Synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives and their cytotoxic activity

Article abstract of DOI:10.1016/j.bmcl.2014.01.038

The propargyl alcohol on reaction with aldoxime and NaOCl in DCM gave exclusively (3-arylisoxazol-5-yl) methanol 1. The compound 1 was oxidized to an aldehyde 2 followed by reaction with aniline resulted in Schiff's base 3. The compounds 3 were further re

Full text of DOI:10.1016/j.bmcl.2014.01.038

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole
derivatives and their cytotoxic activity
a
a
a
b
b
a,
⇑
P. Sambasiva Rao , C. Kurumurthy , B. Veeraswamy , Y. Poornachandra , C. Ganesh Kumar , B. Narsaiah
a
Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The propargyl alcohol on reaction with aldoxime and NaOCl in DCM gave exclusively (3-arylisoxazol-5-
Received 9 October 2013
Revised 23 December 2013
Accepted 16 January 2014
Available online xxxx
yl) methanol 1. The compound 1 was oxidized to an aldehyde 2 followed by reaction with aniline resulted
in Schiff’s base 3. The compounds 3 were further reacted with various aldehydes having
a-hydrogen
using molecular iodine as catalyst and which yielded 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole deriva-
tives 4. All the final compounds 4 were screened against four human cancer cell lines (A549, COLO
2
05, MDA-MB 231 and PC-3) and among these compounds 4n showed potent cytotoxicity against all
Keywords:
Aldoxime
Isoxazole
the cell lines at IC50 values of <12 M.
l
Ó 2014 Elsevier Ltd. All rights reserved.
Quinoline
Jones reagent
Cytotoxic activity
Quinoline and their derivatives, which usually possess diverse
biological activities, play an important role as versatile building
blocks for the synthesis of natural products and as therapeutic
The propargyl alcohol was reacted with aldoxime and NaOCl
in DCM at room temperature obtained exclusively (3-aryl iso-
xazol-5yl) methanol 1. The methanol 1 was further oxidized to
an aldehyde 2 by using Jones reagent at 0 °C and further reacted
with aniline in acetonitrile at room temperature furnishing Schiff’s
base 3. All the Schiff’s bases 3 were further reacted with various
1
agents. In particular, 2-arylquinolines are biologically active and
2
3
occur in number of antimalarial and antitumor agents. Therefore,
the synthesis of quinolines have attracted much attention in
organic synthesis. The classic methods for the synthesis of quino-
aldehydes having
a-hydrogen in THF using molecular iodine as a
lines include Skraup, Doebner–von Miller,5 Conrad–Limbach,
4
6
catalyst and obtained 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole
derivatives 4 in high yield. The sequence of reaction involves imine
complexes with iodine followed by attack of active methylene of
enolized aldehyde and cyclized to give quinoline derivatives 4.
7
8
Combes, Pfitzinger and a number of general synthetic methods
have also been reported. However, some of these methods suffer
9
from several disadvantages such as harsh reaction conditions, mul-
ti step, a large amount of promoters and long reaction times.
Therefore, the development of new synthetic approaches using
mild reaction conditions remains an active research area. Alterna-
tively, the isoxazole due to their unique chemical and structural
properties, received much attention over the past decade and
R
R
ii
i
OH
CHO
R
N
N
O
1
OH
N
O
OH
2
10–12
found wide application in medicinal chemistry.
In order to
iii Ph-NH2
construct isoxazole ring system, several synthetic methods have
R1
O
1
3,14
been developed.
Based on the importance of both the scaffolds
iv
1
5–17
that is, quinoline, isoxazole and in continuation of our efforts
N
N
R
R1
R
to develop new synthetic routes for promising molecules, herein
we report a mild and efficient molecular iodine-catalyzed synthe-
sis of 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives from
imines and enolizable aldehydes.
CHO
O
N
N
4
3
R = C6H5, 4-FC6H4, 4-CH3C6H4, 4-CF3C6H4.
R1 = C2H5, C3H7, n-C4H9, n-C5H11.
Scheme 1. Synthesis of 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives
Reagents and conditions: (i) NaOCl, DCM, rt, 8 h. (ii) Jones reagent, acetone, 0 °C,
30 min. (iii) CH CN, rt, 6 h. (iv) I , THF reflux, 3-4 h.
3 2
⇑
Corresponding author. Tel.: +91 40 27193630; fax: +91 40 27160387.
E-mail address: narsaiah@iict.res.in (B. Narsaiah).
http://dx.doi.org/10.1016/j.bmcl.2014.01.038
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Sambasiva Rao, P.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.01.038

2
P. Sambasiva Rao et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
OH
R1
R1
CHO
H
OH
R1
I2
R1
O
H
OHC
N
R
N
I2
O
R
N
H
N
R
O
N
N
OH
R1
O
R1
O
R1
air(O )
-H2O
2
N
N
R
N
H
R
R
H
O
N
N
N
Scheme 2. Mechanism of 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives.
Table 1
Table 2
a
Preparation of compounds 3a–d and 4a–o
In vitro cytotoxicity of compounds 3a–d and 4a–o
S. No.
Compd
R
C
4-FC
4-CH
4-CF
R1
Yielda (%)
mp (°C)
S. No.
Compd
bIC50 values (in
lM)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
6
H
5
–
–
–
–
82
79
74
78
81
78
74
69
76
72
69
81
79
78
72
73
72
69
64
112–114
115–117
118–120
126–128
72-74
74–76
75–76
78–80
102–104
98–100
106–108
88–90
89–90
87–89
A549
COLO205
MDA-MB-231
PC-3
6
H
4
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
48.1 ± 0.22
89.1 ± 0.41
–
–
3
C
6
H
4
34.5 ± 0.42
33.1 ± 0.36
41.2 ± 0.09
36.5 ± 0.12
3
C
6
H
4
32.0 ± 0.11
28.9 ± 0.23
29.4 ± 0.22
31.6 ± 0.24
C
C
C
C
6
6
6
6
H
H
H
H
5
5
5
5
2 3
CH CH
38.9 ± 0.44
41.3 ± 0.51
37.4 ± 0.08
35.7 ± 0.36
(CH
(CH
(CH
2
2
2
)
)
)
2
3
4
CH
CH
CH
3
3
3
–
–
–
–
52.5 ± 0.21
48.9 ± 0.42
47.2 ± 0.12
51.3 ± 0.26
–
–
–
–
4-FC
4-FC
4-FC
4-CH
4-CH
4-CH
4-CH
4-CF
4-CF
4-CF
4-CF
6
6
6
H
4
H
4
H
4
CH
2
CH
3
92.3 ± 0.23
–
–
–
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
)
)
2
CH
CH
3
3
–
–
–
–
3
10
11
12
13
14
15
16
17
18
51.3 ± 0.26
50.3 ± 0.14
48.4 ± 0.36
42.2 ± 0.27
3
C
3
C
3
C
3
C
6
6
6
6
H
H
H
H
4
4
4
4
CH
3
27.5 ± 0.22
25.3 ± 0.33
24.2 ± 0.44
26.3 ± 0.35
)
2
)
3
)
4
CH
CH
CH
3
3
3
–
–
–
–
–
–
–
–
91–93
–
–
–
–
3
C
6
H
4
CH
2
CH
3
118–120
122–124
126–127
128–130
–
–
–
–
4m
4n
4o
3
3
3
C
6
C
6
C
6
H
H
H
4
4
4
(CH
(CH
(CH
)
2 2
)
2 3
)
2 4
CH
CH
CH
3
3
3
–
–
–
–
4m
4n
4o
43.9 ± 0.33
9.4 ± 0.34
28.3 ± 0.41
0.8 ± 0.22
42.2 ± 0.24
11.9 ± 0.22
24.5 ± 0.42
0.7 ± 0.42
36.5 ± 0.28
10.4 ± 0.11
22.1 ± 0.12
0.8 ± 0.44
33.8 ± 0.18
10.8 ± 0.35
30.2 ± 0.17
0.6 ± 0.28
a
19
Isolated yields
c
20
Dox
a
Exponentially growing cells were treated with different concentrations of N-
All the products 3 and 4 were screened for cytotoxicity against
A549, COLO 205, MDA-MB 231 and PC-3 human cancer cell lines
by MTT assay method and compounds which showed promising
activity at micro molar concentration have been identified. The de-
tails of reactions outlined in Schemes 1 and 2 and products were
tabulated in Table 1.
The N-((3-arylisoxazol-5-yl)methylene)aniline (3a–d) and 5-(3-
alkylquinolin-2-yl)-3-aryl isoxazole derivatives (4a–o) were tested
for in vitro cytotoxicity against A549, COLO 205, MDA-MB 231 and
PC-3 human cancer cell lines by MTT assay. IC50 values of the test
compounds for 24 h on A549, COLO 205, MDA-MB 231 and PC-3
cell lines was calculated and presented in Table 2. It is evident from
the results that, most of the compounds showed significant de-
crease in cell viability in all the tested cell lines in a concentra-
tion-dependent manner. Compounds 3b, 3c, 3d, 4b, 4f, 4g, 4m,
((3-arylisoxazol-5-yl)methylene)aniline derivatives 3a–d and 5-(3-alkylquinolin-2-
yl)-3-aryl isoxazole derivatives 4a–o for 24 h and cell growth inhibition was ana-
18
lyzed through MTT assay
.
b
IC50 is defined as the concentration, which results in a 50% decrease in cell
number as compared with that of the control cultures in the absence of an inhibitor.
The values represent the mean ± SE of three individual observations.
c
Dox—Doxorubicin was employed as positive control, – indicates IC50 value
>
100 lM.
Acknowledgments
Authors are thankful to the Council of Scientific & Industrial Re-
search (CSIR), New Delhi, India for providing funding through XII
five year plan project DITSF code:CSC-0204. Authors (P. Sambasiva
Rao, C. Kurumurthy, B. Veeraswamy and Y. Poornachandra) are also
thankful to CSIR for providing financial assistance in the form of
Senior Research Fellowship and contingency grant.
4
n and 4o exhibited significant activity against all the cell lines
Supplementary data
(
A549, COLO 205, MDA-MB 231 and PC-3) at IC50 < 50 M. The
l
structure–activity relationship revealed that fluorine or trifluoro-
methyl group at fourth position of phenyl in isoxazole ring was
found to promote the activity while the hydrogen or methyl group
had no additional advantage in improving the activity. Among all
the derivatives, compound 4n showed potent cytotoxicity against
all the tested cell lines (A549, COLO 205, MDA-MB 231 and PC-3)
at IC50 < 12 lM. Doxorubicin was used as a positive control. Slight
structural modification of these active derivatives may yield pro-
spective anticancer drugs.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.01.038.
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