Potential anti-proliferative agents from 1,4-benzoxazinone-quinazolin-4(3H)-one templates

Article abstract of DOI:10.1016/j.bmcl.2017.10.044

A novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a–n by employing Pd-catalyzed C[sbnd]H arylation in presence of 5–10% phosphine ligand in good to excellent yields and evaluated for their anti-proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with GI₅₀ values ranging from 0.37 to 2.73 μM respectively against A549, HeLa, and MDA-MB-231, while compound 7f showed significant activity against MDA-MB-231 with GI₅₀ value 0.58 μM, 7j showed significant activity against A549 with GI₅₀ value 0.32 μM and 7l showed significant activity against HeLa with GI₅₀ value 0.37 μM. This is the first report on the synthesis and in vitro anti-proliferative evaluation of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids.

Full text of DOI:10.1016/j.bmcl.2017.10.044

Accepted Manuscript
Potential anti-proliferative agents from 1,4-Benzoxazinone-quinazolin-4(3H)-
one templates
Rajitha Bollu, Saleha Banu, Suresh Kasaboina, Rajashaker Bantu, Lingaiah
Nagarapu, Sowjanya Polepalli, Nishant Jain
PII:
S0960-894X(17)31038-7
https://doi.org/10.1016/j.bmcl.2017.10.044
BMCL 25373
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
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9 October 2017
19 October 2017
Please cite this article as: Bollu, R., Banu, S., Kasaboina, S., Bantu, R., Nagarapu, L., Polepalli, S., Jain, N., Potential
anti-proliferative agents from 1,4-Benzoxazinone-quinazolin-4(3H)-one templates, Bioorganic & Medicinal
Chemistry Letters (2017), doi: https://doi.org/10.1016/j.bmcl.2017.10.044
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Bioorganic & Medicinal Chemistry Letters
jour nal homepage: www.elsevier. com
Potential anti-proliferative agents from 1,4-Benzoxazinone-quinazolin-4(3H)-one
templates
Rajitha Bollua, Saleha Banua, Suresh Kasaboinaa, Rajashaker Bantua, Lingaiah Nagarapua*, Sowjanya
Polepallib, Nishant Jainb
aOrganic Chemistry Division-II (CPC), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad- 500007, India.
b Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India.
Fax: + 91 40 27193382; Tel: +91 40 27191509; E-mail: lnagarapuiict@yahoo.com/nagarapu@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
A
novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-
acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n by employing Pd-catalyzed C-H arylation in
presence of 5-10% phosphine ligand in good to excellent yields and evaluated for their anti-
proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-
MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with
GI50 values ranging from 0.37 to 2.73 µM respectively against A549, HeLa, and MDA-MB-231,
while compound 7f showed significant activity against MDA-MB-231 with GI50 value 0.58 µM, 7j
showed significant activity against A549 with GI50 value 0.32 µM and 7l showed significant
activity against HeLa with GI50 value 0.37 µM. This is the first report on the synthesis and in vitro
anti-proliferative evaluation of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids.
.
Accepted
Available online
Keywords:
C-C Coupling,
1,4-benzoxazinone,
Quinazolinone
anti-proliferative,
apoptosis,
2009 Elsevier Ltd. All rights reserved.
cell lines.
Research and development of potent and effective
isolated from the roots of Capparis sikkimensis displayed
significant in vitro antitumor activity in various human cell
lines5 and both the derivatives of compound (III) are potential
non-nucleoside SGLT2 inhibitors for the treatment of type 2
diabetes.6 Compound SLV-314 (IV) was evaluated on binding
to dopamine D2 receptors and serotonin reuptake sites. These
classes of compounds proved to be potent in vitro dopamine
D2 receptor antagonist and in addition were highly active as
serotonin reuptake inhibitors7 and a series of benzoxazine-
rhodanine (V) have been developed as potent inhibitors of
PI3Kᵧ in enzymatic and cell based assays.8 The compound
(VI) displayed significant anticonvulsant activity.9 Moreover,
benzoxazinone derivatives are also known to exhibit other
anticancer agents represents one of the most important
advances in therapeutics, not only in the control of serious
infections, but also in the prevention and treatment of some
infectious complications of therapeutic modalities such as
cancer chemotherapy, surgery and hospital acquired
infections. The majority of pharmaceuticals and biologically
active agrochemicals are heterocyclic while countless
additives and modifiers used in industrial applications ranging
from cosmetics, reprography, information storage and plastics
are heterocyclic in nature.1 Nitrogen containing heterocyclic
compounds have maintained the interest of researchers
through decades of historical development of organic
synthesis. Among the nitrogen heterocycles, 1,4-
benzoxazinone is the important scaffold present in various
agrochemicals and primarily used by plants as natural defense
chemicals.2-3
activities such
as anti-inflammatory,10 antiulcer,11
antipyretic,12 antifungal,13 potassium channel modulators,14
antirheumatic agents,15 and plant resistance factors against
microbial diseases and insects.16
In particular, the utility of the 1,4-benzoxazin-3-(4H)-
one scaffold as a privileged structure for the generation of
drug-like libraries in drug-discovery programs has been
amply demonstrated. Benzoxazinone based compounds form
an important class of benzofused heterocycles with a wide
spectrum of biological activities.4 Many compounds are in the
development phase as potential new drugs acting against
different targets. In particular, as shown in Fig.1 compound
(I) exhibited anti-proliferative activity against a wide range of
human tumor cell lines with GI50 mean values at low
micromolar level. Compound (II) Cappamensin A, was
Heck cross coupling reaction has become powerful
method for the clean construction of innumerable class of
chemical architectures. It has emerged as a powerful tool for
the construction of carbon-carbon double bonds. It is
extensively used in the area of small molecule, natural
product and polymer synthesis. 17-23 In this regard, a direct C-
H functionalization of the allylquinazolinones would be a
more desirable alternative. Direct C-H arylation protocol has
been developed as an attractive, atom-economical alternative
to avoid unwanted side products.

Here, we envisioned the use of coupling reactions
through C-H activation by utilizing a Pd catalyst and
successfully synthesized the benzoxazinone bearing
quinazolinone class antiproliferative agents. In this paper, we
reveal the palladium catalyzed intermolecular C-H arylation
as a key step from 4-(2-(4-bromophenyl)-2-oxoethyl)-2H-
benzo[b][1,4]oxazin-3(4H)-one
to
synthesize
1,4-
benzoxazine-acetylphenylallyl quinazolin-4(3H)-one hybrids
as a new class of anti proliferative agents.
As shown in Fig.1 Compound (VII), which is a
quinazolinone derived Schiff’s base, was designed and
synthesized as novel antioxidant and anti-inflammatory
agent.24 The cytotoxic alkaloid Luotonin A (VIII) and its
derivatives infused with quinazolinone moiety are clinically
proven anti-cancer agents25 and compound (IX) a novel
precursor for MJL1-109-2, a known nonpeptide CRHR-1
antagonist, was successfully synthesized employing Pd-
catalyzed C-H arylation (Fig.1).26
Figure 2: Design strategy and anti-proliferative evaluation of
new analogues 7a-n against A549, HeLa and MD-MB-231.
One of the key intermediate 4-(2-(4-bromophenyl)-
2-oxoethyl)-2H benzo[b][1,4] oxazin-3(4H)-one (2) was
accomplished by reaction of 2H-benzo[b][1,4]oxazin-3(4H)-
one with 2,4'-dibromo acetophenone. The synthetic step
involved in the presence of K2CO3 and catalytic amount of
TBAI, a secondary amine 1 was reacted with 2,4'-dibromo
acetophenone in DMF solution about 1 h to give the
corresponding tertiary amine 2 under room temperature, in
good yield (Scheme-1). 3-Allyl-2-phenylquinazolin-4(3H)-
one, another key fragment for the synthesis of these novel
quinazolinone analogues, was synthesized by the
condensation of anthranilamide (3) with various
benzaldehydes (a-n) in presence of phase transfer catalyst
TBAHS in methanol at 80 °C for 2 h to afford 2-phenyl-2,3-
dihydro quinazolinones 4a-n and subsequently in the second
step compounds 4a-n were refluxed with KMnO4 in acetone
at 56 °C for 1 h , to give compounds 5a-n. Then it was
followed by the reaction with allylbromide in presence of
K2CO3 at room temperature for 8 h to yield 3-allyl
quinazolinone derivatives 6a-n (Scheme 2).
Figure 1: Structures of 1,4-benzoxazinone, quinazolinone
and Pd-coupling based bioactive compounds.
Molecular hybridization, which covalently combines
two or more drug pharmacophores into a single molecule, is
an effective tool to design highly active novel entities. The
clubbed pharmacophores may act on multiple therapeutic
targets and offer the advantage of overcoming inevitable drug
resistance.27 A literature survey revealed that modification on
quinazolinone pharmacophore may result in increase of its
biological potencies. Considering the above facts, it is of our
interest to integrate both 1, 4-benzoxazinone and allyl
quinazolinone pharmacophore units in one molecular
platform to generate a newer scaffold for anti-proliferative
evaluation. Inspired by the applications of quinazolinone
derivatives in the field of medicinal chemistry, especially in
the treatment of cancer, we aimed to develop novel
benzoxazinone bearing quinazolinone derivatives as
antitumor agents by Heck- cross coupling. In continuation to
our ongoing research activities,28a-g to discover and develop
tumor growth inhibitors and apoptotic inducers as potential
new anti cancer-agents, we herein reported an efficient
method for the synthesis of novel 1,4-benzoxazine-
acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n in good
to excellent yields (Fig.2) and evaluated for their in vitro
anti-proliferative activity against three human cancer cell
lines such as A549 (lung), HeLa (cervical) and MDA-MB-
231 (breast) using a SRB cell proliferation assay to estimate
the viability or growth.
Scheme1: Synthesis of 4-(2-(4-bromophenyl)-2-oxoethyl)-
2H-benzo[b] [1,4]oxazin-3(4H)-one (2).
Scheme 2: Synthesis of 3-allyl quinazolin-4(3H)-ones 6a-n.
Synthesis
of
targeted
1,4-benzoxazinone-
acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n were
achieved by Pd catalyzed Heck-cross coupling reaction
[Pd(OAc)2, PPh3, K2CO3, DMF:H2O (2:1), at 120 oC for 16 h]
of
4-(2-(4-bromophenyl)-2-oxoethyl)-2H
benzo[b][1,4]oxazin-3(4H)-one (2) with substituted 3-
allylquinazolinones 6a-n (Scheme 3). With the compound 4-
(2-(4-bromophenyl)-2-oxoethyl)-2H
benzo[b][1,4]oxazin-
3(4H)-one (3) in hand, we carried out an intermolecular
coupling reactions with substituted allylquinazolinones
through C-H arylation.

Table 1: aGI50 values of the tested compounds against three
human cancer cell lines.
Compound
A549
HeLa
MDA-
MB-231
1.0 0.01
1.5 0.02
1.0 0.01
1.05 0.02
1.03 0.02
1.37 0.05
1.13 0.02
3.6 0.09
13.4 1.9
1.52 0.06
3.4 0.03
0.58 0.02
8.8 0.6
7a
7b
7c
0.81 0.01 1.02 0.01
0.9 0.03 1.4 0.05
0.93 0.02 1.32 0.02
1.0 0.04 0.66 0.04
0.91 0.01 0.88 0.04
7d
7e
7f
7g
6.14 0.3
6.03 0.42
6.76 0.15
2.0 0.07
2.4 0.05
13.0 1.7
2.73 0.02
<0.01
7h
1.36 0.1
0.59 0.05
1.51 0.01
7i
7j
0.32 0.01
0.76 0.03 1.1 0.09
0.67 0.03
7k
Scheme 3: Synthesis of 1,4-benzoxazinone-acetylphenylallyl
quinazolin-4(3H)-one hybrids 7a-n.
7l
7m
0.37 0.04
The synthesized 1,4-benzoxazinone-acetylphenylallyl
quinazolin-4(3H)-one hybrids 7a-n were confirmed on the
basis of their spectral data. In 1H NMR spectra, the
characteristic doublet signal appeared for trans proton 7a-n
in the range of δ 4.93-6.47 ppm with coupling constant 15.8-
17.8 Hz with disappearance of cis proton doublet. The
structures for all these compounds were further confirmed by
HRMS analysis. For instance, 7a displayed a molecular ion
0.61 0.01 0.55 0.04
0.91 0.01 0.62 0.01
7n
Nocodazoleb
<0.01
<0.01
Combretastatinb 0.056 0.0 0.084 0.00 0.046 0.0
01 01
2
aGI50: 50% Growth inhibition, concentration of drug (in µM)
resulting in a 50% reduction in net protein increase compared
with control cells.
+
peak at m/z 572.21800 [M+H] suggesting the molecular
formula of C35H29O5N3. Additionally, the IR spectra for the
target compounds 7a-n exhibited characteristic absorption
bands at 3000-3100 cm-1, 1662-1680 cm-1, 1500 cm-1and 1050
cm-1 which corresponded to =C-H, C=O, C=C, and C-N
respectively.
bPositive controls.
In conclusion, we have developed a novel and
efficient protocol for the synthesis of 1,4-benzoxazinone-
acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n
The in vitro anti-proliferative activity of the designed
compounds 7a-n were evaluated against a panel of three
different human cancer cell lines, A549 (lung), HeLa
(cervical) and MDA-MB-231 (breast) summarized in Table
1. The compounds were picked for an advanced assay against
these three human cancer cell lines at five different
concentrations (0.01, 0.1, 1, 10, 100 µM). 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 the
standard drugs, Nocodazole and Combretastatin. 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.
under palladium catalyst. This sequence tolerates a wide
range of substituted allyl quinazolinones, which proceed
very cleanly, and provide the title compounds in good to
excellent yields and the entire series of synthesized
derivatives were evaluated for anti-proliferative activity
against three different human cancer cell lines, namely
A549, HeLa and MDA-MB-231 (lung, cervical and
breast cancer respectively). In general, the majority of
target compounds displayed moderate to promising
activity against the tested cancer cell lines. Based on the
activity results, compound 7f showed significant activity
against MDA-MB-231 with GI50 value 0.58
showed significant activity against A549 with GI50 value
0.32 M and 7l showed significant activity against HeLa
with GI50 value 0.37 M. We succeeded in the
µM and 7j
µ
µ
Based on Table 1, the synthesized compounds 7a-n
showed significant to moderate cancer cell growth inhibition
with GI50 values ranging from 0.32 to 13.4 µM. In particular,
Compounds 7d, 7f, 7l and 7n exhibited promising anti-
proliferative activity with GI50 values ranging from 0.37 to
2.73 µM respectively against all cell lines, like A549, HeLa,
and MDA-MB-231. It was observed that, modification on
quinazolinone pharmacophore [NO2, CF3, 2,4-dimethoxy,
trimethoxy, 2-F, 4-OCH3, 3-OCH3, 2,4-DiCl] was associated
with a significant increase in the growth inhibitory effect
against A549, HeLa, and MDA-MB-231 human cancer cell
lines.
modification on quinazolinone moiety along with 1,4-
benzoxazinone and double bond linker which played a
crucial role in exhibiting promising anti-proliferative
activities. In light of the above, these studies might
provide insights to develop new drug leads in the pursuit
of more effective anti-proliferative agents.
Acknowledgements
The authors gratefully acknowledge the financial
support through the project: DST-SERB/EMEQ-078/2013
and the Council of Scientific and Industrial Research (CSIR),
New Delhi for the award of fellowship to RB.

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General procedure for synthesis of 1,4-benzoxazinone-
acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n by
Heck reaction:
To a suspension of compound allylquinazolinones (6a-
n, 1.1 mmol), 4-bromobenzoxazinone (2) (1 mmol), K2CO3
(1.2 mmol), PPh3 (0. 1 mmol) and Pd(OAc)2 (0.1 mmol) in
o
DMF:H2O (2:1, 200 mL) was refluxed for 16 h at 120 C.
Then the solvent was evaporated under vacuum. The residue
obtained was extracted with diethyl ether and water. The
combined organic phases was washed with water, dried over
sodium sulphate and evaporated under vacuum. The residue
obtained was purified over column chromatography over
silica gel and recrystallized from ethanol to afford the
following compounds.
2-(4-Ethoxyphenyl)-3-((E)-3-(4-(2-(2,3-dihydro-3-oxobenzo
[b] [1,4]oxazin-4-yl)acetyl) phenyl)allyl) quinazolin-4(3H)-
one (7a):
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o
Light brown solid (75% yield): m.p: 120 C; IR (KBr, ν ):
3451, 2927, 1680, 1601, 1500, 1469, 1398, 1282, 1233, 1109,
1050, 979, 753, 697, 478 cm-1; 1H NMR (500 MHz, CDCl3): δ
1.25 (t, J = 13.8 Hz, 3H, CH3), 4.00-4.09 (m, 2H, CH2), 4.45-
4.49 (m, 1H, N-CH2), 4.72 (s, 2H, N-CH2), 5.01-5.06 (m, 1H,
N-CH2), 5.3 (s, 2H, CH2-O), 6.08 (d, J = 16.0 Hz, 1H, trans-
H), 6.28-6.33 (m, 1H, allylic-H), 6.59 (d, J = 7.6 Hz, 1H, Ar-
H), 6.91-7.09 (m, 5H, Ar-H), 7.34-7.37 (m, 3H, Ar-H), 7.48-
7.56 (m, 2H, Ar-H), 7.76-7.81 (m, 2H, Ar-H), 7.93 (d, J = 8.3
Hz, 2H, Ar-H), 8.38 (d, J = 7.9 Hz, 1H, Ar-H) ; 13C NMR (75
MHz, CDCl3): δ 21.3, 47.7, 48.1, 67.3, 114.5, 117.0, 117.2,
122.7, 124.0, 126.7, 126.8, 127.3, 127.7, 129.1, 129.4, 131.8,
132.2, 133.1, 134.2, 140.0, 145.0, 156.3, 161.9, 165.0, 191.0;
MS (ESI): m/z 572 [M+H]+; HRMS: Calcd for C35H29O5N3:
572.21800, Found : 572.21695.
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2177.

Graphical Abstract
Leave this area blank for abstract info.
Potential anti-proliferative agents from
1,4-Benzoxazinone-quinazolin-4(3H)-one templates
Rajitha Bollua, Saleha Banua, Suresh Kasaboinaa, Rajashaker Bantua, Lingaiah Nagarapua*, Sowjanya
Polepallib, Nishant Jainb
A newly synthesized 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a-n showed moderate to
excellent anti-proliferative activity against A549, HeLa, MDA-MB-231human cancer cell lines.
Design strategy and anti-proliferative evaluation of new analogues 7a-n against A549, HeLa and MD-MB-231.

Research Highlights
1,
•
Novel
4-benzoxazinone-
acetylphenylallyl quinazolins have been
synthesized
efficiently.
• Evaluated for their anti-proliferative
activity against four human cel lines.
• Compounds 7a-n showed GI50 values
ranging from 0.32 to 13.4 µM.
• 7f, 7j, 7l showed good anti-proliferative
activity with GI50 values 0.58, 0.32, 0.37
µM.