Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole

Article abstract of DOI:10.1016/j.bmcl.2013.12.005

By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric molecules with substituted primary amines have been synthesized. Evaluation of these molecules over 60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound 10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of compounds with GI₅₀ value of 1.64 μM. Compound 11 (GI₅₀ value of 0.81 μM) showed almost twenty and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while compound 12 (GI₅₀ value of 4.52 μM) has four fold more activity than quinazoline and benzimidazole analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon cancer cell lines and prostate cancer cell lines at five dose concentrations with GI₅₀ values of 0.34 and 0.31 μM, respectively.

Full text of DOI:10.1016/j.bmcl.2013.12.005

Bioorganic & Medicinal Chemistry Letters 24 (2014) 624–629
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro antitumor evaluation of primary amine
substituted quinazoline linked benzimidazole
⇑
Kamaldeep Paul , Alka Sharma, Vijay Luxami
School of Chemistry and Biochemistry, Thapar University, Patiala 147004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2013
Revised 16 November 2013
Accepted 2 December 2013
Available online 8 December 2013
By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric
molecules with substituted primary amines have been synthesized. Evaluation of these molecules over
60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound
10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of
compounds with GI50 value of 1.64
and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while
compound 12 (GI50 value of 4.52 M) has four fold more activity than quinazoline and benzimidazole
lM. Compound 11 (GI50 value of 0.81 lM) showed almost twenty
Keywords:
Quinazoline
Benzimidazole
Primary amines
Antitumor activity
l
analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon
cancer cell lines and prostate cancer cell lines at five dose concentrations with GI50 values of 0.34 and
0.31 lM, respectively.
Ó 2013 Elsevier Ltd. All rights reserved.
Cancer is rolling to be a leading health problem in developed as
well as developing countries.1–9 Surpassing heart diseases; it is
taking the position number one killer due to various worldwide
factors. The enormous cancer incidence increases the search for
latest, safer and efficient anticancer agents, aiming the prevention
or the cure of this illness. In the path of identifying various chem-
ical substances which may serve as leads for designing novel anti-
tumor agents, nitrogen-containing heterocycles are of particular
interest.10 Quinazoline and benzimidazole moieties have been
identified as new classes of cancer chemotherapeutic agents with
significant therapeutic efficacy against solid tumors. Benzimid-
azole has evolved as an important heterocyclic system due to its
presence in a wide range of bioactive compounds like anthilmen-
tic,11,12 antihistaminics,13,14 antiulcers,15 antihypertensives, antitu-
mor, antiviral, antimicrobial,16 anticonvulsants, anti-inflammatory
agents, antiallergic, analgesics and anticoagulants.17 Quinazoline
compounds have also attracted attention to anticancer research
and several attempts were made for modifying the quinazoline
nucleus to improve their antitumor activities. These modifications
have resulted in a large number of compounds having diverse
pharmacological activities. Among them 4-[6-nitro-2-(4-phenoxy-
phenylamino) quinazoline-4-ylamino] benzoic acid has been
shown to exhibit exquisitely potent and selective human Pin1
inhibitors.18 2,4-Disubstituted quinazoline also exhibited as potent
tyrosine kinase and cellular phosphorylation inhibitors,19 aurora
kinase inhibitors,20dihydrofolate reductase inhibitors,7 G9a
inhibitors,21 anti-inflammatory,22 antiviral,23 and antitubercular
agents.24 Derivatives of 2-thieno-4(3H)-quinazolinone, 2-furano-
4(3H)-quinazolinone and thiazolo[2,3-b]quinazoline have shown
in vitro antitumor activity in human cancer cell lines.8,25 Moreover,
quinazolines exerted their anticancer activity through inhibition of
the DNA repair enzyme system.26 Molecular hybridization is a rel-
atively new terminology in the field of drug design and develop-
ment involving the fusion of two or more pharmacophoric
subunits from the molecular structure of ligands/prototypes previ-
ously reported to have an inhibitory effect against the target pro-
tein or disease. The newly designed architecture can lead to
compounds having improved affinity and efficiency than the par-
ent compounds with reduced side effects, while retaining the
desired characteristics of original template. Various literature
reports have explored this methodology in designing newer
analogues as potential candidates for biological evaluation.27
Encouraged by our previous successful research efforts28 in this
regard, it was decided further to extend the above methodology to
identify more quinazoline–benzimidazole hybrids. In view of the
above mentioned knowledge based facts of different pharmaco-
phores and in continuation of our research programme, we have
synthesized quinazoline–benzimidazole hybrids along with incor-
poration of primary amines and electronic environment to get sin-
gle molecule framework.
These hybrid molecules consisted of planar heterocyclic
ring (quinazoline) as central core that can act as a scaffold to carry
two functionalized branches at positions 2 and 4, in such a way to
accommodate a benzimidazole ring at 4-position and primary
amines at 2-position of quinazoline. Introduction of alkyl and allyl
⇑
Corresponding author. Tel.: +91 94656 70595; fax: +91 175 236 4498.
E-mail address: kpaul@thapar.edu (K. Paul).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.005

K. Paul et al. / Bioorg. Med. Chem. Lett. 24 (2014) 624–629
625
H- Acceptor
N
N
Cl
N
H-donor
CH3
N
N
R2
N
H2N
+
NH
NHR
Hydrophobic
region
R1
N
Quinazoline
Lipophillicity
enhancer
Benzimidazole
N
NHR
H- Acceptor
H-donor
Quinazoline-benzimidazole hybrids
Figure 1.
N
N
N
N
CH3
CH3
CH3
RNH2
NH
N
N
H2N
NH
3a
IPA, Reflux
N
N
O
Cl
4
N
NHR
t
.
r
,
N
Cl
4a
NH2
A
P
3
NH2CONH2
POCl / TEA
I
NH
3
N
5-13
160 oC
Reflux
COOH
N
H
O
N
Cl
2
1
1
2
I
P
A
,
N
r
.
t
N
N
CH3
CH3
H2N
N
N
NH
NH
CH3
RNH2
N
N
N
3b
IPA, Reflux
N
NHR
N
Cl
14-15
4b
Scheme 1.
groups at respective 1- and 2-positions of benzimidazole and aryl
groups of quinazoline moiety are also known to increase lipid sol-
ubility of polar compounds, a character very much needed for the
activity (Fig. 1). Primary amines with different electronic with-
drawing groups as well as bulky groups (benzimidazole) were cho-
sen for the substitution at C2-position of quinazoline. These
compounds were screened for their in vitro antitumor activity in
full NCI 60 cell lines panel assay includes nine tumor subpanels
namely; leukemia, non-small cell lung, colon, CNS, melanoma,
ovarian, renal, prostate and breast cancer cells.
The synthetic strategy to prepare the target compounds 5–15
has been illustrated in Scheme 1. Stirring of anthranilic acid and
urea at 160 °C for 6 h to give 1H-quinazolin-2,4-dione (1) followed
by refluxing with phosphorus oxychloride and triethylamine for
7 h afforded 2,4-dichloro-quinazoline (2). Compound 2 was stirred
with 3a and 3b28 in isopropyl alcohol (IPA) at room temperature
for
8–12 h
gave
(3-allyl-2-methyl-3H-benzimidazol-5-yl)-
(2-chloro-quinazolin-4-yl)-amine (4a) with 92% yield and (1-allyl
-2-methyl-1H-benzimidazol-5-yl)-(2-chloro-quinazolin-4-yl)-ami
ne (4b) with 82% yield, respectively. Compound 4a was refluxed
with substituted primary amines in IPA for 7–8 h gave compounds
5–13. Similarly, compound 4b was also treated with primary
amines at the same reaction conditions to give compounds
14–15 with moderate to high yields (Table 1). These compounds
were washed with diethyl ether to get the pure compounds.
Furthermore, the purities of these compounds were confirmed by
recording the elemental analysis and HPLC. All the synthesized
compounds were well characterized by FT–IR, 1H and 13C NMR as
well as mass spectroscopy (Supplementary Material).
All the synthesized compounds were submitted to National
Cancer Institute (NCI) disease-oriented human cell lines for screen-
ing assay to be evaluated for their in vitro antitumor activity. The
Table 1
Physicochemical properties of the newly synthesized compounds 4a-b and 5–15
Compd
Starting material
RNH2
Yields (%)
mp (°C)
Molecular formula
C19H16ClN5
C19H16ClN5
C25H22N6S
4a
4b
5
6
7
3a
3b
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
—
—
92
82
60
76
83
70
61
70
62
65
70
65
66
210–215
217–220
200–202 (d)
260–265
110–115
4-Aminobenzenethiol
4-Aminophenol
o-Phenylenediamine
2-Aminopyrimidine
2-Ethanolamine
3-Allyl-2-methyl-3H-benzimidazol-5-ylamine
1-Allyl-2-methyl-1H-benzimidazol-5-ylamine
4-Fluorophenylamine
2,6-Difluorophenylamine
2-Ethanolamine
C
C
25H22N6O
25H23N7
8
9
170–175
190–195
C24H21N7
C21H22N6O
C30H28N8
C30H28N8
C25H21FN6
C25H20F2N6
C21H22N6O
10
11
12
13
14
15
220–222 (d)
180–183
200–205 (d)
215–220(d)
100–105
3-Allyl-2-methyl-3H-benzimidazol-5-ylamine
200–205 (d)
C30H28N8

626
K. Paul et al. / Bioorg. Med. Chem. Lett. 24 (2014) 624–629
Table 2
Percent growth promotion of in vitro subpanel tumor cell lines at 10 lM concentration of compounds 5, 8–12 and 14–15
C E L L L I N E T Y P E
C E L L L I N E
N A M E
5
8
9
1 0
1 1
12
14
1 5
LE U K E M I A
CCRF-CEM
65.48
98.79
92.53
88.20
59.79
90.84
89.82
84.81
93.99
83.00
97.19
70.66
121.00
90.29
88.49
114.43
92.21
96.68
95.74
104.21
99.92
-20.80
-63.18
-43.46
-45.48
-43.32
-57.22
-83.06
-11.29
-52.00
-27.00
-26.83
-23.97
-44.19
-67.14
22.48
51.60
20.95
-5.55
nt
22.43
52.12
81.94
93.77
64.06
56.70
63.44
68.83
92.35
94.81
84.02
101.89
101.27
98.82
106.26
96.33
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
N O N -S M A L L C E L L
LU N G C A N C E R
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
96.51
104.07
61.09
109.12
100.72
102.47
103.80
89.53
87.22
84.79
70.50
92.18
82.84
100.26
97.83
98.09
101.72
106.44
95.48
97.62
73.86
106.67
92.74
2.58
Nt
nt
nt
97.09
100.65
79.82
99.77
94.21
108.79
117.38
99.13
107.88
103.53
-61.45
43.21
67.36
32.77
-13.41
-69.52
-90.73
-92.32
-52.67
-99.54
-79.03
-47.06
-69.16
-92.17
-84.21
-94.80
-100.0
-96.13
75.91
-0.39
85.42
56.03
85.42
63.40
57.94
43.73
80.62
83.32
57.86
78.80
81.91
91.31
95.98
88.09
41.89
89.03
99.96
102.84
100.53
105.53
109.68
C O L O N C A N C E R
121.32
103.01
HCT-116
HCT-15
HT29
93.18
96.49
97.29
96.78
107.97
108.58
77.11
108.24
93.18
98.18
94.21
94.71
-97.80
-51.70
-96.68
-84.76
-80.52
-32.41
-67.46
-93.76
30.64
-96.48
-76.21
-69.45
-93.21
-76.19
-69.78
-86.57
-95.76
-66.14
-96.69
26.89
34.46
18.71
36.60
46.08
66.04
31.44
72.97
96.47
54.57
64.04
105.16
64.48
73.07
68.25
90.88
90.61
94.81
90.22
76.37
90.88
85.59
98.58
93.30
92.10
101.95
100.58
75.43
97.73
85.53
95.28
94.84
65.19
92.22
73.63
97.71
102.91
89.12
55.39
90.48
93.02
97.46
84.67
118.34
72.37
98.93
106.86
102.87
108.75
105.83
112.67
nt
98.59
99.97
90.76
110.79
103.96
105.94
100.33
94.84
86.91
102.82
97.64
78.75
89.76
85.28
99.01
114.51
107.08
100.21
110.62
92.94
101.19
92.59
84.09
112.68
103.41
102.16
97.73
KM12
SW-620
SF-268
SF-295
SF-539
SNB-19
SNB-75
C NS C A N C E R
92.51
145.62
103.87
93.93
92.55
-95.23
U251
91.35
96.99
98.46
88.54
110.78
110.79
101.98
126.99
99.29
96.48
100.00
92.68
90.09
98.33
88.42
106.82
98.95
105.57
109.04
95.65
78.32
103.61
99.00
116.45
87.58
124.13
92.56
-94.19
-88.62
-78.94
-88.35
-78.02
-83.85
-95.95
-94.16
-87.63
-86.95
-47.54
-95.41
-93.30
25.12
-48.65
53.47
-63.69
-93.78
99.49
-80.03
-24.14
-80.72
-74.87
-88.52
-91.43
-90.67
-83.35
-68.26
-88.00
-75.98
-84.13
-88.01
-95.20
-79.76
-83.32
-93.77
-99.79
-100.00
-92.54
-40.90
-23.72
-95.70
-70.60
-99.99
-97.45
-86.37
-97.36
-69.64
-97.20
-94.43
59.59
45.27
74.46
45.20
57.11
58.11
72.01
33.34
92.58
63.17
51.15
51.23
48.25
81.30
33.38
38.40
98.61
76.74
59.90
67.55
58.20
66.55
66.20
82.29
37.40
94.42
93.29
94.54
M E L A N O M A
LOX IMVI
MALME-3M
M14
123.20
109.11
96.87
109.28
103.56
84.07
110.36
83.12
101.95
106.44
88.50
118.45
63.72
97.84
123.73
102.39
48.46
109.44
107.53
121.40
105.50
99.72
101.62
95.76
102.37
108.38
99.55
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
786-0
O V A R I A N C A N C E R
99.27
85.61
114.41
94.29
102.80
104.20
106.28
76.76
102.65
75.59
114.17
97.64
117.98
82.11
106.86
98.87
101.49
104.03
113.02
124.51
104.27
101.08
124.35
96.49
R E N A L C A N C E R
A498
ACHN
CAKI-1
RXF 393
SN12C
100.60
90.54
143.88
93.93
107.16
89.50
TK-10
UO-31
130.13
89.29
P R O S T A T E C A N C E R
B R E A S T C A N C E R
PC-3
81.12
`89.21
93.81
-47.79
-91.73
42.14
69.16
95.82
DU-145
114.11
112.27
107.26
-67.62
-95.96
74.08
98.85
115.29
MCF7
93.19
80.45
82.38
84.38
93.67
84.53
-87.94
-78.76
-89.35
-85.80
26.10
73.75
72.21
72.87
92.43
89.97
MDA-MB-
31/ATCC
HS 578T
BT-549
T-47D
98.12
87.89
71.73
106.36
87.66
82.76
55.84
78.29
91.48
96.46
95.75
119.24
-41.41
72.08
-91.01
-92.76
-48.06
-83.98
-60.35
-84.96
54.42
59.15
35.01
49.30
77.45
92.47
69.01
53.51
100.04
105.73
96.04
MDA-MB-468
118.42
nt, not tested; 30-40% growth inhibition, 40-50% growth inhibition, 50-70% growth inhibition, 70-90% growth inhibition, 90-100% growth inhibition,
highly potent compounds.

K. Paul et al. / Bioorg. Med. Chem. Lett. 24 (2014) 624–629
627
tumor growth inhibition properties of the eight compounds
selected by the NCI, USA, were screened on 60 human tumor cell
exhibited remarkable anticancer activity against renal cancer
A-498 cell line with GI50 value of 0.44 M. Compound 12 showed
anticancer activity against non-small cell lung cancer HOP-92 cell
line with GI50 value of 0.58 M. Obtained data revealed an obvious
broad spectrum sensitivity profile of compound 11 toward all nine
subpanels of cancer cell lines with GI50 values ranging from 2.27 to
l
lines at 10 l
M concentration.29–31 The obtained results of the
tested quinazoline–benzimidazole hybrids 5, 8–12 and 14–15 (Ta-
ble 2) showed distinctive potential pattern of selectivity, as well as
broad-spectrum antitumor activity.
l
Compounds 10 and 11 were found to be broad spectrum against
all nine subpanels of cancer cell lines at primary single high dose
with mean growth percent of À54.60 and À77.59, respectively.
On the other hand, compound 12 also showed remarkably lowest
cell growth promotion against leukemia cancer MOLT-4 and non-
small cell lung HOP-92 cancer cell line with cell growth promotion
of –5.55 and –0.39, respectively. Close examination of the data pre-
sented in Table 2 indicated that compounds 10 and 11 are the most
potent and 12 possess moderate antitumor activity; while com-
pounds 5, 8–9 and 14–15 are the least active anti-tumors in the
present investigation. Among the selected eight compounds,
10–12 were further screened for 5-log dose molar range as these
0.78 lM, TGI values ranging from 5.16 to 0.90 lM. Compound 11
also showed highest potency against melanoma LOX IMVI cancer
cell line and ovarian cancer cell line OVCAR-3 with LC50 values of
6.40 and 0.70 lM, respectively (Supplementary Information). Anti-
cancer activities of quinazoline–benzimidazole hybrids (10–12)
were also compared with reported quinazoline and benzimidazole
derivatives. Compound 10 was almost ten and eleven fold more ac-
tive than respective quinazoline (2-(2-Thieno)-4-[4-sulfonamido
benzylamino]-6-iodoquinazoline)8 also indicates the usefulness
of amines at C2-position and benzimidazole (6-Amino-5-(5,6-di-
methyl-1H-benzimidazol-2-yl)-4-(4-methoxy-phenyl)pyridine-3-
carbonitrile) analogue,33 with full panel mean graph mid-point
have shown prominent cell growth inhibition at 10
l
M concentra-
(MG MID) GI50, TGI and LC50 values of 1.64, 3.28 and 5.50
lM,
tion against variety of cell lines. Compound under investigation 10
respectively. Compound 11 showed twenty and twenty-two fold
Table 3
Compounds 10–12, quinazoline and benzimidazole analogue median growth inhibitory (GI50, lM), total growth inhibitory (TGI, lM) and median lethal concentrations (LC50, lM)
of in vitro subpanel tumor cell lines
Compd
Activity
I
II
III
IV
V
VI
VII
VIII
IX
MG MIDa
10
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
1.74
1.73
3.27
6.15
1.03
2.53
6.14
3.13
14.0
62.7
14.7
1.61
3.13
5.56
0.34
0.81
4.61
3.68
12.2
49.7
16.7
1.68
3.28
5.71
1.10
2.72
6.04
6.79
19.3
50.4
18.2
1.71
3.23
5.38
1.29
2.86
5.43
5.06
16.0
47.0
16.0
1.75
3.55
5.59
1.03
2.44
3.38
5.47
18.9
68.7
15.7
1.54
3.06
5.48
0.98
2.31
4.90
4.50
17.7
52.8
13.6
1.61
3.09
5.79
0.31
0.95
3.62
5.88
18.8
52.2
17.1
1.40
3.07
5.12
0.71
1.69
1.63
3.33
15.6
73.1
12.3
1.64
3.28
5.50
0.81
2.08
4.47
4.52
15.9
57.1
16.9
3.85
b
11
0.47
2.44
b
12
2.83
10.6
b
Quinazoline analogue
23.9
72.3
37.0
37.3
42.4
30.5
42.6
36.1
41.8
32.1
40.5
b
b
b
b
b
b
b
b
b
b
LC50
GI50
TGI
Benzimidazole
Analogue
17.4
62.0
6.32
6.80
34.8
51.5
17.5
21.8
11.2
7.90
23.8
61.8
12.1
18.1
33.4
56.7
b
b
b
b
b
38.2
36.8
b
b
b
b
b
b
b
LC50
I, leukemia cancer; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma cancer; VI, ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast
cancer.
a
Full panel mean-graph midpoint (
l
M.
M).
b
Compounds showed values >100
l
Figure 2. Compounds 10–12, quinazoline and benzimidazole analogue median growth inhibitory (GI50, lM), total growth inhibitory (TGI, lM) and median lethal
concentrations (LC50 M) of in vitro subpanel tumor cell lines.
,
l

628
K. Paul et al. / Bioorg. Med. Chem. Lett. 24 (2014) 624–629
Figure 3. Comparison of full panel mean-graph midpoint (lM) of compounds 10–12 with quinazoline and benzimidazole analogue.
more activity than respective quinazoline and benzimidazole
derivative, with MG MID GI50, TGI and LC50 values of 0.81, 2.08
logue. These three quinazoline hybrids could be considered as use-
ful templates for further development to obtain more potent
antitumor agent (s). Overall results revealed that: (i) quinazoline
is a satisfactory backbone for antitumor activity, (ii) the presence
of benzimidazole at 4-position is essential for activity, (iii) the pres-
ence of substituted primary amines at 2-position of quinazoline is
necessary, (iv) linker between quinazoline and benzimidazole is
essential as H-bond region and (v) regioisomerization of allyl groups
at 1- or 3-position of benzimidazole increases the antitumor activity
as indicated upon comparing compounds 10 and 15.
and 4.47
lM, respectively while compound 12 showed four fold
more active than quinazoline and benzimidazole analogue, with
MG MID GI50, TGI and LC50 values of 4.52, 15.9 and 57.1
respectively (Table 3, Figs. 2 and 3).
lM,
Structure–activity relationship, based on the number of cell lines
proved sensitivity toward each of the synthesized individual com-
pounds revealed that the nature of the substituent on the C2- and
C4-positions of quinazoline improve biological functions. There is
much difference in antitumor activity by orientations of benzimid-
azole present at C4-position which played a key role in the efficiency
of the compound. (3-allyl-2-methyl-3H-benzimi dazol-5-yl)-(2-
amino-quinazolin-4-yl)-amine (5, 8–12) showed more potent
antitumor agents than their regioisomeric analogue (1-allyl-2-
methyl-1H-benzimidazol-5-yl)-(2-amino-quinazolin-4-yl)-a mine
(14–15). Compound 12 were proved to be active member with
antitumor activity against most of the cell lines. Furthermore,
replacement of the 4-fluoroaniline with 3-allyl-2-methyl-3H-ben-
zimidazol-5-ylamine (10) and 1-allyl-2-methyl-1H-benzimidazol-
5-ylamine (11) resulted in a higher growth inhibitory effect. These
results revealed the crucial role of these amines at C2-position of
quinazoline for their antitumor activity. In general, it is observed
that the heteroaryl rings and electron rich aryl groups at C2- position
of quinazoline showed better antitumor activity than the ones with
an aliphatic chain.18,32 The presence of 4-aminobenzenethiol (5)
and 2-aminopyrimidine (8) at C2-position of quinazoline decreased
the antitumor activity while introduction of aliphatic chain (9 and
14) exhibited a dramatic loss of activity against almost all screened
cell lines. This suggested that benzimidazole at C2-position of qui-
nazoline is a critical pharmacophore for growth inhibitory activity.
Amongst the most active compounds 10–12, compound 11 showed
almost two fold and five fold higher activities than compounds 10
and 12, respectively. Compound 11 proved to be higher antitumor
activity to the colon and prostate cancer cell lines than other cell
lines.
Acknowledgment
We thank to Council of Scientific and Industrial Research
(02(0034)/11/EMR-II) for the research Grant. We also thank Punjab
University, Chandigarh for recording NMR and mass spectra. NCI,
USA is gratefully acknowledged for investigating antitumor
activities.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.12.
005.
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in this study as compared to quinazoline and benzimidazole ana-

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