Quinazolinones-Phenylquinoxaline hybrids with unsaturation/saturation linkers as novel anti-proliferative agents

Article abstract of DOI:10.1016/j.bmcl.2016.05.021

A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a-n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a-n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity with GI₅₀ values ranging from 0.06 to 0.2 μM against four cell lines, while compounds 9e and 9k showed significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selective potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a-n). Docking results indicate a sign of good correlation between experimental activity and calculated binding affinity (dock score), suggesting that these compounds could act as promising DNA intercalates.

Full text of DOI:10.1016/j.bmcl.2016.05.021

Bioorganic & Medicinal Chemistry Letters 26 (2016) 3014–3018
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quinazolinones–Phenylquinoxaline hybrids with unsaturation/
saturation linkers as novel anti-proliferative agents
Jyothsna Devi Palem a, Gopi Reddy Alugubelli a, Rajashaker Bantu a, Lingaiah Nagarapu a,
,
⇑
Sowjanya Polepalli b, S. Nishanth Jain b, Raju Bathini c, Vijjulatha Manga c
a Organic Chemistry Division II (CPC), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
c Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Osmania University, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a–n were efficiently synthe-
sized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a–n) with bromophenyl)
quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity
against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and
IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity
Received 3 February 2016
Revised 6 April 2016
Accepted 7 May 2016
Available online 11 May 2016
with GI50 values ranging from 0.06 to 0.2 lM against four cell lines, while compounds 9e and 9k showed
Keywords:
Quinazolinones
Allylphenyl quinoxaline
Heck-cross coupling
Anti-proliferative activity
Cancer cell lines
significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selec-
tive potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and
in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)
quinazolin-4(3H)-ones (9a–n). Docking results indicate a sign of good correlation between experimental
activity and calculated binding affinity (dock score), suggesting that these compounds could act as
promising DNA intercalates.
DNA intercalates
Ó 2016 Elsevier Ltd. All rights reserved.
The quinazolinone moiety containing natural products (Luo-
tonin, Rutaecarpine, Tryptanthrin, Chloroqualone, Alloqualone,
etc.) represent the medicinally and pharmaceutically important
class of compounds,1,2 because of their diverse range of biological
activities such as anti-cancer, diuretic, anti-inflammatory, anti-
convulsant and anti-hypertensive3–6 activity. In recent years,
quinazolinone embedded numerous natural products have been
identified.7–15 The cytotoxic alkaloid Luotonin A and its derivatives
infused with quinazolinone moiety are clinically proven as
anti-cancer agents (Fig. 1).16–24 Previous studies have clearly
demonstrated that Luo functions as DNA topoisomerase-I poison.25
Considering the potent bioactivities of the compounds possessing
Luo pharmacophore, we were interested to synthesize novel Luo
analogues and evaluated their anti-cancer activities such as
cytotoxicity, cell cycle regulation and mechanistic aspects.
programme to discover and develop tumor growth inhibitors and
apoptosis inducers as a potential new anti-cancer agents, we have
identified several classes of molecules that includes 1H-pyrazole-
5-carboxylic acid, 1H-pyrrolo[3,4-b]quinolin-3(2H)-one, analogues
of (+)-varitriol, novel derivatives of benzosuberones with thiazo-
lidine-2,4-diones and fused coumarin moieties.33 In the present
investigation, we have discovered a novel quinazolinones bearing
allylphenyl quinoxaline hybrids, by employing Heck-cross
methodology to elicit combined anti-tumour efficacy/cytotoxicity
against different cancer cell lines in vitro (HeLa, MIAPACA, MDA-
MB-231and IMR32). Significantly, the compounds 9k, 9h have
shown promising cytotoxicity against the HeLa cancer cell lines
with GI50 values of 0.06 and 0.2 lM, respectively and the com-
pounds 9a, 9g, 9k and 9h displayed the most potent selectivity
against HeLa and MDA-MB-231 cell lines with GI50 values of 0.08
A hybrid anti-cancer agent, which combines different hetero-
cyclic compounds in one, which increases the cytotoxicity and
enhances specificity was recently demonstrated.26 The initial study
proved that pyrroloquinoline nucleus leads to the selective inhibi-
tion of tumor growth.27–32 Recently, as part of our on-going
and 0.4 lM, respectively. Quinazolinone derivatives are reported
as anti-cancer agents and many of them showed good DNA inter-
calation.34,35 To assess the possible intercalating potency of the
synthesized compounds a molecular docking studies were per-
formed using DNA structure obtain from PDB. The protein struc-
ture bound to respinomycin D was downloaded, as it belongs to
anthracycline family of antitumor antibiotics. Since doxorubicin
also belongs to the same family it has been taken as standard.
⇑
Corresponding author. Tel.: +91 40 27191509; fax: + 91 40 27193382.
E-mail addresses: lnagarapuiict@yahoo.com, nagarapu@iict.res.in (L. Nagarapu).
http://dx.doi.org/10.1016/j.bmcl.2016.05.021
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

J. D. Palem et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3014–3018
3015
catalytic amounts of Zr/WO3 at 80 °C. It was further coupled with
3-allylquinazolinone derivatives 5a–n; which were obtained by
the reaction of various benzaldehydes (2a–n) with anthranilamide
(1) in presence of phase transfer catalyst TBAHS in methanol,
followed by oxidation of 2-phenyl-2,3-dihydro qunazolinones
(3a–n) and allylation with allylbromide in presence of K2CO3 at
room temperature for 2-phenyl quinazolin-4(3H)-ones (4a–n)
(Scheme 1).
Under similar Heck-coupling conditions [Pd(OAc)2, PPh3, K2CO3,
DMF/H2O (8:2), 120 °C for 4 h] when 2-(4-bromophenyl)quinoxa-
line (8) was reacted with 3-allyl-2-methylquinazolin-4(H)-one
(5) saturated 2-methyl-3-(3-(4-(quinoxalin-2-yl)phenyl)propyl)
quinazolin-4(3H)-one (9o) was obtained with an yield of 67%
(Scheme 2).
O
N
O
N
O
N
N
N
N
O
N
HN
Rutaecarpine
Tryptanthrin
Luotonin A
Cl
O
N
O
N
N
H2N
N
Cl
F
Chloroqualone
Alloqualone
O
O
N
N
N
N
N
N
All the newly synthesized compounds were characterized by
using 1H NMR, 13C NMR, IR and mass spectrometry. Spectral data
of all synthesized compounds were in good agreement with the
proposed structures. IR spectrum revealed the presence of C@O
bond (1680–1700 cmÀ1) and CH (2928–2934 cmÀ1) functional
groups of compounds 9a–n, which were further confirmed by 1H
NMR. The characteristic proton of quinoxaline displayed at d 9.0–
9.3 ppm and double bond protons appeared as a multiplet at d
6.50–6.30 ppm with coupling constant between 17 and 16 Hz.
Compound 9o indicating the reduction of double bond showed
two additional triplets and one multiplet, one triplet at d 4.16–
N
R
N
R
9a-n
9o
Figure 1. Quinazolinone scaffold containing natural products and its designed
conjugates (9a–n, 9o).
The clinical agent doxorubicin is well-studied of this class but has a
relatively simple molecular architecture in which the pendant
daunosamine sugar residue is in the DNA minor groove. The com-
pounds 9a–9o were evaluated in silico (docking) to identify their
hypothetical binding mode using the NMR structure of the respino-
mycin D intercalation complex with a double stranded DNA mole-
cule (AGACGTCT)2 complex in solution36 derived from NOE
restraints and molecular dynamics simulations.
Synthesis of targeted (E)-2-(4-substituted)-3-(3-(4-(quinoxalin-
2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a–n) were achieved by
Pd catalyzed Heck-cross coupling reaction [Pd(OAc)2, PPh3,
K2CO3, DMF/H2O (8:2), at 120 °C for 4 h] of halo-qunaxolines with
substituted 3-allylquinazolinones. The 2-(4-bromophenyl)quinox-
aline (8) was readily prepared by the reaction of ortho-phenylene
diamine (6) with various phenacyl bromides (7) in presence of
4.01 ppm, another triplet at
d 2.8–2.6 ppm and one proton
appeared as a multiplet at d 2.2–2.1 ppm. The molecular formula
of all the synthesized compounds was confirmed by HRMS data
analysis. For instance, 9a displayed a molecular ion peak at m/z
467.18664 [M+H]+ suggesting the molecular formula of C31H23ON4.
Effects of the compounds on the viability of human cancer cells:
The in vitro anti-proliferative activity of the designed compounds
9a–n was evaluated against four different human cancer cell lines,
HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and
IMR32 (neuroblastoma) summarized in Table 1. The compounds
were picked up for an advanced assay against these four human
O
O
O
i
NH
ii
NH
NH2
NH2
+
RCHO
N
H
R
N
R
iii
2a-n
3a-n
4a-n
1
O
O
N
NH2
NH2
Br
iv
+
N
+
N
8
Br
6
N
7
R
Br
5a-n
CHO Cl
CHO
R =
F
CHO
v
c
a
b
O
N
CHO
O2N
O
CHO
O
CHO
N
f
e
N
N
O
O
d
R
O
CHO
Cl
CHO
9a-n
CHO
O
h
g
Cl
i
F3C
CHO
O
CHO
CHO
CHO
k
j
F
O
l
O
O
m
n
CHO
O
Scheme 1. Synthesis of (E)-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a–n). Reagents and conditions: (i) MeOH, reflux, 2 h; (ii) KMnO4,
acetone, reflux, 1 h; (iii) allyl bromide, K2CO3, DMF, rt, 8 h; (iv) Zr/WO3, 80 °C, 30 min; (v) Pd(OAc)2, PPh3, K2CO3, DMF/H2O (8:2), 120 °C, 4 h.

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J. D. Palem et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3014–3018
O
O
N
N
N
Pd(OAc)2, PPh3
+
N
N
N
8
N
N
K2CO3, DMF:H2O(8:2)
120 oC, 4 h, 83%
Br
9o
5
Scheme 2. Synthesis of 2-methyl-3-(3-(4-(quinoxalin-2-yl)phenyl)propyl)quinazolin-4(3H)-one (9o).
Table 1
(GI50/l
M)a values of the tested compounds against four human cancer cell lines
Compound
HeLa
MIAPACA
MDA-MB-231
IMR32
XP Dockscore
(kcal/mol)
GI50
M)
PGI50
GI50
M)
PGI50
GI50
M)
PGI50
GI50
M)
PGI50
(
l
(
l
(
l
(
l
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
5.1 0.3
5.292
4.158
4.793
5.602
5.920
6.045
5.036
4.500
—
6.045
4.752
—
6.920
7.420
7.494
7.136
7.602
2.8 0.4
6.4 0.06
<0.01
5.552
5.193
—
6.4 0.9
5.193
6.244
5.769
—
6.193
6.853
5.906
—
6.397
—
5.744
—
5.903
5.866
6.207
7.070
7.040
1.01 0.06
<0.01
65 0.9
0.77 0.09
2.8 0.2
<0.01
2.2 0.05
6.3 0.9
2.6 0.05
1.2 0.07
5.3 0.6
0.47 0.05
0.32 0.04
0.28 0.02
0.22 0.001
0.023 0.002
0.075 0.003
5.995
—
4.187
6.113
5.552
—
5.657
5.200
5.585
5.920
5.275
6.327
6.494
6.55
À3.326
À4.405
À4.272
À3.506
À2.286
À3.490
À1.370
À2.488
À3.64
69.5 0.19
16.1 0.2
2.5 0.6
1.2 0.62
0.9 0.4
9.2 0.6
31.6 0.2
>100
0.9 0.02
17.7 0.8
>100
0.12 0.52
0.038 0.021
0.032 0.022
0.073 0.001
0.025 0.001
0.57 0.06
1.7 0.07
<0.01
0.64 0.04
0.14 0.08
1.24 0.08
<0.01
0.4 0.01
<0.01
1.8 0.03
>100
1.25 0.09
1.36 0.01
0.62 0.001
0.085 0.001
0.091 0.005
2.2 0.3
2.1 0.05
6.1 0.5
11.4 0.6
13.6 0.8
4.4 0.2
28.6 0.1
10 0.3
5.657
5.677
5.214
4.943
4.866
5.356
4.543
5
5.657
5.698
5.744
5.920
7.013
7.251
À3.054
À3.004
À3.360
À2.982
À3.501
À4.956
À10.925
À5.597
2.2 0.4
2
0.2
1.8 0.01
1.2 0.001
0.097 0.002
0.056 0.002
6.657
7.638
7.124
Doxo-rubicin
Paclitaxel
a
GI50: 50% growth inhibition, concentration of drug resulting in a 50% reduction in net protein increase compared with control cells.
cancer cell lines at five concentrations (0.01, 0.1, 1, 10, 100
l
M).
Molecules were built using Maestro build panel and prepared
by LigPrep OPLS_2005 force field. The DNA was prepared using
protein preparation module applying the default parameters. Grid
was generated around the active site of the DNA by selecting the
co-crystallized ligand. Receptor Van der Waals scaling for the non-
polar atoms was kept 0.9.37 GLIDE 5.638 was used for molecular
docking. Low energy conformation of the ligands was selected
and docked into the grid using extra precision (XP) docking
mode39–41. The docking calculation of all the compounds are
depicted in Table 1.
Conformation occupying the position between the base pairs
indicates a sign of good intercalation. Hydrogen bonding is an
important factor to understand the binding with hetero atoms,
docking interactions of the doxorubicin with DNA showed three
H-bond interactions. One with DG13 nucleotide and remaining
two H-bonds with DC12 (H), DC12(O), dockscore for doxorubicin
was found to be À10.92 (kcal/mol). The compound 9o and 9c
showed one H-bond interaction with DC4 and DC12, with a dock-
score of À4.95 and À4.27 (kcal/mol) respectively. A regression
analysis between dock score (binding affinity) and pGI50 values
of the synthesised molecules were carried out. It gave a correlation
coefficient r of 0.73 representing significant correlation between
DNA binding (dock score) and anti-proliferative activity. Figure 3
shows the scatter plot of dock score versus pGI50. DNA intercala-
tion with H-bond interactions is illustrated in Figure 2A for dox-
orubicin, Figure 2B for 9o and Figure 2C for 9c compounds
respectively.
GI50 (growth inhibitory activity) was calculated and these values
corresponded to the concentration of the compound causing 50%
decrease in the net cell growth as compared to that of the standard
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 greater or
less than the maximum or minimum concentration tested.
Based on Table 1, the synthesized series of quinazolinones
bearing allylphenyl quinoxaline hybrids 9a–n showed significant
to moderate cancer cell growth inhibition with GI50 values
(0.08–0.2 lM). The effect of various substituents on phenyl ring
was examined. The structure–activity relationship (SAR) study
revealed that the functional group change on phenyl ring is crucial
for inducing anti-proliferative activity against particular cancer cell
lines. Specifically, series of the compounds 9g, 9h, 9f, 9k, 9c, 9b and
9a exhibited promising anti-proliferative activity with GI50 values
less than 0.01 lM, in particular against MIAPACA, MDA-MB-
231and IMR32 human cancer cell lines. Introduction of substituent
(p-Me, p-OCH3, 2,4-di-OCH3, p-Cl, p-NO2 and p-CF3) on phenyl ring
was associated with a significant increase in the growth inhibitory
effect against MIAPACA, MDA-MB-231and IMR32 human cancer
cell lines. In comparison, electron donating groups present on
phenyl ring shows effect on HeLa, MDA-MB-231and IMR32 human
cancer cell lines. Finally, we observed that the series of the com-
pounds 9a–n exhibited good growth inhibitory activity and electron
donating groups present on phenyl ring in 9e, 9d, 9m derivatives
played an important role in the anti-proliferative activity.
Studies of molecular docking: To gain more insight into the inter-
actions of novel quinazolinone derivatives 9a–o, molecular dock-
ing studies were performed. NMR structure of double stranded
DNA molecule (AGACGTCT)2 complex in solution (PDB id: 1N37)
was downloaded from protein data bank (www.rcsb.org). Interac-
tions of the docked DNA with ligands were analyzed to identify
their hypothetical binding mode.
Taken together, we have synthesized a series of novel quinazoli-
none derivatives 9a–o by using Heck cross-coupling reaction of
allylquinazolinones with bromo quinaxolines and evaluated their
in vitro cytotoxicity against HeLa, MDA-MB-23, MIAPACA and
IMR32 cell lines. Among the tested cancer cell lines, compounds
9a, 9e, 9g and 9h exhibited potent activity against four tested
human cancer cell lines, while compounds 9e and 9k were more
potent against HeLa and MIAPACA cell lines and compounds 9b,

J. D. Palem et al. / Bioorg. Med. Chem. Lett. 26 (2016) 3014–3018
3017
9d, 9h and 9j were selectively potent against IMR32 and MDA-MB-
231 cell lines. Carrying out the substitution on quinazolinone was
associated with a distinct tendency to increase the in vitro cyto-
toxic potential. The molecule 9o can act as good intercalating
agent. The synthesized molecules can be considered as lead mole-
cules, and further optimization will result in a good intercalating
agent. This study provides valuable information for further drug
design and in developing more promising anticancer agents.
Acknowledgements
The authors gratefully acknowledge the financial support
through the project: DST-SERB/EMEQ-078/2013 and the University
Grant Commission (UGC), New Delhi for the award of fellowship to
JS.
A
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.05.
021.
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Scaꢀer plot of Gscore vs pGI50
-12
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pGI50
Figure 3. Scatter plot of dock score versus pGI50.
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