Synthesis and biological evaluation of some 1,3-benzoxazol-2(3H)-one hybrid molecules as potential antioxidant and urease inhibitors

Article abstract of DOI:10.1002/jhet.4165

A new series of 1,3-benzoxazol-2(3H)-one hybrid compounds, including coumarin, isatin 1,3,4-triazole and 1,3,4-thiadiazole moieties, were synthesized and biologically evaluated for their antioxidant capacities and anti-urease properties. The synthesized benzoxazole-coumarin (6a–e) and benzoxazole-isatin (10a–c) hybrids showed remarkable urease inhibitory activities with IC₅₀ (μM), ranging from 0.0306 ± 0.0030 to 0.0402 ± 0.0030, while IC₅₀ of standard thiourea is 0.5027 ± 0.0293. The synthesized benzoxazole-triazole (8a–c) and benzoxazole-thiadiazole (9a–c) hybrids showed similar urease inhibitory activities with IC₅₀ (μM), ranging from 0.3861 ± 0.0379 to 0.5126 ± 0.0345. The antioxidant activity of the synthesized compounds was evaluated for their antioxidant activities, such as reducing power and ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt) radical scavenging. The results of ABTS radical scavenging activities of some of the synthesized molecules showed higher activities than standard Trolox, SC₅₀ (μM) = 213.04 ± 18.12. One benzoxazole-coumarin (6f), two benzoxazole-isothiocyanate (7b, 7c), and two benzoxazole-triazole (8b, 8c) derivatives showed higher activities (SC₅₀ (μM) values, 82.07 ± 10.34, 120.19 ± 7.30, 104.58 ± 10.55, 153.26 ± 7.14, and 144.82 ± 10.68, respectively) than standard Trolox, (SC₅₀ (μM) = 213.04 ± 18.12).

Full text of DOI:10.1002/jhet.4165

Synthesis and Biological Evaluation of Some 1,3-Benzoxazol-2(3H)-one Hybrid
Molecules as potential Antioxidant and Urease Inhibitors
Fatih YILMAZ1*, Emre MENTEŞE2 and Bahar BİLGİN SÖKMEN3
1Department of Chemistry and Chemical Process Technology, Vocational School of
Technical Sciences, Recep Tayyip Erdogan University, Rize, Turkey
2Department of Chemistry, Faculty of Art and Sciences, Recep Tayyip Erdogan University,
Rize, Turkey
3Department of Chemistry, Faculty of Art and Sciences, Giresun University, 28049, Giresun,
Turkey.
*fyilmaz@erdogan.edu.tr
Abstract
A new series 1,3-benzoxazol-2(3H)-one hybrid compounds including coumarin, isatin 1,3,4-
triazole and 1,3,4-thiadiazole moieties were synthesized and biologically evaluated for their
antioxidant capacities and antiurease properties. The synthesized benzoxazole-coumarin (6a-
e) and benzoxazole-isatin (10a-c) hybrids showed remarkable urease inhibitory activities with
IC50 (μM) ranging from 0.0306 ± 0.0030 to 0.0402 ± 0.0030, while IC50 of standard thiourea
is 0.5027 ± 0.0293. The synthesized benzoxazole-triazole (8a-c) and benzoxazole-thiadiazole
(9a-c) hybrids showed similar urease inhibitory activities with IC50 (μM) ranging 0.3861 ±
0.0379 to 0.5126 ± 0.0345. The antioxidant activity of synthesized compounds were evaluated
for their antioxidant activities such as reducing power and ABTS (2,2′-azino-bis(3-
ethylbenzothiazoline-6-sulphonic acid) diammonium salt) radical scavenging. The results of
ABTS radical scavenging activities of some of the synthesized molecules showed higher
activities than standard trolox, SC50 (μM)= 213.04 ± 18.12. One benzoxazol-coumarin (6f),
two benzoxazole-isothiocyanate (7b, 7c) and two benzoxazole-triazole (8b, 8c) derivatives
showed higher activities (SC50 (μM) values, 82.07 ± 10.34, 120.19 ± 7.30, 104.58 ± 10.55,
153.26 ± 7.14 and 144.82 ± 10.68, repectively) than standard Trolox, (SC50 (μM)= 213.04 ±
18.12).
Keywords: Benzoxazole, Antioxidant activity, ABTS radical scavenging activity, Antiurease
activity
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1. Introduction
Urease enzyme, (EC 3.5.1.5), is a nickel-dependent metalloenzyme that catalyses
the hydrolysis of urea to carbon dioxide and ammonia [1]. Urease enzyme belongs to
the family of amidohydrolases and
phosphotriesterases.
It
is
found
in
some bacteria, fungi, plants, and some invertebrate animals, and soils, as a soil enzyme. The
increasing amount of ammonia causes rising of pH in the aqueous reaction medium that
causes the survival of Helicobacter pylori [2]. It is known that Helicobacter pylori causes
some gastroduodenal disorders such as peptic gastric, ulcer, gastric cancer [3,4].
Urease inhibitors are promising agents to prevent the effects of ureolytic bacterial
infections [5]. The inhibition of these enzymes has leaded to organic chemists for designing
new molecules which can be used as urease inhibitors. Urease enzyme can be inhibited by
different kinds of compounds such as coumarins, thiadiazoles, triazoles, semicarbazones,
isatins and Schiff bases[6–13]. Over the last years, many antiurease compounds have been
reported and they have received special attentions due to their activities [10,14].
The use of antioxidants is known as the most effective way to protect the human
organism against cellular damages caused by oxidative stress. Oxidative stress can be caused
numerous diseases such as liver damage [15], cancer [16], myocardial infarction
[17], Alzheimer’s disease [18] and Parkinson’s disease [19]. However, there is no certainty on
whether oxidants trigger these diseases, or are produced as a secondary consequence of the
diseases [20]. For these reasons, it is very important to design and synthesize new antioxidant
drugs.
Nitrogen and oxygen containing five membered compounds are important bioactive
compounds because of their wide range of pharmacological applications. Benzoxazole
derivatives have attracted much attention in last years due to their wide use for the synthesis
of new biological compounds. They have become important heterocycle in medicinal
chemistry due to their wide range of biological properties [21–27]. A number of drugs which
have benzoxazole moiety are found in market like nonsteroidal, Priaxim and Benoxaprofen
(as anti-inflammatory drugs), Calcimycin and Boxazomycin B (as antibiotic) and
Chloroxazone (as muscle relaxant).
2
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Previously, we have synthesized and evaluated some quinazolin‐4(3H)‐one-coumarin
hybrid derivatives that showed strong urease activities [28–31]. Then, we have obtained
biological activity results above average close to the target value. Also, in our literature
survey, we have observed the role of benzoxazole moiety in drug design and development.
So, in this work, we have worked on the benzoxazole compounds containing coumarin, 1,2,4-
triazole, 1,2,4-thiadiazole and isatin groups. The aim of this work is to understand the effect
of these moieties with benzoxazole on antioxidant and urease inhibition activities.
2. Result and Discussion
2.1.Chemistry
Initially, 1,3-benzoxazol-2-one (1) compound was synthesized from the reaction of 2-
aminophenol and urea by using HCl as a catalyst.[32] Then, compound 1 was reacted with
ethyl bromoacetate in ethanolic sodium ethoxide to obtain ester derivative (2). 2-(2-Oxo-1,3-
benzoxazol-3(2H)-yl)acetohydrazide (3) was synthesized from the reaction of compound 2
and hydrazine hydrate.
In the next step, 3‐(1H ‐benzotriazol‐1‐ylcarbonyl)‐2H ‐chromen‐2‐ones (5a–f) were
obtained. Firstly, coumarin‐3‐carboxylic acids (4a–f) were synthesized from the reaction of
Meldrum’s acid and salicylaldehyde derivatives in ethanol (containing 1 mL of pyridine). Our
literature search has shown that benzotriazole group is an easy leaving group and thus offers
many advantages for synthetic applications [33]. Therefore, compounds 4a-f were reacted
with 1H ‐benzotriazole in dichloromethane to obtain compounds 5a-f (Scheme 1.).
3
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a
b
Cl
H
H
c
Br
H
H
d
e
H
f
H
H
H
H
Cl
H
R1
R2
R3
N(Et)2
H
H
Cl
OCH3
Scheme 1. Synthesis of compounds 1-5
In the last step, the targeted molecules were prepared. To do this, benzoxazole derivatives
were converted to coumarin derivatives (6a-f) from the reaction of compound 3 and compounds 5a-f
in absolute ethanol. Thiosemicarbazide derivatives (7a-c) were prepared by the nucleophilic addition
of 2-(2-oxo-1,3-benzoxazol-3(2H)-yl)acetohydrazide (3) to corresponding isothiocyanate derivatives.
Intramolecular cyclization of compounds 7a-c in the presence of NaOH solution under reflux
condition resulted in the formation of 1,2,4‐triazole derivatives (8a-c). The cyclization of
compounds 7a-c with concentrated sulfuric acid resulted in the formation of thiadiazole derivatives
(9a-c). We have also prepared benzoxazole-isatin hybrids (10a–c) with Schiff base formation reaction
(Scheme 2.).
4
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Scheme 2. Synthesis of benzoxazole hybrid molecules (6-10)
2.2. Biological Activity
2.2.1. Antioxidant Capacity
Table 1 showed the ABTS radical scavenging activity of synthesized compounds
compared with Trolox. ABTS radical scavenging activity increased with increasing
concentration. Lower SC50 values indicate higher ABTS radical scavenging ability. All of the
compounds (82.07-1241.33 µM) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic
acid (Trolox) as standard antioxidant (SC50= 213.04 ± 18.12 µM) showed ABTS radical
scavenging activity. The lowest and highest activities were found at compounds 1 and 6f,
respectively.
5
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Table 1. The ABTS antioxidant activities of synthesized compounds (1-10).
Compounds
ABTS
Compounds
ABTS
SC50 (μM)*
SC50 (μM)*
1241.33 ± 117.32
503.07± 27.36
472.35 ± 33.52
435.35 ± 37.92
439.90 ± 49.99
427.19 ± 33.96
82.07 ± 10.34
131.13 ± 6.20
120.19 ± 7.30
104.58 ± 10.55
159.21 ± 8.12
153.26 ± 7.14
144.82 ± 10.68
726.59 ± 21.99
690.41 ± 19.93
558.01 ± 28.76
630.92 ± 73.85
549.38 ± 33.75
499.91 ± 44.36
213.04 ± 18.12
1
8a
8b
8c
9a
9b
6a
6b
6c
6d
6e
6f
7a
7b
7c
9c
10a
10b
10c
Trolox
*Values were the means of three replicates ± Standard deviation (SD).
The reducing power capacities of the synthesized compounds were studied at different
concentrations (25-100 µg/mL), and results were compared with butylated hydroxytoluene
(BHT) (Table 2). The reducing power capacity of a compound may serve as a major indicator
for its antioxidant activity [34]. In this study, the reducing ability of compounds synthesized
raised with increasing concentration of samples. Compounds 6a, 6c, 6d, 9a, 9b, 9c, 10a, 10b
and 10c showed similar results. The highest and lowest activity was observed at compounds
6f and 1. 6f and 7b compounds showed higher activity than BHT at all concentrations.
6
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Table 2. The reducing power antioxidant activity of synthesized compounds (1-10).
Reducing
Power
Reducing
Power
Reducing
Power
Compounds
Compounds
Compounds
Absorbance*
Absorbance*
Absorbance*
0.077 ± 0.011
0.095 ± 0.010
0.120 ± 0.011
0.130 ± 0.012
0.088 ± 0.009
0.114 ± 0.011
0.133 ± 0.011
0.159 ± 0.015
0.090 ± 0.011
0.114 ± 0.011
0.133 ± 0.011
0.159 ± 0.015
0.090 ± 0.012
0.108 ± 0.016
0.130 ± 0.012
0.157 ± 0.018
0.093 ± 0.009
0.109 ± 0.011
0.121 ± 0.012
0.131 ± 0.009
0.099 ± 0.008
0.116 ± 0.009
0.135 ± 0.011
0.150 ± 0.013
0.21 ± 0.013
0.251 ± 0.023
0.305 ± 0.028
0.351 ± 0.033
0.156 ± 0.015
0.185 ± 0.013
0.220 ± 0.018
0.316 ± 0.027
0.155 ± 0.018
0.182 ± 0.010
0.223 ± 0.016
0.302 ± 0.023
0.182 ± 0.023
0.202 ± 0.018
0.240 ± 0.013
0.306 ± 0.013
0.154 ± 0.015
0.163 ± 0.004
0.172 ± 0.016
0.208 ± 0.022
0.134 ± 0.01
0.153 ± 0.006
0.171 ± 0.012
0.201 ± 0.021
0.145 ± 0.009
0.173 ± 0.016
0.199 ± 0.022
0.227 ± 0.029
0.089 ± 0.013
0.103 ± 0.016
0.119 ± 0.011
0.143 ± 0.010
0.112 ± 0.010
0.132 ± 0.010
0.153 ± 0.010
0.174 ± 0.012
0.103 ± 0.013
0.130 ± 0.011
0.150 ± 0.012
0.172 ± 0.015
0.106 ± 0.011
0.119 ± 0.010
0.132 ± 0.011
0.150 ± 0.012
0.098± 0.013
0.116 ± 0.011
0.136 ± 0.010
0.153 ± 0.010
0.108 ± 0.009
0.125 ± 0.011
0.138 ± 0.010
0.161 ± 0.011
1
7a
7b
7c
9b
9c
6a
6b
6c
6e
6d
6f
10a
10b
8a
8b
10c
0.121 ± 0.011
0.162 ± 0.018
0.229 ± 0.021
0.301 ± 0.028
BHT
8c
9a
*Values were the means of three replicates ± Standard deviation (SD).
2.2.2. Urease Inhibitory Activity
All newly synthesized compounds showed effective urease inhibitory activities (Table
3). The inhibition was increased with increasing sample concentration. Lower IC50 values
indicate higher enzyme inhibitor activity. All of the synthesized compounds showed urease
inhibitory activity with IC50 value from 0.0306 ± 0.0030 to 1.1143 ± 0.2357 µM, while
7
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thiourea,which is used as standard urease inhibitor, showed IC50 value of 0.5027 ± 0.0293
µM. Compounds 6c, 6d, 6e and 10c proved to be the most potent showing an enzyme
inhibition activity with an IC50= 0.0307 ± 0.039, IC50= 0.0314 ± 0.0040; IC50= 0.0306 ±
0.0030 and IC50= 0.0316 ± 0.0012 μM, respectively. The least active compound 1 had an
IC50= 1.1143 ± 0.2357 μM.
Table 3. The urease activities of synthesized compounds (1-10).
Compounds Urease IC50 (μM)* Compounds Urease IC50 (μM)*
1.1143 ± 0.2357
0.0367± 0.0042
0.0341± 0.0037
0.0307 ± 0.0039
0.0314± 0.0031
0.0306 ± 0.0030
0.0333 ± 0.0029
0.4652 ± 0.0145
0.4441 ± 0.0127
0.3861 ± 0.0379
0.5377 ± 0.0547
0.5049 ± 0.0586
0.3999 ± 0.0302
0.5126 ± 0.0345
0.5031 ± 0.0559
0.4055 ± 0.0382
0.0402 ± 0.0030
0.0367 ± 0.0031
0.0316 ± 0.0012
0.5027 ± 0.0293
1
8a
8b
8c
9a
9b
6a
6b
6c
6d
6e
6f
7a
7b
7c
9c
10a
10b
10c
Thiurea
*Values were the means of three replicates ± Standard deviation (SD).
3. Conclusion
In summary, we have described the design, synthesis, antioxidant and in vitro antiurease
activity of benzoxazole hybrid molecules including coumarin, triazole, thiadiazole and isatin
functionalities. Most of the synthesized compounds displayed significant activity of
antioxidant and antiurease when compared with standard Trolox and thiourea. Among the
synthesized compounds, while most of the benzoxazole-coumarin hybrids showed weak
antioxidant activity, compound 6f, which includes OCH3 group on coumarin cycle, showed
efficient antioxidant activity (SC50= 82.07 ± 10.34 μM). Among the series, isothiocyanate
derivatives showed the most potent antioxidant activity after compound 6f, (SC50= 120.19 ±
7.30 for 7b and SC50= 104.58 ± 10.55 for 7c), while 1,2,4-triazole, 1,2,4-thiadiazole and isatin
derivatives showed weak antioxidant activities. In Urease inhibition studies, most of the
compounds showed more efficient activity than standard thiourea (IC50= 0.5027 ± 0.0293
μM). Among the series, coumarin derivatives (6a-f) and isatin derivatives (10a-c) showed the
most potent urease inhibition activities with IC50 value between 0.0306 ± 0.0030 (for 6f) and
0.0402 ± 0.0030 (for 10a). The results showed that the addition of coumarin and isatin
functionalities to benzoxazole cycle has caused an increase in urease inhibition activities.
8
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4. Experimental section
4.1.Chemistry
4.1.1. Synthesis of 1,3-benzoxazol-2-one (1):
This product was prepared by treating 2-amino phenol and urea in concentrated HCl for
4 hours as reported earlier [32].
Yield: 1.24 g, 92%; m.p.: 135-136 °C, (135 °C [32]).
4.1.2. Synthesis of Ethyl (2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (2):
This product was synthesized according to the literature [32].
Yield: 1.90 g, 86%; m.p.: 90-91 °C, (89 °C [32]).
4.1.3. 2-(2-Oxo-1,3-benzoxazol-3(2H)-yl)acetohydrazide (3):
Yield: 1.50 g, %72; m.p.: 215-217 °C, (215 °C [32]).
4.1.4. Synthesis of compounds 4a-f
These products were synthesized according to the literature [35].
2-Oxo-2H-chromene-3-carboxylic acid (4a): Yield: 1.39 g, 73%; m.p. 189–190 °C, (188 °C
[35]).
6-Chloro-2-oxo-2H-chromene-3-carboxylic acid (4b): Yield: 2.47 g, 76%; m.p. 194–195
°C; (mp 193 °C [36]).
6-Bromo-2-oxo-2H-chromene-3-carboxylic acid (4c): Yield: 1.80 g, 67%; m.p. 195–196 °C
(194–196 °C [35]).
6,8-Dichloro-2-oxo-2H-chromene-3-carboxylic acid (4d): Yield: 1.78 g, 69%; m.p. 222–
223°C (220–224 °C [37]).
7-Diethylamino-2-oxo-2H-chromene-3-carboxylic acid (4e): Yield: 1.95 g, 75%; m.p. 232–
233 °C (230–232 °C [38]).
8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (4f): Yield: 1.95 g, 75%; m.p. 215–216
°C (214–216 °C [39]).
4.1.5. Synthesis of compounds 5a-f
This product was synthesized according to the literature [35].
9
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3-(1H-Benzotriazol-1-ylcarbonyl)-2H-chromen-2-one (5a): Yield: 2.12 g, 73%; m.p. 179–
180 °C (176–177 °C [35]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6-chloro-2H-chromen-2-one (5b): Yield: 2.20 g, 63%;
m.p. 248–249 °C (248–249 °C [40]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6-bromo-2H-chromen-2-one (5c): Yield: 2.52 g, 68%;
m.p. 250–251 °C (m.p. 250–251 °C [37]).
3-(1H-Benzotriazol-1-ylcarbonyl)-6,8-dichloro-2H-chromen-2-one (5d): Yield: 2.34 g,
65%; m.p. 263–264 °C (263–264 °C [38]).
3-(1H-Benzotriazol-1-ylcarbonyl)-7-diethylamino-2H-chromen-2-one (5e): Yield: 2.46 g,
68%; m.p. 210–211 °C (210–211 °C [38]).
3-(1H-Benzotriazol-1-ylcarbonyl)-8-methoxy-2H-chromen-2-one (5f): Yield 2.46 g, 68%;
m.p. 236–237 °C (236–237 °C [41]).
4.1.6. Synthesis of compounds 6a-f
These products were synthesized according to the literature [35]. A solution of
compound 5a–f (0.01 mol) and 2-(2-oxo-1,3-benzoxazol-3(2H)-yl)acetohydrazide (3) (0.011
mol) in ethanol (15 ml) was placed in a round-bottomed flask. The mixture was refluxed for 8
h. After the completion of the reaction (monitored by TLC, ethyl acetate:hexane 3:1), the
mixture was cooled to room temperature, and a solid formed. This crude product was filtered
off and washed with ethanol.
2-Oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-carbohydrazide
1
(6a): Yield: 2.84 g, 75%; m.p.: 300-301 °C; H-NMR (DMSO-d6, 400 MHz): 4.76 (s, 2H,
CH2), 7.17-7.24 (m, 2H, Ar-H), 7.34 (t, J=7.6 Hz, 1H, Ar-H), 7.43 (t, J=7.6 Hz, 1H, Ar-H),
7.49 (d, J=8.4 Hz, 1H, Ar-H), 7.65 (d, J=7.6 Hz, 1H, Ar-H), 7.74 (t, J=7.2 Hz, 1H, Ar-H),
7.97 (d, J=7.2 Hz, 1H, Ar-H), 8.85 (s, 1H, coumarin C4-H), 10.64 (s, 1H, NH), 11.23 (s, 1H,
NH). 13C-NMR (DMSO-d6, 100 MHz): 43.45 (CH2), 111.91, 116.68, 118.38, 118.67, 121.53,
123.27, 123.79, 125.69, 127.03, 130.79, 134.92, 137.49 (Ar-C), 148.49 (coumarin-c4), 154.36
(coumarin-c3), 159.34, 160.22, 164.18, 169.64 (C=O). Elemental Analysis: Found, %: C
60.12; H 3.37; N 11.01. C19H13N3O6. Calculated, %: C 60.16; H 3.45; N 11.08.
6-Chloro-2-oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-
1
carbohydrazide (6b): Yield: 2,56 g, 62%; m.p.: 322-323 °C; H-NMR (DMSO-d6, 400
MHz): 4.75 (s, 2H, CH2), 7.19-7.24 (m, 2H, Ar-H), 7.34 (t, J=7.6 Hz, 1H, Ar-H), 7.45 (d,
10
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J=8.8 Hz, 1H, Ar-H), 7.65 (d, J=7.6 Hz, 1H, Ar-H), 7.85 (d, J=8.8 Hz, 1H, Ar-H), 8.21 (s,
1H, Ar-H), 8.78 (s, 1H, coumarin C4-H), 10.59 (s, 1H, NH), 11.19 (s, 1H, NH). 13C-NMR
(DMSO-d6, 100 MHz): 43.43 (CH2), 111.89, 117.18, 118.97, 119.64, 120.50, 121.52, 123.27,
123.87, 127.05, 132.54, 137.04, 137.44 (Ar-C), 147.08 (coumarin-c4), 153.37 (coumarin c3),
159.24, 160.68, 164.32, 169.69 (C=O). Elemental Analysis: Found, %: C 55.08; H 2.85; N
10.06. C19H12ClN3O6. Calculated, %: C 55.15; H 2.92; N 10.16.
6-Bromo-2-oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-
1
carbohydrazide (6c): Yield: 3.38 g, 74%; m.p.: 327-328 °C; H-NMR (DMSO-d6, 400
MHz): 4.81 (s, 2H, CH2), 7.15-7.23 (m, 2H, Ar-H), 7.36 (t, J=7.6 Hz, 1H, Ar-H), 7.48 (d,
J=8.4 Hz, 1H, Ar-H), 7.61 (d, J=7.6 Hz, 1H, Ar-H), 7.89 (d, J=8.4 Hz, 1H, Ar-H), 8.41 (s,
1H, Ar-H), 8.68 (s, 1H, coumarin C4-H), 10.69 (s, 1H, NH), 11.13(s, 1H, NH). 13C-NMR
(DMSO-d6, 100 MHz): 43.49 (CH2), 110.81, 116.38, 118.94, 119.04, 120.34, 121.59, 123.64,
125.87, 126.95, 133.55, 137.74, 138.44 (Ar-C), 148.02 (coumarin-c4), 154.35, (coumarin c3),
158.26, 160.43, 166.21, 169.53 (C=O). Elemental Analysis: Found, %: C 49.71; H 2.55; N
9.07. C19H12BrN3O6. Calculated, %: C 49.80; H 2.64; N 9.17.
6,8-Dichloro-2-oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-
1
carbohydrazide (6d): Yield: 2.91 g, 65%; m.p.: 317-318 °C; H-NMR (DMSO-d6, 400
MHz): 4.77 (s, 2H, CH2), 7.18-7.25 (m, 1H, Ar-H), 7.35 (t, J=8.0 Hz, 1H, Ar-H), 7.55 (d,
J=8.8 Hz, 1H, Ar-H), 7.65 (d, J=8.8 Hz, 1H, Ar-H), 7.79 (d, J=8.8 Hz, 1H, Ar-H), 8.13 (d,
J=1.6 Hz, 1H, Ar-H), 8.83 (s, 1H, coumarin C4-H), 10.63 (s, 1H, NH), 11.24 (s, 1H, NH).
13C-NMR (DMSO-d6, 100 MHz): 43.48 (CH2), 111.93, 118.75, 119.77, 120.11, 121.54,
123.28, 123.27, 123.77, 127.01, 129.32, 129.63, 134.23, 137.53 (Ar-C), 147.11 (coumarin-
c4), 153.02 (coumarin c3), 159.74, 164.16, 169.59 (C=O). Elemental Analysis: Found, %: C
50.83; H 2.43; N 9.33. C19H11Cl2N3O6. Calculated, %: C 50.91; H 2.47; N 9.38.
7-Diethylamino-2-oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-
1
carbohydrazide (6e): Yield: 3.37 g, 76%; m.p.: 283-284 °C; H-NMR (DMSO-d6, 400
MHz): 1.10 (t, J=7.2 Hz, 6H, 2xCH3), 3.37 (m, 4H, 2xNCH2), 4.75 (s, 2H, CH2), 6.57 (s, 1H,
Ar-H), 6.77 (d, J=8.8 Hz, 1H, Ar-H), 7.17-7.25 (m, 2H, Ar-H), 7.32 (t, J=7.2 Hz, 1H, Ar-H),
7.65 (t, J=6.4 Hz, 2H, Ar-H), 8.65 (s, 1H, coumarin C4-H), 10.50 (s, 1H, NH), 11.14 (s, 1H,
NH). 13C-NMR (DMSO-d6, 100 MHz): 12.72 (2xCH3), 43.43 (CH2), 44.87 (2xNCH2), 96.31,
107.87, 108.06, 110.80, 111.90, 121.51, 123.24, 123.78, 123.03, 137.50 (Ar-C), 148.50
11
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(coumarin-c4), 153.27 (coumarin c3), 157.82 (Ar-C), 160.45, 161.80, 163.96, 169.63 (C=O).
Elemental Analysis: Found, %: C 61.26; H 4.88; N 12.39. C23H22N4O6. Calculated, %: C
61.33; H 4.92; N 12.44.
8-Methoxy-2-oxo-N'-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]-2H-chromene-3-
1
carbohydrazide (6f): Yield: 2.94 g, 72%; m.p.: 326-327 °C; H-NMR (DMSO-d6, 400
MHz): 4.01 (s, 3H, OCH3), 4.72 (s, 2H, CH2), 7.04 (s, 1H, Ar-H), 7.11(d, J=8.4 Hz, 1H, Ar-
H), 7.16-7.24 (m, 2H, Ar-H), 7.35 (t, J=7.2 Hz, 1H, Ar-H), 7.67 (t, J=6.4 Hz, 2H, Ar-H), 8.71
(s, 1H, coumarin C4-H), 10.44 (s, 1H, NH), 11.24 (s, 1H, NH). 13C-NMR (DMSO-d6, 100
MHz): 43.43 (CH2), 44.87 (OCH3), 96.36, 105.35, 107.17, 110.25, 112.45, 117.45, 121.24,
122.56, 123.98, 125.43, 138.46 (Ar-C), 147.54 (coumarin-c4), 154.35 (coumarin c3), 158.48
(Ar-C), 160.21, 162.35, 165.96, 169.47 (C=O). Elemental Analysis: Found, %: C 58.62; H
3.63; N 10.21. C20H15N3O7. Calculated, %: C 58.68; H 3.69; N 10.27.
4.1.7. Synthesis of compounds 7a-c
These compounds were synthesized according to the literature [28]. A mixture of 2-(2-
oxo-1,3-benzoxazol-3(2H)-yl)acetohydrazide
(3) (0.01ꢀmol)
and
corresponding
isothiocyanate (0.011ꢀmol) was refluxed in ethanol (15ꢀmL) for 3ꢀh. The solution was cooled
and a solid appeared. The precipitated product was filtrated and recrystallized from ethanol to
obtain the desired pure product 7a-c.
N-Methyl-2-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]hydrazine carbothioamide (7a):
1
Yield: 2.66 g, 95%; m.p.: 232-233 °C; H-NMR (DMSO-d6, 400 MHz): 3.62 (s, 3H, CH3),
4.68 (s, 2H, CH2), 7.16-7.20 (m, 2H, Ar-H), 7.32 (t, J=7.6 Hz, 1H, Ar-H), 7.62 (d, J=7.6 Hz,
1H, Ar-H), 8.07 (s, 1H, NH), 9.30 (s, 1H, NH), 10.24 (s, 1H, NH). 13C-NMR (DMSO-d6, 100
MHz): 31.34 (CH3), 43.60 (CH2), 111.99, 121.44, 123.22, 123.84, 127.00, 137.47 (Ar-C),
166.47 (C=O), 169.77 (C=S). Elemental Analysis: Found, %: C 47.04; H 4.22; N 19.86.
C11H12N4O3S. Calculated, %: C 47.13; H 4.32; N 19.99.
N-Ethyl-2-[(2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl]hydrazine carbothioamide (7b): Yield:
2.55 g, 87%; m.p.: 235-236 °C; 1H-NMR (DMSO-d6, 400 MHz): 1.04 (t, J=6.4 Hz, 3H, CH3),
3.66 (m, 2H, CH2), 4.68 (s, 2H, CH2), 7.18-7.21 (m, 2H, Ar-H), 7.33 (t, J=8.0 Hz, 1H, Ar-H),
7.62 (d, J=8.0 Hz, 1H, Ar-H), 8.03 (s, 1H, NH), 9.22 (s, 1H, NH), 10.22 (s, 1H, NH). 13C-
NMR (DMSO-d6, 100 MHz): 14.81 (CH3), 43.61 (2CH2), 112.00, 121.45, 123.23, 123.87,
12
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127.00, 137.44 (Ar-C), 166.38 (C=O), 169.86 (C=S). Elemental Analysis: Found, %: C 48.88;
H 4.68; N 18.96.C12H14N4O3S. Calculated, %: C 48.97; H 4.79; N 19.04.
N'-[(4-Methylphenyl)carbonothioyl]-2-(2-oxo-1,3-benzoxazol-3(2H)-yl)acetohydrazide
1
(7c): Yield: 2.69 g, 79%; m.p.: 245-246 °C; H-NMR (DMSO-d6, 400 MHz): 2.27 (s, 3H,
CH3), 4.74 (m, 2H, CH2), 7.13-7.27 (m, 5H, Ar-H), 7.32 (t, J=6.4 Hz, 2H, Ar-H), 7.64 (d,
J=7.6 Hz, 1H, Ar-H), 9.63 (s, 2H, NH), 10.44 (s, 1H, NH). 13C-NMR (DMSO-d6, 100 MHz):
31.00 (CH3), 43.76 (CH2), 112.06, 121.45,121.47, 123.27, 123.80, 126.96, 129.16, 136.75,
137.56 (Ar-C), 169.70 (C=O). Elemental Analysis: Found, %: C 57.21; H 4.47; N
15.63.C17H16N4O3S. Calculated, %: C 57.29; H 4.52; N 15.72.
4.1.8. Synthesis of compounds 8a-c
These compounds were synthesized according to the literature [30]. In a round-
bottomed flask, 1ꢀM NaOH (10ꢀmL) solution and 0.01ꢀmol of compounds 7a-c in ethanol (10
mL) were refluxed for 5ꢀhours. At the end of this time, the mixture was taken in a beaker with
water and the product was precipitated by neutralization with diluted HCl. The product was
filtered off, washed with water and recrystallized from ethanol.
3-[(5-Mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-benzoxazol-2(3H)-one
1
(8a): Yield: 2.25 g, 86%; m.p.: 128-129 °C; H-NMR (DMSO-d6, 400 MHz): 4.45 (s, 3H,
CH3), 5.30 (s, 2H, CH2), 6.46 (t, J=7.6 Hz, 1H, Ar-H), 6.75 (d, J=8.0 Hz, 1H, Ar-H), 6.92 (d,
J=8.0 Hz, 1H, Ar-H), 7.19 (d, J=8.0 Hz, 1H, Ar-H),13.61 (s, 1H, SH). 13C-NMR (DMSO-d6,
100 MHz): 30.42 (CH3), 37.36 (CH2), 112.25, 118.09,123.40, 124.06, 127.09, 132.42, 147.16
(Ar-C), 148.41, 150.42 (C=N), 167.67 (C=S). Elemental Analysis: Found, %: C 50.29; H
3.76; N 21.30. C11H10N4O2S. Calculated, %: C 50.37; H 3.84; N 21.36.
3-[(5-Mercapto-4-ethyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-benzoxazol-2(3H)-one
1
(8b): Yield: 2.45 g, 89%; m.p.: 178-199 °C; H-NMR (DMSO-d6, 400 MHz): 1.15 (t, J=7.2
Hz, 3H, CH3), 4.04 (d, J=7.2 Hz, 2H, CH2), 5.35 (s, 2H, NCH2), 7.21-7.27 (m, 1H, Ar-H),
7.35 (d, J=8.0 Hz, 2H, Ar-H), 7.69 (d, J=8.0 Hz, 1H, Ar-H),13.71 (s, 1H, SH). 13C-NMR
(DMSO-d6, 100 MHz): 13.58 (CH3), 37.62, 39.09 (CH2), 112.23, 121.57, 123.52, 124.11,
127.19, 136.84, 147.33 (Ar-C), 167.49 (C=N), 169.54 (C=S). Elemental Analysis: Found, %:
C 52.09; H 4.31; N 20.20. C12H12N4O2S. Calculated, %: C 52.16; H 4.38; N 20.28.
13
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3-{[5-Mercapto-4-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]methyl}-1,3-benzoxazol-
2(3H)-one (8c): Yield: 2.94 g, 87%; m.p.: 189-190 °C; 1H-NMR (DMSO-d6, 400 MHz): 2.26
(s, 3H, CH3), 4.74 (s, 2H, NCH2), 7.12-7.33 (m, 6H, Ar-H), 7.58-7.64 (m, 2H, Ar-H), 13.91
(s, 1H, SH). 13C-NMR (DMSO-d6, 100 MHz): 21.20 (CH3), 38.10 (CH2), 111.99, 121.54,
127.01, 127.87, 130.48, 130.58, 136.67, 139.94 (Ar-C), 147.51 (2C=N), 169.10 (C=S).
Elemental Analysis: Found, %: C 60.28; H 4.11; N 16.48. C17H14N4O2S. Calculated, %: C
60.34; H 4.17; N 16.56.
4.1.9. Synthesis of compounds 9a-c
These products were synthesized according to the literature procedure [28]. The
compound 7a-c (0.01ꢀmol) was dissolved with cold H2SO4 in the ice bath. The mixture was
stirred in ice bath for nearly an hour and then at room temperature nearly an hour too. At the
end of this time, the mixture was taken in a beaker filled with ice and the product was
precipitated by neutralization with NH3. The product was filtered off and recrystallized from
ethanol.
3-{[5-(Methylamino)-1,3,4-thiadiazol-2-yl]methyl}-1,3-benzoxazol-2(3H)-one (9a):
1
Yield: 2.25 g, 86%; m.p.[: 185-186 °C; H-NMR (DMSO-d6, 400 MHz): 2.25 (s, 3H, CH3),
5.39 (s, 2H, NCH2), 7.18 (d, J=8.0 Hz, 1H, Ar-H), 7.18-7.23 (m, 2H, Ar-H), 7.45 (d, J=8.0
13
Hz, 1H, Ar-H). C-NMR (DMSO-d6, 100 MHz): 38.75 (CH3), 40.56 (CH2), 112.07, 118.11,
129.92, 131.67, 136.50, 138.57 (Ar-C), 153.21 (C=N), 169.39 (C=O). Elemental Analysis:
Found, %: C 50.31; H 3.75; N 21.32. C11H10N4O2S. Calculated, %: C 50.37; H 3.84; N 21.36.
3-{[5-(Ethylamino)-1,3,4-thiadiazol-2-yl]methyl}-1,3-benzoxazol-2(3H)-one
(9b):
1
Yield: 2.23 g, 81%; m.p.: 167-168 °C; H-NMR (DMSO-d6, 400 MHz): 1.15 (t, J=7.2 Hz,
3H, CH3), 4.42 (q, J=7.2 Hz, 2H, CH2), 5.42 (s, 2H, NCH2), 7.21 (d, J=7.6 Hz, 1H, Ar-H),
7.25-7.39 (m, 2H, Ar-H), 7.55 (d, J=7.6 Hz, 1H, Ar-H). 13C-NMR (DMSO-d6, 100 MHz):
11.53 (CH2), 39.75 (CH2), 40.56 (CH2), 112.55, 118.26, 130.94, 133.61, 135.52, 139.69 (Ar-
C), 154.76 (C=N), 169.87 (C=O). Elemental Analysis: Found, %: C 52.05; H 4.30; N 20.16.
C12H12N4O2S. Calculated, %: C 52.16; H 4.38; N 20.28.
3-({5-[(4-Methylphenyl)amino]-1,3,4-thiadiazol-2-yl}methyl)-1,3-benzoxazol-2(3H)-
1
one (9c): Yield: 2.57 g, 76%; m.p.: 198-199 °C; H-NMR (DMSO-d6, 400 MHz): 2.20 (s,
3H, CH3), 5.41 (s, 2H, NCH2), 7.10 (d, J=8.0 Hz, 2H, Ar-H), 7.18-7.23 (m, 1H, Ar-H), 7.34-
14
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13
7.42 (m, 4H, Ar-H), 7.65 (d, J=8.0 Hz, 1H, Ar-H). C-NMR (DMSO-d6, 100 MHz): 20.75
(CH3), 40.98 (CH2), 112.07, 118.11, 121.75, 123.53, 124.12, 127.51, 129.92, 131.67, 136.50,
138.57 (Ar-C), 153.21 (C=N), 169.39 (C=O). Elemental Analysis: Found, %: C 60.23; H
4.10; N 16.45. C12H12N4O2S. Calculated, %: C 60.34; H 4.17; N 16.56.
4.1.10. Synthesis of compounds 10a-c
These products were synthesized according to the literature procedure [42]. Equimolar
quantities (0.01 mol) of isatin derivative and compound 3 were dissolved in warm ethanol (40
mL) containing glacial acetic acid (0.5 mL). The reaction mixture was refluxed for 5 h
(monitored by TLC, ethylacetate:Hexane, 3:1) and then kept at room temperature overnight.
The resulting solid was washed with ethanol, dried and recrystallised from ethanol to afford
compounds 10a-c.
2-(2-Oxo-1,3-benzoxazol-3(2H)-yl)-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]
1
acetohydrazide (10a): Yield: 2.79 g, 83%, m.p.: 223-224 °C; H-NMR (DMSO-d6, 400
MHz): 5.23 (s, 2H, NCH2), 6.91 (d, J=7.6 Hz, 1H, Ar-H), 7.04 (brs, 1H, Ar-H), 7.20 (t, J=8.4
Hz, 1H, Ar-H), 7.32-7.39 (m, 3H, Ar-H), 7.69 (d, J=8.0 Hz, 1H, Ar-H), 8.14 (d, J=8.4 Hz,
1H, Ar-H), 10.84 (s, 1H, NH), 11.64 (s, 1H, NH). 13C-NMR (DMSO-d6, 100 MHz): 44.36
(CH2), 96.76, 110.41, 112.07, 118.11, 119.75, 122.59, 124.12, 128.41, 130.12, 132.51,
136.78, 139.65 (Ar-C), 147.71 (C=N), 163.34, 165.71, 169.39 (C=O). Elemental Analysis:
Found, %: C 60.63; H 3.51; N 16.54. C17H12N4O4. Calculated, %: C 60.71; H 3.60; N 16.66.
N'-[5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-2-(2-oxo-1,3-benzoxazol-
3(2H)-yl)acetohydrazide (10b): Yield: 2.66 g, 72%; m.p.: 239-240°C; 1H-NMR (DMSO-d6,
400 MHz): 5.22 (s, 2H, NCH2), 6.92 (d, J=8.4 Hz, 1H, Ar-H), 7.18-7.23 m, 1H, Ar-H), 7.34
(brs, 2H, Ar-H), 7.32-7.39 (m, 3H, Ar-H), 7.43 (brs, 1H, Ar-H), 7.69 (d, J=8.0 Hz, 1H, Ar-
H), 8.35 (s, 1H, Ar-H), 10.86 (s, 1H, NH), 11.87 (s, 1H, NH). 13C-NMR (DMSO-d6, 100
MHz): 44.67 (CH2), 98.72, 110.22, 113.17, 116.17, 118.71, 120.36, 122.19, 125.44, 131.35,
135.41, 137.39, 140.47 (Ar-C), 148.27 (C=N), 163.24, 168.01, 169.49 (C=O). Elemental
Analysis: Found, %: C 55.01; H 2.92; N 15.03. C17H11ClN4O4. Calculated, %: C 55.07; H
2.99; N 15.11.
N'-[5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-2-(2-oxo-1,3-benzoxazol-
3(2H)-yl)acetohydrazide (10c): Yield: 3.27 g, 79%; m.p.: 256-257 °C; 1H-NMR (DMSO-d6,
15
This article is protected by copyright. All rights reserved.

400 MHz): 5.22 (s, 2H, NCH2), 6.92 (d, J=8.4 Hz, 1H, Ar-H), 7.18-7.23 m, 1H, Ar-H), 7.34
(brs, 2H, Ar-H), 7.32-7.39 (m, 3H, Ar-H), 7.43 (brs, 1H, Ar-H), 7.69 (d, J=8.0 Hz, 1H, Ar-
H), 8.35 (s, 1H, Ar-H), 10.96 (s, 1H, NH), 11.88 (s, 1H, NH). 13C-NMR (DMSO-d6, 100
MHz): 44.76 (CH2), 99.70, 110.23, 114.57, 116.77, 118.31, 121.30, 123.69, 126.48, 132.36,
134.48, 138.30, 141.40 (Ar-C), 147.22 (C=N), 162.23, 165.55, 168.41 (C=O). Elemental
Analysis: Found, %: C 49.07; H 2.62; N 13.43. C17H11BrN4O4. Calculated, %: C 49.18; H
2.67; N 13.49.
4.2.Biological Activity
4.2.1. ABTS+ scavenging activity
The ABTS+ scavenging activities of the synthesized compounds were measured
according to the procedure described by Arnao et al. (2001) [43].
4.2.2. Reducing power
The reducing power capacities of the synthesized compounds were determined
according to the method described by Oyaizu (1986) [44].
4.2.3. Urease inhibition assay
Urease inhibitory activities of the synthesized compounds were assayed according to the
previously reported procedure [45].
Acknowledgements
This work was supported by Research Fund of Recep Tayyip Erdogan University under
the Project Number of FBA-2018-858. Author thanks all the colleagues in the project unit for
this support.
Conflict of Interest
The authors declare no conflict of interest.
REFERENCES
[1] B. Zambelli, F. Musiani, S. Benini, S. Ciurli, Acc. Chem. Res. 2011, 44 (7), 520.
[2] H. L. T. Mobley, R. P. Hausinger, Microbiol. Rev. 1989, 85.
[3] Zaheer-ul-Haq, M. A. Lodhi, S. Ahmad Nawaz, S. Iqbal, K. Mohammed Khan, B. M.
Rode, Atta-ur-Rahman, M. I. Choudhary, Bioorg. Med. Chem. 2008, 16 (6), 3456.
16
This article is protected by copyright. All rights reserved.

[4] T. Tanaka, M. Kawase, S. Tani, Life Sci. 2003, 73 (23), 2985.
[5] M. Hanif, M. Saleem, M. T. Hussain, N. H. Rama, S. Zaib, M. A. M. Aslam, P. G.
Jones, J. Iqbal, J. Braz. Chem. Soc. 2012, 23 (5), 854.
[6] O.-U.-R. Abid, T. M. Babar, F. I. Ali, S. Ahmed, A. Wadood, N. H. Rama, R. Uddin,
Zaheer-Ul-Haq, A. Khan, M. I. Choudhary, ACS Med. Chem. Lett. 2010, 1 (4), 145.
[7] H. Pervez, Z. H. Chohan, M. Ramzan, F.-U.-H. Nasim, K. M. Khan, J. Enzyme Inhib.
Med. Chem. 2009, 24 (2), 437.
[8] S. Perveen, K. M. Khan, M. A. Lodhi, M. I. Choudhary, Atta-ur-Rahman, W. Voelter,
Lett. Drug Des. Discov. 2008, 5 (6), 401.
[9] S. Shamim, K. M. Khan, U. Salar, F. Ali, M. A. Lodhi, M. Taha, F. A. Khan, S.
Ashraf, Z. Ul-Haq, M. Ali, et al., Bioorg. Chem. 2018, 76, 37.
[10] M. Taha, A. Wadood, Bioorg. Chem. 2018, 78, 411.
[11] P. A. Channar, A. Saeed, S. Afzal, D. Hussain, M. Kalesse, S. A. Shehzadi, J. Iqbal,
Mol. Divers. 2020.
[12] A. Saeed, A. Imran, P. A. Channar, M. Shahid, W. Mahmood, J. Iqbal, Chem. Biol.
Drug Des. 2015, 85 (2), 225.
[13] M. A. S. Aslam, S. Mahmood, M. Shahid, A. Saeed, J. Iqbal, Eur. J. Med. Chem. 2011,
46 (11), 5473.
[14] P. Kafarski, M. Talma, J. Adv. Res. 2018, 13, 101.
[15] J. Arauz, E. Ramos-Tovar, P. Muriel, Ann. Hepatol. 2016, 15 (2), 160.
[16] F. S. Aldawsari, R. P. Aguiar, L. A. M. Wiirzler, R. Aguayo-Ortiz, N. Aljuhani, R. K.
N. Cuman, J. L. Medina-Franco, A. G. Siraki, C. A. Velázquez-Martínez, Bioorganic
Med. Chem. Lett. 2016, 26 (5), 1411.
[17] M. Q. Hassan, M. S. Akhtar, M. Akhtar, J. Ali, S. E. Haque, A. K. Najmi, Redox Rep.
2015, 20 (6), 275.
[18] A. Nunomura, R. J. Castellani, X. Zhu, P. I. Moreira, G. Perry, M. A. Smith, J.
Neuropathol. Exp. Neurol. 2006, 65 (7), 631.
[19] A. Wood-Kaczmar, S. Gandhi, N. W. Wood, Trends Mol. Med. 2006, 12 (11), 521.
[20] Y. Teng, X. Li, K. Yang, X. Li, Z. Zhang, L. Wang, Z. Deng, B. Song, Z. Yan, Y.
Zhang, et al., Eur. J. Med. Chem. 2017, 125, 335.
[21] E. Menteşe, F. YIlmaz, N. Karaali, S. Ülker, B. Kahveci, Russ. J. Bioorganic Chem.
2014, 40 (3), 336.
[22] F. Yilmaz, M. Menteşe, Rev. Roum. Chim. 2017, 62 (12), 941.
[23] F. Yılmaz, N. Karaali, S. Şaşmaz, Bull. Chem. Soc. Ethiop. 2017, 31 (2), 351.
17
This article is protected by copyright. All rights reserved.

[24] X. Yuan, Q. Yang, T. Liu, K. Li, Y. Liu, C. Zhu, Z. Zhang, L. Li, C. Zhang, M. Xie, et
al., Eur. J. Med. Chem. 2019, 179, 147.
[25] A. Kaur, D. P. Pathak, V. Sharma, S. Wakode, Bioorg. Med. Chem. 2018, 26 (4), 891.
[26] D. Seenaiah, P. R. Reddy, G. M. Reddy, A. Padmaja, V. Padmavathi, N. Siva krishna,
Eur. J. Med. Chem. 2014, 77, 1.
[27] A. M. Vijesh, A. M. Isloor, P. Shetty, S. Sundershan, H. K. Fun, Eur. J. Med. Chem.
2013, 62, 410.
[28] E. Menteşe, G. Akyüz, M. Emirik, N. Baltaş, Bioorg. Chem. 2019, 83, 289.
[29] G. Akyüz, F. Ş. Beriş, B. Kahveci, E. Menteşe, J. Heterocycl. Chem. 2019, 56 (11),
3065.
[30] E. Menteşe, G. Akyüz, F. Yılmaz, N. Baltaş, M. Emirik, Arch. Pharm. (Weinheim).
2018, 351 (12), 1800182.
[31] G. Akyüz, E. Menteşe, M. Emirik, N. Baltaş, Bioorg. Chem. 2018, 80, 121.
[32] M. Safakish, Z. Hajimahdi, R. Zabihollahi, M. R. Aghasadeghi, R. Vahabpour, A.
Zarghi, Med. Chem. Res. 2017, 26 (11), 2718.
[33] A. R. Katritzky, B. V Rogovoy, Chem. – A Eur. J. 2003, 9 (19), 4586.
[34] S. Meir, J. Kanner, B. Akiri, S. Philosoph-Hadas, J. Agric. Food Chem. 1995, 43 (7),
1813.
[35] B. Kahveci, F. Yilmaz, E. Menteşe, S. Ülker, Chem. Heterocycl. Compd. 2015, 51 (5),
447.
[36] P. G. Baraldi, A. Bovero, F. Fruttarolo, D. Preti, M. A. Tabrizi, M. G. Pavani, R.
Romagnoli, Med. Res. Rev. 2004, 24 (4), 475.
[37] B. S. Creaven, D. A. Egan, K. Kavanagh, M. McCann, A. Noble, B. Thati, M. Walsh,
Inorganica Chim. Acta. 2006, 359 (12), 3976.
[38] M. Danko, E. Szabo, P. Hrdlovic, Dye. Pigment. 2011, 90 (2), 129.
[39] E. E. Shults, S. P. Bondarenko, M. M. Shakirov, I. Y. Bagryanskaya, G. A. Tolstikov,
Russ. J. Org. Chem. 2010, 46 (11), 1709.
[40] I. Kostova, Curr. Hiv Res. 2006, 4 (3), 347.
[41] F. Yılmaz, E. Menteşe, N. Baltaş, Russ. J. Bioorganic Chem. 2019, 45 (6), 575.
[42] M. Özil, E. Menteşe, F. Yilmaz, F. Islamoǧlu, B. Kahveci, J. Chem. Res. 2011, 35 (5),
268.
[43] M. B. Arnao, A. Cano, M. Acosta, Food Chem. 2001, 73 (2), 239.
[44] M. Oyaizu, Japanese J. Nutr. Diet. 1986, 44 (6), 307.
[45] E. Menteşe, M. Emirik, B. B. Sökmen, Bioorg. Chem. 2019, 86, 151.
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