Synthesis and antiproliferative activity of new 1,2,3-triazole/flavone hybrid heterocycles against human cancer cell lines

Article abstract of DOI:10.1134/S1070363217080357

A series of new 1,2,3-triazole/flavone hybrid heterocycles were synthesized from 6-amino flavone via key intermediate N-propargyl flavone 6 by adopting the Sharpless Click reaction. Copper(I) catalyzed 1,3-dipolar cycloaddition reaction that gave products in high yields. All the synthesized compounds were screened for their in vitro antiproliferative activity against four human cancer cell lines, HeLa (cervical cancer cell line), MIA PaCa (pancreatic cancer cell line), MDA-MB-231 (breast cancer cell line), and IMR 32 (neuroblastoma cancer cell line). Compounds 7a, 7b, 7d, 7g (GI₅₀ = 0.01–0.68 μM) demonstrated promising antiproliferative activity.

Full text of DOI:10.1134/S1070363217080357

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 8, pp. 1864–1871. © Pleiades Publishing, Ltd., 2017.
Synthesis and Antiproliferative Activity
of New 1,2,3-Triazole/Flavone Hybrid Heterocycles
1
Against Human Cancer Cell Lines
a
b,c
d
T. Sowjanya , Y. Jayaprakash Rao *, and N. Y. S. Murthy
a
Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad, 500072 India
Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad, 500004 India
e-mail: yjpr_19@yahoo.com
Department of Chemistry, Telangana University, Nizamabad, 503322 India
b
*
c
d
Department of Chemistry, Anurag Group of Institutions, Hyderabad, 500088 India
Received May 18, 2017
Abstract—A series of new 1,2,3-triazole/flavone hybrid heterocycles were synthesized from 6-amino flavone
via key intermediate N-propargyl flavone 6 by adopting the Sharpless Click reaction. Copper(I) catalyzed 1,3-
dipolar cycloaddition reaction that gave products in high yields. All the synthesized compounds were screened
for their in vitro antiproliferative activity against four human cancer cell lines, HeLa (cervical cancer cell line),
MIA PaCa (pancreatic cancer cell line), MDA-MB-231 (breast cancer cell line), and IMR 32 (neuroblastoma
cancer cell line). Compounds 7a, 7b, 7d, 7g (GI50 = 0.01–0.68 µM) demonstrated promising antiproliferative
activity.
Keywords: aminoflavone, 1,2,3-triazoles, click chemistry, antiproliferative activity
DOI: 10.1134/S1070363217080357
INTRODUCTION
their A-ring demonstrated tyrosine-kinase inhibitory
effect against p56 , an enzyme of 56 kDa [11]. 5,7,4'-
lck
Flavone containing molecules (natural and syn-
thetic) have attracted attention due to their wide range
of bioactivity, including cancer prevention by
interfering with cell proliferation, survival, cell
signaling and regulating the immune system [1].
Synthetic flavones, flavone-8-acetic acid (1), and
flavopiridol (2) [2–4], are anticancer drugs (see
figure). Besides 8-substitued flavones demiflin and
flavoxate (3) [5] are coronary vasodilatation and
diuretic drugs. Recently amino flavones and amino
derivatives have shown antiproliferative activity
against several renal, breast and ovarian cancer cell
lines [6, 7]. 7-Aminoflavone exhibited anti-bacterial
effects against, among others, M. tuberculosis strains
Triamino-6-hydroxyflavone
p56 , while 6,4'-diamino-7-hydroxyflavone and
5,7,3'-triamino-6-hydroxyflavone
active against EGFr and p60
flavone, 5-amino-4'-dimethylaminoflavone and 6-
amino-4'-(dimethylamino)flavone exhibited antipro-
liferative activity against the MCF-7 breast cancer cell
line [13].
selectively
inhibited
lck
were
relatively
v-src
[12]. 5,4'-Diamino-
Several 1,4-disubstituted-1,2,3-triazoles displayed a
broad spectrum of applications in pharmacy, agri-
culture and industry [14] 1,2,3- Triazole is a versatile
scaffold of many biologically active molecules such as
anti-allergic [15], anti-HIV [16], β-lactamase
inhibitory [17], anti-cancer [18, 19], and selective β3
adrenergic receptor agonists [20]. 1,4-Disubstituted
1,2,3-triazoles exhibited remarkable antiproliferative
activity against broad range of human cancer cell lines.
Carboxyamido triazole (CAI) (IV), 1,2,3-triazole
containing an anti-cancer agent, is now available on
the market (see figure) [21, 22]. The Huisgen 1,3-
dipolar cyclo addition at terminal alkyne with an
[8, 9]. 6-Amino-5,7-dihydroxyflavone as an α-
glucosidase inhibitor showed promising activity in the
micromolar range [10]. A number of aminoflavones
belonging to this second subclass has shown high
cytotoxic, antiproliferative or kinase inhibitory effects.
4
'-Aminoflavone with one or more hydroxy groups in
1
The text was submitted by the authors in English.
1
864

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF NEW 1,2,3-TRIAZOLE/FLAVONE
1865
N
Cl
HO
CH COOH
2
H
HO
O
O
O
O
Flavopiridol (2)
Flavone-8-acetic acid (1)
Aantiproliferative activity)
(
Kinase inhibitor)
(
O
H N
2
N
O
O
N
H N
N
2
N
O
O
Cl
Cl
CH3
O
Cl
Flavoxate (or) urispas (3)
antimuscarinic activity)
Carboxyamido-triazole (CAI) (4)
(
(
anti-cancer activity)
Representative biologically active flavones and triazoles.
organo azide is the general method for the synthesis of
,2,3-triazoles [23, 24]. The major limitation of this
methodology is low regioselectivity, products are
mixtures of 1,4 and 1,5 regio isomers. The Sharpless
Cu(I) catalyzed ligation of azide and terminal alkyne is
the efficient protocol for the regioselective synthesis of
exclusively 1,4-disubstituted 1,2,3-triazole and flavone
hybrids. The products were screened for anti-
proliferative activity against four human cancer cell
lines such as HeLa (cervical cancer cell line), MIA
PaCa (pancreatic cancer cell line), MDA-MB-231
(breast cancer cell line), and IMR32 (neuroblastoma
cancer cell line).
1
1
,4-disubstituted 1,2,3-triazoles [25, 26]. This reaction
has become increasingly attractive due to constructing
a variety of multivalent structures such as sugar hetero
dimers, glycoconjugates, and calyx sugars, dendritic
and polymeric materials. In the current study we
pursued the synthesis of hybrid heterocycles
containing both scaffolds in a single molecule by
adopting click chemistry and obtained 1,2,3-triazole–
flavone hybrids in high yields. The hybrid molecules
obtained by combining two bioactive molecules
usually exhibit significantly higher biological activity
than their individual fragments. Therefore, the
combination of these biologically active heterocycles
in a single molecular structure could impart it high
antiproliferative activity.
Azides were prepared by two methods according to
literature procedures [27, 29]. (1) By the reaction of
substituted alkyl halides with sodium azide in DMF
medium. (2) By diazotization of aromatic primary
amines followed by substitution with sodium azide. 5-
Acetamido-2-hydroxy acetophenone (3) was con-
densed with benzoyl chloride in presence of potassium
carbonate in acetone to form intermediate diketone 4.
The diketone was cyclized under the action of
hydrogen chloride in methanol to yield 6-aminoflavone
5
[9, 10].
6-Amino flavone 5 upon treatment with propargyl
bromide in K CO /acetone medium gave the single
2 3
product identified, according to spectral data, as mono
propargyl amino flavone 6 (Scheme 1). Formation of
dipropargyl was not detected. The compound 6 reacted
RESULTS AND DISCUSSION
The two fragments were combined via the click
reaction under Sharpless conditions [27, 28] and gave
further with various azides in DMF–H O medium
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

1
866
SOWJANYA et al.
Scheme 1. Synthetic pathway to 7a–7n.
OH
O
OH
OH
O
a
b
c
Ph
H N
O
AcHN
2
AcHN
AcHN
O
O
3
1
2
4
d
O
O
O
O
Ph
e
f
N
H
R
N
H
O
N
H N
2
N
N
O
7
a−7n
O, pyridine, reflux, 3 h, 90%; b: ZnCl
methanolic HCl, reflux, 1 h, 70%; e: propargyl bromide, K
O (1 : 1), 1 h, 75%.
6
5
a: Ac
2
2 2 3
, 180°C, 2 h , 75%; c: benzoyl chloride, K CO , acetone, reflux, 3 h, 85%; d:
2
CO
3
, acetone, reflux, 8 h, 65%; f: copper iodide, azides, DMF–
H
2
CN
R =
(7a),
(7b),
(7c),
(7d),
(7e),
(7f),
CH3
(7g),
NO2
F
Cl
(
7h),
(7i),
NO2
(7j),
(7k),
(7l),
Cl
(
7m),
(
7n).
under the Sharpless click addition using CuI as a
catalyst and gave exclusively the regio isomers of 1,4-
disubstituted 1,2,3-triazole/flavone hybrid heterocycles
1.0, 10, and 100 μM). GI (growth inhibitory activity)
50
was calculated and these values corresponded to the
concentration of the compound causing 50% decrease
in the net cell growth as compared with the stranded
drugs, doxorubicin and paclitaxel. Results were
calculated for each of these parameters if the level of
activity was reached, however, if the effect was not
achieved, the value was expressed as higher or lower
than maximum or minimum concentration tested.
7
a–7n (Scheme 1). The structures of compounds were
justified by spectral and analytical data (Table 1).
All the synthesized products were evaluated for
their in vitro antiproliferative activity.
Antiproliferative activity. Effects of the com-
pounds on the viability of human cancer cells. The in
vitro antiproliferative activity of the synthesized
compounds (6 and 7a–7n) was evaluated against four
different human cancer cell lines, HeLa (cervical),
MIA PaCa (pancreatic), MDA-MB-231 (breast), and
IMR 32 (neuroblastoma) (see table). The compounds
were applied for an advanced assay against these four
human cancer cell lines at concentrations 0.01, 0.1,
Among the tested compounds 7b demonstrated the
most potent activity against MDA-MB-231 cell line
with GI50 ≤ 0.01µM. Some compounds showed very
low or no toxicity against cancer cell lines.
The structure-activity relationship (SAR) study
revealed that the nature and position of substituents on
1,2,3-triazole and flavone cycles influenced the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF NEW 1,2,3-TRIAZOLE/FLAVONE
1867
Antiproliferative activity of compounds 6, 7a–7n and reference molecules against HeLa, MIA PaCa, MDA-MB-231, and
IMR 32 of human cancer cell lines
a
Antiproliferative activity (GI50, µM)
Compounds
HeLa
>100
MIA PaCa
7.7±0.4
MDA-MB-231
1.33±0.1
0.36±0.09
<0.01
IMR 32
1.8±0.1
6
7
7
7
7
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
>100
1.5±0.08
9.1±0.2
5.3±0.01
2.0±0.05
6.3±0.9
28.9±0.4
27.8±0.2
87.9±0.9
29.2±0.3
92.1±0.4
59.9±0.4
>100
10.3±0.3
1.0±0.08
2.4±0.32
34.0±0.6
3.7±0.1
5.0±0.5
0.11±0.01
2.7±0.07
16.8±0.1
10.1±0.4
11.2±0.6
3.8±0.09
4.6±0.08
19.2±0.2
13.4±0.6
18.5±0.4
9.6±0.3
0.43±0.03
1.35±0.3
6.6±0.9
g
h
i
0.68±0.02
6.2±0.4
32.1±0.7
9.3±0.3
25.8±0.4
>100
7.9±0.5
j
7.9±0.5
8.2±0.2
k
l
>100
22.5±0.9
4.2±0.09
12.1±0.5
8.13±0.05
0.097±0.002
0.056±0.002
11.2±0.09
10.5±0.3
4.6±0.08
5.8±0.02
0.023±0.002
0.075±0.003
79.8±0.6
62.2±0.3
49.8±0.5
0.073±0.001
0.025±0.001
m
n
Doxorubicin
Paclitaxel
0.085±0.001
0.091±0.005
a
GI50: 50% Growth inhibition, concentration of drug (µM) resulting in a 50% reduction in net protein increase compared with control cells.
antiproliferative activity. In particular, the compounds
b showed the promising activity (GI50 ≤ 0.01 µM).
Activity was further enhanced in the presence of an
electron withdrawing group at benzene ring attached to
the 1,2,3-triazole fragment.
N-(3-Acetyl-4-hydroxyphenyl)acetamide (3). A mix-
ture of 2-aminophenol (1) (1.0 mmol), acetic an-
hydride (2.2 mmol) and pyridine (3.0 mmol) was
heated at 100°C for 2 h. The reaction mixture was
poured into ice cold water, filtered, dried and recrys-
tallized from hexane as colorless needles, mp 152°C
7
EXPERIMENTAL
(
[9]: 159–160°C).
All reagents were purchased from Merck and other
commercial sources and used without further
purification. Melting points were determined (uncor-
rected) in open capillary tubes on a Buchi 530 melting
point apparatus. TLC was performed to monitor
progress of the reactions and assess purity of the
compounds. Chromatograms were visualized under
UV light. IR spectra (KBr) were recorded on a IR
Prestige-21 Shimadzu spectrophotometer. Mass spectra
The diacetyl derivative 2 (1.0 mmol) was mixed
with anhydrous ZnCl (1.5 mmol) and heated to 180°C
2
for 2 h. The reaction mixture was treated with ice cold
water and concentrated HCl. The solid product was
filtered off, dried and recrystallized from ethanol as
pale yellow needles, mp 157°C ([9]: 159–160°C).
N-[4-Hydroxy-3-(3-oxo-3-phenylpropanoyl)phenyl]-
acetamide (4). A mixture of 5-acetamido-2-hydroxy-
acetophenone 3 (1.0 mmol), benzoyl chloride (2.2 mmol),
acetone (150 mL) and potassium carbonate (2.5 mmol)
was refluxed for 8 h. Acetone was removed and the
residue was diluted with water and acidified with
were measured on a “Hewlett-Packard” HP GS/MS
1
5
890/5972. H NMR spectra were measured on a
Bruker DPX operating at 400 MHz in CDCl or
3
DMSO-d using TMS as the internal standard.
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

1
868
SOWJANYA et al.
dilute HCl. A solid yellow compound 4 was filtered
off, dried and crystallized from ethanol to give shiny
yellow crystals. Yield 80%, mp 182°C ([9]: 185°C).
water were added and the reaction mixture was
extracted with diethyl ether. The organic layer was
dried by anhydrous Na SO and concentrated under
2 4
reduced pressure giving a desired aryl azides.
6-Amino-2-phenyl-4H-chromen-4-one (5). 6-Acet-
amidoflavone 4 (1.0 mmol) was refluxed with metha-
nolic hydrogen chloride for 3 h. Upon removal of the
solvent, the solution was cooled down and ammonia
was added to make the media basic. The yellow solid
was filtered off, washed thoroughly with water and
crystallized from ethanol as yellow crystals. Yield
b. Aniline or its substituted derivative (1.0 mmol)
was dissolved in HCl and cooled to 0–5°C. Dilute
NaNO (2.0 mmol) was added to the reaction mixture
2
drop wise (exothermic reaction). 10 Min later NaN3
1.5 mmol) was added at 0–5°C. Progress of the
(
reaction was monitored by TLC. When aniline was
completely consumed or progress of the reaction
stopped, water was added and the reaction mixture was
extracted with ethyl acetate (5%) in hexane. Organic
layer was dried with anhydrous Na SO and con-
–
1
5
3
6
8
5%, mp 191°C ([9]: 192°C). IR spectrum, ν, cm :
1
439 (NH ), 1690 (C=O). H NMR spectrum, δ, ppm:
2
.80 s (2H), 6.87 s (1H), 7.10 m (2H), 7.50 d (J =
.78 Hz, 1H), 7.58 m (3H), 8.05 d (J = 4.57 Hz, 2H).
C NMR spectrum, δ, ppm: 104.2, 113.9, 118.3,
21.9, 124.1, 126.2, 128.0, 128.6, 130.1, 142.9, 146.8,
2
4
1
3
centrated under reduced pressure, giving a desired aryl
azide.
1
1
7
7
+
62.7, 181.3. MS: m/z 238.1 [M + H] . Found, %: C
Synthesis of 6-[(1-substituted-1H-1,2,3-triazol-4-
yl)methylamino]-2-phenyl-4H-chromen-4-ones (7a–
n). A mixture of 2-phenyl-6-(prop-2-ynyl amino)-4H-
5.66; H 4.72; N 5.84. C H NO . Calculated, %: C
1
5
11
2
5.94; H 4.67; N 5.90.
-Phenyl-6-(prop-2-yn-1-ylamino)-4H-chromen-
-one (6). 6-Amino flavone 5 (1.0 mmol) was dis-
7
2
chromen-4-one (6) (1.0 mmol) with azide (1.0 mmol),
4
CuI (0.2 mmol) and 8 mL DMF–H O (1 : 1) was
2
solved in dry K CO -acetone solution (1.0 mmol) and
2
3
stirred at room temperature and progress of the
reaction was monitored by TLC. When the starting
material was completely consumed or when the
progress of the reaction stopped, the reaction mixture
was poured onto crushed ice and settled for 1h. The
solid was filtered off. The crude product was purified
by column chromatography giving a desired product
propargyl bromide (1.5 mmol) was added drop wise to
the reaction mixture. The reaction mixture was
refluxed for 8 h and the progress of the reaction was
monitored by TLC. After completion of reaction
acetone was distilled off. The reaction mixture was
poured into cold water and extracted with ethyl
acetate. The organic layer was separated and dried
with anhydrous Na SO and concentrated under
7
a–7n.
2
4
6
-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methylamino]-
reduced pressure. The crude product was purified by
column chromatography giving the desired 2-phenyl-
2
1
-phenyl-4H-chromen-4-one (7a). Yield 82%, mp
–
1
1
40–142°C. IR spectrum, ν, cm : 3138.2 (NH). H
6
6
-(prop-2-ynyl amino)-4H-chromen-4-one (6). Yield
–
1
NMR spectrum, δ, ppm: 4.50 s (2H), 5.52 s (2H), 6.79
5% mp 99–100°C. IR spectrum, ν, cm : 3200.0
1
s (1H), 7.06 m (1H), 7.25 m (1H), 7.41 m (7H), 7.53 m
(
NH), 1714.4 (C=O). H NMR spectrum, δ, ppm: 2.25
1
3
(
3H), 7.92 s (2H). C NMR spectrum, δ, ppm: 52.7,
t (J = 2.40 Hz, 1H), 4.04 s (2H), 4.10 m (1H), 6.80 s
1
1
1
02.3, 105.8, 119.1, 121.2, 123.0, 124.2, 126.3, 126.6,
27.8, 128.0, 128.3, 128.7, 129.1, 131.5, 136.2, 145.4,
(
(
1H), 7.08 m (1H), 7.38 d (J = 7.58 Hz, 1H), 7.48 d
J = 7.58 Hz, 1H), 7.52 m (3H), 7.91 m (2H). C NMR
13
+
46.2, 148.2, 161.6, 177.1. MS: m/z 409.1 [M + H] .
spectrum, δ, ppm: 52.3, 90.1, 98.60, 123.7, 125.1,
Found, %: C 72.99; H 4.99; N 14.00. C H N O .
1
1
37.4, 140.1, 143.1, 144.5, 147.3, 149.6, 150.4, 162.8,
68.4, 181.2, 196.8. MS: m/z 276.2 [M + H] . Found,
25 20
4
2
+
Calculated, %: C 73.51; H 4.94; N 13.72.
-[(1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl-
amino]-2-phenyl-4H-chromen-4-one (7b). Yield 75%,
%
: C 77.99; H 4.99; N 5.17. C H NO . Calculated,
18 13 2
6
%: C 78.53; H 4.76; N 5.09.
Synthesis of azides. a. A mixture of an aryl or
–
1
1
mp 147–150°C. IR spectrum, ν, cm : 3140.1 (NH). H
NMR spectrum, δ, ppm: 4.55 s (2H), 5.62 s (2H), 6.78
s (1H), 7.04 d (J = 8.41 Hz, 2H), 7.30 d (J = 8.41 Hz,
2H), 7.41 m (7H), 7.90 s (1H), 8.20 d (J = 7.58 Hz,
aliphatic bromide (connected to CH group) (1.0 mmol)
2
with NaN (1.5 mmol) and 5 mL of polyethylene
3
glycol-400 was stirred at room temperature and the
progress of the reaction was monitored by TLC. When
the aryl bromide was completely consumed or the
progresses of the reaction stopped, 50 mL of cold
1
3
1H). C NMR spectrum, δ, ppm: 57.0, 102.4, 104.5,
112.2, 118.5, 120.0, 121.0, 123.2, 126.4, 128.0, 128.3,
128.7, 129.2, 130.0, 130.4, 143.2, 145.4, 145.7, 147.9,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF NEW 1,2,3-TRIAZOLE/FLAVONE
1869
+
1
6
6
63.7, 182.2. MS: m/z 453.9 [M + H] . Found, %: C
6-{[1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl-
amino}2-phenyl-4H-chromen-4-one (7g). Yield 71%,
6.10; H 4.33; N 15.53. C H N O . Calculated, %: C
25
19
5
4
–
1
1
6.22; H 4.22; N 15.44.
-{[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]methyl-
amino}-2-phenyl-4H-chromen-4-one (7c). Yield 79%,
mp 110–113°C. IR spectrum, ν, cm : 3138.2 (NH). H
NMR spectrum, δ, ppm: 4.32 s (2H), 4.53 s (2H), 6.79
s (1H), 7.07 d (J = 8.78 Hz, 1H), 7.35 d (J = 6.46 Hz,
H), 7.43 d (J = 8.78 Hz, 1H), 7.48 d (J = 6.46 Hz,
H), 7.52 m (5H), 7.92 m (2H). C NMR spectrum, δ,
ppm: 57.0, 102.5, 112.2, 115.4, 118.5, 120.0, 123.2,
mp 132–134°C. IR spectrum, ν, cm : 3138.4 (NH). H
NMR spectrum, δ, ppm: 4.50 s (2H), 6.95 s (1H), 7.12
m (1H), 7.30 m (1H), 7.60 m (6H), 7.95 m (2H), 8.08
6
13
–
1
1
m (2H), 8.85 s (1H). C NMR spectrum, δ, ppm:
1
1
1
04.8, 111.2, 118.5, 119.2, 120.0, 123.0, 125.9, 126.4,
27.7, 128.0, 128.9, 129.9, 130.1, 132.4, 136.4, 141.0,
45.1, 146.3, 149.0, 159.9, 179.0. MS: m/z 428.0 [M] .
+
2
2
1
3
Found, %: C 67.11; H 4.10; N 13.08. C24
Calculated, %: C 67.21; H 4.00; N 13.06.
H N O Cl.
17 4 2
1
1
4
24.8, 126.4, 128.0, 128.7, 130.4, 130.7, 131.9, 142.3,
6-{[1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl-
amino}-2-phenyl-4H-4-one (7h). Yield 72%, mp 138–
140°C. IR spectrum, ν, cm : 3140.4 (NH). H NMR
spectrum, δ, ppm: 4.49 s (2H), 6.94 s (1H), 7.11 d (J =
43.2, 145.7, 159.9, 163.7, 182.2. Mass spectrum: m/z
+
–1
1
27.0 [M + H] . Found, %: C 70.43; H 4.50; N 13.15.
C H FN O . Calculated, %: C 70.41; H 4.49; N 13.14.
25
19
4
2
8
7
.10 Hz, 1H), 7.20 d (J = 7.90 Hz, 2H), 7.26 d (J =
.90 Hz, 2H), 7.60 m (5H), 7.95 d (J = 8.10 Hz, 1H),
2
-{[4-([4-Oxo-2-phenyl-4H-chromen-6-ylamino]-
methyl)-1H-1,2,3-triazol-1yl]methyl}benzonitrile (7d).
Yield 61%, mp 152–154°C. IR spectrum, ν, cm :
138.5 (NH). H NMR spectrum, δ, ppm: 4.53 s (2H),
.74 s (2H), 6.78 s (1H), 7.05 m (2H), 7.52 m (6H),
.66 m (4H), 7.91 s (1H). C NMR spectrum, δ, ppm: 42.4,
05.2, 112.1, 113.3, 114.2, 115.8, 119.2, 120.0, 123.2,
24.6, 126.5, 127.8, 128.6, 129.8, 130.5, 132.1, 133.0,
30.0, 141.0, 142.3, 143.2, 145.7, 164.2, 180.0. MS:
m/z 435.4 [M + H] . Found, %: C 71.09; H 4.45; N 16.20.
1
3
–
1
8.06 s (1H), 8.80 s (1H). C NMR spectrum, δ, ppm:
104.8, 111.2, 118.5, 119.2, 120.0, 123.0, 125.9, 126.4,
1
146.3, 159.9, 179.0. MS: m/z 428.0 [M] . Found, %: C
6
C 67.21; H 4.00; N 13.06.
1
3
5
7
1
1
1
28.0, 128.9, 129.9, 130.1, 132.4, 132.8, 141.0, 145.1,
+
13
7.11; H 4.10; N 13.08. C H N O Cl. Calculated, %:
24 17 4 2
6-{[1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl]methyl-
amino}-2-phenyl-4H-chromen-4-one (7i). Yield 68%,
mp 101–104°C. IR spectrum, ν, cm : 3099.3 (NH). H
NMR spectrum, δ, ppm: 4.66 s (2H), 6.79 s (1H), 7.11
m (1H), 7.39 m (1H), 7.47 m (1H), 7.53 m (3H), 7.74
m (1H), 7.92 m (2H), 8.09 m (1H), 8.13 s (1H), 8.31 s
+
–
1
1
C H N O . Calculated, %: C 71.04; H 4.42; N 16.16.
2
6
19
5
2
6
-[(1-Phenyl-1H-1,2,3-triazol-4-yl)methylamino]-
2
1
-phenyl-4H-chromen-4-one (7e). Yield 74%, mp
42–143°C. IR spectrum, ν, cm : 3136.8 (NH). H
NMR spectrum, δ, ppm: 4.62 s (2H), 6.79 s (1H), 7.10
m (1H), 7.43 m (3H), 7.52 m (5H), 7.73 m (2H), 7.92
m (2H), 7.97 s (1H). C NMR spectrum, δ, ppm:
02.3, 105.8, 119.1, 121.2, 123.0, 124.2, 126.1, 126.6,
27.8, 128.0, 128.7, 129.1, 131.5, 136.2, 145.4, 146.2,
–
1
1
1
3
(
1
1H), 8.60 s (1H). C NMR spectrum, δ, ppm: 102.3,
05.8, 119.1, 121.2, 123.0, 124.2, 126.1, 126.6, 127.8,
128.0, 128.3, 128.7, 129.1, 131.5, 136.2, 145.4, 146.2,
13
+
1
%
48.2, 161.6, 177.1. MS: m/z 440.1 [M + H] . Found,
1
1
1
: C 65.51; H 3.95; N 15.96. C H N O . Calculated,
24 17 5 4
+
%: C 65.60; H 3.90; N 15.94.
48.2, 161.6, 177.1. MS: m/z 395 [M + H] . Found, %:
C 72.92; H 4.66; N 14.27. C H N O . Calculated, %:
6-[(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)methyl-
amino]-2-phenyl-4H-chromen-4-one (7j). Yield 69%,
24
18
4
2
C 73.08; H 4.60; N 14.20.
-[(1-m-Tolyl-1H-1,2,3-trizol-4-yl)methylamino]-
-phenyl-4H-chromen-4-one (7f). Yield 73%, mp
–
1
1
mp 129–130°C. IR spectrum, ν, cm : 3134.2 (NH). H
NMR spectrum, δ, ppm: 1.83 m (4H), 2.08 m (4H),
3.71 m (1H), 4.00 s (2H), 6.70 m (4H), 7.26 m (6H).
6
2
1
–
1
1
05–107°C. IR spectrum, ν, cm : 3138.0 (NH). H
1
3
C NMR spectrum, δ, ppm: 25.7, 42.4, 62.8, 104.5,
NMR spectrum, δ, ppm: 2.40 s (3H), 4.50 s (2H), 6.68
m (4H), 6.94 s (1H), 7.12 d (J = 8.03 Hz, 1H), 7.45 d
1
1
12.2, 118.5, 120.0, 123.2, 124.8, 128.0, 128.2, 128.7,
30.4, 142.3, 143.2, 145.7, 163.3, 182.0. MS: m/z
(
(
J = 8.03 Hz, 1H), 7.60 m (5H), 8.09 s (1H), 8.70 s
1H). C NMR spectrum, δ, ppm: 24.5, 104.5, 112.2,
+
1
3
387.2 [M + H] . Found, %: C 71.42; H 5.80; N 14.46.
C H N O . Calculated, %: C 71.48; H 5.74; N 14.42.
2
3
22
4
2
1
1
1
4
4
18.5, 119.2, 120.0, 124.8, 126.5, 127.0, 128.0, 128.4,
28.7, 129.1, 130.2, 138.4, 141.2, 145.3, 146.0, 162.2,
78.1. MS: m/z 409.0 [M] . Found, %: C 73.31; H
6-[(1-Butyl-1H-1,2,3-triazol-4-yl)methylamino]-2-
phenyl-4H-chromen-4-one (7k). Yield 68%, mp 109–
+
–
1
1
.99; N 13.79. C H N O Calculated, %: C 73.51; H
111°C. IR spectrum, ν, cm : 3129.4 (NH). H NMR
spectrum, δ, ppm: 1.33 m (5H), 1.87 m (2H), 4.34 t
25
20
4
2.
.94; N 13.72.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

1
870
SOWJANYA et al.
(
(
1
J = 7.19 Hz, 2H), 4.52 s (2H), 6.79 s (1H), 7.07 m
1H), 7.35 d (J = 8.90 Hz, 1H), 7.42 d (J = 8.90 Hz,
H), 7.52 m (4H), 7.92 s (2H). C NMR spectrum, δ,
yields is developed. The compounds were screened for
in vitro antiproliferative activity against human cancer
cell lines HeLa, MIA PaCa, MDA-MB-231, and IMR
32. Some products inhibited growth of human cancer
cell lines. The compound 7b showed the highest
activity (GI50 < 0.01) against breast cancer cell line
(MDA-MB-231) than reference drugs Doxorubicin and
Paclitaxel. The compounds 7a, 7d, 7g exhibited
promising antiproliferative activity against breast
cancer cell line (MDA-MB-231) and neuroblastoma
cancer cell line (IMR 32).
1
3
ppm: 13.8, 20.3, 30.6, 42.4, 52.2, 104.5, 112.2, 118.5,
1
1
20.0, 123.2, 124.8, 126.4, 128.0, 128.7, 130.4, 142.3,
+
43.2, 145.7, 163.7, 182.2. MS: m/z 374.9 [M + H] .
Found, %: C 70.17; H 5.99; N 15.21. C H N O .
2
2
22
4
2
Calculated, %: C 70.57; H 5.92; N 14.96.
-[(1-Pentyl-1H-1,2,3-triazol-4-yl)methylamino]-
-phenyl-4H-chromen-4-one (7l). Yield 75%, mp 107–
6
2
1
–
1
1
08°C. IR spectrum, ν, cm : 3140.7 (NH). H NMR
spectrum, δ, ppm: 1.29 m (9H), 4.32 t (J = 7.19 Hz,
ACKNOWLEDGMENTS
2
1
H), 4.53 s (2H), 6.79 s (1H), 7.07 d (J = 8.20 Hz,
H), 7.35 d (J = 8.20 Hz, 1H), 7.52 m (5H), 7.92 s
The authors are thankful to Vetindia Pharma-
ceuticals Ltd, Leavo Chem. Laboratories for providing
lab facilities to carry out this work. We also thankful to
K. Sudha Sravanti, Centre for Chemical Biology,
Indian Institute of Chemical Technology, Hyderabad
for biological evaluation.
1
3
(
2H). C NMR spectrum, δ, ppm: 14.5, 22.5, 28.1,
4
1
1
6
6
2.4, 52.7, 104.5, 112.2, 119.1, 120.0, 123.2, 124.8,
26.4, 128.0, 128.7, 130.4, 142.3, 143.2, 145.7, 163.7,
82.2. MS: m/z 389.1 [M + H] . Found, %: C 71.00; H
+
.29; N 14.4. C H N O . Calculated, %: C 71.11; H
23
24
4
2
.23; N 14.42.
-[(1-Hexyl-1H-1,2,3-triazol-4-yl)methylamino]-
-phenyl-4H-chromen-4-one (7m). Yield 77%, mp
The authors have declared no conflict of interest.
REFERENCES
6
2
1
–
1
1
12–115°C. IR spectrum, ν, cm : 3099.5 (NH). H
1
2
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4
1
3
1
H), 7.52 m (2H), 7.91 s (2H). C NMR spectrum, δ,
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3
1
1
4
12.2, 118.5, 120.0, 123.2, 124.8, 126.4, 128.0, 128.7,
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2
4
26
4
2
1
0.1161/01.CIR.100.6.659
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1
1
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1
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7
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(
7
7
2
1
1
.31 Hz, 1H), 7.35 d (J = 7.31 Hz, 1H), 7.51 m (5H),
1
3
.91 s (2H). C NMR spectrum, δ, ppm: 14.1, 22.8,
7.2, 28.4, 29.4, 31.9, 42.4, 52.5, 104.5, 112.2, 118.5,
20.0, 123.2, 124.8, 126.4, 128.0, 128.7, 130.4, 142.3,
+
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2
6
30
4
2
9
. Vijaya Lakshmi, M. and Subba Rao, N.V., Ind. J.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 8 2017

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