicity assay
The cytotoxicity of the different compounds (shown below)
was studied by means of a colorimetric micro culture assay
using MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tet-
razolium bromide (Botta et al., 2007). 1 9 104 cells/well
were seeded in 100 lL DMEM, supplemented with 10 %
FBS in each well of 96-well micro culture plates and
incubated for 24 h at 37 °C in a CO2 incubator. The desired
concentrations of the compounds were made and added to
the wells with respective vehicle control. After 24 h of
incubation, 10 lL MTT (5 mg/mL) was added to each well
and the plates were further incubated for 4 h. Then the
supernatant from each well was carefully removed, for-
mazan crystals were dissolved in 100 lL of DMSO, and
absorbance was recorded at 540-nm wavelength.
1
1610, 1437; H NMR (DMSO-d6, 300 MHz) d: 6.98 (d,
2H, J = 8.7 Hz); 7.46 (m, 1H); 7.58 (m, 2H); 7.92 (m,
2H); 8.09 (m, 3H); 8.41 (d, J = 8.1 Hz, 1H); 9.6 (bs,
–OH); 13C NMR (DMSO-d6, 75 MHz) d 111.1 (Ar–C3),
116.2 (O–Ph–C3&C5), 117.7 (O–Ph–C2&C6), 121.7 (Ar–
C10), 125.5 (Ar–C9), 125.7 (Ar–C5), 127.1 (Ar–C4), 128.8
(Ar–C7&C8), 129.1 (Ar–C6), 131.0 (O–Ar–C1), 137.07
(Ar–C1), 147.4 (Ar–C2), 160.8 (O–Ph–C4), 162.5 (oxa-
zole–C=N).
Conclusion
In summary, we prepared a small library of 2-(4-((1-alkyl/
aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)naphtho[1,2-d]-
oxazoles by an efficient three-step protocol and studied
their in vitro and in vivo protein tyrosine phosphatase 1B
(PTP1B) inhibitory activity. In this study, two of the
compounds 4k and 4l were found to exhibit good PTP1B
inhibitory activity and low cytotoxicity.
Synthesis of 2-(4-(prop-2-yn-1-yloxy)phenyl)-
naphtho[1,2-d]oxazole 3
4-(Naphtho[1,2-d]oxazole-2-yl)phenol 2 (1.3 g, 4.98 mmol),
propargyl bromide (0.89 g, 7.47 mmol), dry acetone
(15 mL), and K2CO3 (2 g, 14.9 mmol) were taken into a
25 mL round bottomed flask fitted with a condenser and
nitrogen balloon. The mixture was refluxed for 4 h and after
completion of the reaction (TLC), the reaction mixture was
cooled to room temperature and filtered. The filtrate was
concentrated under reduced pressure and the crude product
was purified by normal column chromatography (silica gel 60–
120 mesh, ethyl acetate–hexane: 1:10) to obtain 2-(4-(prop-
2-yn-1-yloxy)phenyl)naphtho[1,2-d]oxazole 3b (1.45 g,
98 %, m.p. 117–120 °C) in the form of a white powder. The
spectral data obtained for 3b are as follows: 1H NMR
(CDCl3, 300 MHz): d 2.49 (s, 1H), 4.73 (s, 2H), 7.04–7.09
(d, J = 9.0 Hz, 2H), 7.45–7.50 (t, J = 7.0 Hz, 1H),
7.57–7.62 (t, J = 7.0 Hz, 1H), 7.63–7.67 (d, J = 8.0 Hz,
1H), 7.69–7.73 (d, J = 8.0 Hz, 1H), 7.87–7.92 (d,
J = 8.0 Hz, 1H), 8.21–8.26 (d, J = 9.0 Hz, 2H), 8.51–8.55
(d, J = 9.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz,): d 56.1
(OCH2), 78.8 (acetylene–C2), 79.7 (acetylene–C1), 111.4
Experimental
The melting points of all the compounds were recorded on
Veego melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin-Elmer FT-IR 240-C
spectrophotometer using KBr optics. NMR spectra were
obtained using the Bruker Avance 300 MHz and Inova
400 MHz instruments in DMSO-d6 or CDCl3 using TMS
as the internal standard. Electron impact (EI) and chemical
ionization (CI) mass spectra were recorded on a VG 7070
H 5 instrument at 70 eV. All high-resolution spectra were
recorded on QSTARXL hybrid MS/MS system (Applied
Biosystems, USA) under electrospray ionization. All the
reactions were monitored by thin-layer chromatography
(TLC) on precoated silica gel 60 F254 (mesh); spots were
visualized with UV light. Merck silica gel (60–120 mesh)
was used for column chromatography.
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(Ar–C3), 116.0 (O–Ph–C3&C5), 120.2 (O–Ph–C2&C6),
122.1 (Ar–C10), 125.8 (Ar–C9), 126.1 (Ar–C5), 127.4 (Ar–
C4), 129.1 (Ar–C7&C8), 131.2 (Ar–C6), 137.2 (Ar–C1),
147.8 (Ar–C2), 160.1 (O–Ph–C4), 162.1 (oxazole–C=N); EI
(m/z) 299 (M)?; IR (KBr, cm-1): 3350, 2218, 1615, 1435.
(d, J = 7.1 Hz, 2H), 7.94–7.97 (d, J = 7.9 Hz, 1H),
8.24–8.27(d, J = 8.6 Hz, 2H), 8.42 (s, 1H), 8.48–8.50 (d,
J = 7.7 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz): d 28.9
(OCH3), 61.1 (Ar–OCH2), 110.3 (Ar–C3), 113.8 (triazole–
Ar–C3&C5), 114.2 (O–Ph–C3&C5), 114.8 (O–Ph–C2&C6),
119.6 (triazole–C2), 121.3 (triazole–Ph–C2&C6), 121.5
(O–Ph–C1), 121.9 (Ar–C10), 124.7 (Ar–C5), 125.7 (Ar–C4),
128.1 (Ar–C9), 128.4 (Ar–C6), 28.5 (Ar–C7&C8), 129.2
(O–Ph–C1), 129.8 (triazole–Ar–C1), 130.5 (triazole–C1),
142.8 (nap–C1), 143.5 (nap–C2), 155.4 (O–Ar–C4), 159.04
(triazole–Ar–C4), 160.2 (oxazole–C=N); ESI (m/z) 449
([M?H]?); ESI-HRMS: m/z obtained for C27H21N4O3
([M?H]?): 449.1467 (Calcd. 449.1454).
Typical procedure for the synthesis of 1,2,3-triazole-
functionalized 2-aryl-naphtho[1,2-d]oxazoles 4a–l
2-(4-(Prop-2-yn-1-yloxy)phenyl)naphtho[1,2-d]oxazole
3
(50 mg, 0.17 mmol), phenyl azide (30 mg, 0.25 mmol),
dry THF (7 mL), and CuI (3 mg, 0.016 mmol) were taken
into a 25 mL round bottomed flask fitted with a condenser
and nitrogen balloon. The mixture was heated at 50 °C for
6 h and after completion of the reaction (TLC), the reaction
mixture was cooled to room temperature and filtered. The
filtrate was concentrated under reduced pressure and the
crude product obtained was purified by normal column
chromatography (silica gel 60–120 mesh, ethyl acetate–
hexane: 1:2) to obtain 4a (65 mg, 93 %, m.p. 189–191 °C)
in the form of a white powder.
2-(4-((1-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-
yl)methoxy)phenyl)naphtho[1,2-d]oxazole (4c)
1
White powder, Yield (93 %); m.p. 185–189 °C; H NMR
(DMSO-d6, 300 MHz): d 5.38 (s, 2H), 7.27–7.29 (d,
J = 8.6 Hz, 2H), 7.52–7.57 (t, J = 7.3 Hz, 1H), 7.64–7.69
(t, J = 7.7 Hz, 1H), 7.83–7.84 (d, J = 4.1 Hz, 2H),
8.00–8.03 (d, J = 8.1 Hz, 1H), 8.23–8.24 (d, J = 8.6 Hz,
2H), 8.25–8.28 (d, J = 5.6 Hz, 2H), 8.44–8.47 (d,
J = 8.1 Hz, 1H), 9.08 (s, 1H); 13C NMR (DMSO-d6,
75 MHz,): d 61.1 (OCH2), 110.8 (Ar–C3), 115.4 (O–Ph–
C3&C4), 116.6 (O–Ph–C2&C6), 119.4 (triazole–C1), 121.2
(triazole–Ar–C2), 123.2 (Ar–C10), 123.8 (O–Ph–C1), 125.0
(Ar–C9), 125.2 (triazole–Ar–C4), 125.5 (Ar–C5), 126.9
(Ar–C4), 128.5 (Ar–C6), 128.7 (Ar–C7&C8), 130.7 (tria-
zole–Ar–C1), 131.0 (triazole–Ar–C3), 132.7 (triazole–Ar–
C5), 136.7 (Ar–CF3), 136.8 (triazole–C1), 143.6(Ar–C1),
147.2 (Ar–C2), 160.4 (O–Ph–C4), 161.6 (oxazole–C=N);
ESI (m/z) 486 ([M?H]?); ESI-HRMS: m/z obtained for
C27H17N4O2F3Na ([M?Na]?): 509.1201 (Calcd. 509.1191).
Characterization data obtained for 4a–l
2-(4-((1-Phenyl-1H-1,2,3-triazole-4-yl)phenyl)-
naphtho[1,2-d]oxazole (4a)
1
White powder, Yield (92 %); m.p. 189–191 °C; HNMR
(DMSO-d6, 300 MHz): d 5.37 (s, 2H), 7.29–7.31 (d,
J = 8.0 Hz, 2H), 7.46–7.49 (t, J = 7.0 Hz, 1H), 7.55–7.60
(m, 3H), 7.67–7.70 (t, J = 7.0 Hz, 1H), 7.87–7.88 (d,
J = 5.0 Hz, 2H), 7.90–7.91 (d, J = 8.0 Hz, 2H), 8.04–8.06
(d, J = 8.0 Hz, 1H), 8.23–8.25 (d, J = 9.0 Hz, 2H),
8.44–8.46 (d, J = 8.0 Hz, 1H), 8.90 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz,): d 61.1 (O–CH2), 110.8 (Ar–C3),
115.3 (O–Ph–C3&C5), 119.5 (triazole–C2) 119.9 (O–Ph–
C2&C6),), 121.5 (triazole–Ph–C2&C6), 122.7 (Ar–C10),
125.2 (O–Ph–C1), 125.5 (Ar–C9), 126.8 (Ar–C5), 128.5
(triazole–Ph–C3&C5), 128.5 (Ar–C4), 128.7 (Ar–C7&C8),
129.6 (Ar–C6), 130.7 (triazole–ph–C4), 136.5 (triazole–ph–
C1), 136.8 (Ar–C1), 143.2 (triazole–C2), 147.3 (Ar–C2),
160.4 (O–Ph–C4), 161.6 (oxazole–C=N); ESI (m/z) 419
([M?H]?); ESI-HRMS: m/z obtained for C26 H19 N4O2
([M?H]?): 419.1508 (Calcd. 419.1504).
2-(4-((1-(3-Chlorophenyl)-1H-1,2,3-triazol-
4yl)methoxyphenyl)naptho[1,2-d]oxazole (4d)
1
White powder, Yield (98 %); m.p. 144–148 °C; H NMR
(DMSO-d6, 300 MHz): d 5.36 (s, 2H), 7.20–7.21 (d,
J = 8.0 Hz, 2H), 7.40–7.41 (d, J = 7.0 Hz, 1H), 7.49–7.52
(m, 1H), 7.61–7.64 (t, J = 8.0 Hz, 1H), 7.71–7.73 (d,
J = 9.0 Hz, 1H), 7.76–7.78 (d, J = 9.0 Hz, 1H), 7.80–8.82
(d, J = 8.0 Hz, 1H), 7.93–7.95 (d, J = 7.0 Hz, 2H),
8.24–8.26 (d, J = 8.0 Hz, 2H), 8.48–8.50 (d, J = 8.0 Hz,
1H), 8.64 (s, 1H); 13C NMR (DMSO-d6, 75 MHz,): d 61.3
(OCH2), 111.3 (Ar–C3), 114.8 (O–Ph–C3&C5), 115.4 (O–
ph–C2&C6), 119.2 (triazole–C2), 121.2 (triazole–Ar–C5),
121.6 (triazole–Ar–C6), 122.5 (triazole–Ar–C2), 122.7 (O–
Ph–C1), 123.6 (Ar–C10), 124.0 (Ar–C9), 125.7 (Ar–C5),
126.0 (Ar–C4&C6), 127.4 (Ar–C7&C8), 129.3 (triazole–
Ar–C4), 131.1 (triazole–Ar–C3), 135.2 (triazole–Ar–C1),
140.3 (Ar–C1), 143.7 (triazole–C2), 148.9 (Ar–C2), 160.4
2-(4-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-
4yl)methoxy)phenyl)naptho[1,2-d]oxazole (4b)
1
White powder, Yield (87 %); m.p. 158–162 °C; H NMR
(DMSO-d6, 500 MHz): d 3.86 (s, 3H), 5.35 (s, 2H),
7.01–7.04 (d, J = 8.6 Hz, 2H), 7.20–7.23 (d, J = 8.6 Hz,
2H), 7.49–7.54 (t, J = 7.5 Hz, 1H), 7.61–7.66 (t,
J = 7.5 Hz, 1H), 7.71–7.73 (d, J = 9.2 Hz, 2H), 7.74–7.77
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(O–Ph–C4), 161.6 (oxazole–C=N); ESI (m/z) 553 ([M?H]?);
ESI-HRMS: m/z obtained for C26H18N4O2Cl ([M?H]?):
553.1408 (Calcd. 553.1395).
J = 7.1 Hz, 1H), 7.62–7.65 (t, J = 7.1 Hz, 1H), 7.73–7.75
(d, J = 9.2 Hz, 1H), 7.77–7.78 (d, J = 9.2 Hz, 1H), 7.94
(s, 1H), 7.95–7.97 (d, J = 9.2 Hz, 1H), 8.21–8.23 (d,
J = 9.2 Hz, 2H), 8.47–8.48 (d, J = 8.1 Hz, 1H); 13C NMR
(DMSO-d6, 75 MHz,): d 13.6 (CH3), 20.3 (CH2), 29.5
(CH2), 48.2 (CH2–N), 61.2 (OCH2), 110.8 (Ar–C3), 115.3
(O–Ph–C3&C5), 119.5 (O–Ph–C2&C6), 119.9 (triazole–
C2), 121.5 (Ar–C10), 122.7 (Ar–C9), 125.2 (O–Ph–C1),
125.5 (Ar–C5), 126.8 (Ar–C4), 128.2 (Ar–C6), 128.5 (Ar–
C7), 128.7 (Ar–C8), 136.8 (Ar–C1), 143.2 (triazole–C1),
147.3 (Ar–C2), 160.4 (O–Ph–C4), 161.6 (oxazole–C=N);
ESI (m/z) 399 ([M?H]?); ESI-HRMS: m/z obtained for
C24H23N4O2 ([M?H]?): 399.1743 (Calcd. 399.1737).
2-(4-((1-(3-Chloro-4-fluorophenyl)-1H-1,2,3-triazol-
4yl)methoxy)phenyl)naptho[1,2-d]oxazole (4e)
(White powder, 96 %, m.p. 193–196 °C): 1H NMR (DMSO-
d6, 300 MHz): d 5.40 (s, 2H), 7.33–7.35 (d, J = 8.8 Hz, 2H),
7.59–7.62 (t, J = 7.8 Hz, 1H), 7.67–7.69 (d, J = 8.8 Hz,
1H), 7.71–7.74 (t, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.97–8.01
(m, 3H), 8.11–8.12 (d, J = 7.8 Hz, 1H), 8.24–8.25 (d,
J = 8.8 Hz, 2H), 8.44–8.45 (d, J = 7.8 Hz, 1H), 9.03(s, 1H);
13C NMR (DMSO-d6, 75 MHz,): d 61.4 (OCH2), 111.3 (Ar–
C3), 115.1 (O–Ph–C3&C5), 118.2 (O–Ph–C2&C6), 121.2
(triazole–C2), 121.5 (Ar–C9), 121.7 (triazole–Ar–C3), 122.0
(Ar–C10), 122.7 (O–Ph–C1), 123.6 (triazole–Ar–C5), 125.7
(Ar–C5), 126.0 (Ar–C4&C6), 127.4 (Ar–C7&C8), 129.1 (tri-
azole–Ar–C2), 131.0 (triazole–Ar–C1), 140.1 (Ar–C1), 143.8
(triazole–C1), 148.8 (Ar–C2), 158.3 (O–Ph–C4), 160.7 (tria-
zole–Ar–C4), 162.5 (oxazole–C=N); ESI (m/z) 471
([M?H]?); ESI-HRMS: m/z obtained for C26H17N4O2FCl
([M?H]?): 471.1205 (Calcd. 471.1201).
2-(4-((1-Hexyl-1H-1,2,3-triazol-
4yl)methoxy)phenyl)naptho[1,2-d]oxazole (4h)
1
White powder, Yield (92 %); m.p. 109–112 °C; H NMR
(DMSO-d6, 300 MHz): d 0.86–0.89 (t, J = 6.1 Hz, 3H),
1.28–1.35 (m, 6H), 1.86–1.90 (m, 2H), 4.34–4.37 (t,
J = 7.1 Hz, 2H), 5.26 (s, 2H), 7.17–7.19 (d, J = 9.2 Hz,
2H), 7.50–7.53 (t, J = 7.1 Hz, 1H), 7.62–7.65 (t,
J = 7.1 Hz, 1H), 7.73–7.75 (d, J = 9.2 Hz, 1H), 7.77–7.78
(d, J = 9.2 Hz, 1H), 7.94 (s, 1H), 7.95–7.97 (d,
J = 9.2 Hz, 1H), 8.21–8.23 (d, J = 9.2 Hz, 2H), 8.47–8.48
(d, J = 8.1 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz,): d
14.1 (CH3), 22.8 (CH2), 26.5 (CH2), 28.4 (CH2), 31.6
(CH2–N), 61.0 (OCH2), 110.8 (Ar–C3), 114.3 (O–Ph–
C3&C5), 119.5 (O–Ph–C2&C6), 120.1 (Ar–C10), 123.8
(Ar–C9), 125.0 (O–Ph–C1), 125.3 (Ar–C5), 126.5 (Ar–C4),
127.3 (Ar–C6), 136.5 (Ar–C1), 142.3 (triazole–C1), 147.2
(Ar–C2), 60.3 (O–Ph–C4), 161.5 (oxazole–C=N); ESI (m/
z) 427 ([M?H]?); ESI-HRMS: m/z obtained for
C26H27N4O2 ([M?H]?): 427.2137 (calcd. 427.2134).
2-(4-((1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-
4yl)methoxy)phenyl)naptho[1,2-d]oxazole (4f)
1
White powder, Yield (95 %); m.p. 151–155 °C; H NMR
(DMSO-d6, 300 MHz): d 5.37 (s, 2H), 7.24–7.26 (d,
J = 8.8 Hz, 2H), 7.33–7.38 (m, 1H), 7.52–7.55 (t,
J = 7.9 Hz, 1H), 7.63–7.66 (t, J = 7.9 Hz, 1H), 7.77–7.79
(d, J = 8.8 Hz, 1H), 7.81–7.83 (d, J = 8.8 Hz, 1H),
7.89–7.91 (d, J = 8.8 Hz, 1H), 7.92–7.94 (d, J = 7.9 Hz,
1H), 7.98–8.01 (d, J = 8.8 Hz, 1H), 8.23–8.25 (d,
J = 8.8 Hz, 2H), 8.45–8.47 (d, J = 7.9 Hz, 1H), 8.51 (s,
1H); 13C NMR (DMSO-d6, 75 MHz,): d 61.01 (OCH2),
111.1 (Ar–C3), 112.8 (O–Ph–C2&C6), 115.5 (O–Ph–
C3&C5), 119.4 (triazole–C2), 121.5 (Ar–C10), 124.3 (Ar–
C9), 125.4 (triazole–Ar–C2&C5), 125.6 (triazole–Ar–C6),
125.7 (Ar–C5), 126.5 (Ar–C4), 127.1 (Ar–C6), 127.6 (Ar–
C7&C8), 128.8 (O–Ph–C1), 130.8 (triazole–Ar–C1), 136.7
(Ar–C1), 142.8 (triazole–C2), 145.9 (Ar–C2), 147.4 (tria-
zole–Ar–C3&C4), 160.5 (O–Ph–C4), 161.7 (oxazole–C=N);
ESI (m/z) 455 ([M?H]?); ESI-HRMS: m/z obtained for
C26H17N4O2F2 ([M?H]?): 455.2137 (Calcd. 455.2134).
n2-(4-((1-(3,3,4,4,5,5,6,6,7,7,8,8-Tridecafluorooctyl)-
1H-1,2,3-triazol-4yl)methoxy)phenyl)naptho
[1,2-d]oxazole (4i)
1
White powder, Yield (87 %); m.p. 153–157 °C; H NMR
(DMSO-d6, 500 MHz): d 2.83–2.88 (m, 2H), 4.73–4.76 (t,
J = 7.9 Hz, 2H), 5.28 (s, 2H), 7.15–7.17 (d, J = 8.9 Hz,
2H), 7.49–7.52 (t, J = 7.9 Hz, 1H), 7.61–7.64 (t,
J = 7.9 Hz, 1H), 7.70–7.72 (d, J = 8.9 Hz, 1H), 7.75–7.77
(d, J = 8.9 Hz, 1H), 7.93–7.95 (d, J = 7.9 Hz, 1H), 8.09
(s, 1H), 8.23–8.25 (d, J = 8.9 Hz, 2H), 8.48–8.50 (d,
J = 7.9 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz,): d 34.3
(CH2), 37.4 (CH2–N), 61.0 (OCH2), 109.0 (CF2), 111.1
(Ar–C3), 112.8 (CF2), 115.5 (O–Ph–C3&C5), 117.5 (CF2),
118.2 (CF3), 119.4 (O–Ph–C2&C6), 121.5 (triazole–C2),
122.3 (Ar–C10), 125.4 (O–Ph–C1), 125.6 (Ar–C9), 125.7
(Ar–C5), 126.5 (Ar–C4), 127.1 (Ar–C6), 127.6 (Ar–C7),
128.7 (Ar–C8), 136.7 (Ar–C1), 142.8 (triazole–C1), 147.4
2-(4-((1-Butyl)-1H-1,2,3-triazol-4yl)methoxy)-
phenyl)naptho[1,2-d]oxazole (4g)
1
White powder, Yield (90 %); m.p. 114–117 °C; H NMR
(DMSO-d6, 300 MHz): d 0.86–0.89 (t, J = 6.1 Hz, 3H),
0.92–1.85 (m, 4H), 4.34–4.37 (t, J = 7.1 Hz, 2H), 5.38 (s,
2H), 7.17–7.19 (d, J = 9.2 Hz, 2H), 7.50–7.53 (t,
123

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Med Chem Res (2014) 23:2062–2069
(Ar–C2), 160.5 (O–Ph–C4), 161.7 (oxazole–C=N); ESI
(m/z) 689 ([M?H]?); ESI-HRMS: m/z obtained for
C28H18N4O2F13([M?H]?): 689.1222 (Calcd. 689.1219).
J = 9.0 Hz, 2H), 7.59–7.62 (t, J = 7.0 Hz, 1H), 7.71–7.74
(t, J = 7.0 Hz, 1H), 7.96 (s, 1H), 8.00–8.02 (d,
J = 8.0 Hz, 2H), 8.11–8.13 (d, J = 8.0 Hz, 1H), 8.19–8.21
(d, J = 8.0 Hz, 2H), 8.24–8.26 (d, J = 9.0 Hz, 2H),
8.44–8.45 (d, J = 8.0 Hz, 1H), 9.15 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz,): d 61.1 (OCH2), 110.8 (Ar–C3),
115.4 (O–Ph–C3&C5), 116.6 (O–Ph–C2&C6), 119.4 (tria-
zole–C2), 121.4 (Ar–C10), 123.1 (O–Ph–C1), 123.8 (tria-
zole–Ar–C3&C5), 125.0 (Ar–C5), 125.2 (Ar–C9), 125.5
(Ar–C4), 126.9 (Ar–C6), 128.5 (Ar–C7), 128.7 (Ar–C8),
130.7 (triazole–C2&C6), 131.0 (triazole–Ar–C1), 132.7
(Ar–C1), 136.7 (triazole–Ar–C4), 136.8 (Ar–CF3), 143.6
(triazole–C1), 147.2 (Ar–C2), 160.4 (O–Ph–C4), 161.6
(oxazole–C=N); ESI (m/z) 486 ([M?H]?); ESI-HRMS: m/
z obtained for C27H17N4O2F3Na ([M?Na]?): 509.1191
(Calcd. 509.1201).
2-(4-((1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluorodecyl)-1H-1,2,3-triazol-
4yl)methoxy)phenyl)naptho[1,2-d]oxazole (4j)
1
White powder, Yield (93 %); m.p. 158–162 °C; H NMR
(DMSO-d6, 500 MHz): d 2.81–2.99 (m, 2H), 4.71–4.75 (t,
J = 6.7 Hz, 2H), 5.20 (s, 2H), 7.21–7.24 (d, J = 8.1 Hz,
2H), 7.48–7.55 (t, J = 6.9 Hz, 1H), 7.61–7.67 (t,
J = 6.6 Hz, 1H), 7.74–7.77 (d, J = 8.8 Hz, 1H), 7.79–7.82
(d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.96–7.99 (d,
J = 7.7 Hz, 1H), 8.23–8.26 (d, J = 8.3 Hz, 2H), 8.47–8.49
(d, J = 8.1 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz,): d
34.0 (CH2), 37.3 (CH2–N), 61.0 (OCH2), 111.1 (O–Ph–
C3&C5), 112.8 (CF2), 114.5 (CF2), 118.9 (O–Ph–C2&C6),
120.0 (CF3), 121.5 (triazole–C2), 122.1 (Ar–C10), 125.4
(O–Ph–C1), 125.4 (Ar–C9), 126.5 (Ar–C5), 127.6 (Ar–C4),
128.7 (Ar–C6), 128.8 (Ar–C7), 130.8 (Ar–C8), 136.7 (Ar–
C1), 142.8 (triazole–C1), 147.4 (Ar–C2), 160.2 (O–Ph–C4),
161.5 (oxazole–C=N); ESI (m/z) 789 ([M?H]?); ESI-
HRMS: m/z obtained for C30H18N4O2F17 ([M?H]?):
789.1231 (Calcd. 789.1223).
Acknowledgments Authors are thankful to the Director, IICT for
the encouragement and support. NC is thankful to UGC, New Delhi
for the award of SRF; and AK is thankful to CSIR, New Delhi for the
award of SRF. SKB is thankful to DBT for the financial support
(Project No. BT/HRD/35/02/09/2008).
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