The synthesis of 4,7-disubstituted-2H-benzo[b][1,4]-oxazin-3(4H)-ones using Smiles rearrangement and their in vitro evaluation as platelet aggregation inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.02.014

A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure-activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC₅₀ = 9.20 μM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC₅₀ = 7.07 μM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.

Full text of DOI:10.1016/j.bmcl.2014.02.014

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1479–1483
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis of 4,7-disubstituted-2H-benzo[b][1,4]-oxazin-3(4H)-
ones using Smiles rearrangement and their in vitro evaluation
as platelet aggregation inhibitors
Shuai Xia a, Ji-Qiang Liu a, Xiu-Hua Wang a, Ye Tian b, Yu Wang a, Jing-Huan Wang a, Liang Fang c,
,
⇑
Hua Zuo a,
⇑
a College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
b Department of Medicinal Chemistry and Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
c Department of Oncology, The Ninth People’s Hospital of Chongqing, Chongqing 400700, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation
inhibitors for structure–activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rear-
rangement for the preparation of benzoxazine, was proven to be more efficient than the conventional
methods. Biological evaluation demonstrated that among all the synthesized compounds, compound
Received 21 November 2013
Revised 31 January 2014
Accepted 4 February 2014
Available online 14 February 2014
9u (IC50 = 9.20
trol (IC50 = 7.07
antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.
Ó 2014 Elsevier Ltd. All rights reserved.
lM) exhibited the most potent inhibition activity compared with aspirin, the positive con-
lM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa
Keywords:
4,7-Disubstituted-2H-benzo[b][1,4]oxazin-
3(4H)-one
Structure–activity relationships (SAR)
Smiles rearrangement
Platelet aggregation
Molecular docking
Ischemic heart disease and cerebrovascular disease are the two
leading death causes for adults aged 15–59 years throughout the
world nowadays, which get to even bring about one fifth deaths
to them.1 Thrombosis, as a consequence of the losing balance be-
tween coagulation function and anticoagulant function in blood,
turns out to be the potential fact that leads to the diseases such
as ischemic stroke,2 myocardial infarction,3 angina pectoris,4 and
so on.
As a vital process in primary stage for the formation of
haemostasis, platelet aggregation, activated by thrombin which
principally transforms the soluble fibrinogen to the insoluble fibrin,
may have close relationship with thrombosis.5 Thus, in 1960s,
Coller B.S. firstly reviewed that platelet aggregation inhibitors ap-
peared to be a logical approach for antithrombtic therapy.6 Accord-
ing to the mode of action the inhibitors of platelet aggregation can
be classified as: (1) substances affecting metabolism of arachidonic
acid; (2) agents affecting ADP depending pathway of platelet aggre-
gation; (3) the platelet activation factor (PAF) receptor antagonists.7
However, such mostly clinically utilized antiaggregatory agents
suffer from the flaws of the insufficiency of the efficacy and selectiv-
ity in affecting platelet aggregation. Besides, these agents only inhi-
bit one possible way of the platelets activation, while the platelet
aggregation could be generated through other approaches.8
The final obligatory step of the platelet aggregation is that the
fibrinogen binds to the activated platelet fibrinogen receptors (gly-
coprotein IIb/IIIa; GPIIb/IIIa) regardless of which agonist is in-
volved in initiation of platelet aggregation (ADP, epinephrine,
collagen, PAF and others).9,10 It is suggested that blockade of
GPIIb/IIIa receptors might be a desirable therapeutic strategy be-
cause GPIIb/IIIa is platelet specific and the monoclonal antibodies
to GPIIb/IIIa are more potent than aspirin. Furthermore, inhibition
of GPIIb/IIIa still leaves platelet adhesion largely intact and platelet
adhesion may contribute to hemostasis without leading to ische-
mic damage.6 Consequently, a number of nonpeptide mimics have
been investigated and found to be potent inhibitors of platelet
aggregation.11 In this way, besides the conventional platelet aggre-
gation inhibitors such as aspirin and ticlopidine, novel molecules
including eptifibatide, tirofiban and lamifiban have been intro-
duced into clinical application as therapeutically useful antiaggre-
gatory agents (Fig. 1).12
⇑
Corresponding authors. Tel./fax: +86 23 6825 1225.
E-mail addresses: fangliangfranc@gmail.com (L. Fang), zuohua@swu.edu.cn (H. Zuo).
http://dx.doi.org/10.1016/j.bmcl.2014.02.014
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

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S. Xia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1479–1483
NH
OH
NH
H2N
N
H
O
O
O
H2N
O
H
N
H
N
HN
N
H
N
O
HN
O
O
O
CO2H
N
S
S
H2N
O
N
H
N
H
O
HO
O
Lamifiban
Eptifibatide
Figure 1. Chemical structures of some clinical platelet aggregation inhibitors.
could perform desire glycoprotein IIb/IIIa receptor antagonistic
activity. Furthermore, Anderluh and co-workers even reported a
novel class of 1,4-benzoxazin-3(4H)-one derivatives possessing
both thrombin inhibitory and fibrinogen receptor antagonistic
activity in the same molecule.32
H
N
R
HO2C
CO2H
N
O
S
NH
4
O
S
Cl
R = H Ticlopidine
OCOCH3
BuO
O
According to our previous work, 2H-benzo[b][1,4]oxazin-3(4H)-
one analogues proved to be potent inhibitors of platelet aggrega-
tion.33 Smiles rearrangement, an intramolecular nucleophilic
aromatic substitution reaction discovered in 1931 by Samuel
Smiles through the conversion of iso-b-naphthol sulfide into 2-
napthol-1-sulfide,34 was the prominent reaction for the synthesis
of them. Compared with the conventional methods featuring harsh
conditions and expensive catalysts35 for example, palladium cata-
lyzed coupling cyclocondensation reaction,36 p-ClPIFA or PIFA cat-
alyzed intramolecular electrophilic substitution reaction to form
the benzoxazin skeleton,37 Smiles rearrangement method is char-
acterized with high selectivity, mild reaction conditions and good
to excellent yield.38
Herein, we designed and synthesized a set of new benzoxazine
scaffold, aiming at enhancing the activity as platelet aggregation
inhibitors compared to the molecules prepared before33 in ADP-
induced platelet rich plasma or exploring the specific
structure-activity relationships. Also, we performed the docking
computation to discover the plausible mechanism of platelet aggre-
gation inhibition of these synthesized compounds.
Aspirin
R = CO2Me Clopidogrel
Tirofiban
In spite of the clinically useful antiaggregatory agents, explora-
tion for effective and safe platelet aggregation inhibitors as GPIIb/
IIIa receptor antagonists are, still remains challenging not only in
terms of identifying the clinical indications for which these agents
will be efficacious with acceptable safety margins, but also in
terms of moving this novel approach from short-term-use para-
digms to potential long-term indications without damaging activ-
ity.13 Additionally, from accumulated data in the various clinical
trials with this class of drugs, low doses of antagonists may acti-
vate the receptor, resulting in increased aggregation.14 Therefore,
it is of tremendous interest to seek for new ideal GPIIb/IIIa antag-
onist in antithrombotic research these years.15–17
Benzoxazines, with nitrogen atom and oxygen atom contained
in the heterocyclic ring, manifest diverse pharmaceutical functions,
for example, antimicrobial,18–20 anti-tumor,21 antifungal activ-
ity,22,23 renin inhibition24 and puromycin-sensitive aminopepti-
dase inhibition activity,25 and as antagonist of nonsteroidal
progesterone receptor.26 Besides, benzoxazine analogues were also
found to show desirable activity as platelet aggregation inhibitors.
In 2000, Dudley et al. discovered an approach to 2-phenyl-2H-1,4-
benzoxazin-3(4H)-one derivatives and identified them as consider-
able inhibitors of a factor Xa.27 Jakobsen et al. reported that 2-aryl
substituted-4H-3,1-benzoxazin-4-ones could be the inhibitors of
the tissue factor/factor VIIa-induced coagulation.28,29 As for the
GPIIb/IIIa receptor antagonist, Anderluh et al.30 and Ilaš et al.31
demonstrated that substituted-2H-1,4-benzoxazine derivatives
Encouraged by our previous work,33 with 3-bromo-4-hydroxy-
benzaldehyde (3) as starting material, through the introduction
of pharmacologically active heterocyclic moiety morpholyl or
piperizyl ring to the benzoxazine core, the protocol for the
synthesis of 4,7-disubstituted-2H-benzo[b][1,4]oxazin-3(4H)-one
9a–u was quite straightforward and efficient involving the
reduction of aldehydes, halogenation of alcohols, N-acylation,
Williamson ether synthesis, followed by Smiles rearrangement
of the intermediate 8 (Scheme 1). Herein, the reduction of
3-bromo-4-hydroxybenzaldehyde (3) by NaBH4 in ethanol gave
X
NH
OH
Br
OH
OH
Br
OH
Br
b
, c
X
a
6
Br
HO
N
Br
OHC
7
4
5
3
O
d
R1
Cl
R1NH2
e
N
H
1
2
R1
N
O
O
R1
O
X
N
H
X
f
N
N
Br
O
8
9
R
1 = ethyl, i-propyl, propyl, n-butyl, benzyl
X = O, NPh, N-oFPh, N-pFPh and N-CH2Ph
Scheme 1. Synthesis of 4,7-disubstituted-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives (9a–u). Reagents and conditions: (a) NaBH4, EtOH, rt; (b) phosphorus tribromide,
CH2Cl2, rt; (c) K2CO3, CH3CN, rt; (d) chloroacetyl chloride, K2CO3, 0–5 °C; (e) K2CO3, CH3CN, reflux; (f) Cs2CO3, DMF, 120 °C.

S. Xia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1479–1483
1481
2-bromo-4-(hydroxymethyl)phenol (4) in a yield higher than 90%,
which was then brominated to afford 2-bromo-4-(bromo-
methyl)phenol (5). The morpholyl or piperizyl ring was then
conveniently introduced to the 7-position methylene of the inter-
mediate 5 by the reaction of it with the heterocyclic compound
6, which gave the compound 7 as a crucial substrate for the con-
struction of the target molecules. The O-alkylated product 8 was
cyclized to 2H-benzo[b][1,4]oxazin-3(4H)-one 9 using Smiles rear-
rangement, as the desired compound for antiaggregatory assay.
During the exploration of the target molecules, we found that
the aldehyde group in 3-bromo-4-hydroxybenzaldehyde (3) was
extremely unstable in the presence of the base under Smiles rear-
rangement condition, so we firstly converted the aldehyde moiety
into hydroxyl and then obtained the benzoxazin skeleton in the
last step of the reactions. Whereas, in an alternative method
involving firstly the formation of benzoxazine ring followed by
the introduction of heterocyclic ring to the aldehyde moiety, the
by-products formed in the process greatly decreased the yields of
the reactions. The Smiles rearrangement reaction was performed
under Cs2CO3/DMF condition, for its moderate basicity, good solu-
bility and the high yield it brought, compared with other bases like
NaH, K2CO3, NaOH and EtONa in various solvents. Further experi-
ments revealed that 120 °C was the best reaction temperature
inducing the rearrangement. For the amines containing sterically
hindered R1 group in general, the conversion to the target mole-
cules led to lower yields in the rearrangement reaction (the
Table 1
In vitro anti-platelet aggregation of the benzoxazinone derivatives in platelet rich plasma
a
a
Compd
Structure
IC50
(lM)
Compd
Structure
IC50
(
lM)
F
N
O
O
N
O
O
O
N
9a
10.45 0.17
11.02 0.09
9k
11.11 0.13
13.35 0.18
N
N
N
N
F
F
N
O
O
N
O
O
N
9b
9l
O
N
O
O
O
N
O
O
N
9c
9.63 0.19
9m
9n
11.43 0.13
15.24 0.09
N
N
N
N
O
N
O
N
O
O
N
9d
14.40 0.11
O
F
9e
12.15 0.15
9o
19.45 0.21
N
O
N
O
O
O
N
N
N
O
F
N
O
O
O
O
N
O
O
O
O
O
N
N
N
N
9f
10.11 0.09
10.82 0.17
12.82 0.20
15.46 0.14
9p
9q
9r
9s
12.66 0.11
13.58 0.13
13.79 0.17
17.12 0.10
N
N
N
N
N
N
N
N
N
O
F
N
O
N
O
9g
9h
9i
N
F
N
O
N
O
N
F
N
O
N
O
N
F
9j
13.87 0.11
9t
15.34 0.16
9.20 0.11
N
O
N
O
O
O
N
N
N
N
N
O
N
9u
N
O
Aspirin
Ticlopidine
7.07 0.14
3.72 0.08
a
Inhibitory activity was assayed by testing the changes in optical density of ADP-induced platelet rich plasma. Data were presented as mean values SDs of the three
independent experiments.

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S. Xia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1479–1483
compounds 9a, 9f, 9k and 9p with smaller R1 had higher yields 75%
than their analogues, 55–65%). All the synthesized 21 molecules
(9a–u) were confirmed by spectra data (1H NMR, 13C NMR, and
HRMS) and possessed perfect stability.
Then the synthesized compounds 9a–u were evaluated for their
inhibitory activity in ADP-induced rich platelet plasma of New Zea-
land rabbit39 and the anti-platelet aggregation drugs aspirin and
ticlopidine were used as positive controls (Table 1).
benzoxazine ring displayed higher activity compared with the
compounds containing the groups with stereospecific blockade.
Furthermore, docking calculation revealed that the compound 9u
could be docked in the binding site of GPIIb/IIIa receptor quite well
and a hydrogen bond formed between the carbonyl oxygen of the
benzoxazine moiety and the amino acid residue SER123 of the
receptor. Aiming at improve their levels of anti-aggregation activ-
ity, further structural optimization of 2H-benzo[b][1,4] oxazin-
3(4H)-one derivatives is well under way, along with more detailed
biological testing of the most active compound.
As shown in Table 1, all the synthesized compounds 9a–u dis-
played platelet aggregation inhibition activity, with the IC50 values
ranging from 9.20 to 19.45
Especially, the IC50 values of compounds 9c and 9u were lower
than 10 M, very close to that of aspirin. Among all the synthesized
lM, as well as the positive controls.
Acknowledgments
l
compounds, the compounds with sterically less hindered group in
R1 (ethyl, isopropyl and propyl) displayed higher activity compared
with the compounds containing the groups with stereospecific
blockade (benzyl). Generally, the compounds with a morpholyl
ring at 7-position of the 2H-benzo[b][1,4]-oxazin-3(4H)-one, 9a–
e, gave a higher pharmacological potency than those with than
those with phenylpiperizyl, 4-fluorophenylpiperizyl and 2-
fluorophenyl piperizyl substituents. Furthermore, the polarity of
the target molecules had a remarkable effect on their activity as
platelet aggregation inhibitors. Compound 9u, the most polar
molecule, had the lowest IC50 value among all the synthesized
compounds. To our disappointment, when the drug-active
fluorine-substituted phenylpiperizyl rings were introduced to the
benzoxazin scaffolds (9k–t), these derivatives performed relatively
less potent against the ADP-induced platelet rich plasma.
We would like to thank the National Natural Science Founda-
tion of China (21002081), the Fundamental Research Funds for
the Central Universities, PR China (XDJK2012B012), and The Pro-
ject Sponsored by the Scientific Research Foundation for the Re-
turned Overseas Chinese Scholars for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02
.014.
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