Synthesis and Pharmacological Evaluation of 4-Aryloxyquinazoline Derivatives as Potential Cytotoxic Agents

Article abstract of DOI:10.1002/jhet.3683

In the present study, novel 4-aryloxyquinazoline derivatives were synthesized and screened for in vitro cytotoxicity on human cancer cell lines at 10 μM. Some of the synthesized compounds displayed moderate to significant and selective cytotoxic activity

Full text of DOI:10.1002/jhet.3683

Month 2019
Synthesis and Pharmacological Evaluation of 4-Aryloxyquinazoline De-
rivatives as Potential Cytotoxic Agents
*
Anjleena Malhotra, Tejinder Kaur, and Ranju Bansal
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
*E-mail: ranju29in@yahoo.co.in
Received October 16, 2018
DOI 10.1002/jhet.3683
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In the present study, novel 4-aryloxyquinazoline derivatives were synthesized and screened for in vitro
cytotoxicity on human cancer cell lines at 10 μM. Some of the synthesized compounds displayed moderate
to significant and selective cytotoxic activity against various leukemia, melanoma, ovarian, breast, and colon
cancer cell lines. (E)-3-(3,4-Dimethoxyphenyl)-1-(4-(quinazolin-4-yloxy)phenyl)prop-2-en-1-one (9b) was
the most potent compound among all with an average growth inhibition of 70% against leukemia cancer cell
lines. The compound also produced strong inhibition (75%) of colon cancer cell lines with 42.58% lethality
of HCT-116 cell line.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
derivatives are inhibitors of epidermal growth factor
receptor (EGFR) [16–18], which plays an important role
in regulation of proliferation, differentiation, metastasis,
and survival of cell [19].
Cancer is considered to be the most perilous disease
shuddering the mankind nowadays. One in eight deaths
occurring worldwide is due to cancer. Overall, the
number and mortality rate of cancer patients are
increasing day by day [1,2]. Till date, no single effective
treatment for cancer is available [3]. Moreover, the
approved cytotoxic drugs produce harmful side effects
which further degrade the quality of life [4]. Therefore,
the successful therapy for cancer is based not only on
potentiating existing biological activity but also to
minimize the fatal side effects of anticancer agents.
Quinazoline moiety is considered as an active scaffold
which possesses wide collection of biological activities
such as analgesic [5], anti-inflammatory [6],
anticonvulsant [7], antitubercular [8], antimalarial [9],
antioxidant [10], antifungal [11], anti-HIV [12], and
anticancer activities [13–15]. Gefitinib (I) and lapatinib
(II) are representative quinazoline-based clinically used
anticancer agents (Fig. 1). These 4-anilinoquinazoline
Similarly, 4-aryloxyquinazoline derivative III shown in
Figure 1 is also reported as a potent anticancer agent with
inhibitory effects on multi-tyrosine kinases, that is,
EGFR, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-ß, c-
Kit, c-Met, Src, and Raf in the nanomolar range. Also, it
strongly inhibits PC3, HT29, and MCF-7 cancer cell lines
with IC50 ranging from 1.94 to 2.78 μM [20].
Considering these observations, a new series of 4-
aryloxyquinazolines is designed and synthesized (Fig. 2)
by reversing the para substituents of phenyl ring present
at 4-position of quinazoline ring of lapatinib (II), a potent
reversible dual tyrosine kinase quinazoline-based inhibitor.
Bioconjugation approach in which two biomolecules are
linked together was followed to prepare another series of 4-
aryloxyquinazolines. Keeping in mind the promising
anticancer properties of various chalcone derivatives [21],
bioconjugates of quinazoline and chalcone have been
© 2019 Wiley Periodicals, Inc.

A. Malhotra, T. Kaur, and R. Bansal
Vol 000
Figure 1. Structures of some potent anticancer quinazoline derivatives.
comparison to the other substituents [22]; therefore, such
moieties were chosen for the synthesis of conjugates in
the current study. The compounds were then screened for
in vitro cytotoxicity against a panel of 60 cell lines.
RESULTS AND DISCUSSION
Figure 2. Proposed chemical structures of synthesized compounds.
The synthetic pathways for the synthesis of two series of
4-aryloxyquinazoline derivatives are depicted in
Schemes
1
and 2. The key intermediate 4-
prepared as shown in Figure 2. It is observed that
substituents with a higher degree of oxidation increases
the anticancer potential of chalcones to a higher extent in
chloroquinazoline (1) was synthesized according to the
reported procedure [23]. Schiff bases 4a–f were
synthesized by refluxing aldehyde 2, which was prepared
Scheme 1. Synthesis of compounds 5a–f. Reagents and reaction conditions: (i) 4-hydroxybenzaldehyde, DMF, 70°C (ii) substituted aniline (3a–f),
methanol, reflux (iii) NaBH4, methanol, stirring.
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4-Aryloxyquinazolines as Potential Cytotoxic Agents
Scheme 2. Synthesis of 4-aryloxyquinazolines 9a–d. Reagents and reaction conditions: (i) 60% sodium hydroxide, requisite aldehyde (7a–d), room
temperature (ii) ethyl methyl ketone, K2CO3, reflux, 80°C, 3 h.
by
treating
4-hydroxybenzaldehyde
with
4-
N═CH–N– of quinazoline nucleus was prominently
present in the H-NMR spectra of all the bioconjugates.
1
chloroquinazoline (1), with requisite aniline 3a–f. Further
reduction of 4a–f with sodium borohydride gave target 4-
aryloxyquinazolines 5a–f.
In vitro cell line assay. All the newly synthesized 4-
aryloxy quinazolines were submitted to National Cancer
Institute, USA, for in vitro antineoplastic activity. Of all,
only two 4-aryloxyquinazolines 5d and 5f with
anilinomethyl linkage and all four chalcone–quinazoline
bioconjugates 9a–d were selected for evaluation of
cytotoxicity against 60 cell lines. The outcome of the
single dose (10 μM) screen is summarized in Table 1. 4-
Aryloxyquinazoline analogues 5d and 5f displayed
moderate but selective inhibition of leukemia cell lines. At
10 μM, the compound 5f produced ~70% inhibition of
CCRF-CEM and HL-60 (TB) leukemia cell lines with a
mean percent growth inhibition of 47.16% against six
leukemia cell lines. On the other hand, chalcone–
quinazoline bioconjugates 9b (dimethoxy) and 9c
(trimethoxy) produced considerably strong inhibitory
effects on several leukemia, colon, ovarian, and breast
cancer cell lines, the effects being more pronounced on
leukemia cell lines with mean percent growth inhibition of
69.31% and 62.05%, respectively. Dimethoxy substituted
conjugate 9b displayed 99.61%, 90.81%, and 83.61%
growth inhibition of RPMI-8226, K-562, and SR leukemia
cell lines, respectively. In particular, compound 9b
showed prominent inhibitory effects against various colon
cancer cell lines with mean percent inhibition of 75%. It is
Stretching vibrations due to secondary N–H and diaryl
ether functionalities were observed at ~3200 and
1200 cmꢀ1 in IR spectra of all the derivatives. Protons of
the methylene linker resonated as distinctive singlet at δ
~4.30 and ~48 ppm in H-NMR and 13C-NMR spectra,
1
respectively. Details of spectral analysis can be found in
Supporting Information.
Substituted chalcones 8a–d were prepared by Claisen–
Schmidt condensation of p-hydroxyacetophenone (6) with
different substituted aromatic aldehydes 7a–d in alkaline
medium (Scheme 2). All the chalcones were assigned E-
1
configuration on the basis of H-NMR spectral analysis
as trans-coupled vinylic protons resonate as doublets at δ
~7.60 and 7.67 ppm (Jtrans = 15.56 Hz). Further,
chalcone–quinazoline bioconjugates 9a–d were prepared
by treating corresponding chalcone 8a–d with 4-
chloroquinazoline (1).
α,β-Unsaturated carbonyl stretching vibrations were
observed at ~1660 cmꢀ1 in IR spectra of target
bioconjugates. Bioconjugation of quinazoline with
respective chalcone was confirmed by disappearance of
the downfield broad singlet (δ ~10) of hydroxyl proton;
however, a characteristic singlet at ~8.80 ppm for –
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A. Malhotra, T. Kaur, and R. Bansal
Vol 000
Table 1
Percentage growth of cancer cells treated with 4-aryloxyquinazolines at 10 μM.
Growth percent
Cell line
5d
5f
9a
9b
9c
9d
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
65.68
53.15
72.97
62.25
70.52
83.83
32.29
82.90
46.40
54.67
9.19
56.56
0.39
16.74
36.64
77.11
30.77
70.76
59.41
61.46
62.36
71.60
63.28
67.81
61.63
71.93
54.31
12.05
62.28
24.27
38.13
71.48
64.86
70.28
75.16
76.68
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
95.22
88.65
98.90
114.39
83.26
97.01
90.45
97.98
56.63
86.34
84.95
102.58
98.87
90.49
86.02
93.27
96.08
45.44
95.09
92.84
84.91
100.05
93.22
90.76
93.65
100.20
58.46
59.17
77.69
87.73
84.60
76.05
88.38
88.38
53.54
53.54
73.12
86.95
81.94
109.27
98.49
80.28
69.49
84.51
52.72
97.77
95.67
93.55
99.70
89.95
92.21
95.51
104.23
59.22
132.93
109.12
85.58
88.74
93.90
95.07
105.60
120.50
100.82
86.92
87.14
107.65
75.01
111.77
107.14
37.39
88.57
93.55
94.45
104.97
85.42
29.05
ꢀ42.58
24.29
27.45
22.56
32.18
109.36
107.76
52.76
41.45
79.69
19.42
53.20
117.04
108.28
45.06
91.42
96.95
97.01
107.82
HT29
KM12
SW-620
107.42
CNS cancer
SF-268
SF-295
SF-539
SNB-19
84.86
94.95
74.38
95.41
78.16
87.89
75.21
89.07
84.55
94.30
83.31
90.44
83.41
96.52
98.47
100.13
84.78
98.84
74.82
85.74
73.54
64.94
74.82
50.93
81.07
86.67
63.57
68.62
69.48
60.34
89.41
97.46
94.16
99.12
77.14
104.76
SNB-75
U251
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGROVI
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal cancer
786-0
88.50
104.10
92.34
97.47
100.60
105.10
85.15
108.04
87.42
62.05
101.99
89.12
83.50
91.72
102.37
74.90
103.55
81.35
86.57
74.01
87.44
90.59
98.43
103.29
93.55
102.16
89.44
13.82
77.54
64.32
39.09
89.79
104.16
72.48
93.76
76.89
40.43
98.87
73.82
50.56
94.63
89.40
80.99
93.34
65.89
89.31
86.25
91.34
94.34
96.26
101.30
92.67
105.87
94.56
94.06
99.12
80.75
104.27
101.05
89.85
127.84
87.19
75.40
75.79
97.94
84.47
78.59
113.26
76.81
96.80
81.93
103.14
95.75
88.77
97.67
33.52
43.77
70.38
92.88
85.10
80.28
91.07
66.50
35.59
73.64
88.17
74.91
70.31
83.58
89.61
103.89
86.60
103.89
100.90
95.59
99.35
90.84
84.28
117.83
88.18
83.18
70.41
87.02
94.07
97.76
83.88
108.46
63.11
83.59
84.59
120.12
88.68
93.85
71.90
82.35
98.93
88.13
78.98
96.59
51.05
82.19
103.77
84.32
68.30
100.14
51.57
90.51
97.50
108.56
93.46
100.32
74.29
A498
RXF 393
SN 12C
TK-10
UO-31
Prostate cancer
PC-3
96.88
88.00
99.03
82.05
75.64
98.72
(Continues)
Journal of Heterocyclic Chemistry
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Month 2019
4-Aryloxyquinazolines as Potential Cytotoxic Agents
Table 1
(Continued)
Growth percent
Cell line
5d
5f
64.42
9a
9b
61.88
9c
21.41
9d
DU-145
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
99.75
85.29
100.85
103.59
73.09
84.19
94.16
82.76
76.79
57.92
62.65
97.35
92.92
78.72
75.57
96.21
8.88
27.01
86.47
97.12
58.03
35.88
13.78
63.38
100.68
97.50
84.34
72.19
91.45
105.27
90.59
74.21
58.92
101.86
81.62
88.53
60.64
52.29
28.37
T-47D
MDA-MB-468
also noted that the compound is highly toxic for HCT-116
colon cancer cell line with 42.58% lethality. Strong
inhibition of breast cancer cell lines was observed with
trimethoxy-substituted chalcone–quinazoline bioconjugate
9c. It seems that chalcon substituents with higher degree
of oxidation have pronounced toxic effects on the cancer
cells. Strategic replacement of amino methyl linker of 4-
aryloxyquinazolines 5a–f with α,β-unsaturated carbonyl
linker in case of chalcone–quinazoline conjugates seems
to be good approach to produce improved and encou
raging results. The results suggest that substitution of
electron donating group on phenyl ring is an important
structural feature required for the cytotoxic activity.
chloroform (CDCl3) or deuterated dimethyl sulfoxide
(DMSO-d6) as solvents containing tetramethylsilane as
internal standard (chemical shifts in δ, ppm). The spin
multiplicities are indicated by symbols, s (singlet), d
(doublet), t (triplet), q (quartet), p (pentet), m (multiplet),
and br (broad). Mass spectra were obtained on a
WATERS Q-TOF mass spectrophotometer. Elemental
analyses were carried out on a Thermo Scientific FLASH
2000 CHN Elemental Analyzer. Plates for thin-layer
chromatography (TLC) were prepared with silica gel G
according to method of Stahl (E. Merck) using ethyl
acetate as solvent and activated at 110°C for 30 min.
Iodine was used to develop the TLC plates. Anhydrous
sodium sulfate was utilized as drying agent. All solvents
were distilled prior to use according to standard
procedures. Anthranilic acid, quinazoline(3H)-4-one, and
4-chloroquinazoline were synthesized as per reported
procedures [23–25]. Synthesis of 4-(quinazolin-4-yloxy)
benzaldehyde was carried out by modifications of the
reported procedure [26]. In vitro cancer cell line assays of
the newly synthesized compounds were carried out at
NCI, USA.
CONCLUSION
In conclusion, two series of 4-aryloxyquinazoline
derivatives have been synthesized and evaluated for their
cytotoxic potential. The quinazoline analogues exhibited
moderate to significant and selective cytotoxic activity
against various cell lines. Anilinomethyl derivative 5f and
chalcone–quinazoline bioconjugates 9b and 9c produced
significant growth inhibition of some leukemia cell
lines. Additionally, strong inhibition of colon, ovary,
melanoma, and breast cancer cell lines was observed in
case of compound 9b. The study provides valuable
information in studying structure activity relationship of
quinazolines for anticancer activity.
Synthesis. 4-(Quinazolin-4-yloxy)benzaldehyde (2).
4-
Chloroquinazoline (1.22 mmol) was added to a stirred
and heated suspension of 4-hydroxybenzaldehyde
(1.22 mmol) and anhydrous potassium carbonate (0.4 g)
in dimethyl formamide (5 mL). The reaction mixture
was further heated at 80°C for 4 h with continuous
stirring. The completion of reaction was monitored by
TLC. Reaction mixture was filtered to remove excess of
potassium carbonate, and cold water was added to the
filtrate. The solid obtained was filtered and recrystallized
from ethanol to get 2. Yield: (0.155 g, 51.09%), m.p.
118–120°C. FTIR νmax (KBr): 3055.50 (aromatic C-H),
2733.78 (aldehydic C-H), 1702.33 (C═O), 1618.79
(C═C ring), 1571.08 (C═N), 1490.28 (C═C ring),
EXPERIMENTAL
Instrumentation and chemicals.
Melting points were
determined on a Veego melting point apparatus and are
uncorrected. Infrared (wave numbers in cmꢀ1) spectra
1
were
recorded
on
Perkin-Elmer
RX1
FTIR
1217.54 (C-O-C), 908.32, 846.05, and 776.83 cmꢀ1. H-
spectrophotometer model using potassium bromide
pellets. 1H-NMR spectra were obtained on a Bruker
Avance II 400 MHz spectrometer using deuterated-
NMR (CDCl3): δ 7.48 (d, 2H, Jo = 8.52 Hz, ArH, meta
to –CHO), 7.72 (td, 1H, Jo = 8.20 Hz, Jm = 1.03 Hz,
ArH, quinazoline), 7.97 (td, 1H, Jo
= 8.20 Hz,
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A. Malhotra, T. Kaur, and R. Bansal
Vol 000
Jm = 1.03 Hz, ArH, quinazoline), 8.03–8.08 (m, 3H, ArH,
ortho to –CHO and quinazoline), 8.39 (d, 1H,
Jo = 8.30 Hz), 8.79 (s, 1H, -N═CH-N), and 10.06 ppm
(s, 1H, –CHO).
General procedure for the synthesis of Schiff bases 4a–f.
2957.00 (asymmetric C-H aliphatic), 2841.12 (symmetric
C-H aliphatic), 1617.83 (C═C ring), 1572.48 (C═N),
1512.65, 1393.09, 1211.88 (C-O-C), 1163.35 (C-F),
1108.00, 1017.70, 815.46, and 764.35 cmꢀ1 1H-NMR
.
(CDCl3, 400 MHz): δ 3.92 (br s, 1H, -NH), 4.34 (s, 2H, -
CH2-), 6.57–6.60 (m, 2H, ArH, meta to fluoro), 6.89 (t,
2H, Jo = 8.72 Hz, ArH, ortho to fluoro), 7.25 (d, 2H,
Jo = 8.52 Hz, ArH, ortho to oxy), 7.48 (d, 2H,
Jo = 8.44 Hz, ArH, meta to oxy), 7.67 (td, 1H,
Jo = 8.08 Hz, Jm = 1.00 Hz, ArH, quinazoline), 7.91
(td, 1H, Jo = 8.40 Hz, Jm = 1.40 Hz, ArH, quinazoline),
8.01 (d, 1H, Jo = 8.40 Hz, ArH, quinazoline), 8.38
(d, 1H, Jo = 8.24 Hz, ArH, quinazoline), and 8.77 ppm
(s, 1H, -N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ
A
solution of 4-(quinazolin-4-yloxy)benzaldehyde
(2, 0.80 mmol) and requisite aniline derivative 3a–f
(0.80 mmol) was refluxed in anhydrous methanol. The
completion of reaction was monitored by TLC. The
precipitated solid was filtered, washed with methanol, and
dried. The obtained Schiff bases 4a–f were sufficiently
pure to be used directly for the synthesis of anilinomethyl
analogues 5a–f.
General procedure for synthesis of 4-[4-(substituted
anilinomethyl)phenoxy]quinazolines 5a–f. To a solution of
3
48.41 (CH2), 113.68 (2 × ArCH, JC-F = 7 Hz), 115.71
respective
4-[4-(substituted
anilinomethyl)phenoxy]
2
(2 × ArCH, JC-F = 22 Hz), 116.44 (ArC), 122.06
quinazoline 4a–f (0.42 mmol) in dry methanol, sodium
borohydride (0.84 mmol) was added in small amounts
with continuous stirring. The mixture was further stirred
for 2 h, and the reaction was monitored by TLC. On
completion, methanol was removed under vacuum, and
cold water was added to the residue. The solid obtained
was filtered, washed, dried, and recrystallized in
methanol to yield the corresponding quinazoline
derivative 5a–f.
(2 × ArCH), 123.61 (ArCH), 127.64 (ArCH), 127.92
(ArCH), 128.85 (2 × ArCH), 134.18 (ArCH), 137.04
4
(ArC), 144.34 (ArC, JC-F = 2 Hz), 151.50 (ArC), 151.69
1
(ArC), 154.22 (ArCH), 155.95 (ArC, JC-F = 234 Hz),
and 166.99 ppm (ArC). ESI-MS: 346.15 [M + H]+. Anal.
calcd for C21H16FN3O: C, 73.03; H, 4.67; N, 12.17%.
Found: C, 72.71; H, 4.52; N, 12.40%.
4-[4-(3-Chloro-4-fluoroanilinomethyl)phenoxy]
quinazoline (5c).
Yield: (0.127 g, 84.11%), m.p. 168–
4-[4-(p-Chloroanilinomethyl)phenoxy]quinazoline
170°C. FTIR νmax (KBr): 3314.12 (N–H), 3056.51 (C-H
aromatic), 2940.80 (asymmetric C-H aliphatic), 2837.08
(symmetric C-H aliphatic), 1615.54 (C═C ring),
1573.60 (C═N), 1503.66 (C═C ring), 1218.51 (C-O-C),
(5a).
Yield: (0.12 g, 80.00%), m.p. 150–152°C. FTIR
νmax (KBr): 3284.16 (N–H), 3046.37 (C-H aromatic),
2937.80 (asymmetric C-H aliphatic), 2833.37 (symmetric
C-H aliphatic), 1608.72 (C═C ring), 1572.10 (C═N),
1493.44 (C═C), 1393.68, 1214.37 (C-O-C), 1168.42,
1070.28 (C-Cl), 909.11, and 815.01 cmꢀ1 1H-NMR
.
1072.38 (C-Cl), 1019.32, 813.45, and 771.77 cmꢀ1. H-
1
(CDCl3, 400 MHz): δ 4.34 (s, 2H, -CH2NH-), 6.46–
6.50 (m, 1H, ArH, ortho to chloro), 6.66 (dd, 1H,
Jo = 6.02 Hz, Jm = 2.90 Hz, ArH, meta to fluoro),
6.96 (t, 2H, Jo = 8.82 Hz, ArH, ortho to fluoro), 7.27
(d, 2H, Jo = 8.56 Hz, ArH, ortho to oxy), 7.48 (d, 2H,
Jo = 8.48 Hz, ArH, meta to oxy), 7.69 (td, 1H,
Jo = 8.10 Hz, Jm = 1.02 Hz ArH, quinazoline), 7.94
NMR (CDCl3, 400 MHz): δ 4.37 (s, 2H, -CH2NH-), 6.62
(d, 2H, Jo = 8.76 Hz, ArH, meta to chloro), 7.15 (d, 2H,
Jo = 8.84 Hz, ArH, ortho to chloro), 7.25 (d, 2H,
Jo = 8.20 Hz, ArH, ortho to oxy), 7.49 (d, 2H,
Jo = 8.48 Hz, ArH, meta to oxy), 7.70 (t, 1H,
Jo
Jo
Jo
=
=
=
8.06 Hz, ArH, quinazoline), 7.95 (t, 1H,
8.42 Hz, ArH, quinazoline), 8.07 (d, 1H,
8.40 Hz, ArH, quinazoline), 8.40 (d, 1H,
(td, 1H, Jo
quinazoline), 8.04 (d, 1H, Jo
=
8.44 Hz, Jm
=
=
1.44 Hz, ArH,
8.32 Hz, ArH,
quinazoline), 8.39 (dd, 1H, Jo
=
8.24 Hz,
Jo = 8.20 Hz, ArH, quinazoline), and 8.79 ppm (s, 1H, -
N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 47.99 (CH2),
114.15 (2 × ArCH), 116.40 (ArC), 122.12 (2 × ArCH),
122.57 (ArC), 123.68 (ArCH), 127.71 (ArCH), 127.82
(ArCH), 128.91 (2 × ArCH), 129.16 (2 × ArCH), 134.40
(ArCH), 136.66 (ArC), 143.69 (ArC), 151.34 (ArC),
151.52 (ArC), 154.11 (ArCH), and 167.13 ppm (ArC).
ESI-MS: 362.13 [M + H]+, 364.15 [MH + 2]+. Anal.
calcd for C21H16ClN3O: C, 69.71; H, 4.46; N, 11.61%.
Found: C, 69.45; H, 4.78; N, 11.98%.
Jm = 1.00 Hz, ArH, quinazoline), and 8.79 ppm (s, 1H,
-N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 48.13
3
(CH2), 112.10 (ArCH), 113.81 (ArCH, JC-F = 6 Hz),
2
116.43 (ArC), 116.90 (ArCH, JC-F = 23 Hz), 121.28
2
(ArC, JC(Cl)-F = 18 Hz), 122.19 (2 × ArCH), 123.66
(ArCH), 127.70 (ArCH), 127.93 (2 × ArCH), 128.87
3
(ArCH, JC-F = 6 Hz), 134.24 (ArCH), 136.43 (ArC),
144.89 (ArC), 149.92 (ArC), 151.64 (ArC), 152.29
1
(ArC), 152.92 (ArC, JC-F = 245 Hz), 154.27 (ArCH),
and 166.99 ppm (ArC). ESI-MS: 380.83 [M + H]+,
382.04 [MH + 2]+. Anal. calcd for C21H15ClFN3O: C,
66.41; H, 3.98; N, 11.06%. Found: C, 66.62; H, 4.23;
N, 10.78%.
4-[4-(p-Fluoroanilinomethyl)phenoxy]quinazoline
(5b).
νmax (KBr): 3266.80 (N–H), 3041.41 (C-H aromatic),
Yield: (0.13 g, 86.12%), m.p. 136–138°C. FTIR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
4-Aryloxyquinazolines as Potential Cytotoxic Agents
νmax (KBr): 3358.42 (broad O-H, N–H), 3006.91 (C-H
aromatic), 2938.69 (asymmetric C-H aliphatic), 2833.33
(symmetric C-H aliphatic), 1615.23 (C═C ring), 1575.27
(C═N), 1500.19, 1380.72, 1202.85 (C-O-C stretch),
4-[4-(p-Methylanilinomethyl)phenoxy]quinazoline
(5d). Yield: (0.12 g, 79.47%), m.p. 128–130°C. FTIR
νmax (KBr): 3310.45 (N–H), 3004.40 (C-H aromatic),
2856.67 (symmetric C-H aliphatic), 1614.30 (C═C ring),
1571.76 (C═N), 1505.98 (C═C ring), 1200.92 (C-O-C),
1068.96, 1017.43, 916.82, and 827.41 cmꢀ1 1H-NMR
.
1
906.17, and 812.58 cmꢀ1. H-NMR (CDCl3, 400 MHz):
(DMSO-d6, 400 MHz): δ 4.31 (s, 2H, -CH2NH-), 5.37
(br s, 1H, -OH, D2O exchangeable), 6.56 (d, 2H,
Jo = 8.76 Hz, ArH, ortho to hydroxy), 6.71 (d, 2H,
Jo = 8.76 Hz, ArH, meta to hydroxy), 7.23 (d, 2H,
Jo = 8.48 Hz, ArH, ortho to oxy), 7.49 (d, 2H,
Jo = 8.48 Hz, ArH, meta to oxy), 7.69 (t, 1H,
δ 2.17 (s, 3H, -CH3), 3.24 (br s, 1H, -NH-), 4.28 (s, 2H, -
CH2NH-), 6.51 (d, 2H, Jo = 8.40 Hz, ArH, meta to
methyl), 6.92 (d, 2H, Jo = 8.12 Hz, ArH, ortho to
methyl), 7.16 (d, 2H, Jo = 8.68 Hz, ArH, ortho to oxy),
7.41 (d, 2H, Jo = 8.56 Hz, ArH, meta to oxy), 7.59
(t, 1H, Jo = 8.16 Hz, ArH, quinazoline), 7.83 (t, 1H,
Jo
Jo
Jo
=
=
=
8.06 Hz, ArH, quinazoline), 7.94 (d, 1H,
8.32 Hz, ArH, quinazoline), 8.00 (d, 1H,
8.28 Hz, ArH, quinazoline), 8.38 (d, 1H,
Jo
Jo
=
=
8.42 Hz, ArH, quinazoline), 7.93 (d, 1H,
8.44 Hz, ArH, quinazoline), 8.30 (d, 1H,
Jo = 8.08 Hz, ArH, quinazoline), and 8.73 ppm (s, 1H, -
N═CH-N). 13C-NMR (DMSO-d6, 100 MHz): 47.32
(CH2), 113.59 (2 × ArCH), 115.57 (2 × ArCH), 115.71
(ArC), 121.49 (2 × ArCH), 123.20 (ArCH), 127.35
(ArCH), 127.57 (ArCH), 128.30 (2 × ArCH), 134.06
(ArCH), 138.11 (ArC), 141.27 (ArC), 148.45 (ArC),
150.67 (ArC), 151.12 (ArC), 153.59 (ArCH), and
166.32 ppm (ArC). ESI-MS: 344.17 [M + H]+. Anal.
calcd for C21H17N3O2: C, 73.46; H, 4.99; N, 12.24%.
Jo = 8.32 Hz, ArH, quinazoline), and 8.70 ppm (s, 1H, -
N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 20.42 (CH3),
48.17 (CH2), 113.08 (2 × ArCH), 116.47 (ArC), 122.00
(2 × ArCH), 123.66 (ArCH), 126.99 (ArC), 127.64
(ArCH), 127.92 (ArCH), 128.89 (2 × ArCH), 129.82
(2 × ArCH), 134.19 (ArCH), 137.48 (ArC), 145.74
(ArC), 151.40 (ArC), 151.69 (ArC), 154.28 (ArCH), and
167.06 ppm (ArC). ESI-MS: 342.11 [M + H]+. Anal.
calcd for C22H19N3O: C, 77.40; H, 5.61; N, 12.31%.
Found: C, 77.05; H, 5.89; N, 12.48%.
Found: C, 73.74; H, 4.74; N, 12.61%.
General procedure for the synthesis of chalcones 8a–d.
Sodium hydroxide (60%, 10 mL) was added to a stirred
solution of p-hydroxyacetophenone (3.762 mmol) in
ethanol (10 mL). The reaction mixture was stirred for
1 h, and then requisite aldehyde 7a–d (3.762 mmol) was
added to it. The completion of reaction was monitored by
TLC. On completion, reaction mixture was poured on
crushed ice and neutralized with conc. hydrochloric acid.
The solid obtained was filtered and recrystallized from
methanol to afford the corresponding chalcones 8a–d
[27,28].
4-[(4-(Quinazolin-4-yloxy)phenyl)methylamino]benzoic
acid (5e).
Yield: (0.127 g, 84.11%), m.p. 230–234°C.
FTIR νmax (KBr): 3261.84 (N–H), 3057.84 (C-H
aromatic), 2989.89 (asymmetric C-H aliphatic), 2860.19
(symmetric C-H aliphatic), 1665.58 (C═O), 1599.16
(C═N), 1491.94 (C═C ring), 1381.36, 1296.74, 1204.50
(C-O-C), 1168.54, 1016.86, 910.50, and 843.67 cmꢀ1
.
1H-NMR (DMSO-d6, 400 MHz):
δ 4.43 (d, 2H,
J = 5.92 Hz, -CH2NH-), 6.66 (d, 2H, Jo = 8.84 Hz, ArH,
meta to carboxyl), 7.07 (t, 1H, J = 6.00 Hz, -CH2NH-),
7.29 (d, 2H, Jo = 8.56 Hz, ArH, ortho to oxy), 7.49
(d, 2H, Jo = 8.48 Hz, ArH, meta to oxy), 7.72 (d, 2H,
Jo = 8.76 Hz, ArH, ortho to carboxyl), 7.76 (td, 1H,
Jo = 8.22 Hz, Jm = 1.98 Hz, ArH, quinazoline), 7.97–
8.04 (m, 2H, ArH, quinazoline), 8.36 (d, 1H,
Jo = 7.96 Hz, ArH, quinazoline), 8.71 (s, 1H, -N═CH-N),
and 12.01 ppm (br s, 1H, -COOH). 13C-NMR (DMSO-
d6, 100 MHz): δ 45.43 (CH2), 111.14 (2 × ArCH) 115.60
(ArC), 117.34 (ArC), 121.87 (2 × ArCH), 123.26
(ArCH), 127.42 (ArCH), 127.85 (ArCH), 128.37
(2 × ArCH), 131.07 (2 × ArCH), 134.37 (ArCH), 136.97
(ArC), 150.95 (ArC), 151.09 (ArC), 152.24 (ArC),
153.73 (ArCH), 166.33 (ArC), and 167.50 (C═O). ESI-
MS: 372.16 [M + H]+. Anal. calcd for C22H17N3O3: C,
71.15; H, 4.61; N, 11.31%. Found: C, 70.87; H, 4.82; N,
10.99%.
(E)-1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-
1-one (8a).
Yield: (0.33 g, 65.2%), m.p. 178–182°C.
FTIR νmax (KBr): 3123.64 (O-H), 1629.45 (C═O),
1564.50 (C═C), 1219.14 (asymmetric C-O-C), 1164.52
(C-O), 1027.74 (symmetric C-O-C) and 816.67 cmꢀ1
.
1H-NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H, OCH3),
6.89 (d, 2H, Jo = 8.72 Hz, ArH, ortho to hydroxy), 6.95
(d, 2H, Jo = 8.76 Hz, ArH, ortho to methoxy), 7.60
(d, 1H, Jtrans = 15.56 Hz, -CO-CH═CH), 7.67 (d, 1H,
Jtrans
= 14.88 Hz, -CO-CH═CH), 7.69 (d, 2H,
Jo = 8.72 Hz, ArH, meta to methoxy), 7.99 (d, 2H,
Jo = 8.72 Hz, ArH, meta to hydroxy), and 10.15 ppm (br
s, 1H, OH).
(E)-3-(3,4-Dimethoxyphenyl)-1-(4-hydroxyphenyl)prop-2-
en-1-one (8b).
Yield: (0.32 g, 62.4%), m.p. 196–200°C.
FTIR νmax (KBr): 3238.89 (O-H), 1620.15 (C═O),
1505.51 (C═C), 1263.82 (asymmetric C-O-C), 1154.64
4-[4-(p-Hydroxyanilinomethyl)phenoxy]quinazoline
(C-O), 1027.97 (symmetric C-O-C), and 816.84 cmꢀ1
.
(5f).
Yield: (0.128 g, 84.77%), m.p. 186–188°C. FTIR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Malhotra, T. Kaur, and R. Bansal
Vol 000
1H-NMR (DMSO-d6, 400 MHz): δ 3.87 (s, 3H, OCH3),
3.92 (s, 3H, OCH3), 6.89 (d, 2H, Jo = 8.72 Hz, ArH,
ortho to hydroxy), 6.93 (d, 1H, Jo = 8.32 Hz, 5′-CH,
veratrole), 7.24 (dd, 1H, Jo = 8.32 Hz, Jm = 1.88 Hz, 6′-
CH, veratrole), 7.36 (d, 1H, Jm = 1.92 Hz, 2′-CH,
veratrole), 7.61 (d, 1H, Jtrans = 15.48 Hz, -CO-CH═CH),
7.66 (d, 1H, Jtrans = 15.48 Hz, -CO-CH═CH), 8.00
(d, 2H, Jo = 8.88 Hz, ArH, meta to hydroxy), and
10.15 ppm (br s, 1H, OH).
Jo = 8.72 Hz, ArH, ortho to methoxy), 7.42 (d, 2H,
Jo = 8.60 Hz, ArH, meta to carbonyl), 7.45 (d, 1H,
Jtrans
Jo = 8.70 Hz, ArH, meta to methoxy), 7.70 (t, 1H,
Jo 7.44 Hz, ArH, quinazoline), 7.84 (d, 1H,
Jtrans 15.42 Hz, -CO-CH═CH), 7.97 (t, 1H,
= 15.42 Hz, -CO-CH═CH), 7.63 (d, 2H,
=
=
Jo = 7.08 Hz, ArH, quinazoline), 8.06 (d, 1H, Jo = 8.4 Hz,
ArH, quinazoline), 8.18 (d, 2H, Jo = 8.60 Hz, ArH, ortho
to carbonyl), 8.40 (d, 1H, Jo = 7.96 Hz, ArH, quinazoline),
and 8.80 ppm (s, 1H, -N═CH-N). 13C-NMR (CDCl3,
100 MHz): δ 55.45 (OCH3), 114.49 (2 × ArCH), 116.33
(ArC), 119.39 (CH═CH), 122.11 (2 × ArCH), 123.54
(ArCH), 127.55 (ArC), 127.86 (2 × ArCH), 128.03
(ArCH), 130.32 (2 × ArCH), 130.37 (ArCH), 134.24
(ArCH), 136.39 (ArC), 145.02 (CH═CH), 151.85 (ArC),
154.04 (ArCH), 155.76 (ArC), 161.79 (ArC), 166.58
(ArC), and 189.21 ppm.(C═O). Anal. calcd for
C24H18N2O3: C, 72.80; H, 4.89; N, 6.79%. Found: C,
72.66; H, 5.11; N, 6.97%.
(E)-1-(4-Hyroxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-
2-en-1-one (8c).
Yield: (0.31 g, 61.2%), m.p. 228–
232°C. FTIR νmax (KBr): 3123.63 (O-H), 1625.93
(C═O), 1501.04 (C═C), 1281.41 (asymmetric C-O-C),
1130.06 (C-O), 1031.47 (symmetric C-O-C), and
824.08 cmꢀ1 1H-NMR (DMSO-d6, 400 MHz): δ 3.77
.
(s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
6.89 (d, 2H, Jo = 8.72 Hz, ArH, ortho to hydroxy), 7.07
(s, 2H, ArH, 2′ and 6′-CH), 7.62 (d, 1H,
Jtrans
Jtrans
=
=
15.48 Hz, -CO-CH═CH), 7.73 (d, 1H,
15.52 Hz, -CO-CH═CH), 8.03 (d, 2H,
(E)-3-(3,4-Dimethoxyphenyl)-1-(4-(quinazolin-4-yloxy)
Jo = 8.72 Hz, ArH, meta to hydroxy), and 10.24 ppm
(br s, 1H, OH).
phenyl)prop-2-en-1-one (9b).
Yield: (0.28 g, 56.7%),
m.p. 134–136°C. FTIR νmax (KBr): 3064.25 (C-H
aromatic), 2935.78 (C-H aliphatic), 1649.04 (C═O),
1565.61 (C═C), 1368.12 (C-N), 1238.92 (asymmetric
C-O-C), 1166.70 (C-O), 1024.04 (symmetric C-O-C),
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(4-hydroxyphenyl)
prop-2-en-1-one (8d).
Yield: (0.37 g, 74.4%), m.p.
192–194°C. FTIR νmax (KBr): 3112.01 (O-H), 1610.77
(C═O), 1570.21 (C═C), 1237.63 (asymmetric C-O-C),
1165.82 (C-O), 1029.36 (symmetric C-O-C), and
1
and 840.64 cmꢀ1. H-NMR (CDCl3, 400 MHz): δ 3.94
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.91 (d, 1H,
804.49 cmꢀ1 1H-NMR (DMSO-d6, 400 MHz): δ 6.05
.
Jo
Jm
=
=
8.32 Hz, 5′-CH, veratrole), 7.18 (d, 1H,
1.88 Hz, 2′-CH, veratrole), 7.26 (dd, 1H,
(s, 2H, O-CH2ꢀO), 6.85–6.90 (m, 3H, ArH, ortho to
hydroxy and 5′-CH), 7.16 (dd, 1H, Jo = 8.04 Hz,
Jm = 1.52 Hz, ArH, 6′-CH), 7.40 (d, 1H, Jm = 1.36 Hz,
ArH, 2′-CH), 7.60 (br s, 2H, CO-CH═CH), 8.01 (d, 2H,
Jo = 8.64 Hz, ArH, meta to hydroxy), and 10.1 ppm
(br s, 1H, OH).
General procedure for the synthesis of quinazoline chalcone
bioconjugates 9a–d. To a refluxing and stirred suspension
Jo = 8.32 Hz, Jm = 1.84 Hz, 6′-CH, veratrole), 7.42
(d, 1H, Jtrans = 15.62 Hz, -CO-CH═CH), 7.43 (d, 2H,
Jo = 8.72 Hz, ArH, meta to carbonyl), 7.70 (t, 1H,
Jo
=
8.12 Hz, ArH, quinazoline), 7.81 (d, 1H,
Jtrans
=
15.62 Hz, -CO-CH═CH), 7.94 (t, 1H,
8.40 Hz, ArH, quinazoline), 8.04 (d, 1H,
8.40 Hz, ArH, quinazoline), 8.17 (d, 2H,
Jo
Jo
=
=
Jo = 8.68 Hz, ArH, ortho to carbonyl), 8.39 (d, 1H,
Jo = 8.32 Hz, ArH, quinazoline), and 8.79 ppm (s, 1H,
N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 55.99
(OCH3), 55.03 (OCH3), 110.10 (ArCH), 111.15
(ArCH), 116.01 (ArC), 119.68 (CH═CH), 122.11
(2 × ArCH), 123.11 (ArCH), 123.52 (ArCH), 127.79
(ArCH), 127.86 (ArCH), 128.05 (ArC), 130.21
(2 × ArCH), 134.38 (ArCH), 136.21 (ArC), 145.29
(CH═CH), 149.28 (2 × ArC), 151.55 (ArC), 151.87
(ArC), 154.01 (ArCH), 155.77 (ArC), 166.55 (ArC),
and 189.19 ppm (C═O). Anal. calcd for C25H20N2O4:
C, 75.38; H, 4.74; N, 7.33%. Found: C, 75.57; H,
4.47; N, 7.59%.
of respective chalcones 8a–d (1.22 mmol) and anhydrous
potassium carbonate (0.6 g) in ethyl methyl ketone, 4-
chloroquinazoline (1.22 mmol) was added. The reaction
mixture was further stirred and refluxed for 2–3 h. The
reaction was monitored by TLC. On completion, the
reaction mixture was filtered to remove excess potassium
carbonate, and solvent was removed under vacuum to give
a yellow solid product, which was recrystallized from
methanol to afford the corresponding bioconjugates 9a–d.
(E)-3-(4-Methoxyphenyl)-1-(4-(quinazolin-4-yloxy)phenyl)
prop-2-en-1-one (9a).
Yield: (0.32 g, 62.9%), m.p. 134–
138°C. FTIR νmax (KBr): 3068.33 (C-H aromatic), 2847.67
(C-H aliphatic), 1662.58 (C═O), 1595.51 (C═C), 1381.01
(C-N), 1212.84 (asymmetric C-O-C), 1158.81 (C-O),
(E)-3-(3,4,5-Trimethoxyphenyl)1-(4-(quinazolin-4-yloxy)
1
1022.62 (symmetric C-O-C), and 806.74 cmꢀ1. H-NMR
phenyl)prop-2-en-1-one (9c).
Yield: (0.27 g, 47.2%),
(CDCl3, 400 MHz): δ 3.87 (s, 3H, OCH3), 6.95 (d, 2H,
m.p. 130–136°C. FTIR νmax (KBr): 3062.29 (C-H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
4-Aryloxyquinazolines as Potential Cytotoxic Agents
aromatic), 2938.08 (C-H aliphatic), 1650.04 (C═O),
1561.04 (C═C), 1364.42 (C-N), 1236.92 (asymmetric
C-O-C), 1133.30 (C-O), 1028.04 (symmetric C-O-C),
(C═O). Anal. calcd for C24H16N2O4: C, 72.72; H, 4.07;
N, 7.07%. Found: C, 73.10; H, 4.35; N, 6.82%.
In vitro cancer cell line assay. The human tumor cell
lines of the cancer screening panel were grown in RPMI
1640 medium containing 5% fetal bovine serum and
2 mM of L-glutamine [29]. For a typical screening
experiment, cells were inoculated into 96-well microtiter
plates in 100 μL at plating densities ranging from 5000 to
40,000 cells/well depending on the doubling time of
individual cell lines. After cell inoculation, the microtiter
plates were incubated at 37°C, 5% CO2, 95% air, and
100% relative humidity for 24 h prior to addition of
experimental drugs.
1
and 800.04 cmꢀ1. H-NMR (CDCl3, 400 MHz): δ 3.89
(s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 7.14 (d, 1H, Jm = 1.84 Hz, ArH, 6′-CH), 7.20
(d, 1H, Jm = 1.00 Hz, ArH, 2′-CH), 7.42 (d, 1H,
Jtrans
Jo = 8.96 Hz, ArH, meta to carbonyl), 7.70 (t, 1H,
Jo 8.12 Hz, ArH, quinazoline), 7.81 (d, 1H,
Jtrans
= 15.56 Hz, -CO-CH═CH), 7.43 (d, 2H,
=
=
15.56 Hz, -CO-CH═CH), 7.94 (t, 1H,
8.40 Hz, ArH, quinazoline), 8.04 (d, 1H,
8.4 Hz, ArH, quinazoline), 8.17 (d, 2H,
Jo
Jo
=
=
Jo = 8.68 Hz, ArH, ortho to carbonyl), 8.39 (d, 1H,
Jo = 8.32 Hz, ArH, quinazoline), and 8.79 ppm (s, 1H,
N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 54.77
(OCH3), 55.99 (OCH3), 56.03 (OCH3), 110.10 (ArCH),
111.15 (ArCH), 116.31 (ArC), 119.68 (CH═CH),
122.11 (ArCH), 123.30 (ArCH), 123.52 (ArC), 127.79
(ArCH), 127.86 (ArCH), 128.05 (ArC), 130.37
(2 × ArCH), 134.38 (ArCH), 136.21 (ArC), 145.29
(CH═CH), 149.28 (ArC), 151.55 (ArC), 151.87 (ArC),
154.01 (ArCH), 155.77 (ArC), 166.55 (ArC), and
189.19 ppm (C═O). Anal. calcd for C26H22N2O5: C,
70.58; H, 5.01; N, 6.33%. Found: C, 70.34; H, 5.29;
N, 6.04%.
After 24 h, two plates of each cell line were fixed in situ
with TCA to represent a measurement of the cell
population for each cell line at the time of drug addition
(Tz). Experimental drugs were solubilized in DMSO at
400-fold the desired final maximum test concentration
and stored frozen prior to use. At the time of drug
addition, an aliquot of frozen concentrate was thawed and
diluted to twice the desired final maximum test
concentration with complete medium containing
50 μg/mL of gentamicin. Additional four, 10-fold or one-
half log serial dilutions were made to provide a total of
five drug concentrations plus control. Aliquots of 100 μL
of these different drug dilutions were added to the
appropriate microtiter wells already containing 100 μL of
medium, resulting in the required final drug
concentrations. Following drug addition, the plates were
incubated for an additional 48 h at 37°C, 5% CO2, 95%
air, and 100% relative humidity. For adherent cells, the
assay was terminated by the addition of cold TCA. Cells
were fixed in situ by the gentle addition of 50 μL of cold
50% (w/v) TCA (final concentration, 10% TCA) and
incubated for 60 min at 4°C. The supernatant was
discarded, and the plates were washed five times with tap
water and air dried. Sulforhodamine B (SRB) solution
(100 μL) at 0.4% (w/v) in 1% acetic acid was added to
each well, and plates were incubated for 10 min at room
temperature. After staining, unbound dye was removed
by washing five times with 1% acetic acid, and the plates
were air dried. Bound stain was subsequently solubilized
with 10 mM of trizma base, and the absorbance was read
on an automated plate reader at a wavelength of 515 nm.
For suspension cells, the methodology was the same
except that the assay was terminated by fixing settled
cells at the bottom of the wells by gently adding 50 μL
of 80% TCA (final concentration, 16% TCA). Using the
seven absorbance measurements [time zero (Tz),
control growth (C), and test growth in the presence of
drug at the five concentration levels (Ti)], the
percentage growth was calculated at each of the drug
concentrations levels. Percentage growth inhibition was
calculated as
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(4-(quinazolin-4-
yloxy)phenyl)prop-2-en-1-one (9d).
Yield: (0.29 g,
56.1%), m.p. 142–144°C. FTIR νmax (KBr): 3062.91
(C-H aromatic), 2917.52 (C-H aliphatic), 1654.26
(C═O), 1582.71 (C═C), 1373.73 (C-N), 1245.23
(asymmetric
C-O-C),
1163.83
(C-O),
1029.00
(symmetric C-O-C), and 912.03 cmꢀ1
.
1H-NMR
(CDCl3, 400 MHz): δ 5.97 (s, 2H, O-CH2-O), 6.79 (d,
1H, Jo = 8.00 Hz, 5′-CH, aromatic), 7.08 (dd, 1H,
Jo = 8.08 Hz, Jm = 1.68 Hz, ArH, 6′-CH), 7.11 (d,
1H, Jm = 1.56 Hz, ArH, 2′-CH), 7.33 (d, 1H,
Jtrans
Jo = 8.68 Hz, ArH, meta to carbonyl), 7.64 (t, 1H,
Jo 8.16 Hz, ArH, quinazoline), 7.72 (d, 1H,
Jtrans
= 15.56 Hz, -CO-CH═CH), 7.36 (d, 2H,
=
=
15.56 Hz, -CO-CH═CH), 7.88 (t, 1H,
8.40 Hz, ArH, quinazoline), 7.97 (d, 1H,
8.40 Hz, ArH, quinazoline), 8.10 (d, 2H,
Jo
Jo
=
=
Jo = 8.68 Hz, ArH, ortho to carbonyl), 8.33 (d, 1H,
Jo = 8.28 Hz, ArH, quinazoline), and 8.72 ppm (s, 1H,
N═CH-N). 13C-NMR (CDCl3, 100 MHz): δ 101.69 (O-
CH2-O), 106.68 (ArCH), 108.74 (ArCH), 116.35
(ArC), 119.73 (CH═CH), 122.15 (2 × ArCH), 123.54
(ArCH), 125.54 (ArCH), 127.86 (ArCH), 128.08
(ArC), 129.30 (ArCH), 130.38 (2 × ArCH), 134.38
(ArCH), 136.19 (ArC), 144.98 (CH═CH), 148.98
(2 × ArC), 150.05 (ArC), 151.90 (ArC), 154.05
(ArCH), 155.85 (ArC), 166.57 (ArC), and 189.00 ppm
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Malhotra, T. Kaur, and R. Bansal
Vol 000
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½ðTi ꢀ TzÞ=ðC ꢀ TzÞꢁꢂ100 for concentrations for which Ti≥Tz
½ðTi ꢀ TzÞ=Tzꢁꢂ100 for concentrations for which Ti < Tz:
Acknowledgments. The authors are thankful to INSPIRE,
Department of Science and Technology (reg. no. IF140866) and
University Grant Commission, New Delhi, for providing
financial support. The authors express appreciation to National
Cancer Institute, Bethesda, Maryland, USA, for evaluation of
compounds for in vitro antineoplastic activity.
CONFLICT OF INTEREST
Authors declare no conflict of interest.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet