Synthesis and free radical scavenging activity of 2-alkyl/arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)acetamide compounds

Article abstract of DOI:10.1016/j.tetlet.2016.01.079

The synthesis of a new series of organochalcogen-derivatives, 2-alkyl/arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)acetamides 5a-r, provided products in satisfactory yields, which varied from 42% to 95%. All these novel compounds were screened for their in vitro free radical scavenging activity against 2,2-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. Compounds 5 (m, h, i, f, q, g, l, c, n) were effective scavengers against the ABTS radical species but less effective on scavenging the DPPH radical, indicating that the antioxidant effect of these compounds were related to protonated radical scavenger activity.

Full text of DOI:10.1016/j.tetlet.2016.01.079

Accepted Manuscript
Synthesis and free radical scavenging activity of 2-alkyl/arylchalcogenyl-N-(4-
aryl-1,3-thiazol-2-yl)acetamides compounds
Lucas Wolf, Natália Quoos, João C.P. Mayer, Diego de Souza, André C. Sauer,
Luana Meichtry, Vandreza Bortolotto, Marina Prigol, Oscar E.D. Rodrigues,
Luciano Dornelles
PII:
S0040-4039(16)30078-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.079
TETL 47243
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2015
20 January 2016
21 January 2016
Please cite this article as: Wolf, L., Quoos, N., Mayer, J.C.P., Souza, D.d., Sauer, A.C., Meichtry, L., Bortolotto,
V., Prigol, M., Rodrigues, O.E.D., Dornelles, L., Synthesis and free radical scavenging activity of 2-alkyl/
arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)acetamides compounds, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.079
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis and free radical scavenging activity of
2-alkyl/arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)
acetamides compounds
Lucas Wolf , Natália Quoos , João C. P. Mayer , Diego de Souza , André C. Sauer , Luana Meichtry ,
Vandreza Bortolotto b, Marina Prigol b, Oscar E. D. Rodrigues a, Luciano Dornelles a,*
a
a
a
a
a
b

1
Tetrahedron Letters
Synthesis and free radical scavenging activity of 2-alkyl/arylchalcogenyl-N-(4-
aryl-1,3-thiazol-2-yl)acetamides compounds
a
a
a
Lucas Wolf a, Natália Quoos a, João C. P. Mayer , Diego de Souza , André C. Sauer , Luana Meichtry b,
Vandreza Bortolotto b, Marina Prigol b, Oscar E. D. Rodrigues a, Luciano Dornelles a,*
a Departamento de Química, Universidade Federal de Santa Maria, CEP 97.105-900 Santa Maria, RS, Brazil.
b Universidade Federal do Pampa, UNIPAMPA, Campus Itaqui, CEP 97.650-000 Itaqui, RS, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of a new series of organochalcogen-derivatives, 2-alkyl/arylchalcogenyl-N-(4-
aryl-1,3-thiazol-2-yl)acetamides 5a–r, provided products in satisfactory yields, which varied
from 42–95%. All these novel compounds were screened for their in vitro free radical
scavenging activity against 2,2-diphenyl-2-picrylhydrazyl (DPPH) and 2,2’-azino-bis-(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. Compounds 5 (m, h, i, f, q, g, l, c, n)
were effective scavengers against the ABTS radical species but less effective on scavenging the
DPPH radical, indicating that the antioxidant effect of these compounds were related to
protonated radical scavenger activity.
Available online
Keywords:
Heterocyclic
Thiazole
Organochalcogen
Antioxidant effect
 2015 Elsevier Ltd. All rights reserved.
Introduction
detoxification in a normal cellular metabolism is important to
keep mammalian cells in a healthy condition.
The exploration of new biologically active compounds
remains an area of intense research in medicinal chemistry.
Compounds containing
The accumulation of excessive reactive oxygen species
(ROS) can damage lipids, proteins, carbohydrates, and DNA in
cells, leading to oxidative stress, loss of cell function, and
ultimate apoptosis or necrosis.12c
a heterocyclic nucleus confer a
biologically important function, which serve as a key model in
developing various therapeutic agents.1 One of these heterocyclic
moieties refers to 1,3-thiazole, which has an active-membered
ring containing three carbon, one sulfur and one nitrogen atoms.
The thiazole ring is found naturally in vitamin B1 (thiamine),
which is responsible for assisting the body in releasing energy
from carbohydrates during metabolism and in the synthesis of
neurotransmitters, such as acetylcholine.2 In recent years,
applications of thiazoles have been found in the development of
antifungal,3 antimicrobial,4 anti-inflammatory,5 anticonvulsant
6
and antiparasitic drugs.7 Among the best known thiazolic
compounds are sulfathiazole (an important antimicrobial drug),8
Meloxicam (an important nonsteroidal anti-inflammatory drug),9
Pateamine A (an antiproliferative agent in tumor cell cultures)10
and Ritonavir (Norvir®), a drug used against HIV8,11 (Fig. 1).
The development of biologically active molecules can have its
biological potential affected by several factors12 such as those
related to the generation of balanced oxidants. Thus
Figure 1. Important thiazole nucleus-containing bioactive molecules.
———
All of the above-mentioned biochemical processes are
common problems in various diseases, such as cancer,
inflammation, atherosclerosis, and cardiovascular disease.
Therefore, exploring antioxidant chemicals that scavenge ROS
 Corresponding author. Tel.: +55-55 3220 8761; fax: +55-55 3220 8031.
E-mail address: ldornel@gmail.com (L. Dornelles).

2
Tetrahedron Letters
may be of great value in preventing the onset and propagation
The insertion of organochalcogen in N-(4-aryl-1,3-thiazol-2-
of oxidative stress.12
yl)-2-chloro-acetamide structure was then performed in order to
find a versatile route that could give the desired product in
satisfactory yields. Therefore, a new methodology developed by
Braga et. al. was chosen based on replacing halogen by a
chalcogen.17 The referring methodology presents advantages,
such as a simple reaction procedure combined with cost-
effectiveness and low toxicity of the employed reactants. Two
separate strategies were carried out in this study in order to obtain
the chalcogen-substituted product. The first approach Method I,
comprises the insertion of substituted sulfides derived from base-
treated commercially available thiols. The second Method II,
consists of inserting of aromatic selenides derived from their
respective previously prepared diselenides.
Organochalcogens have been widely studied given their
antioxidant activity, which confers neuroprotection, antiulcer,
and antidiabetic properties. More specifically, selenium-
containing molecules may be better nucleophiles (and therefore
antioxidants) than classical antioxidants leading to design
synthetic organoselenium compounds.13 As a consequence,
several reports have described the antioxidant activity of
organoselenium compounds in different experimental models.14
Considering the importance of reported 1,3-thiazole
derivatives as bioactive molecules, the present study proposed to
develop a simple and efficient methodology for preparing
substituted 1,3-thiazole derivatives, containing sulfur or selenium
as chalcogen substituent (Fig. 2).
In our initial screening experiments, 2-chloro-N-(4-phenyl-
1,3-thiazol-2-yl)acetamide 4a and thiophenol were selected as
substrates to optimize the reaction conditions. Preliminary
experiments showed that the reaction using K2CO3, Na2CO3, and
Et3N as base and in DCM (5 mL) as solvent under argon
atmosphere at room temperature provided the formation of the
product 5a in moderate yields (Table 1, entries 1-3). After that, a
series of experiments under varied conditions in terms of
solvents, temperature, and reaction time was carried out as
illustrated in Table 1. By elevating the temperature to 82 °C and
using Et3N in MeCN, N-(4-phenyl-1,3-thiazol-2-yl)-2-
(phenylthio)acetamide 5a in 88% yield was obtained (Table 1,
entry 8).
Figure 2. Target molecule.
In order to evaluate the pharmacological effectiveness of these
compounds, a standard assay of antioxidant activity was
performed. Studies that offer a rapid technique for screening the
radical scavenging activity (RSA) of specific compounds, such as
2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis-(3-
thylbenzothiazoline-6-sulfonic acid) (ABTS) radical, have been
used for the determination of scavenger mechanism of
antioxidant compounds.15
Table 1
Optimization of the reaction conditions for the synthesis of N-(4-phenyl-1,3-
thiazol-2-yl)-2-(phenylthio)acetamidea
Results and discussion
Entry
Solvent
Base
Temp.
(°C)
r.t.
r.t.
r.t.
r.t.
66
82
82
Time
(h)
12
12
12
12
3
3
3
3
Yieldb
(%)
40
55
68
73
74
58
70
Starting materials derived from arylethanones were obtained
through described experimental procedures found in literature as
illustrated in Scheme 1. Initially, starting compounds were
prepared through N-bromosuccinimide (NBS) halogenation of
various arylethanones, employing catalytic amounts of p-
toluenesulfonic acid (PTSA) in acetonitrile (MeCN), which led to
the derivatives 1-aryl-2-bromoethanones 2a-e in good yields.16
Compounds 2a-e were conveniently converted into their
respective 2-amino-1,3-thiazoles 3a-e through the reaction with
thiourea (NH2)2CS, and sodium hydrogen sulfate (NaHSO4) in
water, giving products in satisfactory yields (60-85%). The
following step yielded N-(4-aryl-1,3-thiazol-2-yl)-2-chloro-
acetamide 4, employing 2-amino-4-aryl-1,3-thiazole 3 and
chloracetyl chloride in triethylamine (Et3N) and tetrahydrofuran
(THF) at room temperature.
1
2
3
4
5
6
7
8
DCM
DCM
DCM
MeCN
THF
MeCN
MeCN
MeCN
Na 2CO3
K2CO3
Et3N
Et3N
Et3N
Na 2CO3
K2CO3
Et3N
82
88
a
Reactions were performed with 2-chloro-N-(4-phenyl-1,3-thiazol-2-
yl)acetamide 4a (1 mmol), thiophenol (1 mmol), base (1.5 mmol), and 5mL
of solvent under argon atmosphere.
b Yields for isolated pure products.
After studies to determine the ideal reaction conditions, to
access the generality of this method, and to test the tolerance of
functional groups as well as their effects on the insertion of
substituted sulfides derived, 2-chloro-N-(4-phenyl-1,3-thiazol-2-
yl)acetamide 4a was examined under the optimized conditions
(Table 1, entries 1–8). The influence of substituents at the R2
position of thiol was examined (Table 2, entries 1–7). Results
indicated that the reaction was not sensitive to the electronic
effects of the substituents directly bonded to the aromatic ring.
When thiol had its aromatic ring substituted by Me, OMe, or Cl
group, it gave similar yields (Table 2, entries 2–4). The presence
of an alkyl group directly bonded to the sulfur atom also afforded
the respective products in moderate yields (Table 2, entry 5–7).
The influence of the substituents in N-(4-aryl-1,3-thiazol-2-
yl)-2-chloro-acetamide was also evaluated. The presence of an
electron-donating group on the aromatic ring gave products in
good yields (Table 2, entries 8–9). The aromatic ring with
Scheme 1. Synthesis of the compounds 4a-e.

3
electron-withdrawing groups also worked well and gave products
in good yields (Table 2, entries 10–11). In order to expand the
scope of the methodology to other chalcogens, selenium
derivatives of N-(4-aryl-1,3-thiazol-2-yl)-2-chloro-acetamide
were prepared.
having the aromatic ring substituted by the Cl group gave the
product in low a yield (Table 2, entry 18).
A wide range of spectrophotometric assays were adopted to
measure the antioxidant capacity, and two types of approaches
were used: inhibition assays in which the extent of the
scavenging by hydrogen- or electron-donation of a pre-formed
free radical is the marker of antioxidant activity, and assays
involving the presence of antioxidant system during the
generation of the radical. The scavenger activity of proton
radicals by the protonated radical ABTS18 and the evaluation of
the free radical scavenging activity of antioxidants employed in
the DPPH assay is shown in Table 3.19 The EC50 values of the
scavenging activity on ABTS radical followed the order 5m > 5h
≥ 5i ≥ 5f ≥ 5q ≥ 5g ≥ 5l ≥ 5c > 5n. Compound 5m (EC50 of 16.10
µM) was more potent in scavenging the activity of ABTS radical
than compounds 5h, 5i, 5f, 5g, 5q, 5c, and 5n (EC50 of 22.5;
23.3; 25.00; 26.33; 25.03; 29.50 and 45.67 µM, respectively) and
ascorbic acid (EC50 = 21.67 µM). The ABTS radical scavenging
activity of compounds 5h, 5i, 5f, 5g, 5q, and 5c was similar than
that of ascorbic acid. Compounds 5a, 5b, 5d, 5e, 5j, 5k, 5o, 5p,
and 5r showed ABTS radical scavenging activity at
concentrations higher than 100 μM. The Imax of compounds on
ABTS radical followed the order 5i ≥ 5n ≥ 5h > 5m ≥ 5f ≥ 5g >
5q ≥ 5c > 5l, and was higher than 50% (Table 3). In the DPPH
assay, antioxidants could reduce the stable radical DPPH to the
yellow-colored DPPH. The compound is thus capable of
donating hydrogen to a free radical to remove the extra electron
(responsible for the activity of free radicals). In addition, proton-
radical scavenging is an important attribute of antioxidants.
Compounds 5a-r showed DPPH radical scavenging activity at
concentrations higher than 100 μM. The Imax of compounds
5a-r was lower than 20% (Table 3).
Table 2
Scope of substrates: synthesis of 2-alkyl/arylchalcogenyl-N-(4-aryl-1,3-
thiazol-2-yl)acetamides.
Yielda
(%)
Entry
R1
R2
Y
Product
1
2
3
4
5
H
H
H
H
H
Ph
S
S
S
S
S
88 b
92 b
93 b
95 b
90 b
5a
5b
5c
5d
5e
4-MeC6H4
4-OMeC6H4
4-ClC6H4
Bn
Furan-2-yl-
methyl
6
H
S
82 b
5f
7
H
Me
OMe
NO2
Br
Pr
S
S
77 b
85 b
85 b
80 b
95 b
75 c
70 c
68 c
42 c
62 c
66 c
58 c
5g
5h
5i
8
Ph
9
Ph
S
10
11
12
13
14
15
16
17
18
Ph
S
5j
Ph
Ph
S
5k
5l
H
Se
Se
Se
Se
Se
Se
Se
Me
OMe
NO2
Br
Ph
5m
5n
5o
5p
5q
5r
Ph
Table 3
Ph
Calculated Half Maximal Effective Concentration (EC50) and Maximal
Inhibition (Imax) of Compounds 5a-r on scavenging activity of DPPH and
ABTS radicals.
Ph
H
4-MeC6H4
4-ClC6H4
H
ABTS
DPPH
a Yields for isolated pure products.
b Reactions performed in the presence of compound 4 (1 mmol), R1SH (1
mmol), Et3N (1.5 mmol), MeCN (5 mL), 82 °C, 3 h, under argon
atmosphere.
Compounds
EC50(µM)
Imax (%)
12.33 ± 4.93
43.33 ± 1.15
59.00 ± 4.24
34.33 ± 6.65
46.67 ± 8.32
72.02 ± 8.00
69.30 ± 5.56
89.33 ± 5.03
95.67 ± 5.85
2.66 ± 2.51
7.411± 4.58
56.21 ± 2.12
77.33 ± 4.16
92.67 ± 3.05
3.66 ± 3.51
18.10 ± 1.73
61.30 ± 0.41
16.33 ± 1.15
98.00 ± 5.15
EC50 (µM)
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
31.40
Imax (%)
> 100
> 100
29.50
> 100
> 100
25.00
26.33
22.5
3.33 ± 0.57
1.66 ± 0.88
10.05 ± 5.60
11.00 ± 6.08
9.66 ± 2.37
17.33 ± 9.01
11.66 ± 2.08
4.28 ± 2.93
11.33 ± 7.76
5.00 ± 4.35
11.66 ± 2.08
4.20 ± 0.58
3.34 ± 2.03
10.00 ± 5.19
11.00 ± 4.18
5.33 ± 4.23
2.33 ± 2.02
1.40 ± 0.02
98.63 ± 1.96
5a
5b
c Reactions performed in the presence of compound 4 (1 mmol), NaBH4
(1.38 mmol), R2SeSeR2 (0.55 mmol), EtOH / THF (1:2.5; 7 mL), r.t., 12 h,
under argon atmosphere.
5c
5d
5e
5f
The compound 5l was obtained in good yield by the treatment
of the compound 4a with phenylselenolate anion generated by
the reduction of diphenyl diselenide with sodium borohydride,
using a mixture of THF and ethanol (2.5:1) as solvent (Table 2,
entry 12). To access the generality of this method and to test the
tolerance of functional groups as well as their effects on the
5g
5h
23.3
5i
> 100
> 100
27.67
16.10
45.67
> 100
> 100
25.03
> 100
21.67
5j
5k
substitution,
a
series of N-(4-aryl-thiazol-2-yl)-2-chloro-
5l
acetamide 4a-e with (ArSe)2 (Table 2, entries 13-18) was
examined under the same reaction conditions of entry 12 in Table
2.
5m
5n
5o
The influence of the substituents at the R1 position of N-(4-
aryl-1,3-thiazol-2-yl)-2-chloro-acetamide (Table 2, entries 13–
16) was examined. Results indicated that the reaction was not
sensitive to electronic effects of the substituents directly bonded
to the Aryl grouping, derived from arylethanones 1a-e. When
compounds 4b and 4c had the aromatic ring substituted by the
Me or OMe group, they gave similar yields (Table 2, entries 13–
14). The presence of an electron-withdrawing group on the
aromatic ring substituted by the NO2 or Br group gave products
in low yields (Table 2, entries 15–16). Experiments with (ArSe)2
presenting aromatic ring and an electron-donating group also
worked well and gave products in good yield under the standard
reaction conditions (Table 2, entry 17). The reaction with (ArSe)2
5p
5q
5r
Ascorbic
acid
The different effect of compounds in the DPPH and ABTS
assays may be due to the different chemical structures of these
two radicals. In addition, it could be rationalized that the nitrogen
atom into pyridine ring is important for the scavenging activity of
proton radicals. The same results are demonstrated by Luchese et
al.20 where 2,2’-dipyridyl diselenide presented better ABTS

4
Tetrahedron Letters
Res. 2002, 27, 297; (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem.
radical scavenging activity than other disubstituted diaryl
Rev. 2004, 104, 6255.
15 Apak, R.; Güçlü, K.; Özyürek, M.; Çelik, S. E. Microchim. Acta 2008,
160, 413.
diselenides; however, it did not present DPPH radical scavenging
activity.
16 Rostamizadeh, S.; Aryan, R.; Ghaieni, H. R.; Amani, A. M. Monatsh
Chem. 2008, 139, 1241.
17 (a) Braga, A. L.; Severo, W. A. F.; Schwab, R. S.; Rodrigues, O. E. D.;
Dornelles, L.; Braga, H. C.; Lüdtke, D. S. Tetrahedron Lett. 2009, 49,
3005; (b) Alberto, E. E.; Soares, L. C.; Sudati, J. H.; Borges, A. C. A.;
Rocha, J. B. T.; Braga, A. L. Eur. J. Org. Chem. 2009, 25, 4211.
18 Thaipong, K.; Boonprakob, U.; Crosby, K.; Cisneros–Zevallos, L.;
Byrne, D. H. J. Food Compos. Anal. 2006, 19, 669.
19 Krishnaraju, A.V.; Rao, C. V.; Rao, V. N.; Reddy, K. N.; Trimurtulu, G.
Am. J. Infect. Dis. 2009, 2, 60.
Conclusions
Synthesis and scavenging activities of compounds 2-
alkyl/arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)acetamides 5a-r
against ABTS and DPPH radicals were reported. The chosen
methodologies exhibited simplicity and fastness in their
performance, providing products in yields that vary from
moderate to excellent. The methodology also enabled the
synthesis of a number of compounds with different functional
groups. The compounds 5 (m, h, i, f, q, g, l, c, n) were effective
scavengers against ABTS radical species but less effective on
scavenging the DPPH radical, indicating that the antioxidant
effect of these compounds were related to protonated radical
scavenger activity.
20 Luchese, C.; Brandão, R.; Acker, C. I.; Nogueira, C. W. Mol. Cell.
Biochem. 2012, 367, 153.
Acknowledgements
The authors gratefully acknowledge CNPq, CAPES, and
FAPERGS for financial support.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References and Notes
1
(a) Maccioni, E.; Cardia, M. C.; Bonsignore, L.; Plumitallo, A.;
Pellerano, M. L.; De Logu, A. Il Farmaco 2002, 57, 809; (b) Vicini, P.;
Geronikaki, A.; Incerti, M.; Busonera, B.; Poni, G.; Cabras, C. A.; La
Colla, P. Bioorg. Med. Chem. 2003, 11, 4785.
2
(a) Shatursky, O. Y.; Volkova, T. M.; Romanenko, O. V.; Himmelreich,
N. H.; Grishin, E. V. Biochim. Biophys. Acta. 2007, 1768, 207; (b)
Kashyap, S. J.; Garg; V. K.; Sharma, P. K.; Kumar, N.; Dudhe, R.;
Gupta, J. K. Med. Chem. Res. 2012, 21, 2123.
3
4
5
(a) Bharti, S. K.; Nath, G.; Tilak, R.; Singh, S. K. Eur. J. Med. Chem.
2010, 45, 651; (b) Singh, U. P.; Bhat, H. R.; Gahtori, P. J. Mycol. Med.
2012, 22, 134.
(a) Padmavathi, V.; Kumari, C. P.; Venkatesh, B. C.; Padmaja, A. Eur. J.
Med. Chem. 2011, 46, 5317; (b) Desai, N. C.; Bhatt, N.; Somani, H.;
Trivedi, A. Eur. J. Med. Chem. 2013, 67, 54.
(a) Giri, R. S.; Thaker, H. M.; Giordano, T.; Williams, J.; Rogers, D.;
Sudersanam, V.; Vasu, K. K. Eur. J. Med. Chem. 2009, 44, 2184; (b)
Deb, P. K.; Kaur, R.; Chandrasekaran, B.; Bala, M.; Gill; D.; Kaki, V. R.;
Akkinepalli, R. R.; Mailavaram, R. Med. Chem. Res. 2014, 23, 2780.
(a) Azam, F.; Alkskas, I. A.; Khokra, S. L.; Prakash, O. Eur. J. Med.
Chem. 2009, 44, 203; (b) Siddiqui, N.; Ahsan, W. Eur. J. Med. Chem.
2010, 45, 1536.
(a) El-Desoky, H. S.; Ghoneim, M. M.; Abdel-Galeil, M. M. J. Braz.
Chem. Soc. 2010, 21, 669; (b) Ferrari, S.; Morandi, F.; Motiejunas, D.;
Nerini, E.; Henrich, S.; Luciani, R.; Venturelli, A.; Lazzari, S.; Calò, S.;
Gupta, S.; Hannaert, V.; Michels, P. A. M.; Wade, R. C.; Costi, M. P. J.
Med. Chem. 2011, 54, 211.
6
7
8
9
De Souza, M. V. N.; Ferreira, S. B.; Mendonça, J. S.; Costa, M.; Rebello,
F. R. Quim. Nova 2005, 28, 77.
Araniciu, C.; Pârvu, A. E.; Palage, M. D.; Oniga, S. D.; Benedec, D.;
Oniga, I.; Oniga, O. Molecules 2014, 19, 9240.
10 Low, W.–K.; Li, J.; Zhu, M.; Kommaraju, S. S.; Shah–Mittal, J.; Hull,
K.; Jun, O. Liu, J. O.; Romo, D. Bioorg. Med. Chem. 2014, 22, 116.
11 (a) De Souza, M. V. N.; De Almeida, M. V. Quim. Nova 2003, 26, 366;
(b) Sevrioukova, I. F.; Poulos, T. L. J. Med. Chem. 2013, 56, 3733.
12 (a) Sekiguchi, A.; Nishina, A.; Kimura, H.; Fukumoto, R.–H.; Kanoh, K.;
Ishihara, H.; Koketsu, M. Chem. Pharm. Bull. 2005, 53, 1439; (b)
Jaishree, V.; Ramdas, N.; Sachin, J.; Ramesh, B. J. Saudi Chem. Soc.
2012, 16, 371; (c) Ningaiah , S.; Bhadraiah, U. K.; Keshavamurthy, S.;
Javarasetty, C. Bioorg. Med. Chem. Lett. 2013, 23, 4532.
13 Arteel, , G. E.; Sies, H. Environ. Toxicol. Pharmacol. 2001, 10, 153.
14 (a) Rossato, J. I.; Ketzer, L. A.; Centurião, F. B.; Silva, S. J. N.; Ludtke,
D. S.; Zeni, G.; Braga, A. L.; Rubin, M. A.; Rocha, J. B. T. Neurochem.