Synthesis of novel 2-alkyl triazole-3-alkyl substituted quinoline derivatives and their cytotoxic activity

Article abstract of DOI:10.1016/j.bmcl.2013.01.021

The propargyl alcohol on reaction with alkylazides under Sharpless conditions through click chemistry concept gave exclusively 1,4-disubstituted triazoles 2. The compounds 2 were oxidized to aldehydes 3 followed by reaction with aniline resulted Schiff's

Full text of DOI:10.1016/j.bmcl.2013.01.021

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1225–1227
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 2-alkyl triazole-3-alkyl substituted quinoline
derivatives and their cytotoxic activity
P. Sambasiva Rao a, C. Kurumurthy a, B. Veeraswamy a, G. Santhosh Kumar a, P. Shanthan Rao a,
R. Pamanji b, J. Venkateswara Rao b, B. Narsaiah a,
⇑
a Fluoro Organic Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Biology Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
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 alkylazides under Sharpless conditions through click chemistry
concept gave exclusively 1,4-disubstituted triazoles 2. The compounds 2 were oxidized to aldehydes 3
followed by reaction with aniline resulted Schiff’s bases 4. The compounds 4 was further reacted with
Received 17 September 2012
Revised 18 December 2012
Accepted 4 January 2013
Available online 12 January 2013
various aldehydes having
a-hydrogen using molecular iodine as a catalyst and obtained 2-alkyl tria-
zole-3-alkyl substituted quinoline derivatives 5. All the final compounds were screened against four
human cancer cell lines (THP-1, Colo205, U937 & HeLa) and promising compounds have been identified.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkyl azides
Quinoline
Jones reagent
Cytotoxic activity
Quinoline nucleus present in many biologically active mole-
cules and their derivatives play an important role as versatile
building blocks for the synthesis of complex natural products.1–5
Quinoline based compounds with specific substituent at an appro-
priate position known to have wide range of activity. In particular,
2-aryl quinolines were reported as antimalarial and antitumor
agents.6 Recently, 6-fluoroquinolones are considered as potential
antibacterial agents and some of the promising fluoro quinolones
are namely Norfloxacine, Ciprofloxacine, Ofloxacine and so on.
The classic methods for the synthesis of quinolines include Beller
et al.,7 Charmantray et al.,8 Demeunynck et al.,9 Igarashi et al.10
and so on. Recent efforts on synthesis of quinoline derivatives is
mainly by intermolecular [4+2] cycloaddition,11 Baylis–Hillman
approach,12 C–C coupling13–17 and use of iodine as a catalyst.18 Al-
ternatively, the 1,2,3-triazoles due to their unique chemical and
structural properties, received much attention over the past dec-
ades and found wide application in medicinal chemistry.19–23 In or-
der to construct 1,2,3-triazole ring system, several synthetic
methods have been developed.24 Recently Fokin and Sharpless re-
ported Cu(I) catalyzed regioselective synthesis of 1,4-disubsti-
tuted-1,2,3-triazoles.25,26 However, synthesis of 2,3-disubstituted
quinoline derivatives were not been extensively studied.
the synthesis of novel 2-alkyl triazole-3-alkyl substituted quino-
line derivatives using molecular iodine as a catalyst and reporting
here for the first time.
The propargyl alcohol was reacted with alkyl azide 1 in t-buta-
nol in the presence of Cu(OAc)2 under Sharpless conditions and ob-
tained exclusively (1-alkyl substituted-1H-1,2,3-triazol-4yl)
methanol 2. The alcohol 2 was further oxidized into an aldehyde
3 by using Jones reagent followed by the reaction of aniline in acet-
onitrile at room temparature furnished Schiff’s base 4. Compounds
4 were further reacted with aliphatic aldehydes in the presence of
I2 in THF obtained 2-alkyl triazole-3-alkyl substituted quinoline
derivatives 5 in high yields. The sequence of reaction is mainly
the iodine complexes with imine followed by attack of active
methylene of enolised aldehyde and cyclised to give quinoline de-
rivatives. All the products 5 were screened for cytotoxic activity
and promising compounds have been identified. The details of re-
actions outlined in Scheme 1 and products were tabulated in Table
1. The 2-alkyl triazole substituted quinoline derivatives 5a–o were
tested for in vitro cytotoxic activity against THP-1, Colo205, U937
& HeLa human cancer cell lines by MTT assay method.30 IC50 values
of the test compounds for 24 h on THP-1, Colo205, U937 and HeLa
cell lines was calculated and presented in Table 2. It is evident from
the results that, most of the compounds have shown significant de-
crease in cell viability in all the test cell lines on concentration de-
pendent manner. Compounds activity is more specific to U937 cell
lines compared to other three cell lines (THP-1, Colo205 and HeLa).
Among the derivatives, compound 5b and 5e exhibited significant
Based on the importance of both the scaffolds that is, Quinoline,
1,2,3-triazole and in continuation of our efforts on synthesis of po-
tential molecules,27–29 we have developed an efficient method for
⇑
Corresponding author. Tel.: +91 40 27193630; fax: +91 40 27160387.
E-mail address: narsaiahbanda84@gmail.com (B. Narsaiah).
activity on U937 cells at IC50 <20 lg/ml and other derivatives also
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.021

1226
P. Sambasiva Rao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1225–1227
R
OH
OH
N
N
i
N3
I
NaN3
+
N
R
R
ii
1
2 a-c
2a R= (CH2)9CH3
2b R= (CH2)2-(CF2)7-CF3
2c R= 4-FC6H4
iii
R
R1-CH2-CHO
v
R
R1
N
N
Ph
Ph-NH2
iv
N
N
N
N
CHO
N
N
N
R
N
N
3 a-c
4 a-c
5a-o
3a R= (CH2)9CH3
3b R= (CH2)2-(CF2)7-CF3
3c R= 4-FC6H4
4a R= (CH2)9CH3
4b R= (CH2)2-(CF2)7-CF3
4c R= 4-FC6H4
R
1 = CH3, C2H5, (CH2)2CH3
(CH2)3CH3, (CH2)4CH3.
Scheme 1. (i) Acetone:water (3:1), reflux, 8 h; (ii) Cu(OAc)2, t-BuOH, rt, 18 h; (iii) Jones reagent, acetone, 0 °C, 30 min; (iv) Ph-NH2, CH3CN, rt, 6 h; (v) I2, THF, reflux, 4–5 h.
<90 lg/ml. The compound 5h showed moderate activity on only
Table 1
one cell line (HeLa). The structure verses activity studies reveal
that the increase in aliphatic chain length on C-3 position has no
additional advantage in improving the activity, however the in-
crease in length of aliphatic chain on triazole ring found to pro-
mote activity.
Compounds 5f–j having perfluoroalkyl chain on triazole ring do
not contribute to improve the activity inspite of increasing the ali-
phatic chain length on C-3 position which is in consistent with the
earlier statement. Based on the relative activity among the cell
lines the order of sensitivity is U937 > HeLa > THP-1 > Colo205.
Though, these derivatives are comparatively less potent than the
commercially available drug molecule, 5-fluorouracil (positive
control); nevertheless slight structural modification of these active
derivatives may yield as prospective anticancer drugs.
Preparation of compounds 5a–o
S. No Compound
R
R1
Yield (%) mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
(CH2)9CH3
(CH2)9CH3
(CH2)9CH3
(CH2)9CH3
(CH2)9CH3
(CH2)2-(CF2)7-CF3 CH3
(CH2)2-(CF2)7-CF3 C2H5
(CH2)2-(CF2)7-CF3 (CH2)2CH3 88
(CH2)2-(CF2)7-CF3 (CH2)3CH3 89
CH3
C2H5
(CH2)2CH3 85
(CH2)3CH3 86
(CH2)4CH3 88
81
83
61–62
67–69
68–70
73–74
78–80
85
86
108–109
110–112
118–120
124–126
131–133
96–98
106–108
98–100
95–97
(CH2)2-(CF2)7-CF3 (CH2)4CH3
90
89
91
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
CH3
C2H5
(CH2)2CH3 92
(CH2)3CH3 94
(CH2)4CH3 94
106–108
Acknowledgments
Authors are thankful to Dr. J. S. Yadav, Director, IICT for his con-
stant encouragement and authors (P.S.R., C.K., B.V. and G.S.K.) are
also thankful to CSIR for providing financial assistance in the form
of Senior Research Fellowship
shown good activity on U937 cell line at <70
compounds 5a & 5i had shown potent cytotoxicity on two cell lines
(colo205 & HeLa) at <50 lg/ml, and 5b & 5e on THP-1 and U937 at
l
g/ml. However, the
Table 2
In vitro cytotoxicity of 2-alkyl triazole-3-alkyl substituted quinoline derivatives against THP-1, Colo205, U937 & HeLa human cancer cells by MTT assay
S. No.
Compound
THP-1
Colo205
U937
HeLa
a
IC50 (lg/ml)
1
5a
—
44.46 3.69
—
28.17 2.91
2
3
4
5
6
7
8
5b
5c
5d
5e
5f
5g
5h
34.28 2.61
—
—
87.97 1.29
—
—
—
—
—
—
—
12.72 3.21
26.57 1.47
25.24 2.2
18.19 3.74
56.57 1.5
55.93 0.97
—
—
—
—
—
—
—
75.83 2.98
95.21 4.24
—
37.79 3.12
9
5i
5j
5k
5l
5m
5n
5o
—
—
—
—
—
—
—
—
—
—
—
59.11 1.92
—
65.58 3.3
—
67.43 2.14
66.16 1.4
67.49 2.34
0.87 0.21
32.8 3.19
—
—
—
—
—
—
10
11
12
13
14
15
Control
—
78.32 2.52
—
0.54 0.13
5-Fluorouracilb
4.03 0.84
1.28 0.73
Exponentially growing cells were treated with different concentrations of 2-alkyl triazole-3-alkyl substituted quinoline derivatives for 24 h and cell growth inhibition was
analyzed through MTT assay.
a
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 and were
calculated using the respective regression analysis. The values represent the mean SE of three individual observations.
b
5-Fluorouracil was employed as positive control, — indicates IC50 value >100 lg/ml.

P. Sambasiva Rao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1225–1227
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