Synthesis and Biological Evaluation of Some Succinimide Hybrid Molecules

Article abstract of DOI:10.1134/S1068162019060402

In this study, a new series of succinimide hybrid molecules containing isothiocyanate, coumarin, isatin, and furan moieties was synthesized and screened for α-glucosidase and antioxidant activities. Preliminary results revealed that all molecules showed good α-glucosidase inhibition effectiveness. Antioxidant activities of the hybrid molecules were determined using cupric reducing antioxidant capacity (CUPRAC) and ferric reducing antioxidant power (FRAP) assays. Also, the radical scavenging activities of the synthesized compounds were assayed by using ABTS^?+?and DPPH^??methods. The results showed that all compounds exhibited moderated to high scavenging activity.

Full text of DOI:10.1134/S1068162019060402

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, No. 6, pp. 575–584. © Pleiades Publishing, Ltd., 2019.
Synthesis and Biological Evaluation of Some Succinimide
Hybrid Molecules
Fatih Yılmaza, Emre Menteşeb, 1, and Nimet Baltaşb
aVocational School of Technical Studies, Department of Chemistry and Chemical Processing Technology,
Recep Tayyip Erdogan University, Rize, 53100 Turkey
bDepartment of Chemistry, Faculty of Arts and Sciences, Recep Tayyip Erdogan University, Rize, 53100 Turkey
Received March 13, 2019; revised April 23, 2019; accepted June 17, 2019
Abstract—In this study, a new series of succinimide hybrid molecules containing isothiocyanate, coumarin,
isatin, and furan moieties was synthesized and screened for α-glucosidase and antioxidant activities. Prelim-
inary results revealed that all molecules showed good α-glucosidase inhibition effectiveness. Antioxidant
activities of the hybrid molecules were determined using cupric reducing antioxidant capacity (CUPRAC)
and ferric reducing antioxidant power (FRAP) assays. Also, the radical scavenging activities of the synthe-

ABTS+
sized compounds were assayed by using
and
methods. The results showed that all com-
DPPH
pounds exhibited moderated to high scavenging activity.
Keywords: pyrrolidine-2,5-diones, α-glucosidase, coumarin, isatin, furan, antioxidant activity
DOI: 10.1134/S1068162019060402
INTRODUCTION
Succinimides (pyrrolidine-2,5-diones) are import-
ant natural heterocyclic compounds. They have been
used as valuable reagents for the preparation of natural
or synthetic compounds in organic chemistry. Also,
they have been used as protease and cholinesterase
inhibitors [9] and show anticonvulsant and antioxi-
dant activity in medicinal chemistry. In the literature,
it has been found that succinimides with different sub-
stituents at the nitrogen atom show good biological
activity. Also, in a study with succinimide derivatives,
it has been found that when the spiro nucleus was
introduced to the nitrogen atom of the pyrrolidine-
2,5-dione cycle, it had positive effect on biological
activity [10].
α-Glucosidase is a membrane-bound enzyme
located at the epithelium of the small intestine; it cat-
alyzes the cleavage of 1,4-α-glucopyranoside bonds to
form glucose [1–3]. Therefore, this enzyme has an
important factor to keep glucose level in a normal area.
The α-glucosidase inhibition can lead to decrease in
the hydrolysis of carbohydrates and the absorption of
glucose in the small intestine. Thus, α-glucosidase
inhibitors decrease the glucose levels and it has been
considered as an important target for treatment of type II
diabetes [4].
The α-glucosidase inhibitors, which are currently
being used in the clinic, are acarbose, voglibose, and
miglitol. However, these inhibitors are costly and not
free from side effects, including gastrointestinal intol-
erability and diarrhea and various related side effects
such as abdominal discomfort and flatulence [5, 6].
For these reasons, it is very important to synthesize
new α-glucosidase inhibitors with minor side effects.
Coumarins (2H-chromen-2-one) are commonly
obtained from plants and they are classes of phenolic
compounds. More than 1300 of its derivatives have
been identified so far. Coumarins show very rare side
effects on human body [11]. Also, they are known to
exhibit many pharmacological activities, like antioxi-
dant [12], antifungal [13], anti-inflammatory [14],
and anticancer activities [15]. Also, coumarin is used
regularly as an important nucleus in medicinal chem-
istry.
In recent years, a lot of efforts have been made to
identify the structural features for potent α-glucosi-
dase inhibitors and antioxidants. As a result, it has
been found that a nitrogen hetero atomic system with
at least one carbonyl group contributes significantly to
inhibition of α-glucosidase and antioxidant activity
[16]. This approach is found noticeable in discovery of
Antioxidants delay or inhibit the oxidation of cellu-
lar substrates by direct radical scavenging or indirect
antioxidant action [7]. Therefore, antioxidant activity
can be useful. Reactive oxygen species (ROS) are
products of normal cellular metabolism. When they
are generated at low and controlled levels, they act as
second messengers [8].
1 Corresponding author: e-mail: emre.mentese@erdogan.edu.tr.
575

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FATIH YILMAZ et al.
new drug candidates. Additionally, our research group
has a long standing interest in research to identify that
hybrid molecules, which include coumarin moiety,
generally show high biological effect. Coumarin moi-
ety enhances the activity.
RESULTS AND DISCUSSION
Chemistry
In the first part of the study, 1-(4-hydroxyphe-
nyl)pyrrolidine-2,5-dione (I) was prepared according
to the previously reported procedure [17]. This com-
pound was treated with ethyl bromoacetate in acetone
in the presence of K2CO3 to obtain ethyl [4-(2,5-
dioxopyrrolidin-1-yl)phenoxy]acetate (II). Com-
pound (II) was reacted with hydrazine monohydrate
In the view of above facts, the present study
describes different hybrid compounds of succinimide
containing coumarin, isothiocyanate, furan, or isatin.
Preliminary results showed that all hybrid molecules
showed good α-glucosidase inhibition compared to
the standard acarbose (% inhibition: 93.86 1.21) and
good antioxidant capacity.
to
obtain
2-[4-(2,5-dioxopyrrolidin-1-yl)phe-
noxy]acetohydrazide (III), which is the key interme-
diate for preparing hybrid molecules (Scheme 1).
O
O
O
H2N
OH
BrCH2COOEt
O
N
OH
N
O
OEt
O
AcOH, reflux
K2CO3, Acetone
O
O
O
(I)
(II)
O
NH2NH2H2O
Ethanol reflux
N
O
NHNH2
O
O
(III)
Scheme 1. Synthesis of 2-[4-(2,5-dioxopyrrolidin-1-yl)phenoxy]acetohydrazide (III).
In the second part of the study, 2,2-dimethyl-1,3- pounds were reacted with 1H-benzotriazole in CH2Cl2
dioxane-4,6-dione and salicylaldehyde derivatives
were reacted in ethanol in the presence of catalytic
amount of pyridine to obtain coumarin-3-carboxylic
acid derivatives (IV–IX) and (XVI). Then, these com-
to obtain coumarin-1H-benzotriazole derivatives (X–XV)
and (XVII), which are the intermediates for coumarin
hybrid molecules (Scheme 2).
N
O
O
O
O
O
O
N
R1
R2
N
H
R1
R2
R1
R2
N
N
O
H
OH
N
Pyridine
+
Ethanol
reflux, 6 hours
SOCl2, CH2Cl2
H3C
H3C
O
O
OH
O
O
R3
O
R3
R3
(IV)−(IX)
(X)−(XV)
N
H
N
O
O
O
O
N
H
N
OH
Pyridine
O
OH
N
+
N
Ethanol
reflux, 6 hours
SOCl2, CH2Cl2
H3C
H3C
O
O
O
O
O
(XVI)
(XVII)
IV, X: R1: H, R2: H, V, XI: R1: Cl, R2: H, R3: H, VI, XIII: R1: Br, R2: H, R3: H, VII, XIII: R1: Cl, R2: H, R3: Cl, VIII,
XIV: R1: H, R2: N(et)2, R3: H, IX, XV: R1: H, R2: H, R3: OCH3
Scheme 2. Synthesis of coumarin-1H-benzotriazole derivatives (X–XV) and (XVII).
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SYNTHESIS AND BIOLOGICAL EVALUATION
577
In the last part of the study, to synthesize succinim- (XVII), isothiocyanate derivatives, furan, and isatin,
ide hybrid molecules, 2-[4-(2,5-dioxopyrrolidin-1- one by one, to obtain succinimide hybrid molecules
yl)phenoxy]acetohydrazide (III) was reacted with (Scheme 3).
coumarin-1H-benzotriazole derivatives (X–XV) and
O
R1
R2
N
N
N
O
O
O
O
O
R3
N
O
NH NH
R1
R2
O
O
O
R3
(XVIII)−(XXIII)
O
O
NH
NH
O
N
N
O
O
N
O
O
O
O
N
O
(XXIV)
O
O
O
O
S
N
R
N
O
NH
H2N
N
O
NHNH
R NH
S
O
O
O
(III)
(XXV)−(XXVI)
O
O
O
H
N
O
NHN
O
O
O
(XXVII)
O
O
O
N
O
NHN
N
H
O
O
N
H
(XXVIII)
XVIII: R1: H, R2: H, R3: H, XIX: R1: Cl, R2: H, R3: H, XX: R1: Br, R2: H, R3: H, XXI: R1: Cl, R2: H, R3: Cl,
XXII: R1: N(et)2, R3: H, XXIII: R1: H, R2: H, R3: OCH3, XXV: R: CH3, XXVI: R: C2H5
Scheme 3. Synthesis of compounds (XVIII–XXVIII).
Spectral data of the target compounds agree with succinimide cycle (around of 160 ppm), two of them
the proposed structures. In 1H NMR spectra of com-
pounds (XVIII) and (XXIV), two NH signals were reg-
istered at about 10 and 11 ppm and coumarin C-4 pro-
ton resonated at about 9 ppm. Also, OCH2 and two
CH2 signals (in succinimide cycle) were detected at
coming from hydrazide (around of 163 ppm), and one of
them coming from coumarin cycle (around of 165 ppm).
Coumarin C-3 and C-4 carbons were detected at
about 155 and 145 ppm, respectively.
1
In H NMR spectra of compounds (XXV–XXVI),
about 5 and 4 ppm, respectively. In 13C NMR spectra
of these compounds, five C=O signals were regitered
between 165 and 160 ppm, two of them coming from
three NH and an OCH2 signals were registered in the
range of 9–11 ppm and at about 5 ppm. In 13C NMR
spectra of these compounds, C=S and OCH2 signals
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FATIH YILMAZ et al.
Table 1. FRAP (mM FeSO4 · 7H2O equivalent per mg of
compound) and CUPRAC (mM Trolox/mg compound)
test results for all the synthesized compounds
reaction of antioxidants with the CUPRAC reagent,
bis(neocuproine) copper(II) cation [Cu(II)−Nc], where
absorbance is recorded at the maximal light absorp-
tion wavelength of 450 nm. TEAC values of the com-
pounds are summarized in Table 1. The maximum
antioxidant capacity in the CUPRAC method was
observed for compound (XXII) with 8.12 0.04 mM
TEAC/mg compound (Table 1). Besides, compounds
(XIX), (XXI), (XXIII), and (XXVI) showed good
TEAC values.
FRAP values,
mM FeSO4 · 7H2O/mg
compound
TEAC values,
Compounds mM Trolox/mg
compound
(XVIII)
(XIX)
(XX)
3.607 0.040
6.020 0.011
6.305 0.028
1.959 0.017
8.118 0.043
8.028 0.051
2.723 0.045
5.675 0.136
8.073 0.096
1.539 0.017
1.914 0.006
2.601 0.028
0.402 0.003
0.375 0.003
0.307 0.013
0.355 0.005
2.008 0.003
1.693 0.002
0.662 0.024
0.481 0.019
1.118 0.008
0.793 0.002
(XXI)
With FRAP assay, the sample compounds were
tested for their ability to reduce iron(III) to iron(II)
ions. The absorbance of TPTZ−Fe+2 complex was
measured at 593 nm. The absorbances measured for
the samples were converted to FeSO4 · 7H2O equiva-
lent antioxidant capacity values obtained from the
[FeSO4 · 7H2O] absorbance calibration graph. The
values of equivalent antioxidant capacity are reported
in Table 1.
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
(XXVIII)
were detected at about 170 and 60 ppm. The other
C=O signals were between 160 and 165 ppm.
DPPH 
Radical Scavenging Assay
1H NMR spectra of compounds (XXVII) and
(XXVIII) contained NH signals at about 11 and 10 ppm
(isatin NH). N=CH signal (for compound (XXVII))
was at 9 ppm. In 13C NMR spectra of these compounds,
N=CH and N=C signals were at about 145 ppm and
C=O signals were between 160 and 170 ppm. Also, all
compounds showed correct elemental analysis results.
The total radical scavenging capacity of the com-
pounds was determined and compared to that of

ascorbic acid and BHT by using the
radical
DPPH
scavenging assay. DPPH radical scavenging activity
results of the compounds and standards are summa-
rized in Table 2. Compounds (XXV) and (XXVI)
showed fairly high DPPH radical scavenging activity,
at 240, 60, and 15 μg/mL final concentrations (Table 2).

CUPRAC and FRAP Antioxidant Activity Results
Also, these compounds had efficient
radical
DPPH
The CUPRAC method is based on the absorbance scavenging activity when compared to BHT as a refer-
measurement of the CUPRAC chromophore, Cu(I)- ence compound at 60 and 15 μg/mL final concentra-
neocuproine (Nc) chelate, formed as a result of the redox tions.

DPPH
Compound
(XVIII)
ABTS
Table 2.
and
+ radical scavenging activities (%) of the compounds and standards at various final concentrations
DPPH
ABTS+
method, % radical scavenging
method, % radical scavenging
240 μg/mL
60 μg/mL
15 μg/mL
24 μg/mL
6 μg/mL
1.5 μg/mL
17.99
50.74
52.98
26.18
32.75
52.98
46.15
91.72
90.45
30.65
10.17
91.94
91.87
7.44
22.70
23.33
11.79
15.01
23.08
16.13
86.72
86.48
12.03
6.70
4.47
9.31
9.18
35.29
90.71
90.86
34.43
89.00
90.71
90.71
90.71
91.29
19.43
15.29
91.43
91.39
17.71
75.00
72.86
16.57
54.71
72.86
65.00
77.00
80.86
11.43
10.29
90.71
36.58
12.86
31.71
33.71
10.71
21.43
31.57
26.57
55.29
53.29
10.00
9.29
(XIX)
(XX)
(XXI)
5.83
6.33
8.81
8.06
81.00
80.15
5.33
3.47
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
(XXVIII)
Ascorbic acid
BHT
88.21
75.56
81.51
60.05
36.43
14.21
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SYNTHESIS AND BIOLOGICAL EVALUATION
579
ABTS+
Table 3. Saccharomyces cerevisiae α-glucosidase inhibitory
activity of selected compounds at final concentration of
50 μg/mL α-glucosidase
Radical Cation Decoloration Assay
ABTS is a stable free radical at room temperature
and is the most simple, fast, and low costly method
among the antioxidant assay. The total radical scav-
enging capacity of the compounds was determined
and compared to that of ascorbic acid and BHT by
α-Glucosidase
Compound
IC50, μg/mL
% inhibition
ABTS+
ABTS+
(XVIII)
(XIX)
(XX)
59.62 1.20
80.29 0.98
78.81 1.05
73.10 2.45
76.93 1.12
74.74 0.85
62.45 1.66
82.68 1.56
82.82 0.89
56.45 1.77
64.17 2.34
93.86 1.21
42.04 0.67
20.00 0.88
20.08 0.74
27.52 1.24
22.80 1.56
25.03 0.75
41.74 2.22
18.70 1.86
19.25 0.58
46.35 1.44
40.00 2.08
12.05 0.57
using the
radical scavenging assay.
radical scavenging activity results of compounds and
standards are summarized in Table 2. Compounds
+
(XXI)
(XX–XXIV) showed fairly high
radical scav-
ABTS
enging activity when compared to other compounds,
at all tested concentrations (Table 2).
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
(XXVIII)
Acarbose
α-Glucosidase Inhibition Assay
All synthesized compounds were evaluated for their
in vitro inhibitory activity against α-glucosidase. All
compounds showed inhibition at various concentra-
tions. α-Glucosidase inhibition (%) and IC50 values of
all compounds having inhibitory activity are summa-
rized in Table 3. Among the tested compounds,
(XXIV) showed the most significant α-glucosidase
122.64 (Ar-C), 155.25, 157.21 (2C), 163.27 (C=O). Anal.
calcd for C14H15NO5: C 60.64; H 5.45; N 5.05; Found, %:
C 60.52; H 5.31; N 4.92.
inhibition with IC50 value of 18.70
1.86 mg/mL.
α-Glucosidase inhibition effectiveness of the com-
pounds, which are more active than acarbose, can be
listed as follows, from the most active molecules to the
least active molecules: (XXV) > (XXVI) > (XIX) > (XX) >
(XXII) > (XXIII) > (XXI) > (XXVIII) > (XXIV) >
(XVIII) > (XXVII) (Table 3).
2-[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]acetohy-
drazide (III). This compound was synthesized accord-
ing to the literature [20]. Yield 2.05 g (78%). mp
1
>300°C. H NMR: 2.81 (s, 4H, 2CH2), 3.60 (s, 2H,
OCH2), 4.31 (s, 2H, NH2), 7.53 (d, J = 6.0, 2H, Ar-
H), 7.69 (d, J = 6.0, 2H, Ar-H), 9.32 (s, 1H, NH). 13C
NMR: 28.12, 30.01 (CH2), 54.41 (OCH2), 105.13,
121.32, 122.01 (2C), 122.33, 123.46, (Ar-C), 156.23,
158.22, 164.21 (C=O). Anal. calcd for C12H13N3O4: C
54.75; H 4.98; N 15.96; Found, %: C 54.63; H 4.87; N
15.84.
EXPERIMENTAL
All the chemicals were obtained from Merck,
Sigma-Aldrich, or Fluka. All reaction progress was
monitored by TLC on silica gel plates (Merck 60, F254
,
0.2 mm). The melting points were determined in cap-
illary tubes on Stuart SMP30 melting point apparatus
Synthesis of compounds (IV–IX) and (XVI). These
compounds were synthesized according to the litera-
ture [20].
2-Oxo-2H-chromene-3-carboxylic acid (IV). Yield
1.39 g (73%). mp 189–190°C (mp 188°C [19]).
6-Chloro-2-oxo-2H-chromene-3-carboxylic acid (V).
Yield 2.47 g (76%). mp 194–195°C (mp 193°C [21]).
6-Bromo-2-oxo-2H-chromene-3-carboxylic acid
(VI). Yield 1.80 g (67%). mp 195–196°C (mp 194–
196°C [19]).
6,8-Dichloro-2-oxo-2H-chromene-3-carboxylic
acid (VII). Yield 1.78 g (69%). mp 222–223°C (mp
220–224°C [22]).
7-Diethylamino-2-oxo-2H-chromene-3-carboxylic
acid (VIII). Yield 1.95 g (75%). mp 232–233°C (mp
230–232 °C [23]).
1
and uncorrected. H and 13C NMR spectra (400 and
100 MHz, respectively) were obtained in DMSO-d6
using a Varian-Mercury (tetramethylsilane as internal
standard): chemical shifts are expressed in δ values
(ppm). The elemental compositions were determined
on a CarloErba 1106 CHN analyzer; the experimental
values were in agreement ( 0.4%) with the calculated
ones.
1-(4-Hydroxyphenyl)pyrrolidine-2,5-dione
(I).
This compound was synthesized according to the liter-
ature [18]. mp 188–190°C (185–187°C [18]).
Ethyl [4-(2,5-dioxopyrrolidin-1-yl)phenoxy]ace-
tate (II). This compound was synthesized according to
the literature [19]. mp 155–156°C. 1H NMR: 1.75 (q,
J = 7.6, 3H, CH3), 2.73 (s, 4H, 2CH2), 3.45 (s, 2H,
OCH2), 4.45 (t, J = 7.6, 2H, OCH2), 7.88 (d, J =
7.2, 2H, Ar-H), 8.00 (d, J = 7.2, 2H, Ar-H).
13C NMR: 10.53 (CH3), 29.09, 31.05 (CH2), 55.05,
61.75 (OCH2), 112.44, 114.18, 117.09, 119.98, 120.78,
8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid
(IX). Yield 1.95 g (75%). mp 215–216°C (mp 214–
216°C [24]).
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FATIH YILMAZ et al.
3-Oxo-3H-naphtho[2,1-b]pyran-2-carboxylic acid m/z: 348.0203 [M (Cl35)þNa], 350.0156 [M
(XVI). Yield 1.61 g (67%). mp 238–239°C (mp 236– (Cl37)þNa].
237 °C [25]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6,8-dichloro-
2H-chromen-2-on (7b) Yield: 2.34 g (65%), mp: 263–
Synthesis of compounds (X–XV) and (XVII). These
compounds were synthesized according to the litera-
ture [20].
3-(1H-Benzotriazol-1-ylcarbonyl)-2H-chromen-
2-one (X). Yield 2.12 g (73%). mp 179–180°C (mp
176–177° [19]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-2H-
chromen-2-one (XI). Yield 2.20 g (63%). mp 248–
249°C (mp 248–249°C [26]).
1
264°C, H NMR (DMSO-d6), d, ppm: 8.76– 8.67
(1H, s, coumarin C-4); 8.29 (1H, s, coumarin H-7),
8.27 (1H, s, coumarin H-5), 8.11–7.99 (2H, m, Ar-
H), 7.85 (1H, t, J 1/4 7.2 Hz, Ar-H), 7.67 (1H, t, J 1/4
7.2 Hz, Ar-H). 13C APT (DMSO-d6), d, ppm: 163.9
(C–O); 158.1 (C–O coumarin C-2); 152.4 (coumarin
C-3); 148.7 (coumarin C-4); 146.8; 138.4; 133.1;
132.4; 129.9; 128.4; 123.1; 121.9; 116.0; 1114.1; 112.0
(Ar-C). LC-MS, m/z: 359.0207 [M (Cl35) (Cl35)],
361.0153 [M (Cl35)(Cl37)].
3-(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-2H-
chromen-2-on (7a) Yield: 2.20 g (63%), mp: 248–
3-(1H-Benzotriazol-1-ylcarbonyl)-7-diethylamino-
2H-chromen-2-on (7c) Yield: 2.46 g (68%), mp: 210–
211°C (lit. 212–214°C [36]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6-bromo-2H-
chromen-2-one (XII). Yield 2.52 g (68%). mp 250–
251°C (mp 250–251°C [22]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6,8-dichloro-
2H-chromen-2-one (XIII). Yield 2.34 g (65%). mp
263–264°C (mp 263–264°C [23]).
3-(1H-Benzotriazol-1-ylcarbonyl)-7-diethylamino-
2H-chromen-2-one (XIV). Yield 2.46 g (68%). mp
210–211°C (mp 210–211°C [23]).
3-(1H-Benzotriazol-1-ylcarbonyl)-8-methoxy-2H-
chromen-2-one (XV). Yield 2.46 g (68%). mp 236–
237°C. 1H NMR: 3.96 (s, 3H, OCH3), 7.57 (d, J = 7.2,
1H, Ar-H), 7.77 (t, 1H, J = 7.2 Hz, Ar-H), 7.98 (s,
1H, Ar-H), 7.99–8.11 (m, 3H, Ar-H), 8.29 (s, 1H, Ar-
H), 8.74 (s, 1H, Ar-H). 13C NMR: 62.14, 114.20,
119.11, 119.35, 120.77, 122.62, 127.56, 129.51, 130.92,
131.78, 134.44, 145.91, 146.92, 153.46, 157.29, 162.75.
Anal. calcd for C17H11N3O4: C 63.55; H 3.45; N 14.08;
Found, %: C 63.47; H 3.40; N 14.01.
2-(1H-Benzotriazole-1-carbonyl)-3H-naphtho[2,1-
b]pyran-3-one (XVII). (CAS Registry Number:
886124-23-8) Yield 2.47 g (72%). mp 267–268°C.
1H NMR: 7.64–7.77 (m, 4H, Ar-H), 7.88 (t, J =
7.6, 1H, Ar-H), 8.00 (d, J = 7.6, 1H, Ar-H), 8.28–
8.35 (m, 3H, Ar-H), 8.85 (d, J = 8.4, 1H, Ar-H), 9.96
(s, 1H, Ar-H). 13C NMR: 112.44, 114.18, 117.09,
119.98, 120.78, 122.64, 127.09, 127.50, 129.51, 131.07,
131.74, 136.67, 144.66, 145.98, 155.25, 157.21, 163.27.
Anal. calcd for C20H11N3O3: C 70.38; H 3.25; N 12.31;
Found, %: C 70.26; H 3.18; N 12.20.
1
249°C, H NMR (DMSO-d6), d, ppm: 8.74 (1H, s,
H-4); 8.29–8.05 (2H, m, Ar-H); 8.05 (1H, d, J1/4 2.4 Hz,
Ar-H); 7.98–7.79 (2H, m, Ar-H); 7.68–7.64 (1H, m,
Ar-H); 7.64 (1 H, d, J 1/4 8.0 Hz, Ar-H). 13C APT
(DMSO-d6), d, ppm: 162.8 (C–O); 157.3 (C–O cou-
marin C-2); 153.2 (coumarin C-3); 146.9 (coumarin
C-4); 145.9; 134.4; 131.7; 130.9; 129.5; 127.5; 122.6;
120.7; 119.3; 119.1; 114.2 (Ar-C). LC-MS, m/z:
348.0203 [M (Cl35)þNa], 350.0156 [M (Cl37)þNa]3-
(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-2H-chromen-
1
2-on (7a)Yield: 2.20 g (63%), mp: 248–249°C, H
NMR (DMSO-d6), d, ppm: 8.74 (1H, s, H-4); 8.29–8.05
(2H, m, Ar-H); 8.05 (1H, d, J 1/4 2.4 Hz, Ar-H);
7.98–7.79 (2H, m, Ar-H); 7.68–7.64 (1H, m, Ar-H);
7.64 (1H, d, J 1/4 8.0 Hz, Ar-H).
13C APT (DMSO-d6), d, ppm: 162.8 (C–O); 157.3
(C–O coumarin C-2); 153.2 (coumarin C-3); 146.9
(coumarin C-4); 145.9; 134.4; 131.7; 130.9; 129.5;
127.5; 122.6; 120.7; 119.3; 119.1; 114.2 (Ar-C). LC-MS,
m/z: 348.0203 [M (Cl35)þNa], 350.0156 [M
(Cl37)þNa]3-(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-
2H-chromen-2-on (7a) Yield: 2.20 g (63%), mp: 248–
1
249°C, H NMR (DMSO-d6), d, ppm: 8.74 (1H, s,
H-4); 8.29–8.05 (2H, m, Ar-H); 8.05 (1H, d, J 1/4
2.4 Hz, Ar-H); 7.98–7.79 (2H, m, Ar-H); 7.68–7.64
(1H, m, Ar-H); 7.64 (1H, d, J 1/4 8.0 Hz, Ar-H).
13C APT (DMSO-d6), d, ppm: 162.8 (C–O); 157.3
(C–O coumarin C-2); 153.2 (coumarin C-3); 146.9
(coumarin C-4); 145.9; 134.4; 131.7; 130.9; 129.5;
127.5; 122.6; 120.7; 119.3; 119.1; 114.2 (Ar-C). LC-MS,
m/z: 348.0203 [M (Cl35)þNa], 350.0156 [M
(Cl37)þNa]3-(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-
2H-chromen-2-on (7a) Yield: 2.20 g (63%), mp: 248–
249°C, 1H NMR (DMSO-d6), d, ppm: 8.74 (1H, s, H-4);
8.29–8.05 (2H, m, Ar-H); 8.05 (1H, d, J 1/4 2.4 Hz,
Ar-H); 7.98–7.79 (2H, m, Ar-H); 7.68–7.64 (1H, m,
Ar-H); 7.64 (1H, d, J 1/4 8.0 Hz, Ar-H).
Synthesis of compounds (VIIIa–f) and (IX). A solu-
tion of 2-[4-(2,5-dioxopyrrolidin-1-yl)phenoxy]ace-
tohydrazide (III) (0.01 mol) and compounds (X–XV)
or (XVII) (0.012 mol) in dimethyl sulfoxide (10 mL)
was taken in a flask. The mixture was refluxed for 8 h.
After the completion of the reaction (monitored by
13C APT (DMSO-d6), d, ppm: 162.8 (C–O); 157.3
(C–O coumarin C-2); 153.2 (coumarin C-3); 146.9 TLC, EtOAc–hexane, 3 : 1), the mixture was cooled
(coumarin C-4); 145.9; 134.4; 131.7; 130.9; 129.5; down to room temperature, and the product was pre-
127.5;122.6; 120.7; 119.3; 119.1; 114.2 (Ar-C). LC-MS, cipitated by addition of water. It was filtrated off and
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
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2019

SYNTHESIS AND BIOLOGICAL EVALUATION
581
washed with ethanol and pure water to obtain the
product.
7-Diethylamino-N'-{[4-(2,5-dioxopyrrolidin-1-yl)-
phenoxy]acetyl}-2-oxo-2H-1-benzopyran-3-carbohy-
drazide (XXII). Yield 2.80 g (55%). mp 331–332°C.
1H NMR: 1.23 (q, J = 8.2, 6H, 2CH3), 2.11 (t, J = 8.2,
4H, 2CH2), 2.52 (s, 4H, 2CH2), 4.56 (s, 2H, OCH2),
6.77–7.42 (m, 4H, Ar-H), 7.61–7.88 (m, 3H, Ar-H),
8.69 (s, 1H, coumarin H-4), 9.81 (s, 1H, NH), 10.16
(s, 1H, NH). 13C NMR: 12.75 (2CH3), 28.68, 31.92
(CH2), 44.85 (NCH2), 66.57 (OCH2), 109.15, 111.62,
115.66, 120.41, 122.11, 125.73, 126.54, 132.19, 136.51,
137.31, 139.51, 141.59, 143.36 (Ar-C), 147.15 (couma-
rin C-4), 154.11 (coumarin C-3), 157.90 (2C), 160.21,
165.91, 167.01 (C=O). Anal. calcd for C26H26N4O7: C
61.65; H 5.17; N 11.06; Found, %: C 61.54; H 5.11; N
11.01.
N'-{[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]acetyl}-
2-oxo-2H-1-benzopyran-3-carbohydrazide (XVIII).
Yield 3.25 g (75%). mp 315–316°C. 1H NMR: 2.79 (s,
4H, 2CH2), 4.96 (s, 2H, OCH2), 7.24–7.30 (m, 2H,
Ar-H), 7.44 (d, J = 7.2, 2H, Ar-H), 7.65–7.90 (m,
3H, Ar-H), 7.98–8.00 (m, 1H, Ar-H), 8.90 (s, 1H,
coumarin H-4), 10.66 (s, 2H, NH). 13C NMR: 28.12,
30.01 (CH2), 56.43 (OCH2), 110.60, 114.19, 114.29,
116.69 (2C), 118.84, 119.11, 125.68, 129.14, 130.02
(2C), 134.70, 134.90 (Ar-C), 141.22 (coumarin C-4),
148.56 (coumarin C-3), 153.81, 154.90, 158.22,
160.27, 164.71 (C=O). Anal. calcd for C22H17N3O7: C
60.69; H 3.94; N 9.65; Found, %: C 60.57; H 3.82; N
9.53.
8-Methoxy-N'-{[4-(2,5-dioxopyrrolidin-1-yl)phe-
noxy]acetyl}-2-oxo-2H-1-benzopyran-3-carbohydra-
zide (XXIII). Yield 2.19 g (47%). mp 319–320°C.
1H NMR (DMSO-d6, 400 MHz): 2.51 (s, 4H, 2CH2),
3.53 (s, 3H, OCH3), 4.59 (s, 2H, OCH2), 6.67–7.32
(m, 3H, Ar-H), 7.51–7.79 (m, 5H, Ar-H), 8.72 (s, 1H,
coumarin H-4), 9.79 (s, 1H, NH), 10.12 (s, 1H, NH).
13C NMR (DMSO-d6, 100 MHz): 28.68, 31.92 (CH2),
55.31 (OCH3), 66.57 (OCH2), 110.11, 112.23, 116.35,
120.46, 122.15, 126.46, 127.98, 131.59, 135.53, 136.69,
140.27, 142.12, 142.19 (Ar-C), 146.39 (coumarin C-4),
155.29 (coumarin C-3), 156.86 (2C), 160.28, 165.69,
167.19 (C=O). Anal. calcd for C23H19N3O8: C 59.36; H
4.11; N 9.03; Found, %: C 59.19; H 4.03; N 8.86.
6-Chloro-N'-{[4-(2,5-dioxopyrrolidin-1-yl)phe-
noxy]acetyl}-2-oxo-2H-1-benzopyran-3-carbohydra-
zide (XIX). Yield 2.84 g (63%). mp 325–326°C.
1H NMR: 2.66 (s, 4H, 2CH2), 4.52 (s, 2H, OCH2),
6.74–7.03 (m, 3H, Ar-H), 7.43 (s, 1H, Ar-H), 7.61–
7.90 (m, 4H, Ar-H), 8.89 (s, 1H, coumarin H-4), 9.45
(s, 1H, NH), 10.11 (s, 1H, NH). 13C NMR: 27.15,
29.51 (CH2), 64.55 (OCH2), 109.11, 114.41, 115.91,
120.53, 122.53, 125.89, 126.11, 134.34, 135.67, 136.39,
138.28, 139.31, 141.30 (Ar-C), 147.12 (coumarin C-4),
154.40 (coumarin C-3), 155.93 (2C), 158.42, 165.25,
165.87 (C=O). Anal. calcd for C22H16ClN3O7: C 56.24;
H 3.43; N 8.94; Found, %: C 56.12; H 3.31; N 8.85.
N'-{[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]acetyl}-2-
oxo-2H-1-benzopyran-3-oxo-3H-naphtho[2,1-b]pyran-
2-carbohydrazide (XXIV). Yield 2.70 g (54%). mp >
6-Bromo-N'-{[4-(2,5-dioxopyrrolidin-1-yl)phe-
noxy]acetyl}-2-oxo-2H-1-benzopyran-3-carbohydra-
zide (XX). Yield 2.89 g (57%). mp 337–338°C.
1H NMR: 2.72 (s, 4H, 2CH2), 4.54 (s, 2H, OCH2),
6.66–7.55 (m, 4H, Ar-H), 7.60–7.90 (m, 4H, Ar-H),
8.98 (s, 1H, coumarin H-4), 9.55 (s, 1H, NH), 10.12
(s, 1H, NH). 13C NMR: 26.14, 28.01 (CH2), 65.51
(OCH2), 108.12, 112.62, 114.81, 121.49, 123.46, 124.81,
127.34, 133.31, 135.29, 137.33, 138.01, 140.36, 142.35
(Ar-C), 148.11 (coumarin C-4), 155.43 (coumarin C-3),
156.98 (2C), 159.23, 164.96, 167.07 (C=O). Anal.
calcd for C22H16BrN3O7: C 51.38; H 3.14; N 8.17;
Found, %: C 51.25; H 3.09; N 8.10.
1
350°C. H NMR: 2.49 (s, 4H, 2CH2), 4.67 (s, 2H,
OCH2), 6.68–7.31 (m, 5H, Ar-H), 7.51–7.79 (m, 3H,
Ar-H), 7.82–7.91 (m, 2H, Ar-H), 8.77 (s, 1H, couma-
rin H-4), 9.86 (s, 1H, NH), 10.11 (s, 1H, NH). 13C
NMR: 28.77, 31.69 (CH2), 65.59 (OCH2), 108.45,
109.13, 113.29, 115.38, 121.26, 122.69, 124.32, 125.70,
126.98, 128.63, 130.16, 132.29, 134.15, 137.16, 139.15,
141.46, 143.01 (Ar-C), 147.16 (coumarin C-4), 154.71
(coumarin C-3), 157.71 (2C), 159.61, 165.34, 167.67
(C=O). Anal. calcd for C26H19N3O7: C 64.33; H 3.95;
N 8.66; Found, %: C 64.22; H 3.86; N 8.59.
Synthesis of compounds (XXV–XXVI). These com-
6,8-Dichloro-N'-{[4-(2,5-dioxopyrrolidin-1-yl)-
phenoxy]acetyl}-2-oxo-2H-1-benzopyran-3-carbohy-
drazide (XXI). Yield 2.75 g (56%). mp 347–348°C.
1H NMR: 2.66 (s, 4H, 2CH2), 4.61 (s, 2H, OCH2),
6.72–7.35 (m, 3H, Ar-H), 7.60–8.02 (m, 3H, Ar-H),
8.98 (s, 1H, coumarin H-4), 9.87 (s, 1H, NH), 10.11
(s, 1H, NH). 13C NMR: 26.19, 27.90 (CH2), 65.50
(OCH2), 109.15, 111.62, 115.66, 120.41, 122.11, 125.73,
126.54, 132.19, 136.51, 137.31, 139.51, 141.59, 143.36
(Ar-C), 147.15 (coumarin C-4), 154.11 (coumarin C-3),
pounds were synthesized according to the literature [27].
2-{[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]acetyl}-
N-methylhydrazine-1-carbothioamide (XXV). Yield
1
2.52 g (75%). mp 225–226°C. H NMR: 2.17 (s, 3H,
CH3), 2.54 (s, 4H, 2CH2), 3.49 (s, 2H, OCH2), 7.67
(d, J = 7.2, 2H, Ar-H), 7.95 (d, J = 7.2, 2H, Ar-H),
9.02 (s, 1H, NH), 9.86 (s, 1H, NH), 10.11 (s, 1H,
NH). 13C NMR: 23.75, 27.60 (CH2), 33.78 (CH3),
59.59 (OCH2), 111.46, 114.76, 117.01, 119.16, 120.79,
157.90 (2C), 160.21, 165.91, 167.01 (C=O). Anal. 123.64 (Ar-C), 150.61, 162.34, 161.67 (C=O), 167.15
calcd for C22H15Cl2N3O7: C 52.40; H 3.00; N 8.33; (C=S). Anal. calcd for C14H16N4O4S: C 49.99; H 4.79;
Found, %: C 52.31; H 2.92; N 8.23.
N 16.66; Found, %: C 49.83; H 4.63; N 16.52.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 6 2019

582
FATIH YILMAZ et al.
2-{[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]acetyl}- inhibitor. The assays were done in triplicate. The IC50
N-ethylhydrazine-1-carbothioamide (XXVI). Yield
values were determined as the concentration of com-
1
2.65 g (75%). mp 235–236°C. H NMR: 1.09 (t, J = pound that gives 50% inhibition of maximal activity.
7.6, 3H, CH3), 2.19 (q, J = 7.6, 2H, CH2), 2.61 (s, 4H,
2CH2), 3.56 (s, 2H, OCH2), 7.72 (d, J = 7.2, 2H, Ar-
Antioxidant Activity Methods
H), 7.98 (d, J = 7.2, 2H, Ar-H), 9.11 (s, 1H, NH), 9.91
(s, 1H, NH), 10.04 (s, 1H, NH). 13C NMR: 12.71
(CH3), 27.75, 31.60 (CH2), 40.15 (CH2), 65.59
(OCH2), 112.14, 115.79, 118.66, 119.89, 121.81, 124.49
(Ar-C), 151.39, 163.30, 164.43 (C=O), 168.98 (C=S).
Anal. calcd for C15H18N4O4S: C 51.42; H 5.18; N
15.99; Found, %: C 51.37; H 5.04; N 15.85.
Antioxidant activities of the synthesized com-
pounds were determined by using CUPRAC (cupric
reducing antioxidant capacity), FRAP (ferric reducing
+
antioxidant power),
[2,2'-azino-bis(3-ethyl-
ABTS

benzothiazoline-6-sulfonic acid)], and
diphenyl-1-picrylhydrazyl) assays.
(2,2-
DPPH
Synthesis of compounds (XXVII) and (XXVIII).
These compounds were synthesized according to the
literature [27].
Cupric reducing antioxidant capacity (CUPRAC)
assay. The cupric reducing antioxidant capacity of the
synthesized compounds was determined by a reported
method [7]. Briefly, to a test tube, 1 mL each of
10 mM Cu(II) chloride (Sigma Chemical Co, USA),
7.5 mM neocuprine (Sigma Chemical Co, USA), and
NH4Ac (Fluka Chemical Co., Switzerland) buffer
(1 M, pH 7.0) solutions were added. About 5 μL of
compound solution in DMSO and 1.095 mL of water
were added to the initial mixture so as to make the
final volume 4.1 mL. The tubes were stoppered, and
after 30 min, the absorbance at 450 nm was recorded
against a reagent blank containing no compound.
Trolox® (Sigma Chemical Co, USA) was also tested
under the same conditions as a standard antioxidant
compound. The standard curve was linear between
32 mM and 0.125 mM Trolox® (r2 = 0.999).
CUPRAC values are expressed as mM Trolox® equiv-
alent of 1 mg synthesized compound.
Ferric reducing antioxidant power (FRAP) assay.
FRAP activities indicate total reducing potential of
samples. The method utilizes the measurement of
absorbance at 593 nm caused by the Fe2+−TPTZ
complex. The ferric reducing antioxidant power
(FRAP) assay was used to determine total antioxidant
capacity. The FRAP reagent used was made by mixing
25 mL acetate buffer (300 mM, pH 3.6) with 2.5 mL of
10 mM TPTZ solution in 40 mM HCl and 2.5 mL of
20 mM FeCl3 · 6H2O solution. Next, 100 μL of the
sample was mixed with 3 mL of freshly prepared
FRAP reagent and incubated for 5 min at room tem-
perature. Absorbance was read at 593 nm against the
reagent blank. FeSO4 · 7H2O was used as a positive con-
trol to construct a reference curve at six different concen-
trations (15.63−31.25−62.5− 125−250−500−1000 μM,
r2 = 0.999). FRAP values are expressed as mM
FeSO4 · 7H2O equivalent per mg of compound, calcu-
2-[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]-N'-[(furan-
2-yl)methylidene]acetohydrazide (XXVII). Yield 2.94 g
(86%). mp 336–337°C. 1H NMR: 2.67 (s, 4H, 2CH2),
3.74 (s, 2H, OCH2), 6.73–7.13 (m, 2H, Ar-H), 7.35–
7.72 (m, 3H, Ar-H), 7.89 (d, J = 7.0, 2H, Ar-H), 8.56
(s, 1H, CH), 11.15 (s, 1H, NH). 13C NMR: 27.89,
31.56 (CH2), 65.49 (OCH2), 110.65, 111.56, 112.16,
114.59, 117.32, 120.89, 122.45, 125.78, 126.21, 130.56
(Ar-C), 145.17 (C=N), 155.49, 164.11, 165.76 (C=O).
Anal. calcd for C17H15N3O5: C 59.82; H 4.43; N 12.31;
Found, %: 59.69; H 4.31; N 12.24.
2-[4-(2,5-Dioxopyrrolidin-1-yl)phenoxy]-N'-(2-oxo-
1,2-dihydro-3H-indol-3-ylidene)acetohydrazide (XXVIII).
Yield 2.94 g (86%). mp 336–337°C. 1H NMR: 2.72 (s,
4H, 2CH2), 3.82 (s, 2H, OCH2), 6.67–7.15 (m, 3H,
Ar-H), 7.27–7.82 (m, 4H, Ar-H), 7.94 (s, 1H, Ar-H),
8.76 (s, 1H, CH), 10.95 (s, 1H, NH), 12.05 (s, 1H,
NH). 13C NMR: 27.39, 32.12(CH2), 66.39 (OCH2),
108.45, 110.12, 113.79, 115.97, 118.27, 121.38, 123.67,
126.58, 127.50, 130.78, 132.56, 139.41 (Ar-C), 147.11
(C=N), 155.54, 158.18, 164.19, 165.69 (C=O). Anal.
calcd for C20H16N4O5: C 61.22; H 4.11; N 14.28;
Found, %: 61.09; H 4.02; N 14.15.
α-Glucosidase Activity Assay
α-Glucosidase enzyme (from Saccharomyces cere-
visiae, Sigma-Aldrich) inhibition activities of the syn-
thesized compounds were determined spectrophoto-
metrically according to the literature procedure [28].
Briefly, the solution of α-glucosidase (20 U/mL) was
prepared in a phosphate buffer (pH 6.8, 50 mM). The
synthesized compounds were dissolved in methanol
(70%). In test tubes, 200 μL of test samples, 5 μL of
the α-glucosidase solution (20 U/mL), and 1245 μL of
the buffer solution were added and incubated at 37°C.
After a 15-min incubation period, 250 μL of p-nitro- lated as the FeSO4 · 7H2O concentration from the
phenyl-α-D-glucopyranoside (2 mM, Sigma-
Aldrich) was added and change in absorbance was
monitored for 20 min at 400 nm. Test compounds
were replaced by methanol (14% final) as control.
graph corresponding to the absorbance observed with
the sample [3].
DPPH
free radical scavenging assay. The DPPH
Acarbose (Sigma-Aldrich) was used as a standard radical scavenging activity of the synthesized com-
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
No. 6
2019

SYNTHESIS AND BIOLOGICAL EVALUATION
583
COMPLIANCE WITH ETHICAL STANDARDS
pounds was measured using the published studies [27].
Briefly, 1200 μL of 0.1 mM DPPH (2,2-diphenyl-1-
picrylhydrazyl) solution in methanol was added to
300 μL of the synthesized compound solution in
DMSO. Then, the mixture was kept in the dark for
50 min, and decrease in absorbance at 517 nm was
measured, using a UV-Visible spectrophotometer
(1601UV-Shimadzu, Australia). Ascorbic acid and
BHT were used as positive controls. All measurements
were carried out three times and the results are
expressed as % scavenging of DPPH radical calculated
from the formula
The work has no studies involving humans or animals as
subjects of the study.
Conflict of Interests
Authors declare that they have no conflicts of interests.
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=
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(
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ABTS+
radical was determined according to the liter-
ature [27]. ABTS [2,2'-azino-bis(3-ethylbenzothiazo-
line-6-sulfonic acid)] was dissolved in water to a 7 mM
concentration and diluted to get an absorbance of
0.700 0.020 at 734 nm before usage. After 5 min in
the dark at room temperature, the decrease of absor-
bance of reaction mixture containing 200 μL of com-
+
pound solution and 1800 μL of the
solution
ABTS
was measured. Ascorbic acid and BHT were used as
positive antioxidant. The percentage scavenging was
calculated from the formula
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OD
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) (
×100 .
(
[
)
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