New halogenated chalcones with cytotoxic and carbonic anhydrase inhibitory properties: 6-(3-Halogenated phenyl-2-propen-1-oyl)-2(3H)-benzoxazolones

Article abstract of DOI:10.1002/ardp.201900384

In this study, novel halogenated chalcones, 6-(3-halogenated phenyl-2-propen-1-one)-2(3H)-benzoxazolones (2a–n), were synthesized for the first time (except 2a), and their chemical structures were characterized by ¹H nuclear magnetic resonance

Full text of DOI:10.1002/ardp.201900384

Received: 2 January 2020
Revised: 11 March 2020
Accepted: 27 March 2020
|
|
DOI: 10.1002/ardp.201900384
F U L L P A P E R
New halogenated chalcones with cytotoxic and carbonic
anhydrase inhibitory properties: 6‐(3‐Halogenated phenyl‐2‐
propen‐1‐oyl)‐2(3H)‐benzoxazolones
1
1
1
2
3
Sinan Bilginer
| Halise I. Gul | Feyza S. Erdal | Hiroshi Sakagami | Ilhami Gulcin
1
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Ataturk University,
Erzurum, Turkey
Abstract
In this study, novel halogenated chalcones, 6‐(3‐halogenated phenyl‐2‐propen‐1‐one)‐
2(3H)‐benzoxazolones (2a–n), were synthesized for the first time (except 2a), and their
2
Meikai University School of Dentistry, Meikai
University Research Institute of Odontology
(
M‐RIO), Sakado, Saitama, Japan
1
13
chemical structures were characterized by H nuclear magnetic resonance (NMR),
C
3
Department of Chemistry, Faculty of Science,
NMR, and high‐resolution mass spectrometry spectra. Cytotoxic activities and carbonic
anhydrase (CA) inhibitory effects of the compounds were studied to identify new
possible drug candidate molecules. Cytotoxicity results pointed out that compound 2m,
Ataturk University, Erzurum, Turkey
Correspondence
Sinan Bilginer, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Ataturk
University, TR‐25240 Erzurum, Turkey.
Email: sinanbilginer25@yahoo.com
6
‐[3‐(3‐bromophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone, had the highest cytotoxicity
CC50) and potency selectivity expression (PSE) values. Thus, compound 2m can be
considered as a lead compound of the series in terms of cytotoxicity. When the CA
inhibition results of the compounds were evaluated, it was found that the K values of
the compounds ranged from 30.5 ± 11.3 to 65.5 ± 25.6 µM toward hCA I, and they
ranged from 7.3 ± 1.8 to 58.8 ± 12.3 µM toward hCA II. However, the K values of the
(
Funding information
i
Atatürk Üniversitesi, Grant/Award Number:
Project number: 2016/118
i
reference drug, acetazolamide (AZA), were 30.2 ± 7.8 and 4.4 ± 0.6 μM toward hCA I
and hCA II, respectively. According to the results obtained, compounds 2a–n had lower
i i
K values than AZA, whereas compounds 2a, 2b, 2e–g, 2l, and 2n had similar K values,
compared with AZA. So, the compounds 2a, 2b, 2e–g, 2l, and 2n can be considered as
lead molecules of this series for further considerations.
K E Y W O R D S
benzoxazolone, carbonic anhydrase, cytotoxicity, halogenated chalcone
1
| INTRODUCTION
Carbonic anhydrases (CAs) are metalloenzymes acting as
catalysts for the interconversion between carbon dioxide and bi-
carbonate. CAs play several important roles in many physiological
According to the World Health Organization report, it is predicted
[
1]
[4]
that 16.5 million people will die due to cancer by 2040. Thus,
studies on the treatment of cancer continue intensively worldwide.
Although costly research and new treatment options are increasing
in this area, the treatment rates of cancer patients can only be
and physiopathological functions in all organisms. Until now, eight
genetically different CA families (α‐, β‐, γ‐, δ‐, ζ‐, η‐, θ‐, and the
[
4–6]
recently reported ι‐CAs) have been identified.
In mammals, 16
different α‐CA isoforms were isolated with their different catalytic
activities. Of them, some are cytosolic (CA I, CA II, CA III, CA VII, and
CA XIII), some are membrane‐bound isoforms (CA IV, CA IX, CA XII,
CA XIV, and CA XV), CA V is mitochondrial, and CA VI is secreted in
[
2]
achieved by 20–25%.
Anticancer drugs in clinics have low
selectivity, drug resistance problem, and side effects such as
[3]
vomiting, hair loss, and pain. Thus, the researchers are focusing on
the development of new anticancer drug candidates that have high
selectivity and low toxicity.
[
7]
saliva and milk. Three of these isoforms are known as CA‐related
proteins (CARPs); they are noncatalytic (CARP VIII, CARP IX, and
|
Arch Pharm. 2020;e1900384
wileyonlinelibrary.com/journal/ardp
© 2020 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.201900384

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BILGINER ET AL.
|
[
4,6,7]
CARP XI) and do not have zinc in the active site of the enzyme.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
These isozymes are widely distributed in different organs and tissues,
and they have an important role in many physiological processes like
pH and CO
electrolyte secretion.
isozymes is a potential target for treatment and/or diagnosis of many
2
homeostasis, biosynthetic reactions, calcification, and
[
8–10]
Thus, inhibition or activation of these
Compounds 2a–n, 6‐(3‐halogenated phenyl‐2‐propen‐1‐one)‐2(3H)‐
benzoxazolones, were synthesized successfully for the first time
(except compound 2a) according to Scheme 1.
[
7]
diseases. As a result, CA inhibitors/activators have many clinical
uses as antiglaucoma drugs (hCA I, II, IV, XII), diuretics (hCA II, IV, XII,
XIV), antiepileptic drugs (hCA II, IV, XIV, XIV), and antiobesity
As shown in Scheme 1, 2(3H)‐benzoxazolone was acylated by
Friedel–Crafts reaction. A direct acylation of the 2(3H)‐benzoxazolone
[
11–15]
[62]
drugs.
ring is regioselective and always leads to a 6‐acetyl derivative
The α,β‐unsaturated ketones have alkylation ability, especially to-
in good yield and purity. Chalcones 2a, 2b, 2d–g, and 2j–l were syn-
thesized by classical Claisen–Schmidt condensation reaction, whereas
chalcones 2c, 2h, 2m, and 2n were synthesized by a microwave
irradiation method. Claisen–Schmidt condensation reaction occurred
between suitable aldehyde and 6‐acetyl‐2(3H)‐benzoxazolone.
[16,17]
ward thiols.
amino and hydroxyl groups of available nucleic acids,
classical alkylating agents alkylate hydroxyl and amino groups of
They have no reactivity or far less reactivities for
[16,18,19]
whereas
[20]
nucleic acids, and lead to mutagenicity and carcinogenicity.
The level
[21]
1
of glutathione (a thiol compound) increases before the cell division.
According to H nuclear magnetic resonance (NMR) spectra
This can be an advantage for α,β‐unsaturated ketone function bearing
compounds such as chalcones, as they are thiol‐selective alkylators to
of compounds 2a–n, all synthesized compounds (except 2l) were
geometrically pure and had E configuration (coupling constant
J = 15.4–16.1 Hz for vinyl protons, observed at 7.67–8.07 ppm). The
aromatic ring protons and olefinic protons appeared at 7.0–8.0 ppm,
[22–24]
perform selective toxicity against tumor tissues.
Chalcones are major components of natural products, such as fruits,
[25,26]
13
vegetables, tea, and so forth.
Chemically, chalcones are open‐chain
as expected. C NMR spectra of the compounds showed that
flavonoids with two aromatic rings that are linked by a three‐carbon
carbons of carbonyl groups of the compounds appeared at about
187 ppm, as expected. High‐resolution mass spectrometry (HRMS)
results also confirmed the chemical structures of the compounds
with high purity. Spectral data are presented in detail below.
[27]
α,β‐unsaturated carbonyl system.
system is responsible for the biological activities of the chalcones.
Various chalcone derivatives have been reported with many biological
The α,β‐unsaturated carbonyl
[26,28]
[
29,30]
[31]
[32]
activities such as anti‐inflammatory,
antimicrobial, antifungal,
[33]
[34]
[35,36]
[37–39]
antioxidant,
antimalarial,
antileishmanial,
anticancer,
[
40–42]
[43–45]
[46]
cytotoxic,
The drugs and drug candidate compounds developed by medicinal
chemistry studies include significant number of halogenated
Some halogen‐substituted chalcones were reported
CA inhibiting,
and anti‐invasive
activities.
2.2 | Biology
a
2.2.1 | Cytotoxic/anticancer activity
[47,48]
structures.
with strong cytotoxic activities
[28,49–51]
in a limited number of studies.
The cytotoxicities of 13 synthesized compounds have been investigated
in vitro against oral squamous cancer cell line (HSC‐2) and human
normal oral cells (human gingival fibroblast [HGF] and
The benzoxazolone heterocycle is described as a “privileged
scaffold” in the literature due to its chemical reactivity, electronic
[52]
[41,63]
charge distribution, and wide range of bioactivities.
2(3H)‐
human periodontal ligament fibroblast [HPLF]) as reported.
Benzoxazolone and its derivatives exhibit many activities such as
Doxorubicin (DXR) and 5‐fluorouracil (5‐FU), which are clinically in use
for the treatment of several cancers, were used as reference drugs.
Cytotoxicity results of compounds 2a–n are presented in Table 1. All
synthesized compounds, 2a–n, showed a higher cytotoxicity than 5‐FU,
whereas they showed lower cytotoxicity than DXR. According to
Table 1, cytotoxicities of the compounds were in the range 6.6–25.5 μM
toward HSC‐2 cell line. Synthesized compounds were 1.5–5.7 times
more cytotoxic than 5‐FU. When the cytotoxicity results of the
compounds were considered, compound 2m, 6‐[3‐bromophenyl‐2‐
propenoyl]‐2(3H)‐benzoxazolone, was found to be the most potent
cytotoxic molecule of the series toward HSC‐2 cell line according to
CC50 and potency selectivity expression (PSE) values.
[
53,54]
[55,56]
[57]
[58,59]
myorelaxant,
analgesic,
antiviral, anticancer,
and anti‐
[
60]
inflammatory
activities. In a very limited number of studies, some
chalcones bearing 2(3H)‐benzoxazolone with different substituents on
the phenyl ring were reported with their strong cytotoxic activ-
[3,58,61,62]
ities.
Both the selective and strong anticancer activities of
these compounds pointed out the importance of this chemical moiety in
designing new chalcone compounds for possible drug candidate mole-
cules. Thus, we chose the chalcone structure bearing the 2(3H)‐
benzoxazolone heterocycle as the main chemical skeleton for further
investigation.
In this study, we aimed to synthesize new chalcones, 6‐(3‐
halogenated phenyl‐2‐propen‐1‐one)‐2(3H)‐benzoxazolones (2a–n),
which have an α,β‐unsaturated carbonyl system and halogen moiety,
and to investigate their cytotoxicities (toward both tumor cell lines
and nontumor cells) and inhibition profiles toward hCA I and II. We
hope to find out new possible drug candidate molecule(s) that may
stimulate further studies of the researchers working on these fields.
The first point to be considered for the compounds is whether
they are tumor cytotoxins. Therefore, the compounds were also
evaluated against HGF and HPLF nonmalignant cells, as normal cells
surround the tumor cells in an organism. Therefore, tumor selectivity
(TS) values were calculated by dividing the average CC50 value
toward normal cells by the average CC50 value toward cancer cell

BILGINER ET AL.
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|
SCHEME 1 Synthesis of compounds 1 and 2a–n. DMF, dimethylformamide
[
3,28,40,44,51,64,65]
lines as reported
(Table 1). According to results, the
the phenyl ring (2m and 2n), respectively. These compounds had a
similar TS value to DXR or a higher TS value than DXR (Table 1),
whereas they had lower TS values than 5‐FU. According to these
results, compounds 2m and 2n that have TS values over 10 and
TS values of all compounds were >1, which implies that they were
all tumor‐selective compounds. It can be seen from Table 1 that
bromine substituted two compounds at third and fourth positions on
TABLE 1 Cytotoxic activities of compounds 2a–n toward human OSCC cell lines and human oral normal cells
CC50 (μM)
OSCC
HSC‐2
(A)
Human normal oral cells
SD
HGF
SD
HPLF
SD
Mean
(B)
TS
PSE
2
Compounds
(B/A)
3.5
(B/A ) × 100
2
2
2
2
2
2
2
2
2
2
2
2
2
5
a
22.1
8.9
1.2
2.0
1.2
1.0
1.0
6.0
0.9
4.5
1.3
0.5
2.6
0.8
4.5
0.0
0.1
71.0
54.7
68.3
71.0
70.3
76.7
75.0
43.0
62.3
42.3
59.0
52.0
351.3
>1,000
0.7
9.5
83.3
63.3
75.0
75.3
74.0
94.7
92.3
70.3
85.0
73.0
86.0
87.3
40.0
>1,000
>10
14.0
21.5
3.0
77.2
59.0
71.7
73.2
72.2
85.7
83.7
56.7
73.7
57.7
72.5
69.7
195.7
>1,000
>5.3
16
b
c
23.3
38.0
9.5
6.6
74
12.5
8.9
5.7
46
d
e
3.5
8.3
93
18.9
13.3
8.5
0.6
4.4
3.8
20
f
12.9
15.6
26.9
5.0
27.2
5.5
6.4
48
g
9.8
115
9
h
j
25.5
9.5
26.0
15.0
32.8
35.5
19.7
0.0
2.2
7.8
82
k
l
7.5
16.2
5.6
7.7
103
41
13.3
6.6
5.4
m
n
‐FU
19.1
84.3
0.0
10.5
13.3
>28.3
>10.4
158
90
14.7
37.7
0.5
a
0.0
80.7
>2,030
a
DXR
0.0
0.0
Abbreviations: 5‐FU, 5‐fluorouracil; DXR, doxorubicin; HGF, human gingival fibroblast; HPLF, human periodontal ligament fibroblast; OSCC,
oral squamous cell carcinoma; PSE, potency selectivity expression; SD, standard deviation; TS, tumor selectivity.
a
Used as reference drugs.

4
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BILGINER ET AL.
|
similar TS values to DXR can be considered as leads of the series in
terms of cytotoxicities.
PSE value of compound 2m was about two times higher than 5‐FU.
Additionally, compounds 2g (PSE: 115) and 2k (PSE: 102) were other
impressive compounds with PSE values above 100. As a result,
compound 2m that had the highest PSE value, 158, can be considered
as a possible drug candidate of this series for further studies.
Lead compounds should have both high and selective cytotoxicity
for tumors. To identify the most promising compounds in terms of both
high potencies and selective cytotoxicities, the PSE values have been
[3,39–41,63–65]
defined and calculated, as shown in our previous studies.
PSE values of the compounds were in the range of 9–158 (Table 1). The
PSE values of the compounds in the series were >30, except compounds
2.2.2 | CA inhibitory effects
2
a, 2e, and 2h. Thus, these 10 compounds can be used to develop new
analogs.
PSE values of the compounds pointed out that the replacement
Inhibition effects of compounds 2a–n on hCA I and hCA II are
presented in Table 2. Acetazolamide (AZA) was used as a reference
drug. Compounds 2a–n showed lower CA inhibitory effects than the
reference drug, AZA. The IC50 value of AZA was 16.6 μM toward
hCA I, whereas it was 8.4 μM toward hCA II. According to Table 2,
compound 2g with 2,4‐difluoro substituents on the phenyl ring
showed the best inhibitory activity (27.2 μM) toward hCA I, and
compound 2d carrying 2,6‐dichloro substituents on the phenyl ring
showed the best activity (29.1 μM) toward hCA II.
of a hydrogen by a halogen at any position of the phenyl ring
increased the PSE values 1.3–9.9 times (except compound 2h).
The other point to be considered is whether there is any
relationship between cytotoxicities and structural properties of the
compounds. According to the results presented in Table 1, the halogen
substitution at the different position of phenyl ring was found to be a
generally useful modification to increase cytotoxicity (1.2–3.3 times)
and selectivity (1.1–3.8 times; except compound 2h for both
cytotoxicity and selectivity).
K
i
values of the compounds (inhibitory potency) ranged from
30.5 ± 11.3 to 65.5 ± 25.6 μM toward hCA I isoenzyme, whereas they
ranged from 7.23 ± 1.8 to 58.8 ± 12.3 μM toward hCA II isoenzyme. K
Compound 2m, wherein bromine was substituted at the third
position of the phenyl ring, was the most expressive compound of our
series due to its high cytotoxicity and PSE value (158). CC50 and PSE
values of compound 2m were 3.3 and 9.9 times higher than
nonsubstituted compound 1, respectively. Although compound 2m
was 13.2 times less cytotoxic than DXR, it was 5.7 times more
cytotoxic than the other reference compound, 5‐FU. However, the
i
values of AZA were 30.2 ± 7.8 μM and 4.4 ± 0.6 μM toward hCA I and
hCA II, respectively. According to Table 2, compounds 2a–n had
smaller K
i
values than AZA, whereas compounds 2a, 2b, 2e–g, 2l, and
values to AZA. Thus, compounds 2a, 2b, 2e–g, 2l,
2n had similar K
i
and 2n can be considered as lead molecules of this series for further
considerations.
TABLE 2 Inhibitory effects of compounds 2a–n on hCA I and hCA II isoenzymes
IC50 (µM)
i
K (µM)
2
2
Compounds
hCA I
47.5
43.3
47.8
42.8
53.7
67.9
27.2
36.7
73.7
64.2
48.1
48.5
28.8
16.6
r
hCA II
48.1
39.6
44.4
29.1
52.9
53.7
72.6
29.7
55.4
38.5
39.2
31.4
29.5
8.4
r
hCA I
hCA II
2
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
.9406
.9485
.9665
.9607
.9559
.9558
.9346
.9374
.9597
.9558
.9248
.9663
.9364
.9887
.9854
.9456
.9265
.9478
.9436
.9425
.9425
.9538
.9384
.9336
.9448
.9374
.9326
.9825
30.5 ± 11.3
38.8 ± 10.5
46.4 ± 6.7
61.7 ± 3.3
42.8 ± 10.4
38.2 ± 11.4
38.3 ± 5.8
43.6 ± 2.5
57.2 ± 7.7
65.5 ± 25.6
35.6 ± 10.6
51.5 ± 16.5
33.5 ± 4.5
30.2 ± 7.8
36.2 ± 10.3
39.0 ± 1.5
56.2 ± 8.7
34.1 ± 2.2
9.4 ± 2.3
58.8 ± 12.3
25.6 ± 4.7
14.0 ± 2.6
45.4 ± 8.5
45.3 ± 2.2
55.0 ± 9.2
48.1 ± 2.5
7.3 ± 1.8
g
h
j
k
l
m
n
a
AZA
4.4 ± 0.6
Abbreviation: AZA, acetazolamide.
a
2
AZA was used as a standard inhibitor for both hCA I and II isoenzymes. r is a statistical measure of how close the data are to the fitted regression line; it
[
67]
is also known as the coefficient of determination or the coefficient of multiple determinations for multiple regressions.

BILGINER ET AL.
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|
3
| CONCLUSIONS
4.1.3 | Synthesis of chalcone compounds 2a, 2b,
d–g, and 2j–l (Scheme 1)
2
Novel compounds, 6‐(3‐halogenated phenyl‐2‐propen‐1‐one)‐2(3H)‐
benzoxazolones (2a–n), were reported in this study for the first
time (except compound 2a) with their cytotoxicities and inhibitory
effects on hCA I and II isoenzymes. According to the cytotoxicity
results, compound 2m, 6‐[3‐(3‐bromophenyl)‐2‐propenoyl]‐2(3H)‐
benzoxazolone, was the most expressive compound of the study
with a remarkable PSE value (158) for further studies. However,
An aqueous solution of KOH (10%, 5 ml) was added to the mix-
ture of 6‐acetyl‐2(3H)‐benzoxazolone (ketone, 5.6 mmol) and a
suitable aldehyde [benzaldehyde (2a), 2,4‐dichlorobenzaldehyde
(2b), 2,6‐dichlorobenzaldehyde (2d), 2‐fluorobenzaldehyde
(2e), 3‐fluorobenzaldehyde (2f), 2,4‐difluorobenzaldehyde (2g),
2,6‐difluorobenzaldehyde (2j), 2,3‐difluorobenzaldehyde (2k),
2‐bromobenzaldehyde (2l)] in ethanol (5 ml) in a 1:1 mol ratio
(Scheme 1). The mixture was stirred at room temperature for
24 hr. Reactions were followed by TLC. After the reaction
finished, the content of the reaction flask was poured on
ice water (100 ml) and neutralized by HCl (37%). The precipitated
solid product was collected by filtration and washed with
i
according to the K values of compounds 2a–n, obtained by CA
inhibition studies, compounds 2a, 2b, 2e–g, 2l, and 2n can be
considered as leading compounds of the series to develop new hCA
I inhibitors due to similar K
were not found effective to develop new hCA II inhibitors with their
current structure according to their K values compared with AZA.
i
values to AZA, whereas the compounds
i
[
3,58]
cold water.
The crude compounds were purified by
crystallization from a suitable solvent (acetonitrile/ethanol for
compounds 2a, 2b, 2e, 2g, 2j, 2l, acetonitrile/methanol
for compounds 2d and 2f, and ethyl acetate/methanol for
compound 2k).
4
4
4
| EXPERIMENTAL
.1 | Chemistry
.1.1 | General
6‐(3‐Phenyl‐2‐propenoyl)‐2(3H)‐benzoxazolone (2a)
1
Yield 77%. Mp: 230–232°C. H NMR (dimethyl sulfoxide [DMSO]‐d
6
)
1
13
The NMR spectra ( H NMR and
C NMR) were recorded on
δ (ppm) 12.03 (bs, 1H, NH), 8.11 (d, 1H, arom. H, J = 1.2 Hz), 8.07
(dd, 1H, arom. H, J = 8.2 Hz, J = 1.6 Hz), 7.99 (d, 1H, Ar–CH═,
a
Bruker AVANCE III 400 MHz (Bruker, Karlsruhe, Germany)
1
2
1
13
spectrometer [400 MHz ( H) and 100 MHz ( C)]. Chemical shifts
were given as δ values in parts per million. The internal standard was
tetramethylsilane and J values were expressed in hertz. Mass spectra
of the compounds were taken using a liquid chromatography ion
trap–time‐of‐flight tandem mass spectrometer (Shimadzu, Kyoto,
Japan), equipped with an electrospray ionization (ESI) source,
operating in both positive and negative ionization mode. Shimadzu's
LCMS Solution software was used for data analysis. Melting points
were determined using an Electrothermal 9100 instrument (IA9100;
Bibby Scientific Limited, Staffordshire, UK), and were uncorrected.
Reactions were monitored by thin‐layer chromatography (TLC) using
silica gel 60 HF254 (Merck KGaA).
J = 15.5 Hz), 7.89–7.91 (m, 2H, arom. H), 7.74 (d, 1H, ═CHCO,
J = 15.5 Hz), 7.47 (d, 1H, arom. H, J = 1.2 Hz), 7.45 (d, 2H, arom.
1
3
6
H, J = 2.5 Hz), 7.24 (d, 1H, arom. H, J = 8.2 Hz). C NMR (DMSO‐d ) δ
(ppm) 187.8, 154.9, 144.2, 143.9, 135.5, 135.2, 132.3, 131.0, 129.38,
129.37, 129.36, 126.2, 122.3, 110.0. HRMS (ESI–MS) m/z calculated
+
+
[M+H] 266.0812; measured [M+H] 266.0803.
6‐[3‐(2,4‐Dichlorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2b)
1
Yield 86%. Mp: 248–250°C. H NMR (DMSO‐d
6
) δ (ppm) 8.27 (d, 1H,
arom. H, J = 8.5 Hz), 8.11 (d, 1H, arom. H, J = 1.4 Hz), 8.05 (d, 1H,
Ar–CH═, J = 15.5 Hz), 8.04 (dd, 1H, arom. H, J = 8.2 Hz, J = 1.4 Hz),
7.94 (d, 1H, ═CHCO, J = 15.5 Hz), 7.73 (d, 1H, arom. H, J = 2.0 Hz),
1
2
1
3
The InChI keys of the investigated compounds, together with
some biological activity data, are provided as Supporting Information.
7.54 (dd, 1H, J
NMR (DMSO‐d
35.6, 131.9, 131.8, 130.3, 129.9, 128.4, 126.4, 125.4, 110.1, 110.0.
1
= 8.5 Hz, J
2
= 2.0 Hz), 7.23 (d, 1H, J = 8.2 Hz).
C
6
) δ (ppm) 187.4, 154.9, 143.9, 137.4, 136.0, 135.8,
1
+
+
HRMS (ESI–MS) m/z calculated [M+H] 334.0032; measured [M+H]
4
.1.2 | Synthesis of 6‐acetyl‐2(3H)‐benzoxazolone
334.0032.
(
1) (Scheme 1)
6
‐[3‐(2,6‐Dichlorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2d)
1
Dimethylformamide (13 ml, 172 mmol) was slowly added into
aluminum chloride (80 g, 600 mmol), and the mixture was heated at
Yield 90%. Mp: 235–236°C. H NMR (DMSO‐d
6
) δ (ppm) 7.87
1 2
(dd, 1H, arom. H, J = 8.2 Hz, J = 1.7 Hz), 7.82 (d, 1H, Ar–CH═,
4
5°C for 5 min. 2(3H)‐Benzoxazolone (8.1 g, 60 mmol) and acetyl
J = 16.0 Hz), 7.78 (d, 1H, arom. H, J = 1.7 Hz), 7.65 (d, 1H, ═CHCO,
J = 16.0 Hz), 7.59 (d, 2H, arom. H, J = 7.6 Hz), 7.42 (t, 1H, arom.
chloride (6.4 ml, 90 mmol) were added into this solution (Scheme 1).
Then the reaction mixture was heated at 80°C for 3 hr and poured on
ice water (200 ml) with HCl (30 ml, 37%). The precipitated crude
1
3
H, J = 7.6 Hz), 7.09 (d, 1H, arom. H, J = 8.2 Hz). C NMR (DMSO‐
) δ (ppm) 187.3, 158.9, 145.4, 142.9, 136.2, 134.5, 132.9, 131.3,
131.2, 129.53, 129.53, 126.1, 110.3, 108.1. HRMS (ESI–MS) m/z
d
6
[3]
product was filtered and air‐dried, and crystallized from ethanol.
[
3,58]
+
+
(Yield: 77%, m.p: 231–234°C, brown crystals.)
calculated [M+H] 334.0032; measured [M+H] 334.0030.

6
of 8
BILGINER ET AL.
|
6
‐[3‐(2‐Fluorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2e)
6‐[3‐(2‐Bromophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2l)
1
1
Yield 47%. Mp: 218–219°C. H NMR (DMSO‐d
6
) δ (ppm) 12.11 (bs,
Yield 55%. Mp: 239–240°C. H NMR (DMSO‐d
6
) δ (ppm) 12.12 (bs,
= 1.4 Hz), 8.12 (d, 1H,
arom. H, J = 1.4 Hz), 8.08 (d, 1H, arom. H, J = 8.2 Hz), 8.00 (s, 2H, α,β‐
1H, NH), 8.18–8.10 (m, 2H, arom. H), 8.06 (d, 1H, Ar–CH═,
1 2
1H, NH), 8.23 (dd, 1H, arom. H, J = 8.0 Hz, J
J = 15.6 Hz), 8.05 (d, 1H, arom. H, J = 8.1 Hz), 7.83 (d, 1H, ═CHCO,
J = 15.6 Hz), 7.55–7.48 (m, 1H, arom. H), 7.34 (d, 1H, arom. H,
J = 1.4 Hz), 7.29 (d, 1H, arom. H, J = 8.2 Hz), 7.24 (d, 1H, arom. H,
[
66]
protons),
7.42–7.36 (m, 1H), 7.25 (d, 1H, arom. H, J = 8.2 Hz). C NMR (DMSO‐
) δ (ppm) 187.6, 154.9, 143.9, 141.5, 135.7, 135.4, 133.8, 132.6,
131.9, 129.3, 128.7, 126.4, 125.9, 125.1, 110.1, 110.08. HRMS
7.74 (d, 1H, arom. H, J = 8.0 Hz), 7.52–7.47 (m, 1H),
1
3
13
J = 8.1 Hz). C NMR (DMSO‐d
6
) δ (ppm) 187.6, 163.0, 159.7, 154.9,
d
6
143.9, 135.6, 135.2, 133.1, 132.0, 129.5, 126.3, 125.4, 124.3, 122.8,
+
+
+
1
16.5, 110.0. HRMS (ESI–MS) m/z calculated [M+H] 284.0717;
(ESI–MS) m/z calculated [M+H] 343.9917; measured [M+H]
+
measured [M+H] 284.0714.
343.9922.
6
‐[3‐(3‐Fluorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2f)
1
Yield 47%. Mp: 229–230°C. H NMR (DMSO‐d
6
) δ (ppm) 8.13 (d,
= 8.5 Hz,
= 1.5 Hz), 8.05 (d, 1H, Ar–CH═, J = 15.5 Hz), 7.88 (d, 1H, arom. H,
4.1.4 | Synthesis of compounds 2c, 2h, 2m, and 2n
(Scheme 1)
1
H, arom. H, J = 1.5 Hz), 8.08 (dd, 1H, arom. H,
J
1
J
2
J = 8.5 Hz), 7.73 (d, 1H, ═CHCO, J = 15.5 Hz), 7.70 (d, 1H, arom.
H, J = 7.7 Hz), 7.53–7.46 (m, 1H, arom. H), 7.30 (dd, 1H, arom. H,
An aqueous solution of KOH (10%, 2 ml) was added to the mixture of
6‐acetyl‐2(3H)‐benzoxazolone (ketone, 5.6 mmol) and a suitable ben-
zaldehyde [3,4‐dichlorobenzaldehyde (2c), 2,5‐difluorobenzaldehyde
(2h), 3‐bromobenzaldehyde (2m), and 4‐bromobenzaldehyde (2n)] in a
1:1 mol ratio in ethanol (2 ml). Then the reaction mixture was irra-
diated by microwave [(50–80°C, 25–60 W) for 25 min (compounds 2c,
2h, and 2n) and for 30 min (compound 2 m)]. Reactions were followed
by TLC. After the reaction finished, the content of the reaction flask
was poured on ice water (100 ml) and neutralized by HCl (37%). The
1
3
J
1
= 8.3 Hz, J
DMSO‐d ) δ (ppm) 187.7, 164.6, 161.4, 154.9, 143.9, 142.7, 137.8,
35.6, 132.1, 131.3, 126.2, 123.7, 117.7, 115.2, 114.9, 110.0. HRMS
2
= 2.3 Hz), 7.24 (d, 1H, arom. H, J = 8.3 Hz). C NMR
(
6
1
+
+
(
ESI–MS) m/z calculated [M+H] 284.0717; measured [M+H]
2
84.0716.
6
‐[3‐(2,4‐Difluorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2g)
1
[3]
Yield 89%. Mp: 250–251°C. H NMR (DMSO‐d
6
) δ (ppm) 8.28–8.20
solid precipitated was filtered and washed with water. The crude
(
m, 1H, arom. H), 8.06 (d, 1H, arom. H, J = 4.2 Hz), 8.04 (d, 1H arom.
compounds were purified by crystallization from a suitable solvent
[ethyl acetate/methanol (2c), acetonitrile/ethanol (2h), chloroform/
methanol (2m), and methanol/dimethylformamide (2n)].
H, J = 7.0 Hz), 8.00 (d, 1H, Ar–CH═, J = 15.8 Hz), 7.70 (d, 1H, ═CHCO,
J = 15.8 Hz), 7.42–7.34 (m, 1H, arom. H), 7.27 (d, 1H, arom. H,
1
3
J = 7.0 Hz), 7.23 (d, 1H, arom. H, J = 8.2 Hz). C NMR (DMSO‐d
6
) δ
(
ppm) 187.5, 155.1, 144.0, 136.0, 134.2, 131.9, 131.1, 131.0, 126.3,
6‐[3‐(3,4‐Dichlorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2c)
1
1
24.0, 119.8, 119.6, 113.1, 112.8, 110.1, 109.9. HRMS (ESI–MS) m/z
6
Yield 58%. Mp: 299–301°C. H NMR (DMSO‐d ) δ (ppm) 8.26 (d, 1H,
+
+
calculated [M+H] 302.0623; measured [M+H] 302.0612.
arom. H, J = 1.7 Hz), 8.07 (d, 1H, Ar–CH═, J = 15.4 Hz), 8.06 (s, 1H, arom.
H), 8.05 (d, 1H, ═CHCO, J = 15.4 Hz), 7.84 (dd, 1H, arom. H, J = 8.1 Hz,
= 1.7 Hz), 7.68 (s, 1H, arom. H, J = 8.1 Hz), 7.67 (d, 1H, arom. H,
1
6
‐[3‐(2,6‐Difluorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2j)
J
2
1
13
Yield 53%. Mp: 252–254°C. H NMR (DMSO‐d
6
) δ (ppm) 12.13 (bs,
6
J = 8.4 Hz), 7.20 (d, 1H, arom. H, J = 8.4 Hz). C NMR (DMSO‐d ) δ
1H, NH), 7.94 (d, 2H, arom. H, J = 9.8 Hz), 7.86 (d, 1H, Ar–CH═,
(ppm) 187.7, 155.4, 144.2, 141.5, 136.3, 133.31, 133.30, 132.5, 132.1,
J = 15.9 Hz), 7.67 (d, 1H, ═CHCO, J = 15.9 Hz), 7.60–7.50 (m, 1H,
130.76, 130.75, 129.9, 126.5, 124.4, 110.24, 100.23. HRMS (ESI–MS)
+
+
arom. H), 7.27 (d, 1H, arom. H, J = 8.3 Hz), 7.25 (s, 1H, arom. H), 7.24
m/z calculated [M+H] 334.0032; measured [M+H] 334.0025.
1
3
(
d, 1H, arom. H, J = 8.3 Hz). C NMR (DMSO‐d
6
) δ (ppm) 187.8,
1
1
3
63.2, 159.8, 154.8, 144.0, 135.8, 133.0, 131.8, 129.4, 127.7, 126.3,
6‐[3‐(2,5‐Difluororophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2h)
+
1
13.0, 110.1, 109.7. HRMS (ESI–MS) m/z calculated [M+H]
Yield 63%. Mp: 291–293°C. H NMR (DMSO‐d
6
) δ (ppm) 8.11–8.06
+
02.0623; measured [M+H] 302.0613.
(m, 1H, arom. H), 8.05 (d, 1H, Ar–CH═, J = 15.5 Hz), 7.93 (dd, 1H,
arom. H, J = 8.2 Hz, J = 1.6 Hz), 7.84 (d, 1H, arom. H, J = 1.6 Hz), 7.69
1
2
6
‐[3‐(2,3‐Difluorophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2k)
(d, 1H, ═CHCO, J = 15.5 Hz), 7.35–7.29 (m, 2H, arom. H), 7.02 (d, 1H,
13
1
Yield 39%. Mp: 245–247°C. H NMR (DMSO‐d
6
) δ (ppm) 8.08 (s, 1H,
6
arom. H, J = 8.4 Hz). C NMR (DMSO‐d ) δ (ppm) 187.2, 160.8,
arom. H), 8.05 (d, 1H, Ar–CH═, J = 15.4 Hz), 8.04 (d, 1H, arom. H,
J = 8.4 Hz), 7.98–7.94 (m, 1H, arom. H), 7.78 (d, 1H, ═CHCO,
J = 15.4 Hz), 7.58–7.48 (m, 1H, arom. H), 7.35–7.28 (m, 1H, arom. H),
160.3, 158.9, 158.0, 156.4, 146.1, 145.6, 132.8, 129.3, 126.2, 119.3,
+
118.3, 115.1, 110.6, 108.0. HRMS (ESI–MS) m/z calculated [M+H]
+
302.0623; measured [M+H] 302.0610.
1
3
7
1
1
+
6
.23 (d, 1H, arom. H, J = 8.4 Hz). C NMR (DMSO‐d ) δ (ppm) 187.4,
54.9, 151.9, 148.9, 147.5, 143.9, 135.8, 133.9, 131.8, 126.4, 125.6,
6‐[3‐(3‐Bromophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2m)
1
25.2, 124.6, 119.7, 119.4, 110.1. HRMS (ESI–MS) m/z calculated [M
Yield 37%. Mp: 265–267°C. H NMR (DMSO‐d
6
) δ (ppm) 12.10 (bs,
+
+
H] 302.0623; measured [M+H] 302.0616.
1H, NH), 8.20 (s, 1H, arom. H), 8.1 (s, 1H, arom. H), 8.08–8.07 (m, 1H,

BILGINER ET AL.
7 of 8
|
arom. H), 8.05 (d, 1H, Ar–CH═, J = 15.6 Hz), 7.85 (d, 1H, arom. H,
J = 7.7 Hz), 7.68 (d, 1H, ═CHCO, J = 15.6 Hz), 7.62 (d, 1H, arom. H,
J = 8.1 Hz), 7.42–7.38 (m, 1H, arom. H), 7.22 (d, 1H, arom. H,
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3
92, 83.
[
9] A. Innocenti, J. M. Lehtonen, S. Parkkila, A. Scozzafava, C. T. Supuran,
13
J = 8.1 Hz). C NMR (DMSO‐d
6
) δ (ppm) 187.9, 155.2, 144.2, 142.7,
Bioorg. Med. Chem. Lett. 2004, 14, 5435.
1
1
37.9, 135.9, 133.7, 132.3, 131.6, 131.4, 129.1, 126.6, 123.9, 123.1,
[10] C. T. Supuran, Curr. Pharm. Des. 2008, 14, 603.
+
[
11] V. Alterio, A. Di Fiore, K. D'Ambrosio, C. T. Supuran, G. De Simone,
Chem. Rev. 2012, 112, 4421.
10.4, 110.3. HRMS (ESI–MS) m/z calculated [M+H] 343.9917;
+
measured [M+H] 343.9900.
[
12] N. Lolak, S. Akocak, S. Bua, M. Koca, C. T. Supuran, Bioorg. Chem.
2
018, 77, 542.
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25.
6
‐[3‐(4‐Bromophenyl)‐2‐propenoyl]‐2(3H)‐benzoxazolone (2n)
1
7
Yield 81%. Mp: 288–290°C. H NMR (DMSO‐d
6
) δ (ppm) 8.07 (s, 1H,
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arom. H), 8.04 (d, 1H, arom. H, J = 8.2 Hz), 8.00 (d, 1H, Ar–CH═,
J = 16.1 Hz), 7.85 (d, 2H, arom. H, J = 8.4 Hz), 7.68 (d, 1H, ═CHCO,
J = 16.1 Hz), 7.64 (d, 2H, arom. H, J = 8.4 Hz), 7.20 (d, 1H, arom. H,
13
J = 8.2 Hz). C NMR (DMSO‐d
6
) δ (ppm) 187.9, 155.5, 144.3, 143.0,
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136.4, 134.8, 132.5, 132.2, 131.5, 126.5, 124.6, 123.3, 110.3, 110.1.
+
+
HRMS (ESI–MS) m/z calculated [M+H] 343.9917; measured [M+H]
43.9900.
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Cytotoxicity tests were realized as described in our previous
[
[
[
[
[3,28,39–41,51,67–69]
studies.
4
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[
[
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CONFLICT OF INTERESTS
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The authors declare that there are no conflicts of interests.
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Sinan Bilginer
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