DOI: 10.1002/ajoc.
201700339 Full Paper
Se-containing N-Hetercycles
Ultrasound-Assisted Synthesis and Antioxidant Activity of 3-
Selanyl-1 H-indole and 3-Selanylimidazo[1,2-a]pyridine Derivatives
Beatriz M. Vieira,[a] Samuel Thurow,[a] Monaliza da Costa,[a] Angela M. Casaril,[b]
Micaela Domingues,[b] Ricardo F. Schumacher,[a] Gelson Perin,[a] Diego Alves,[a]
Lucielli Savegnago,*[b] and Eder J. Lenard¼o*[a]
Abstract: A simple and rapid method for the selective syn-
thesis of 3-(organylselanyl)-1 H-indoles and 3-(organylselany-
l)imidazo[1,2-a]pyridines catalyzed by CuI/SeO2 under ultra-
sound irradiation was developed. This protocol employs a di-
verse range of 1 H-indoles or imidazo[1,2-a]pyridines and di-
organyl diselenides to afford the corresponding products se-
lectively in good to excellent yields. Moreover, the
antioxidant activity of these compounds was evaluated by
using a wide range of in vitro assays, such as 2-azinobis-3-
Introduction
1 H-Indoles and imidazo[1,2-a]pyridines scaffolds are present in
several leading drugs to treat a diversity of diseases.[1] Eight of
the top 200 selling drugs are indoles, which include the seroto-
nin receptor modulators Sumatriptan and Zolmitriptan. Zolpi-
dem is a worldwide marketed imidazo[1,2-a]pyridine with sed-
ative-hypnotic properties.[1a,b] These drugs are also heterocyclic
compounds, which in fact are the largest and most varied
family of organic compounds in the drug market.
In this context, selenium-containing heterocycles have at-
tracted interest owing to their biochemical and pharmacologi-
cal properties.[2] A number of organoselenium compounds are
known to exhibit antioxidant,[3] antinociceptive,[4] and antide-
pressant-like activities.[5] Selenium is an essential trace metal,
which is incorporated in selenoproteins with antioxidant activi-
ty, such as glutathione peroxidase (GPx) and thioredoxin reduc-
tase (TRx).[6] A proper balance between antioxidant and pro-ox-
[a] B. M. Vieira, S. Thurow, M. da Costa, Prof. R. F. Schumacher, Prof. G. Perin,
Prof. D. Alves, Prof. E. J. Lenard¼o
Centro de CiÞncias Qu&micas, FarmacÞuticas e de Alimentos
Universidade Federal de Pelotas—UFPel
P. O. Box 354, CEP: 96010-900 Pelotas, RS (Brazil)
E-mail: lenardao@ufpel.edu.br
[b] A. M. Casaril, M. Domingues, Prof. L. Savegnago
Centro de Desenvolvimento Tecnoljgico, Unidade Biotecnologia
Universidade Federal de Pelotas—UFPel
P. O. Box 354, CEP: 96010-900 Pelotas, RS (Brazil)
E-mail: lucielli@ufpel.edu.br
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
ajoc.201700339.
Asian J. Org. Chem. 2017, 6, 1635 – 1646
ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-
picrylhydrazyl (DPPH) radical, ferric ion reducing antioxidant
power (FRAP), and inhibition of reactive species formation in
mice cortex. The bioassays revealed that both classes of the
newly synthesized organoselenium compounds present anti-
oxidant activity, with emphasis on the 3-(organylselanyl)-1 H-
indoles. This pharmacological activity opens a wide range of
biological applications where the reduction of oxidative
stress is essential.
idant systems is imperative to maintain the physiologic state
of a cell, avoiding damage to biomolecules (proteins, lipids,
nucleic acids) as a consequence of oxidative stress. In fact, the
excess of reactive species (RS) is implicated in several patholo-
gies, such as cardiovascular disease, diabetes mellitus, cancer,
schizophrenia, depression, aging, and neurodegenerative disor-
ders.[7, 8] The pharmacotherapy available to treat the above-
mentioned conditions often has limitations in long-term treat-
ment and is not fully effective. In an attempt to find alternative
approaches to improve the treatment of diseases related to ox-
idative stress, researchers have focused on using reducing
agents as a complementary therapy alongside with the con-
ventional one.
The synthesis of polyfunctional Se-containing N-heterocyclic
derivatives is an interesting area of research, with the combina-
tion of two or more bioactive parts in one molecule as an ef-
fective strategy for designing new drug candidates.[9] Following
this approach, Zhang and co-workers recently developed a
new class of bioactive compounds by combining the arylselan-
yl moiety with the heterocycle indole (Figure 1).[10] 3-Arylsela-
nylindoles A and B were superior to Combretastatin A-4 in
avoiding the tubulin polymerization and they also presented
antiproliferative activity against three human cancer cell lines.
Similarly, the combination of the structural unit imidazo[1,2-
a]pyridine with an organosulfur group was successfully used in
the design of a new class of inhibitors of human rhinovirus
(C),[11] similar to Enviroxime, and the new anthelminthic D.[12]
In contrast to 3-sulfenylindoles and 3-sulfenylimidazo[1,2-
a]pyridines, for which the synthesis and pharmacological stud-
ies are well described,[1d, 11–13] the number of papers on the syn-
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Figure 1. 3-Arylselanylindoles A and B and 3-thioimidazo[1,2-a]pyridines C
and D with similar effects to Combretastatin A-4 and Enviroxime.
thesis and pharmacology of the selenium analogs is limit-
ed.[10, 13–17]
Among the few methods for the synthesis of 3-selanylin-
doles, the electrophilic aromatic substitution reaction (SEAr) ap-
pears as the most applied strategy to incorporate the organo-
selenium group in such electron-rich heterocycles. Diorganyl
diselenides in combination with I2/FeCl3,[10] (NH4)2S2O8 (only
one example),[13] I2/DMSO,[14] I2/EtOH (only two examples),[15] I2/
FeF3 (only two examples),[16] trichloroisocyanuric acid,[17] or
copper salts[18] have been used to prepare 3-selanylindoles. Al-
ternatively, previously prepared electrophilic selenium species,
such as organylselenium halides, have been employed instead
of diorganyl diselenides.[19] The use of Se0/Na3PO4/CuO in the
presence of 1 H-indole and aryl iodide was recently described
by Luo and co-workers, affording benzoselenopheno[3,2-b]in-
doles in good yields. A green protocol was proposed by Braga
and co-workers, for the synthesis of 3-selanylindoles, by using
a catalytic amount of K2CO3 and ethanol, performed in short
reaction times.[20]
The number of methods to access 3-selanyl-imidazo[1,2-
a]pyridines is even scarcer, with only four papers published so
far.[21–24] The copper-catalyzed C@H bond direct selenation of
imidazo[1,2-a]pyridines by using Se0/CuBr/DMSO at 120 8C for
30 h or PhSeSePh/CuBr at 120 8C for 20 h was reported by Shi-
bahara and Murai and co-workers to prepare symmetrical and
unsymmetrical 3-selanyl-imidazo[1,2-a]pyridines, respectively,
in good yields.[21] A closely related work was de-
scribed by Yasuike and co-workers, in which several
2-(2-iodophenyl)imidazo[1,2-a]pyridines were reacted
with Se0/CuI/DMSO at 130 8C for 3–20 h to form ben-
zo[b]selenophene fused imidazo[1,2-a]pyridines in
moderate to good yields.[21] A type of 3-phenylselanyl
imidazo[1,2-a]pyridines was prepared by Hajra and Scheme 1. General scheme of the present work.
co-workers by using PhSeBr as the electrophile and
polyethylene glycol (PEG)/H2O as the solvent at room
temperature.[23] Despite this, the procedure does not
require a catalyst or heating, and the unstable and hazardous
PhSeBr needs to be previously prepared and the method is re-
stricted to the phenyl-substituted selenium derivative. More re-
cently, Braga and co-workers described the reaction of imida-
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Full Paper
zo[1,2-a]pyridines with RYYR/I2/DMSO at 90 8C for 9 h to pre-
pare a diversity of 3-sulfenyl (Y = S) and 3-selanylimidazo[1,2-
a]pyridines (Y = Se) in very good yields.[24]
As a consequence of the reduced number of methods to
prepare 3-selanylindoles and 3-selanylimidazo[1,2-a]pyridines,
almost nothing is known about their pharmacological activi-
ties.[10] In addition, a problem almost ubiquitous in the current
methodologies is the long reaction time under heating, which
is a limitation both in terms of energy demand and the pres-
ence of thermo sensitive groups in the substrates. Additionally,
there is a scope limitation, especially regarding the groups
that are connected to the selenium atom.
The problem of the long reaction time to access 3-selanylin-
doles was recently assessed by us[18b] and others,[10, 14] through
the use of electromagnetic and ultrasonic irradiation (US). Mi-
crowaves caused a marked acceleration in the FeCl3- and I2-cat-
alyzed selenylation of indoles, whereas ultrasound was effec-
tive in the FeF3- and CuI-promoted reactions. However, the use
of non-conventional energy sources in the synthesis of 3-sela-
nylimidazo[1,2-a]pyridines remains unexplored, whereas only a
few examples were described to prepare the selanylindole ana-
logs.
The use of ultrasonic irradiation (US) has grown substantially
in industrial, medicinal, and research applications.[25] The most
important advantage in using ultrasound-assisted reactions is
the high-energy transference owing to high local temperature
and pressure provided by the cavitation process.[26] In this con-
text, our previous reports regarding the ultrasound-assisted or-
ganochalcogen synthesis showed improvements compared
with the thermal heating method, such as shorter reaction
times and higher yields of the expected products.[18b, 26, 27]
The development of more versatile and milder protocols to
access 3-selanylindoles and 3-selanylimidazo[1,2-a]pyridines is
essential to enable additional studies on their chemistry and
pharmacology. In this way, we describe our results on the ultra-
sound-assisted regioselective selenylation of electron-rich N-
heterocycles 1 by using diorganyl diselenides 2 and CuI/SeO2
as a catalytic system in DMSO, as a versatile and direct meth-
odology to prepare 3-selanylindoles and 3-selanylimidazo[1,2-
a]pyridines 3. In addition, the antioxidant activity of these
compounds was evaluated by using a wide range of in vitro
assays, providing relevant information about the biological ap-
plication of these organoselenium molecules (Scheme 1).
Results and Discussion
A comparative study on the use of microwaves, US, and con-
ventional heating in the copper-catalyzed selenylation of in-
doles in DMSO was recently reported by us.[18b] In this reaction,
1636 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Paper
US was more efficient than the other heating techniques, but
Table 1. Optimization of the reaction conditions to prepare 3 a.[a]
the yields of the desired products were modest in all the ex-
amples using 1 H-indoles and aromatic diselenides, even after
several hours of sonication. Trying to circumvent this draw-
back, we decided to investigate the use of SeO2 as an additive
in the US-promoted reaction. Since the seminal work from H.
L. Riley and co-workers in the 1930s, selenium dioxide has Entry SeO2 Solvent t [min] Yield of 3 a [%]
[mol %]
been studied as a versatile and cheap oxidant of a-methylene
aldehydes and ketones.[28] We wondered if SeO2 could help in 1 – DMSO 90 74[18b]
2 20 DMSO 30 82
this reaction by oxidizing the selenol intermediate to disele- 3 30 DMSO 20 83
nide in one of the reaction steps (see Scheme 2 for a plausible 4 40 DMSO 20 89
mechanism). 5 50 DMSO 20 67
6 100 DMSO 20 47
7 40 THF 60 73
8 40 DMF 40 56
9 40 glycerol 60 39
10 40 toluene 120 19
11 40 H2O 120 NR
12 40 DMSO 120 5[b]
13 40 DMSO 120 40[c]

[a] The reaction was carried out by using 1 a (0.5 mmol), 2 a (0.3 mmol),
CuI (20 mol %), and SeO2 in solvent (0.5 mL) under US (60 % amplitude).
The consumption of starting materials was followed by TLC. [b] The reac-
tion was carried out without CuI. [c] The reaction was carried out by
using 0.25 mmol of 2 a.

solvent, and the starting materials were recovered after

Scheme 2. Proposed mechanism for the formation of 3-selanylimidazo[1,2-
a]pyridines 3.
As previously noted,[18b] 1 H-indole 1 a (0.5 mmol) and di-
phenyl diselenide 2 a (0.3 mmol) react in the presence of CuI
(20 mol %) and DMSO (0.5 mL) as the solvent under US irradia-
tion (60 % amplitude) for 90 min to deliver 3-(phenylselanyl)-
1 H-indole 3 a in 74 % yield (Table 1, entry 1). Our first attempt
to change this picture involved the addition of 20 mol % of
SeO2 in the reaction medium. Fortunately, the reaction pro-
ceeded smoothly, giving the expected product 3 a in 82 %
yield after only 30 min (Table 1, entry 2). By increasing the
amount of SeO2 to 30 mol %, the same yield of 3 a was ob-
tained after 20 min of sonication (Table 1, entry 3) and an even
better yield (89 %) was obtained at the same reaction time
when using 40 mol % of SeO2 (Table 1, entry 4). On the other
hand, when 50 mol % or a quantitative amount (100 mol %) of
SeO2 were used, no improvements were observed, and the 3-
(phenylselanyl)-1 H-indole 3 a was obtained in 67 % and 47 %
yields, respectively (Table 1, entries 5 and 6). Several solvents
with different characteristics were tested in the place of DMSO,
such as H2O, glycerol, THF, toluene, and DMF. However, only
THF and DMF proved adequate for the reaction, even if the
yields were not so good (73 and 58 %) and the reaction times
were longer (60 and 40 min) compared with that using DMSO
(Table 1, entry 4 vs. 7–8). Glycerol and toluene were not good
solvents for this reaction, affording 3 a in only 39 and 19 %
yields after 60 and 120 min of reaction, respectively (Table 1,
entries 9–10). No reaction occurred when using water as the
120 min of reaction (Table 1, entry 11). To confirm the impor-
tance of using CuI, the reaction was performed in its absence,
and a lower yield was obtained even after 120 min (Table 1,
entry 12). Finally, when the same protocol was performed by
using an equivalent amount of diphenyl diselenide 2 a
(0.25 mmol), 3 a was obtained in 40 % yield, revealing that a
slight excess of the selenium species is mandatory to achieve a
good yield of product (Table 1, entry 13).
With the best experimental conditions for the synthesis of
3 a in hand (Table 1, entry 4), we envisaged extending this
methodology to a variety of 1 H-indoles 1 a–c and imidazo[1,2-
a]pyridines 1 d–f and different diorganyl diselenides 2 a–g.
Under the optimized conditions, the desired products 3 a–t
could be efficiently obtained in good to excellent yields and
with short reaction times (Table 2).
As it can be seen in Table 2, SeO2 presented a positive syner-
gistic effect in combination with CuI, compared with the use
of CuI alone, in all the tested examples (Table 2, entries 1–11;
data in parenthesis). The reaction time was drastically reduced
while the products yield increased substantially in all the
tested substrates. For example, 3-[(4-methoxyphenyl)selanyl]-
1 H-indole 3 b was obtained in 75 % yield after 30 min of reac-
tion by using this new protocol, whereas only 23 % yield was
obtained after 20 h when SeO2 was not present (Table 2,
entry 2). This is an outstanding result, as electron-donating
groups in the aromatic ring of the diselenide 2 decrease the
reactivity of the selenium atom to the nucleophilic attack by
the indole 1 a. Equally excellent results were obtained for the
electron-poor diaryl diselenides 2 d–f (R2 = 4-ClC6H4, 4-FC6H4,
and 3-CF3C6H4), which delivered the expected 3-arylselanylin-
doles 3 d–f in 78, 80, and 92 % yields, respectively, after 15–

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 Full Paper

Table 2. CuI/SeO2-catalyzed synthesis of selenium-containing N-heterocycles 3 a–t under ultrasound irradiation.[a,b]

Entry N-Heterocycle 1 Diorganyl diselenide 2 Product 3 t[c] Yield [%][c,d]

1 20 min (1.5 h) 89 (74)

1a 2a 3a

2 1a 30 min (20.0 h) 75 (23)

2b 3b

3 1a 15 min (4.0 h) 78 (59)

2c 3c

4 1a 15 min (7.0 h) 82 (56)

2d 3d

5 1a 30 min (5.0 h) 90 (40)

2e 3e

6 1a 30 min (4.0 h) 87 (73)

2f 3f

7 1a 60 min (5.0 h) 94 (88)

2g 3g

8 2a 20 min (1.0 h) 87 (96)

1b 3h

9 2a 30 min (6.0 h) 96 (61)

1c 3i

10 1b 2d 15 min (1.5 h) 86 (70)

3j

11 1c 2d 15 min (6.0 h) 74 (61)

3k

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 Full Paper

Table 2. (Continued)

Entry N-Heterocycle 1 Diorganyl diselenide 2 Product 3 t[c] Yield [%][c,d]

12 2a 60 min 71

1d 3l

13 1d 2c 30 min 65

3m

14 1d 2b 30 min 57

3n

15 1d 2d 15 min 63

3o

16 1d 2e 60 min 86

3p

17 1d 2f 45 min 76

3q

18 1d 2g 60 min 79

3r

19 2a 15 min 66

1e 3s

20 2a 30 min 70

1f 3t

[a] Reactions were carried out by using 1 (0.5 mmol), 2 (0.3 mmol), CuI (20 mol %), SeO2 (40 mol %) in DMSO (0.5 mL) under US (60 % amplitude). [b] The re-
action time was monitored by TLC until complete consumption of 1. [c] Data in parentheses refer to ref. [18b]. [d] Yields of isolated product.

30 min of reaction (Table 2, entries 4–6).The ortho-substituted drance does not seem negatively affect the reaction (Table 2,
diaryl diselenide 2 c (R2 = 2-tolyl) afforded the corresponding entry 3). A slightly longer time was necessary when dibutyl dis-
product 3 c in 78 % yield after 30 min, indicating that steric hin- elenide 2 g (R2 = C4H9) was used. In this case, 3-(butylselanyl)-

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1 H-indole 3 g was obtained in 94 % yield after 60 min of soni-
cation (Table 2, entry 7). Excellent outcomes were obtained in
the reactions of diphenyl diselenide 2 a with 5-bromo-1 H-
indole 1 b and N-methyl-1 H-indole 1 c, affording 5-bromo-3-
(phenylselanyl)-1 H-indole 3 h and 1-methyl-3-(phenylselanyl)-
1 H-indole 3 i in 87 and 96 % yields after 20 and 30 min of reac-
tion, respectively (Table 2, entries 8–9). The 4-chloro substitut-
ed diphenyl diselenide 2 d also reacted with indoles 1 b and
1 c in a satisfactory way and after 15 min of reaction, the re-
spective 3-arylselanylindoles 3 j and 3 k were isolated in 86 and
74 % yields (Table 2, entries 10–11).
As mentioned before in the Introduction, the methods to
prepare 2-selanylimidazo[1,2-a]pyridines suffer from limited
scope, long reaction times, and are energy intensive proce-
dures. Clearly, there is a demand for faster and general alterna-
tives to access this class of compounds. With this in mind, we
decided to investigate the feasibility of our protocol by using
2-arylimidazo[1,2-a]pyridines instead 1 H-indoles in the reaction
with a diversity of diselenides (Table 2, entries 12–20). In a gen-
eral way, the expected 3-(organylselanyl)-2-arylimidazo[1,2-
a]pyridines 3 l–t were obtained in good yields and short reac-
tion times; however, the starting 2-arylimidazo[1,2-a]pyridines
were less reactive than the 1 H-indoles. The method was
shown to be robust, allowing the synthesis of a diversity of 3-
selanylimidazo[1,2-a]pyridines with different patterns of substi-
tution in both the organylselanyl and the heterocyclic parts. In
contrast to the reaction with indoles, there is no clear influence
of the substituents on the aromatic ring of the diselenide 2,
with electron-rich 2 b,c and electron-poor diselenides 2 d and
2 f giving the respective products 3 l–n and 3 q at nearly the
same yields of around 60–70 % (Table 2, entries 12–15 and 17).
An exception was 2-(4-fluorophenyl)-3-(phenylselanyl)imida-
zo[1,2-a]pyridine 3 p, derived from 1 d and 2 e, which was ob-
tained in 86 % yield after 60 min (Table 2, entry 16). Dibutyl dis-
elenide 2 g efficiently reacted with 2-phenylimidazo[1,2-a]pyri-
dine 1 d to give 3-(butylselanyl)-2-phenylimidazo[1,2-a]pyridine
3 r in 79 % yield after sonication for 60 min (Table 2, entry 18).
Finally, when differently substituted 2-arylimidazo[1,2-a]pyri-
dines 1 e and 1 f were employed, the expected products 3 s
and 3 t were obtained in 66 and 70 % yields, respectively, after
15 and 30 min (Table 2, entries 19 and 20).
A plausible mechanism for the reaction could involve the
formation of intermediate I, by coordination of the selenium
atom of diorganyl diselenide 2 to CuI, as shown in Scheme 2.
Subsequently, a nucleophilic attack by the heterocycle 1 (e.g.,
the 2-arylimidazo[1,2-a]pyridine) delivers II and III. Then, inter-
mediate II releases a proton to form product 3 and selenol, re-
generating CuI. Selenol, in the presence of SeO2/DMSO and air,
is then oxidized to diselenide to initiate a new cycle. The pres-
ence of copper is essential for the reaction; in a control experi-
ment using KI instead CuI, to check if iodine could be involved
like in the Braga’s method using I2/DMSO,[24] no reaction took
place, reinforcing the proposed mechanism.
After the successful synthesis of 3-(organylselanyl)-1 H-in-
doles and 3-selanyl-imidazo[1,2-a]pyridine derivatives in good
to excellent yields in short reaction times, the in vitro antioxi-
dant activity of these compounds was analyzed.
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Full Paper
An antioxidant is defined as a stable molecule capable of
neutralizing free radicals, thus reducing or preventing damage
to biomolecules. Generally, non-enzymatic antioxidants are
also known as reductants, as the scavenger of oxidants by re-
ductants can be a consequence of redox reactions, when the
reactive species are reduced concomitant to the oxidation of
another molecule.[29] In this regard, antioxidant activity can
also be regarded as reducing ability, therefore, redox-linked
colorimetric methods using reductants and readily reduced ox-
idants can be an easy way to access this ability.[29]
Antioxidants are needed to prevent and reduce the forma-
tion of reactive oxygen species (ROS) and reactive nitrogen
species (RNS),[30] which are produced by endogenous systems
in several physiological and pathological states. As an antioxi-
dant can scavenge RS mainly through electron-transfer (ET)
and hydrogen atom transfer (HAT) mechanisms,[31] several col-
orimetric assays have been employed to evaluate the reducing
capacity of natural and synthetic molecules. Among them, the
1,1-diphenyl-2-picryhydrazyl (DPPH) radical scavenger assay is
one of the most widely used in vitro tests.[32] The N-atom-cen-
tered free radical DPPH reacts with both electron and hydro-
gen donors,[31] and therefore can be neutralized by both ET
and HAT pathways.[33] Additionally, DPPH scavenging may be
involved in the anti-inflammatory and anti-ageing activity of
molecules.[32a] In the present work, it was observed that some
of the 3-(organylselanyl)-1 H-indoles are capable of neutralize
the DPPH radical (Table S1 in the Supporting Information).
Compound 3 b exhibited considerably higher scavenger ca-
pacity at 500 mm, whereas compounds 3 a, 3 c, 3 d, 3 e, and 3 g
were also effective in this assay, suggesting that all these com-
pounds may act through ET and/or HAT pathways. Compound-
s 3 a, 3 c, 3 d, and 3 e were statistically efficient at concentra-
tions equal to or higher than 10 mm, whereas the deriva-
tives 3 b and 3 g presented an effect starting from 50 mm. On
the other hand, compounds 3 f, 3 h, 3 i, 3 j, and 3 k were not
able to neutralize the DPPH radical. Based on the percentage
of DPPH radical inhibition, the 3-(organylselanyl)-1 H-indoles ac-
tivities follow the order: 3 b > 3 g > 3 a > 3 c > 3 d + 3 e > 3 f. It
is worth mentioning that the compound 1 a, without the Se,
did not present antioxidant activity in this assay, suggesting
that the addition of selenium may be responsible for the abili-
ty of 3-(organylselanyl)-1 H-indoles to scavenge DPPH radicals.
Moreover, none of the 3-selanyl-imidazo[1,2-a]pyridines deriva-
tives were able to scavenge DPPH radical at any tested con-
centrations, as well as the imidazo[1,2-a]pyridine.
Another spectrophotometric assay widely employed to mea-
sure the reducing potential of compounds is the 2,2’-azino-bis
3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assay. This colori-
metric assay utilizes the radical cation ABTS + C, and its neutrali-
zation is based on the ET mechanism. Usually, ABTS + C scaveng-
ing serves as a marker of total antioxidant activity.[32a] Although
none of 3-selanyl-imidazo[1,2-a]pyridine derivatives were able
to scavenge the ABTS + C·radical in any tested concentration, the
precursor imidazo[1,2-a]pyridine 1 d presented a small effect at
concentrations from 50–500 mm. On the other hand, the major-
ity of 3-(organylselanyl)-1 H-indoles derivatives presented a sig-
nificant antioxidant capacity in the ABTS assay, which was
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

boosted by the presence of selenium in the indole molecule,
as can be seen in Table S2 (in the Supporting Information).
Interestingly, compound 3 b again showed the best reducing
capacity, with the derivatives 3 a, 3 c, 3 d, 3 e, 3 g, 3 h, and 3 j
also presenting activity. All these compounds were excellent
reducing agents in this assay, considering that they scavenged
100 % of the ABTS + C radical. As the maximum inhibition (Imax)
parameter indicates the efficiency of a compound, it is possible
assume that 3 b is the most efficient derivative, with an Imax
reached at 10 mm, whereas the other compounds needed
higher concentrations. Moreover, it is required 4.35 : 0.16 mm
of 3 b to scavenge 50 % (IC50) of the ABTS + C radical. Consider-
ing that the IC50 value reflects the potency of a compound, 3 b
is not only more efficient, but also more potent than the other
3-(organylselanyl)-1 H-indoles (following the order: 3 b , 3 e ,
3 g , 3 h , 3 j < 3 c , 3 d < 3 a). Another interesting finding is
that compounds 3 h and 3 j (containing a bromo substituent
on the indole ring) presented an antioxidant effect in a ET-
based assay, but not in a ET + HAT-based assay. This may indi-
cate that the antioxidant activity of both compounds relies
strongly on their ability to act as a reducing agent and transfer
electrons to a free radical. Interestingly, the presence of bro-
mine was important for the antioxidant and anti-inflammatory
properties of a naturally occurring compound, when compared
with a de-brominated synthetic analog.[34] Moreover, compoun-
d 1 a was able to scavenge ABTS + C radicals starting from 5 mm,
however, it was not able to scavenge 50 % of those radicals, in-
dicating that this compound is less potent than the 3-(organyl-
selanyl)-1 H-indoles that were effective. Similarly, 1 a had the
lower Imax, suggesting that it is also less effective.
To further investigate the reducing capacity of the organose-
lenium derivatives, the ferric ion (Fe3 + ) reducing antioxidant
power (FRAP) assay was performed. Iron, a transition metal es-
sential for life, is the most important inducer of RS produc-
tion,[35] as it can give rise to the highly active hydroxyl radical
(HOC) by the Fenton reaction. In the FRAP assay, Fe3 + acts as
an electron acceptor when converted to the ferrous ion (Fe2 + ).
As previously established, the reducing power is indicative of
the antioxidant ability to convert radicals (electron acceptors)
to stable products.[36]
Table 3. Effect of 3-(organylselanyl)-1 H-indoles and 3-(organylselanyl)imidazo[1,2-a]pyridines against RS formation induced by sodium azide.
% of RS formation
3-(Organylselanyl)-1 H-indole IC50 Imax
3a 24.47 : 1.49 91.69 : 1.21
3b 7.76 : 0.20 87.42 : 1.97
3c 39.43 : 1.80 84.78 : 1.40
3d 20.40 : 11.65 76.99 : 5.03
3e 30.24 : 1.10 94.76 : 0.82
3g 46.93 : 8.62 64.08 : 10.42
3h 13.71 : 4.95 88.57 : 4.18
3i 7.81 : 0.39 72.87 : 9.80
3j 6.27 : 0.13 77.99 : 3.80
3k 38.01 : 3.69 62.30 : 4.36
Values are expressed as mean : SEM. IC50 : concentration required to inhibit 50 % of RS formation. Imax : maximum inhibition of RS formation.
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In the present study, 3-(organylselanyl)-1 H-indoles and 3-se-
lanyl-imidazo[1,2-a]pyridine derivatives exhibited reducing ca-
pacity in the FRAP assay (Table S3 in the Supporting Informa-
tion). It is worth mentioning that compound 3 b exhibited the
highest ferric reducing ability, despite compounds 3 a, 3 c, 3 d,
3 e, 3 g, 3 k, and 3 l presenting a similar reducing power. Com-
pounds 3 a, 3 c, 3 d, 3 e, and 3 k present effects at concentra-
tions equal to or higher than 5 mm, whereas 3 g and 3 i were
active starting from 10 mm. Interestingly, compound 1 a did not
show reducing ability in this assay (data not shown), whereas
compound 1 d was slightly effective only at the highest con-
centrations.
Moreover, as the FRAP assay is also ET-based, it was a sur-
prise to find that derivatives 3 h and 3 j, which scavenged
ABTS + C radicals, did not present reducing capacity. This may be
a consequence of the FRAP reaction media, as previous data
reported that a pH value of 3.6 may impair the antioxidant ac-
tivity of some compounds.[37] Moreover, among the 3-selanyl-
imidazo[1,2-a]pyridine derivatives, 3 p exhibited the higher re-
ducing capacity at 500 mm. In fact, this compound has a me-
thoxy group at the para-position in the selenium-containing
ring, which is also present in compound 3 b.
Besides induction by iron, RS can be generated through im-
pairment in the electron transport chain (ETC). Azide is a
known inhibitor of ETC complex IV,[38] and therefore is used in
vitro as an inducer of RS. These unstable molecules cause
damage to biomolecules, leading to oxidative stress.[39] Particu-
larly, the brain is highly susceptible to oxidative damage owing
to the high oxygen demand, high lipid content, and insuffi-
cient antioxidant defense.[7]
In this sense, increasing evidence has associated oxidative
stress with neuropsychiatric and neurodegenerative disor-
ders.[7, 40] In an attempt to find new molecules with therapeutic
potential, we evaluated the ability of the organoselenium de-
rivatives to decrease the RS formation induced by azide in the
pre-frontal cortex of mice (Table 3 and Table S4 in the Support-
ing Information).
Among the 3-(organylselanyl)-1 H-indoles, compounds 3 a
and 3 i decreased the formation of RS at concentrations equal
to or higher than 0.5 mm, whereas 3 b, 3 d, 3 h, and 3 k were ef-
fective starting from 1 mm. Compounds 3 e and 3 j presented
3-Selanyl-imidazo[1,2-a]pyridine IC50 Imax
3l 9.59 : 0.15 85.20 : 4.33
3m 50.38 : 3.33 82.52 : 6.41
3n 45.10 : 9.74 75.70 : 6.70
3o 30.69 : 4.03 62.18 : 7.79
3p 28.66 : 1.52 84.96 : 2.06
3q 29.54 : 2.30 79.23 : 2.52
3r 3.62 : 0.96 68.04 : 2.39
3s 5.71 :1.70 77.31 : 3.31
3t 32.17 : 1.33 85.27 : 4.66
1641 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

effects starting from 5 mm, 3 c at 10 mm, and 3 g at 50 mm.
Compound 3 f did not show any effect. Based on the Imax
values, the activity of these compounds follows the order:
3e>3a+3h>3b>3c>3j+3d+3i>3g>3k>3 f (not
active), with a maximum inhibition of 94.76 : 0.82 % for 3 e. Re-
garding the IC50, the order is different: 3 j < 3 b , 3 i < 3 h <
3 d , 3 a < 3 e < 3 k , 3 c < 3 g < 3 f, with the lower IC50 of
6.27 : 0.13 mm for 3 j. These data indicate that 3 e is the most
efficient and 3 j is the most potent 3-(organylselanyl)-1 H-indole
derivative in the RS assay. Additionally, indole precursor 1 a
was not able to reduce the formation of RS in mice cortex
(data not shown), indicating that the effect of 3-(organylselan-
yl)-1 H-indole derivatives may occur as a result of the presence
of selenium.
Regarding the 3-selanyl-imidazo[1,2-a]pyridine derivatives,
compounds 3 l, 3 o, 3 p, and 3 s decreased the RS formation in-
duced by azide in mice pre-frontal cortex starting at a concen-
tration of 1 mm. Compounds 3 q and 3 r started at 5 mm; 3 n
and 3 t at 10 mm; and 3 m at concentrations equal to or higher
than 50 mm. The maximum inhibition of RS by these 3-selanyl-
imidazo[1,2-a]pyridines was very similar, following the order:
3 t + 3 l + 3 p + 3 m > 3 q + 3 s + 3 n > 3 r + 3 o, with a maximum
inhibition of 85.27 : 4.66 % for 3 t. On the other hand, regard-
ing the IC50 values, the order is established as follows: 3 r <
3 s < 3 l < 3 p , 3 q , 3 o , 3 t < 3 n , 3 m, considering that a
concentration of 3.62 : 0.96 mm of 3 r decreases 50 % of RS
production. Together, it is possible to suggest that 3 r is the
most potent and 3 t is the most efficient 3-selanyl-imidazo[1,2-
a]pyridine. We also found that imidazo[1,2-a]pyridine precursor
1 d did not reduce the generation of RS (data not shown), sug-
gesting that—similarly to the 3-(organylselanyl)-1 H-indole—
the antioxidant activity of 3-selanyl-imidazo[1,2-a]pyridine de-
pends on the presence of selenium in the structure.
The selenium-containing compounds, the precursor 1 H-
indole 1 a and imidazo[1,2-a]pyridine 1 d were also evaluated
for their ability in scavenging NOC and OHC, ferrous ion chelat-
ing capacity, and superoxide dismutase (SOD)-like activity
assays (data not shown). As none of the compounds presented
a significant effect in these experiments, we can postulate that
the mechanisms of action underlying these assays are not in-
volved in their antioxidant activities.
Considering that SeO2 could be found in trace concentra-
tions in the final products, we also tested this compound in
the biological assays. As expected, SeO2 did not present antiox-
idant activity, indicating that it is not responsible for the anti-
oxidant effects observed in the assays (data not shown).
Taken together, our data supports the idea that the 3-(or-
ganylselanyl)-1 H-indoles 3 a, 3 b, and 3 e and 3-selanyl-imida-
zo[1,2-a]pyridines 3 l, 3 p, and 3 r presented the best overall re-
sults. The presence of selenium has been noticed in several
compounds with promising biological activity. In general, we
may assume that the addition of Se boosts the antioxidant ca-
pacity of 1 H-indole and imidazo[1,2-a]pyridine. This is in agree-
ment with the biological role of this element, as selenium is an
essential micronutrient found in the active site of several anti-
oxidant enzymes. Besides selenium, previous data have indicat-
ed the presence of a methoxy group in antioxidant molecules.
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Full Paper
Scaiano found that the methoxy group is relevant to the free
radical scavenging activity of melatonin.[41] Moreover, methoxy-
lated chalcones are also well known for their powerful antioxi-
dant activities,[42, 43] whereas the 8-OCH3 group on the quino-
lone core is important for the reduction of photogenerated ox-
idative DNA damage and photodegradation in the presence of
UVA irradiation.[44]
Many fluorinated organic molecules exhibit interesting bio-
logical properties with a wide range of applications,[45] and
around 20 % of all licensed pharmaceutical products over the
last 50 years contain a fluorine atom.[46] Rajedra et al. also
found that fluorinated molecules are metabolically non-de-
gradable, which enhances the rate of absorption and transfer
of the drug to the active site in the body.[47] Considering the
biological significance, the electron-withdrawing characteristic
and the scarce availability of naturally occurring fluorine-con-
taining compounds, the synthesis of new fluorinated organic
molecules, such as 3 e, 3 f, 3 p, and 3 q is relevant for the
chemical and medical field.
Overall, the great majority of 3-(organylselanyl)-1 H-indoles
and 3-selanyl-imidazo[1,2-a]pyridines presented significant an-
tioxidant activity, opening the possibility to perform more bio-
logical assays to clarify the knowledge about these promising
compounds. Thus, considering the interesting antioxidant pro-
file of this new class of selenium-containing compounds, and
keeping in mind that the selenium may be responsible for the
biological effects, these molecules could be used in the thera-
py of oxidative stress-related disorders.
Conclusions
A variety of 3-selanyl-1 H-indoles and 3-selanyl-2-arylimida-
zo[1,2-a]pyridines was prepared in one step starting from
easily available 1 H-indoles and 2-arylimidazo[1,2-a]pyridines
and diorganyl diselenides. This copper-catalyzed reaction is
promoted by ultrasound and the presence of selenium dioxide
(40 mol %) as an additive in the reaction medium has a positive
effect both for reducing the reaction time and increasing the
yield of products. Moreover, a screening was performed with
all synthesized compounds to investigate their antioxidant ac-
tivity. It is important to highlight that the original molecules
without selenium did not present significant antioxidant po-
tential, indicating that the addition of selenium may improve
the biological activity of 1 H-indoles and imidazo[1,2-a]pyri-
dines. The 3-(organylselanyl)-1 H-indole derivatives 3 a, 3 b, and
3 e and 3-(organylselanyl)imidazo[1,2-a]pyridines 3 l, 3 p, and
3 r presented significant antioxidant activities. This protocol
could be a valuable tool for the advance of the synthesis and
pharmacological and biochemical studies of selenium-contain-
ing 1 H-indoles and imidazo[1,2a]pyridines.
Experimental Section
Chemistry—General remarks
Reactions were monitored by TLC carried out on Merck silica gel
(60 F254) by using UV light as visualizing agent and 5 % vanillin in
1642 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10 % H2SO4 and heat as developing agents. Column chromatogra-
phy was performed by using silica gel. Proton nuclear magnetic
resonance spectra (1H NMR) were obtained at 300 MHz with a
Varian Gemini NMR and at 400 MHz with Bruker DPX 400 spec-
trometers. Spectra were recorded in CDCl3 solutions. Chemical
shifts are reported in ppm, referenced to tetramethylsilane (TMS)
as the external reference. Hydrogen coupling patterns are de-
scribed as singlet (s), doublet (d), triplet (t), double doublet (dd),
double triplet (dt), and multiplet (m). Coupling constants (J) are re-
ported in Hertz. Carbon-13 nuclear magnetic resonance spectra
(13C NMR) were obtained at 75 MHz with a Varian Gemini NMR and
at 100 MHz with Bruker DPX 400 spectrometers. Chemical shifts
are reported in ppm, referenced to the solvent peak of CDCl3. Low-
resolution mass spectra (MS) were obtained with a Shimadzu GC-
MS-QP2010 mass spectrometer. GC analysis were conducted with a
RESTEC RTX-5MS capillary column (30 m, 0.25 mm id, 0.25 mm film
thickness) by using the products dissolved in ethyl acetate with
the following conditions: injected sample volume was 1.0 mL; He
constant flow, 54.1 mL min@1; initial inlet temperature, 40 8C
ramped to 72 8C at 10 8C min@1 followed by a 5 8C min@1 ramp to
100 8C (held for 10 min) and 10 8C min@1 to 280 8C and held for
20 min (total run time: 56.8 min). The ultrasound-promoted reac-
tions were performed by using a Cole Parmer ultrasonic processor
Model CPX 130, with a maxim power of 130 W, operating at an am-
plitude of 60 % and a frequency of 20 kHz. The temperature of the
reaction under US was monitored by using a Incoterm digital infra-
red thermometer Model Infraterm (Brazil). High-resolution mass
spectra (HRMS) were obtained for all compounds with a LTQ Orbi-
trap Discovery mass spectrometer (Thermo Fisher Scientific). This
hybrid system meets the LTQ XL linear ion trap mass spectrometer
and an Orbitrap mass analyzer. The experiments were performed
by direct infusion of the sample (flow: 10 mL min@1) in the positive-
ion mode using electrospray ionization. Elemental composition cal-
culations for comparison were executed by using the specific tool
included in the Qual Browser module of Xcalibur (Thermo Fisher
Scientific, release 2.0.7) software. Melting point (m.p.) values were
measured with a Marte PFD III instrument with 0.1 8C precision.
Bioassays
The antioxidant activity of 3-(organylselanyl)-1 H-indole and 3-(or-
ganylselanyl)imidazo[1,2-a]pyridine derivatives was evaluated by
the following in vitro assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH)
and 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radi-
cal scavenging activity, nitric oxide (NO) scavenging, hydroxyl radi-
cal (OHC) scavenging, ferric ion reducing antioxidant power (FRAP),
ferrous ion chelating, superoxide dismutase-like activity, and quan-
tification of reactive species (RS) assay in mice cortex. To assess all
biological activities, the compounds were diluted in dimethyl sulf-
oxide (DMSO). All experiments were performed at least three times
in duplicate, following procedures described elsewhere.[48–55] De-
tailed experimental procedures are showed in the Supporting In-
formation.
General procedure for the synthesis of 3-(organylselanyl)-
1 H-indoles (3 a–k) and 3-selanylimidazo[1,2-a]pyridines (3 l–
t)
SeO2 (0.022 g, 0.2 mmol) was added to a 10 mL vial containing a
mixture of indole or imidazo[1,2-a]pyridine 1 (0.5 mmol), diorganyl
diselenide 2 (0.3 mmol), and CuI (0.019 g, 0.1 mmol) in DMSO
(0.5 mL). Then, the ultrasonic probe was introduced into the flask
and the mixture was sonicated at 25 kHz and 60 % amplitude. The
progress of the reaction was monitored by TLC and after the time
Asian J. Org. Chem. 2017, 6, 1635 – 1646 www.AsianJOC.org 1643
Full Paper
indicated in Table 2, the reaction mixture was received in water
(10 mL), extracted with ethyl acetate (3 V 5 mL), dried over MgSO4,
and concentrated under vacuum. The residue was purified by
column chromatography by using silica gel and a mixture of ethyl
acetate/hexanes as the eluent.
3-(Phenylselanyl)-1 H-indole (3 a):[17] White solid; m.p.: 130–131 8C,
lit.:[17] 135.4–137.0 8C; Yield: 0.121 g (89 %); 1H NMR (CDCl3,
300 MHz): d = 8.43 (br s, 1 H), 7.62 (dd, J = 7.9, 1.1 Hz, 1 H), 7.53 (s,
1 H), 7.48–7.39 (m, 2 H), 7.33–7.14 ppm (m, 6 H); 13C NMR (CDCl3,
75 MHz): d = 136.3, 133.8, 131.4, 131.0, 129.9, 128.7, 128.4, 125.6,
122.7, 120.1, 111.2, 98.0 ppm; MS m/z (rel. int.): 273 (18.4), 193
(100.0), 116 (6.4), 77 (7.0).
3-[(4-Methoxyphenyl)selanyl]-1 H-indole (3 b):[18b] White solid;
m.p.: 77–79 8C, lit.:[18b] 77.0–79.0 8C; Yield: 0.114 g (75 %); 1H NMR
(CDCl3, 300 MHz): d = 8.30 (br s, 1 H), 7.64 (ddt, J = 7.6, 1.5, 0.8 Hz,
1 H), 7.32–7.11 (m, 6 H), 6.69–6.65 (m, 2 H), 3.66 ppm (s, 3 H);
13
C NMR (CDCl3, 75 MHz): d = 158.2, 136.2, 131.1, 130.6, 129.7,
123.3, 122.7, 120.6, 120.2, 114.7, 111.3, 99.1, 55.2 ppm; MS m/z (rel.
int.): 303 (13.5), 223 (100.0), 180 (24.8), 77 (12.2).
3-(2-Tolylselanyl)-1 H-indole (3 c):[18b] Yellow solid; m.p.: 104–
106 8C, Lit.:[18b] 104.0–106.0 8C; Yield: 0.112 g (78 %); 1H NMR (CDCl3,
300 MHz): d = 8.30 (br s, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.38 (dd, J =
8.4, 1.6 Hz, 2 H), 7.28–7.22 (m, 1 H), 7.19–7.09 (m, 2 H), 7.02–6.97 (m,
1 H), 6.83–6.81 (m, 2 H), 2.46 ppm (s, 3 H); 13C NMR (CDCl3, 75 MHz):
d = 136.4, 136.0, 134.5, 131.5, 129.8, 127.8, 126.4, 125.3, 122.9,
120.8, 120.3, 111.4, 97.0, 21.2 ppm; MS m/z (rel. int.): 287 (43.6), 206
(80.9), 117 (100.0), 77 (8.4).
3-(4-Chlorophenylselanyl)-1 H-indole (3 d):[18b] White solid; m.p.:
132–133 8C, lit.:[18b] 132–133 8C; Yield: 0.125 g (96 %); 1H NMR
(CDCl3, 300 MHz): d = 8.40 (br s, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.43–
7.39 (m, 2 H), 7.26 (ddd, J = 8.2, 7.0, 1.3 Hz, 1 H), 7.19–7.05 ppm (m,
5 H); 13C NMR (CDCl3, 75 MHz): d = 136.3, 132.0, 131.5, 131.2, 129.9,
129.6, 129.0, 123.0, 121.0, 120.1, 111.4, 97.7 ppm; MS m/z (rel. int.):
307 (19.3), 227 (100.0), 116 (5.8), 77 (4.1).
3-[(4-Fluorophenyl)selanyl]-1 H-indole (3 e):[18b] White solid; m.p.:
117–118 8C, lit.:[18b] 117.0–118.0 8C; Yield: 0.131 g (90 %); 1H NMR
(CDCl3, 300 MHz): d = 8.28 (br s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.39–
7.35 (m, 2 H), 7.27–7.14 (m, 4 H), 6.81 ppm (t, J = 8.6 Hz, 2 H);
13
C NMR (CDCl3, 75 MHz): d = 161.4 (d, 1JC-F = 244.6 Hz), 136.3, 131.0,
130.6 (d, 3JC-F = 7.6 Hz), 129.6, 127.8 (d, 4JC-F = 3.2 Hz), 122.9, 120.9,
120.1, 116.0 (d, 2JC-F = 21.6 Hz), 111.4, 98.4 ppm; MS m/z (rel. int.):
291 (12.9), 211 (100.0), 183 (15.4), 77 (3.8).
3-{[3-(Trifluoromethyl)phenyl]selanyl}-1 H-indole (3 f):[18b] Yellow
solid; m.p.: 70–71 8C, lit.:[18b] 70.0–71.0 8C; Yield: 0.148 g (87 %);
1
H NMR (CDCl3, 300 MHz): d = 8.43 (br s, 1 H), 7.59 (d, J = 7.9 Hz,
1 H), 7.54 (s, 1 H), 7.46 (d, J = 2.5 Hz, 1 H), 7.43 (dt, J = 8.1, 0.9 Hz,
1 H), 7.35–7.23 (m, 3 H), 7.23–7.12 ppm (m, 2 H); 13C NMR (CDCl3,
75 MHz): d = 136.4, 135.2, 131.7, 131.5, 131.1 (q, 2JC-F = 32.2 Hz),
129.6, 129.2, 125.0 (q, 3JC-F = 3.9 Hz), 123.8 (q, 1JC-F = 272.8 Hz),
123.1, 122.3 (q, 3JC-F = 3.8 Hz), 121.1, 120.0, 111.5, 97.1 ppm; MS m/z
(rel. int.): 341 (17.4), 261 (100.0), 116 (8.4), 77 (4.2).
3-(Butylselanyl)-1 H-indole (3 g):[18b] Brown oil; Yield: 0.094 g
(74 %); 1H NMR (CDCl3, 300 MHz): d = 8.13 (br s, 1 H), 7.80–7.67 (m,
1 H), 7.33–7.27 (m, 1 H), 7.25–7.16 (m, 3 H), 2.69–2.63 (m, 2 H), 1.63–
1.50 (m, 2 H), 1.42–1.28 (m, 2 H), 0.84 ppm (t, J = 7.3 Hz, 3 H);
13
C NMR (CDCl3, 75 MHz): d = 136.1, 130.2, 130.0, 122.4, 120.3,
120.1, 111.2, 98.6, 32.6, 28.5, 22.6, 13.5 ppm; MS m/z (rel. int.): 253
(14.3), 196 (15.5), 117 (100.0), 77 (5.4).
5-Bromo-3-(phenylselanyl)-1 H-indole (3 h):[17] White solid; m.p.:
102–104 8C, lit.:[17] 108.1–109.4 8C; Yield: 0.152 g (87 %); 1H NMR
(CDCl3, 400 MHz): d = 8.47 (s, 1 H), 7.76 (d, J = 1.9 Hz, 1 H), 7.42 (d,
J = 2.6 Hz, 1 H), 7.31 (dd, J = 8.6, 1.9 Hz, 1 H), 7.26–7.11 ppm (m,
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

6 H); 13C NMR (CDCl3, 100 MHz): d = 135.0, 133.3, 132.4, 131.8,
129.0, 128.6, 125.9, 125.8, 122.9, 114.3, 112.9, 97.7 ppm; MS m/z
(rel. int.): 351 (36.5), 271 (100.0), 192 (36.9), 115 (12.1), 77 (12.6).
1-Methyl-3-(phenylselanyl)-1 H-indole (3 i):[16] White solid; m.p.:
63–65 8C, lit.:[16] 67.0–68.0 8C; Yield: 0.138 g (96 %); 1H NMR (CDCl3,
400 MHz): d = 7.62 (dt, J = 7.9, 1.0 Hz, 1 H), 7.34 (dt, J = 8.2, 0.9 Hz,
1 H), 7.29–7.18 (m, 4 H), 7.15 (ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.12–7.03
(m, 3 H), 3.77 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 137.4,
135.6, 134.2, 130.6, 128.8, 128.5, 125.4, 122.4, 120.39, 120.36, 109.5,
95.9, 33.0 ppm; MS m/z (rel. int.): 287 (21.8), 207 (100.0), 130 (15.5),
77 (6.7).
5-Bromo-3-(4-chlorophenylselenyl)-1 H-indole (3 j):[19b] White
solid; m.p.: 136–138 8C, lit.:[19b] 118–121 8C; Yield: 0.180 g (94 %);
1
H NMR (CDCl3, 300 MHz): d = 8.47 (br s, 1 H), 7.73–7.72 (m, 1 H),
7.45 (d, J = 2.6 Hz, 1 H), 7.33 (dd, J = 8.6, 1.8 Hz, 1 H), 7.27 (d, J =
8.6 Hz, 1 H), 7.14–7.05 ppm (m, 4 H); 13C NMR (CDCl3, 75 MHz): d =
135.0, 132.4, 131.8, 131.5, 129.9, 129.8, 129.1, 126.0, 122.7, 114.4,
112.9, 97.5 ppm; MS m/z (rel. int.): 385 (4.7), 306 (100.0), 190 (22.1),
114 (15.3), 75 (14.9).
3-(4-Chlorophenylselanyl)-1-methyl-1 H-indole (3 k):[19b] White
solid; m.p.: 116–119 8C, lit.:[19b] 116–119 8C; Yield: 0.138 g (86 %);
1 (q, 3JC-F = 3.8 Hz), 123.5 (q, 3JC-F = 3.6 Hz), 123.0 (q, 1JC-F = 273.4 Hz),
H NMR (CDCl3, 300 MHz): d = 7.57 (dt, J = 7.8, 1.0 Hz, 1 H), 7.35 (dt,
J = 8.2, 1.0 Hz, 1 H), 7.31–7.24 (m, 2 H), 7.21–7.02 (m, 5 H), 3.80 ppm
(s, 3 H); 13C NMR (CDCl3, 75 MHz): d = 137.4, 135.6, 132.4, 131.4,
130.3, 129.8, 128.9, 122.5, 120.5, 120.2, 109.6, 95.5, 33.0 ppm; MS
m/z (rel. int.): 321 (13.1), 240 (100.0), 130.0 (29.0), 77 (13.9).
[23]
2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3 l): Yellow
solid; m.p.: 91.1–93.1 8C, lit.:[23] 48–49 8C; Yield: 0.124 g (71 %);
1 J = 7.6 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.26–7.22 (m, 1 H), 6.87 (t,
H NMR (CDCl3, 400 MHz): d = 8.31 (d, J = 6.8 Hz, 1 H), 8.16 (d, J =
7.2 Hz, 2 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.34 (t,
J = 7.3 Hz, 1 H), 7.27–7.23 (m, 1 H), 7.13–7.07 (m, 5 H), 6.78 ppm (t,
J = 6.7 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 151.7, 147.7, 133.8,
130.8, 129.6, 128.7, 128.3, 128.25, 128.18, 126.6, 126.3, 125.5, 117.5,
112.8, 102.9 ppm; MS m/z (rel. int.): 350 (37.5), 270 (100.0), 193
(9.8), 77 (9.9).
2-Phenyl-3-(2-tolylselanyl)imidazo[1,2-a]pyridine (3 m): White
solid; m.p.: 117.8–119.7 8C; Yield: 0.118 g (65 %); 1H NMR (CDCl3,
400 MHz): d = 8.22 (d, J = 6.9 Hz, 1 H), 8.14–8.11 (m, 2 H), 7.71 (d, J =
9.0 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.35–7.31 (m, 1 H), 7.27–7.23 (m,
1 H), 7.13 (d, J = 7.4 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 6.83 (t, J =
7.6 Hz, 1 H), 6.77 (td, J = 6.8, 1.0 Hz, 1 H), 6.54 (d, J = 7.8 Hz, 1 H),
2.43 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 152.1, 147.8, 136.4,
133.6, 131.2, 130.5, 128.6, 128.3, 128.1, 127.0, 126.8, 126.3, 125.5,
117.4, 112.9, 101.8, 21.0 ppm; MS m/z (rel. int.): 364 (18.5), 283 (7.8),
194 (100.0), 78 (36.6); HRMS: calcd. for C20H16N2Se: 365.0551
[M++H] + ; found: 365.0551.
3-[(4-Methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a]pyridine
(3 n): Yellow oil; Yield: 0.108 g (57 %); 1H NMR (CDCl3, 400 MHz):
d = 8.36 (d, J = 6.7 Hz, 1 H), 8.20 (d, J = 8.1 Hz, 2 H), 7.65 (d, J =
8.8 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.36–7.32 (m, 1 H), 7.23–7.19 (m,
1 H), 7.07 (d, J = 8.5 Hz, 2 H), 6.77 (t, J = 6.8 Hz, 1 H), 6.68 (d, J =
8.5 Hz, 2 H), 3.65 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d = 159.1,
151.2, 147.4, 134.0, 130.8, 128.8, 128.2, 128.1, 126.0, 125.5, 120.5,
117.4, 115.4, 112.7, 104.1, 55.2 ppm; MS m/z (rel. int.): 380 (21.3),
273 (61.4), 194 (100.0), 78 (70.5); HRMS: calcd. for C20H16N2OSe:
381.0500 [M+ +H] + ; found: 381.0500.
3-[(4-Chlorophenyl)selanyl]-2-phenylimidazo[1,2-a]pyridine (3 o):
White solid; m.p.: 135.1–136.6 8C; Yield: 0.121 g (63 %); 1H NMR
(CDCl3, 400 MHz): d = 8.28 (d, J = 6.9 Hz, 1 H), 8.15–8.13 (m, 2 H),
7.69 (d, J = 9.0 Hz, 1 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.3 Hz,
1 H), 7.29–7.24 (m, 1 H), 7.10 (d, J = 8.6 Hz, 2 H), 6.99 (d, J = 8.6 Hz,
2 H), 6.81 ppm (td, J = 6.8, 0.8 Hz, 1 H); 13C NMR (CDCl3, 100 MHz):
Asian J. Org. Chem. 2017, 6, 1635 – 1646 www.AsianJOC.org
Full Paper
d = 151.9, 147.7, 133.6, 132.8, 129.7, 129.5, 129.0, 128.6, 128.4,
128.2, 126.4, 125.3, 117.5, 113.0, 102.4 ppm; MS m/z (rel. int.): 384
(46.5), 304 (100.0), 194 (23.6), 78 (98.6); HRMS: calcd. for
C19H13ClN2Se: 385.0003 [M+ +H] + ; found: 385.0003.
3-[(4-Fluorophenyl)selanyl]-2-phenylimidazo[1,2-a]pyridine (3 p):
Yellow solid; m.p.: 116.5–118.1 8C; Yield: 0.154 g (84 %); 1H NMR
(CDCl3, 400 MHz): d = 8.31 (d, J = 6.8 Hz, 1 H), 8.16 (d, J = 7.4 Hz,
2 H), 7.70 (d, J = 9.0 Hz, 1 H), 7.45–7.34 (m, 3 H), 7.29–7.25 (m, 1 H),
7.07 (dd, J = 8.5, 5.3 Hz, 2 H), 6.87–6.80 ppm (m, 3 H); 13C NMR
(CDCl3, 100 MHz): d = 162.0 (d, 1JC-F = 246.4 Hz), 151.5, 147.5, 133.5,
130.2 (d, 3JC-F = 7.6 Hz), 128.6, 128.4, 128.2, 126.4, 125.3, 125.0 (d,
4
JC-F = 3.3 Hz), 117.5, 116.7 (d, 2JC-F = 21.9 Hz), 113.0, 103.1 ppm; MS
m/z (rel. int.): 368 (44.0), 288 (100.0), 194 (11.3), 78 (75.3); HRMS:
calcd. for C19H13FN2Se: 369.0301 [M+ +H] + ; found: 369.0297.
2-Phenyl-3-{[3-(trifluoromethyl)phenyl]selanyl}imidazo[1,2-a]pyr-
idine (3 q): Yellow solid; m.p.: 93.5–95.7 8C; Yield: 0.159 g (70 %);
1
H NMR (CDCl3, 400 MHz): d = 8.31 (d, J = 6.9 Hz, 1 H), 8.12 (d, J =
7.2 Hz, 2 H), 7.74 (d, J = 9.0 Hz, 1 H), 7.48–7.30 (m, 6 H), 7.22 (t, J =
7.8 Hz, 1 H), 7.10 (d, J = 7.9 Hz, 1 H), 6.89–6.85 ppm (m, 1 H);
13
C NMR (CDCl3, 100 MHz): d = 152.2, 147.8, 133.3, 132.3, 131.9 (q,
2
JC-F = 32.5 Hz), 131.1, 130.0, 128.7, 128.6, 128.3, 126.8, 125.3, 124.9
117.6, 113.3, 101.8 ppm; MS m/z (rel. int.): 418 (50.8), 338 (100.0),
193 (11.7), 78 (79.9); HRMS: calcd. for C20H13F3N2Se: 419.0269
[M+ +H] + ; found: 419.0266.
3-(Butylselanyl)-2-phenylimidazo[1,2-a]pyridine (3 r): Brown oil;
Yield: 0.130 g (79 %); 1H NMR (CDCl3, 400 MHz): d = 8.52 (d, J =
6.8 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 2 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.45 (t,
J = 6.7 Hz, 1 H), 2.64 (t, J = 7.3 Hz, 2 H), 1.45 (quint, J = 7.2 Hz, 2 H),
1.27 (sext, J = 7.3 Hz, 2 H), 0.74 ppm (t, J = 7.3 Hz, 3 H); 13C NMR
(CDCl3, 100 MHz): d = 150.1, 147.0, 134.0, 128.6, 128.0, 127.9, 125.7,
125.4, 117.3, 112.5, 104.2, 31.9, 29.1, 22.5, 13.3 ppm; MS m/z (rel.
int.): 330 (44.0), 288 (100.0), 194 (11.3), 78 (75.3); HRMS: calcd. for
C17H18N2Se: 331.0708 [M+ +H] + ; found: 331.0707.
2-(4-Methoxyphenyl)-3-(phenylselanyl)imidazo[1,2-a]pyridine
(3 s): Yellow oil; Yield: 0.125 g (66 %); 1H NMR (CDCl3, 400 MHz): d =
8.30 (d, J = 6.8 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 2 H), 7.67 (d, J = 9.0 Hz,
1 H), 7.26–7.22 (m, 1 H), 7.16–7.07 (m, 5 H), 6.95 (d, J = 8.8 Hz, 2 H),
6.79–6.75 (m, 1 H), 3.80 ppm (s, 3 H); 13C NMR (CDCl3, 100 MHz): d =
159.8, 151.6, 147.6, 130.9, 129.9, 129.5, 128.1, 126.5, 126.3, 126.2,
125.4, 117.2, 113.7, 112.7, 101.9, 55.1 ppm; MS m/z (rel. int.): 380
(32.9), 300 (100.0), 150 (4.3), 78 (45.6); HRMS: calcd. for
C20H16N2OSe: 381.0514 [M+ +H] + ; found: 381.0514.
2-(4-Fluorophenyl)-3-(phenylselanyl)imidazo[1,2-a]pyridine (3 t):
Yellow solid; m.p.: 99.9–101.1 8C; Yield: 0.129 g (70 %); 1H NMR
(CDCl3, 400 MHz): d = 8.36 (dt, J = 6.9, 1.1 Hz, 1 H), 8.21–8.16 (m,
2 H), 7.71 (dt, J = 9.0, 1.1 Hz, 1 H), 7.33–7.28 (m, 1 H), 7.20–7.10 (m,
7 H), 6.85 ppm (td, J = 6.8, 1.2 Hz, 1 H); 13C NMR (CDCl3, 100 MHz):
d = 163.0 (d, 1JC-F = 248.1 Hz), 150.8, 147.7, 130.7, 130.5 (d, 3JC-F =
8.1 Hz), 130.0 (d, 4JC-F = 3.2 Hz), 129.7, 128.2, 126.7, 126.4, 125.5,
117.4, 115.2 (d, 2JC-F = 21.3 Hz), 113.0, 102.7 ppm; MS m/z (rel. int.):
368 (35.5), 288 (100.0), 211 (7.5), 78 (77.2).
Acknowledgments
The authors are grateful to CNPq, FAPERGS (PRONEM 16/2551-
0000240-1), CAPES, and FINEP for financial support.
1644 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Conflict of interest
The authors declare no conflict of interest.
Keywords: 3-selanyl-1 H-indole · 3-selanylimidazo[1,2-
a]pyridine · antioxidant activity · organoselenium ·
sonochemistry
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Manuscript received: June 8, 2017
Revised manuscript received: July 19, 2017
Accepted manuscript online: July 26, 2017
Version of record online: September 12, 2017
T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim