Catalytic antioxidant activity of bis-aniline-derived diselenides as GPx mimics

Article abstract of DOI:10.3390/molecules26154446

Herein, we describe a simple and efficient route to access aniline-derived diselenides and evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the electronic properties of the substituents determine the charge delocalization and the partial charge on selenium, which correlate with the catalytic performances. The amino group concurs in the stabilization of the selenolate intermediate through a hydrogen bond with the selenium.

Full text of DOI:10.3390/molecules26154446

molecules
Article
Catalytic Antioxidant Activity of Bis-Aniline-Derived
Diselenides as GPx Mimics
Giancarlo V. Botteselle 1,*, Welman C. Elias 2, Luana Bettanin 2, Rômulo F. S. Canto 3, Drielly N. O. Salin 2,
Flavio A. R. Barbosa 2, Sumbal Saba 4 , Hugo Gallardo 2 , Gianluca Ciancaleoni 5 , Josiel B. Domingos 2
,
Jamal Rafique 6,
*
and Antonio L. Braga 2,7,
*
1
Departamento de Química, Universidade Estadual do Centro-Oeste (UNICENTRO),
Guarapuava 85040-167, PR, Brazil
Departamento de Química, Universidade Federal de Santa Catarina (UFSC),
2
Florianópolis 88040-970, SC, Brazil; welmanqmc@gmail.com (W.C.E.); luana_bettanin@hotmail.com (L.B.);
driellyolek@gmail.com (D.N.O.S.); flavioauggusto@gmail.com (F.A.R.B.); hugo.gallardo@ufsc.br (H.G.);
josiel.domingos@ufsc.br (J.B.D.)
Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto
Alegre (UFCSPA), Porto Alegre 90050-170, RS, Brazil; rfscanto@gmail.com
Instituto de Química—IQ, Universidade Federal de Goiás—(UFG), Goiânia 74690-900, GO, Brazil;
sumbalsaba@ufg.br
Department of Chemistry and Industrial Chemistry, University of Pisa, Via G. Moruzzi 13, I-56124 Pisa, Italy;
gianluca.ciancaleoni@unipi.it
Instituto de Química—INQUI, Universidade Federal do Mato Grosso do Sul (UFMS),
Campo Grande 79074-460, MS, Brazil
3
4
5
6
7
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Department of Chemical Sciences, Faculty of Science, University of Johannesburg,
Doornfontein 2028, South Africa
Citation: Botteselle, G.V.; Elias, W.C.;
Bettanin, L.; Canto, R.F.S.; Salin,
D.N.O.; Barbosa, F.A.R.; Saba, S.;
Gallardo, H.; Ciancaleoni, G.;
Domingos, J.B.; et al. Catalytic
Antioxidant Activity of
*
Correspondence: giancarlo@unicentro.br (G.V.B.); jamal.chm@gmail.com (J.R.);
braga.antonio@ufsc.br (A.L.B.)
Abstract: Herein, we describe a simple and efficient route to access aniline-derived diselenides and
evaluate their antioxidant/GPx-mimetic properties. The diselenides were obtained in good yields
via ipso-substitution/reduction from the readily available 2-nitroaromatic halides (Cl, Br, I). These
diselenides present GPx-mimetic properties, showing better antioxidant activity than the standard
GPx-mimetic compounds, ebselen and diphenyl diselenide. DFT analysis demonstrated that the
electronic properties of the substituents determine the charge delocalization and the partial charge
on selenium, which correlate with the catalytic performances. The amino group concurs in the
stabilization of the selenolate intermediate through a hydrogen bond with the selenium.
Bis-Aniline-Derived Diselenides as
GPx Mimics. Molecules 2021, 26, 4446.
https://doi.org/10.3390/
molecules26154446
Academic Editor: Luana Bagnoli
Received: 23 June 2021
Accepted: 20 July 2021
Published: 23 July 2021
Keywords: organoselenides; GPx; DFT; non-bonding interaction; diselenides; anilines
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
In recent years, there has been an increasing interest in synthetic organoselenium
compounds, mainly due to their properties as synthetic intermediates in organic trans-
formations [
These compounds have been recently described as good antioxidants [10
senting anti-inflammatory [12 13], antibacterial [14], antiviral [15], anticancer [16
anti-Alzheimer’s [20 23] and other activities [24 28]. Furthermore, in relation to the
current pandemic of COVID-19, there are some interesting studies available that demon-
strate the effectiveness of organoselenium compound (Ebselen) as an antiviral molecule,
Figure 1 [29–31].
1
–
3
] and material sciences [
4
,
5
], as well as in medicinal chemistry [
11], also pre-
19],
6–9].
,
,
–
–
–
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 4446. https://doi.org/10.3390/molecules26154446
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4446
2 of 11
Figure 1. Ebselen.
Among organoselenium compounds, diorganyl diselenides present important an-
tioxidant and anticancer properties mainly because of the ability of these diselenides to
act as mimetics of the enzyme glutathione peroxidase (GPx) [6,8,11]. This selenoenzyme
possesses a residue of selenocysteine in its active site and is responsible for the reduction
of peroxides to water in our organism, protecting it from oxidative stress and related
diseases [32].
Notable among the polyfunctionalized diselenides, the presence of an amino or car-
bonyl group in close proximity to the selenium moiety has some unique biological features
due to non-bonding interactions [33
ported to be a good antioxidant, preventing the oxidative stress caused by peroxynitrite
and hydroperoxides [36 38]. Moreover, the aniline-derived diselenides, mainly with an
–35]. For example, the bis-2-aniline diselenide is re-
–
amino group in the ortho position, give these compounds two possible reactive centers,
Se-Se bond cleavage and the unshared pair of electrons on the nitrogen. This makes this
class of compounds extremely flexible in functional group interconversions, making it
appropriate for several transformations, mainly in the formation of selenium-containing
heterocycles, such as selenamides [39], benzoselenazines [40], benzoselenazoles [41] and
triazole diselenides [42].
Recently, we reported a new robust methodology for the synthesis of o-aniline-derived
diselenides from the reduction of o-nitrobenzene diselenides. As part of our wider research
program aimed at efficient methodologies for the synthesis of organoselenium compounds
and their biological evaluation [43–50], herein, we report the application of o-aniline-
derived diselenides as potential GPx mimics. For this purpose, different physical-chemical
studies were performed to demonstrate their biological properties, i.e., kinetic profile.
Furthermore, DFT studies were also carried out in order to study the electronic properties
of the substituents for determining the charge delocalization on the selenium atom and its
influence on catalytic performance.
2. Results and Discussion
The bis-o-nitrobenzene diselenides were initially prepared through the nucleophilic
aromatic substitution of o-halonitrobenzenes with K2Se2 (generated in situ) from a modified
simple methodology [51]. After this, we carried out the reduction of bis-o-nitrobenzene
diselenides from a well-established procedure described in the literature [52] using low-
cost iron sulfate heptahydrate (FeSO4.7H2O) to synthesize the aniline-derived diselenides
(Scheme 1).
Scheme 1. Reaction conditions: (i) Se (3.0 mmol), KOH (6.0 mmol), heated until melted for 5 min and H2O (6.0 mL);
(ii) o-halonitrobenzene 1a (1.5 mmol) and THF or DMF (1.5 mL), r.t., 2 h; (iii) bis-nitrobenzene diselenide 2a (1.5 mmol)
and FeSO4.7H2O (5.0 eq), methanol (25.0 mL) and H2O (25.0 mL), reflux, 1 h. NH4OH (15.0 mL), reflux, 10 min.
–f
–e

Molecules 2021, 26, 4446
3 of 11
The aniline-derived diselenides 3a–e were evaluated with regard to GPx-like antioxi-
dant activity. The catalytic parameters were obtained using the Tomoda [53] reaction model,
where the synthesized diselenides were applied as catalysts in the formation of diphenyl
disulfide (PhSSPh) through the reduction of hydrogen peroxide (H2O2) in the presence of
thiophenol (PhSH), which is accompanied by an increase in UV/vis absorbance in 305 nm
(Figure 2a). Then, the absorbance was plotted against diphenyl disulfide concentration to
determine the molar absorptivity at 305 nm (Figure 2b).
Figure 2.
(
a
) UV-Vis spectrum of PhSH oxidation in the presence of H2O2 and diselenide 3b as catalyst.
◦
[PhSH] = 10 mmol L−1, [3b] = 0.01 mmol L−1 and [H2O2] = 15 mmol L−1, in methanol at 25 C; (
b
) Absorbance plot-
ted against diphenyl disulfide concentration. The red line represents the linear fit. The coefficient of molar absorptivity in
305 nm was 1415 L mol cm (R2 = 0.9996).
−1
−1
The catalytic parameters were obtained by fitting the kinetic profiles, that is, initial
rate versus initial PhSH concentration, as shown in Figure 3 for diselenide 3b (for other
compounds, see Figures S31–S38, Pg. S22–S25 in Supplementary Materials), with the
Michaelis–Menten equation (Equation (1)).
Figure 3. Initial rate (V0) plotted against substrate concentration. The initial rates were calculated
from at least two experiments for each concentration of PhSH. The concentrations of 3b and H2O2
were fixed at 1
Menten fit.
×
10−5 and 15
×
10−3 mol L−1, respectively. The red line represents the Michaelis–

Molecules 2021, 26, 4446
4 of 11
Table 1 shows the catalytic constant (kcat), the Michaelis–Menten constant (Km) and
the catalytic efficiency (η where η = kcat/Km) for the reaction with the aniline-derived dise-
lenides 3a to 3e and, for comparison, the well-known catalysts ebselen [35] and diphenyl
diselenide [53].
Table 1. GPx-like catalytic evaluation of aniline-derived diselenides 3a–e.
−5
−1
−1
−1
−1
−1
)
Entry Catalyst (1 × 10 mol L
)
Km (mol L
)
kcat (min
)
η (L mol min
1
0.00170
0.422
248.65
527.78
2
0.00114
0.601
3
4
5
6
7
0.00134
0.00105
0.00187
0.00081
0.00088
0.446
1.185
0.470
0.405
0.918
333.40
1128.57
251.51
500.11
1044.19
The results show that the catalytic efficiency of the aniline-derived diselenides is
structure-dependent, especially regarding the electronic character of the substituents at
the para position related to selenium, with an increase in the catalytic efficiency with the
electron-withdrawal capacity of the substituent (compound 3b), once cleavage of the Se-Se
bond is facilitated. These results suggest that the mechanism of these catalyzed reactions
involves the formation of a zwitterionic form of the selenolate intermediate with a negative
density charge in the selenium atom (Scheme 2a), which is similar to the mechanism
proposed by Tomoda et al. [53].

Molecules 2021, 26, 4446
5 of 11
Scheme 2. Reactive intermediates: (a) selenolate (a–e) and (b) selenyl sulfide.
The structures 3a–e have been optimized by Density Functional Theory (DFT) at the
BP86-D3/def2-TZVP level of theory, using the zero-order regular approximation (ZORA)
to take the relativistic effects into account. In all the optimized geometries (except 3b), an
intramolecular hydrogen bond (HB) exists between the two amine moieties, with distances
that range from 2.624 (3d) to 3.139 (3a) Å. In the case of 3b, the electron-withdrawing
-CF3 group likely makes the lone pair of the nitrogen less available for HBs. The elec-
tronic effect of the group in the para position influences all the atomic charges of the
diselenide system. Indeed, the atomic charges have been computed through the Natural
Population Analysis (see Computational Details) as implemented in NBO 6.0, and for
the selenium, it ranges from 0.063 to 0.123 e for 3c (the most electron-donating group)
and 3b (the most electron-withdrawing one), respectively. The atomic charge on the se-
lenium qualitatively correlates with η, according to which the best catalysts have a more
positive charge on the selenium and a less negative charge on the nitrogen (Figure 4 and
Supplementary Materials). In addition, a similar correlation can be observed between the
atomic charge of the ammonium-selenolate and η: in this case, the best catalysts have a
less negative charge on the selenium, leading to a larger degree of charge delocalization
and, consequently, a more stable intermediate. This is in agreement with the mechanism
proposed by Tomoda [53]. Furthermore, the hydrogen bonding between the ammonium
protons and the selenolate moiety is quite strong and stabilizes the intermediate, hav-
ing an orbital interaction of 8–9 kcal/mol depending on the substituent (Supplementary
Materials), hence making the catalyst more active.
Tomoda et al. [53] also proposed that another reactive intermediate is formed in
the initial step from the reaction of the diselenide with PhSH, that is, the selenyl sulfide
(Scheme 2b). In the case of the aniline-derived diselenides, it seems that the formation
of this intermediate is destabilized by the inductive electron donor capacity of the amine
groups at the ortho position, reflected in their lower catalytic efficiency when compared
with the diphenyl diselenide (Table 1, entries 3 and 2, respectively).
Of the aniline-derived diselenides, the highest catalytic efficiency was observed for
compound 3b (Table 1, entry 4), which was 5 and 2 times more active than the standards
ebselen and diphenyl diselenide, respectively. It is worth noting that the diselenide 3b
was more effective than ebselen, which is a pre-clinical drug candidate with pronounced
biological activities, including, recently, the inhibition of protease Mpro from COVID-19
(SARS-CoV-2) virus [29–31].
Due to the high antioxidant activity of the diselenide 3b as a mimetic of GPx, we
decided to investigate the effectiveness of this methodology at the gram scale. Thus, we
performed the reaction from 20.0 mmol (5.40 g) of the o-halonitrobenzene 1c to afford the
desired nitro-diselenide 2b, followed by its reduction to obtain the bis-aniline-derived 3b
without a significant decrease in the yields (Scheme 3), proving that this protocol could be
used as a robust method in the larger-scale synthesis of this privileged structure.

Molecules 2021, 26, 4446
6 of 11
Figure 4. Catalytic efficiency (
η) plotted against calculated atomic charges for (a) N atom (qN) of aniline-derived diselenides,
(b) Se atom (qSe) of aniline-derived diselenides, and (c) Se atom (qSe) of aniline-derived selenolates.
Scheme 3. Gram-scale reaction for the synthesis of aniline-derived diselenide 3b.
3. Materials and Methods
3.1. GPx-Like Experimental Procedure
The kinetic profile of the oxidation reaction was conducted in a UV-vis Spectropho-
tometer, following the wavelength of diphenyl disulfide formation at 305 nm. Spectroscopic
methanol was used as solvent in the oxidation reaction, and the final volume of cuvett−es1
was kept at 2000
µ
L. The H2O2 and catalyst concentration were fixed in 15 × 10−3 mol L
and 1
to 15
×
10−5 mol L−1 respectively, and the PhSH concentration was varied from 0.5 × 10−3
−3 ◦
10 mol L−1. The temperature was kept at 25 C, and each experiment was run at
×
least 2 times.
3.2. Michaelis–Menten Equation
The GPx-like kinetic profiles were treated using the Michaelis–Menten nonlinear
Equation (1):
k
cat[cat][PhSH]
V =
(1)
(Km + [PhSH])

Molecules 2021, 26, 4446
7 of 11
where the V0 was the initial velocity and kcat and Km were the catalytic rate constant and
Michaelis–Menten constant, respectively. The [cat] and [PhSH] represent the concentration
of the catalyst and thiophenol, respectively.
3.3. Computational Details
All geometries were optimized with ORCA 4.1.0, [54] using the BP86 functional in
conjunction with a triple-ζ quality basis set (ZORA-TZVP) and def2/J auxiliary basis. For
heavy elements (such as selenium and bromine), relativistic effects have been accounted
by using the Zeroth Order Regular Approximation (ZORA) scalar correction. The dis-
persion corrections were introduced using the Grimme D3-parametrized correction and
the Becke Johnson damping to the DFT energy [55]. All the diselenide structures were
−
confirmed to be local energy minima (no imaginary frequencies). Selenolate species show
an unavoidable imaginary frequency correlated with the rotation of the -NH3 moiety.
The atomic charges have been computed by the Natural Population Analysis (NPA) as
implemented in NBO6 [56].
4. Conclusions
In conclusion, we have developed a short and robust synthetic route for the synthesis
of nitro aryl and aniline-derived diselenides in good overall yields. The aniline-derived
diselenides were evaluated as GPx mimetics and the diselenide 3b substituted with the
CF3 group showed the best results, being 5 and 2 times more effective as a GPx mimetic
than the standard catalysts ebselen and diphenyl diselenide, respectively. Furthermore,
DFT analysis was performed for all the diselenides, which demonstrated non-bonding
interaction. This correlates with the GPx activities of these diselenides.
1
Supplementary Materials: The following are available online, H, and 13C NMR spectra of the
1
synthesized compounds (3a
–
e
). Figure S1: H NMR (200 MHz, CDCl3) Spectrum of compound 2a
.
Figure S2: 13C NMR (50 MHz, CDCl3) Spectrum of compound 2a. Figure S3: HRMS spectrum of
compound 2a. Figure S4: H NMR (200 MHz, CDCl3) Spectrum of compound 2b. Figure S5: 13C
1
NMR (50 MHz, CDCl3) Spectrum of compound 2b. Figure S6: HRMS spectrum of compound 2b
.
1
Figure S7: H NMR (200 MHz, CDCl3) Spectrum of compound 2c. Figure S8: 13C NMR (50 MHz,
1
CDCl3) Spectrum of compound 2c. Figure S9: HRMS spectrum of compound 2c. Figure S10: H NMR
(200 MHz, CDCl3) Spectrum of compound 2d. Figure S11: 13C NMR (50 MHz, CDCl3) Spectrum
1
of compound 2d. Figure S12: HRMS spectrum of compound 2d. Figure S13: H NMR (200 MHz,
CDCl3) Spectrum of compound 2e. Figure S14: 13C NMR (50 MHz, CDCl3) Spectrum of compound
2e. Figure S15: ESI-MS spectrum of compound 2e. Figure S16:1H NMR (200 MHz, CDCl3) Spectrum
of compound 3a. Figure S17: 13C NMR (50 MHz, CDCl3) Spectrum of compound 3a. Figure S18:
1H NMR (200 MHz, CDCl3) Spectrum of compound 3b. Figure S19: 13C NMR (50 MHz, CDCl3)
Spectrum of compound 3b. Figure S20: HRMS spectrum of compound 3b. Figure S21: 1H NMR
(200 MHz, CDCl3) Spectrum of compound 3c. Figure S22: 13C NMR (50 MHz, CDCl3) Spectrum
of compound 3c. Figure S23: HRMS spectrum of compound 3c. Figure S24: 1H NMR (200 MHz,
CDCl3) Spectrum of compound 3d. Figure S25: 13C NMR (50 MHz, CDCl3) Spectrum of compound
1
3d. Figure S26: HRMS spectrum of compound 3d. Figure S27: H NMR (200 MHz, CDCl3) Spectrum
of compound 3e. Figure S28: 13C NMR (50 MHz, CDCl3) Spectrum of compound 3e. Figure S29:
ESI-MS spectrum of compound 3e. Figure S30: 77Se NMR (76 MHz, CDCl3) Spectrum of compound
3b. Figure S31: Absorbance plotted against diphenyl disulfide concentration. The red line represents
−1
−1
the linear fit. The coefficient of molar absorptivity in 305 nm was 1415 L mol cm (R2 = 0.9996).
Figure S32: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated
from at least two experiments for each concentration of PhSH. The concentrations of ebselen and
H2O2 were fixed at 5
×
10−5 and 15
×
10−3 mol L−1, respectively. The red line represents the
Michaelis-Menten fit. Figure S33: Initial rate (V0) plotted against substrate concentration. The
initial rates were calculated from at least two experiments for each concentration of PhSH. The
concentrations of diphenyl disulfide and H2O2 were fixed at 5
respectively. The red line represents the Michaelis-Menten fit. Figure S34: Initial rate (V0) plotted
×
10−5 and 15
×
10−3 mol L−1
,
against substrate concentration. The initial rates were calculated from at least two experiments
for each concentration of PhSH. The concentrations of 3c and H2O2 were fixed at 5
×
10−5 and

Molecules 2021, 26, 4446
8 of 11
−3
15 × 10 mol L−1, respectively. The red line represents the Michaelis-Menten fit. Figure S35: Initial
rate (V0) plotted against substrate concentration. The initial rates were calculated from at least
two experiments for each concentration of PhSH. The concentrations of 3a and H2O2 were fixed
−5
−3
at 5 × 10 and 15 × 10 mol L−1, respectively. The red line represents the Michaelis-Menten fit.
Figure S36: Initial rate (V0) plotted against substrate concentration. The initial rates were calculated
from at least two experiments for each concentration of PhSH. The concentrations of 3b and H2O2
−3
were fixed at 5
×
10−5 and 15 × 10 mol L−1, respectively. The red line represents the Michaelis-
Menten fit. Figure S37: Initial rate (V0) plotted against substrate concentration. The initial rates
were calculated from at least two experiments for each concentration of PhSH. The concentrations of
3d and H2O2 were fixed at 5
the Michaelis-Menten fit. Figure S38: Initial rate (V0) plotted against substrate concentration. The
×
10−5 and 15
×
10−3 mol L−1, respectively. The red line represents
initial rates were calculated from at least two experiments for e−ac3h concentration of PhSH. The
−5
concentrations of 3e and H2O2 were fixed at 5
×
10 and 15
×
10 mol L−1, respectively. The red
line represents the Michaelis-Menten fit. Table S1: Atomic charges of nitrogen and selenium according
to NPA. Table S2: Donor-acceptor second order perturbation analysis. Table S3: DFT-computed
energies for optimized geometries (in kcal/mol).
Author Contributions: Conceptualization, G.V.B., J.R. and A.L.B.; synthesis, spectral analysis, char-
acterizations, and reagents/materials, G.V.B., L.B., R.F.S.C., F.A.R.B., S.S., H.G. and J.R.; GPX studies,
W.C.E., D.N.O.S. and J.B.D.; DFT analysis, G.C.; writing—original draft, G.V.B. and J.R. writing—
review and editing, G.V.B., J.R. and A.L.B. wrote the paper. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not Applicable.
Informed Consent Statement: Not Applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Acknowledgments: We gratefully acknowledge “Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior—CAPES” (Finance Code 001), “Conselho Nacional de Desenvolvimento Científico e
Tecnológico—CNPq”, “Instituto Nacional de Ciência e Tecnologia de Catálise em Sistemas Molecu-
lares e Nanoestruturados—INCT-Catálise/CNPq/FAPESC”, “Centro de Excelência para Pesquisa
em Química Sustentável—CERSusChem” (grant 2014/50249-8), “Fundação de Amparo à Pesquisa do
Estado de São Paulo—FAPESP”, (grant 2014/50249-8) “GlaxoSmithKline—GSK” (grant 2014/50249-
8). G.V.B. would like to acknowledge CNPq (429831/2018-8). J.R. would like to acknowledge CNPq
(433896/2018-3 and 315399/2020-1). The authors acknowledge “Laboratório Central de Biologia
Molecular Estrutural (CEBIME)” (UFSC-Brazil) for the HRMS analysis.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds can be checked with the author, G.V.B.
References
1.
2.
3.
4.
5.
6.
7.
Shao, L.; Li, Y.; Lu, J.; Jiang, X. Recent progress in selenium-catalyzed organic reactions. Org. Chem. Front. 2019, 6, 2999–3041.
[CrossRef]
Arora, A.; Sinhg, S.; Oswal, P.; Nautiyal, D.; Rao, G.K.; Kumar, S.; Kumar, A. Preformed molecular complexes of metals with
organoselenium ligands: Syntheses and applications in catalysis. Coord. Chem. Rev. 2021, 438, 213885. [CrossRef]
Rafique, J.; Rampoin, D.S.; Azeredo, J.B.; Coelho, F.L.; Schneider, P.H.; Braga, A.L. Light-mediated seleno-functionalization of
organic molecules: Recent advances. Chem. Rec. 2021. [CrossRef] [PubMed]
Li, Q.; Zhang, Y.; Chen, Z.; Pan, X.; Zhan, Z.; Zhu, J.; Zhu, X. Organoselenium chemistry-based polymer synthesis. Org. Chem.
Front. 2020, 7, 2815–2841. [CrossRef]
Xiao, X.; Shao, Z.; Yu, L. A perspective of the engineering applications of carbon-based selenium-containing materials. Chin.
Chem. Lett. 2021. [CrossRef]
Nogueria, C.W.; Barbos, N.V.; Rocha, J.B.T. Toxicology and pharmacology of synthetic organoselenium compounds: An update.
Arch. Toxicol. 2021, 95, 1179–1226. [CrossRef] [PubMed]
Braga, A.L.; Rafique, J. Synthesis of biologically relevant small molecules containing selenium. Part A. Antioxidant compounds.
In The Chemistry of Organic Selenium and Tellurium Compounds; Rappoport, Z., Ed.; Wiley: Chichester, UK, 2013; Volume 4,
pp. 989–1052.

Molecules 2021, 26, 4446
9 of 11
8.
9.
Barbosa, N.V.; Nogueira, C.W.; Nogara, P.A.; Bem, A.F.; Aschner, M.; Rocha, J.B. Organoselenium compounds as mimics of
selenoproteins and thiol modifier agentes. Metallomics 2017, 9, 1703–1734. [CrossRef]
Braga, A.L.; Rafique, J. Synthesis of biologically relevant small molecules containing selenium. Part C. Miscellaneous biological
activities. In The Chemistry of Organic Selenium and Tellurium Compounds; Rappoport, Z., Ed.; Wiley: Chichester, UK, 2013; Volume 4,
pp. 1119–1174.
10. Santi, C.; Bagnoli, L. Celebrating two centuries of research in selenium chemistry: State of the art and new prospective. Molecules
2017, 22, 2124. [CrossRef]
11. Mugesh, G.; Singh, H.B. Synthetic organoselenium compounds as antioxidants: Glutathione peroxidase activity. Chem. Soc. Rev.
2000, 29, 347–357. [CrossRef]
12. He, X.; Zhong, M.; Li, S.; Li, X.; Li, Y.; Li, Z.; Gao, Y.; Ding, F.; Wen, D.; Lei, Y.; et al. Synthesis and biological evaluation of
organoselenium (NSAIDs-SeCN and SeCF3) derivatives as potential anticancer agents. Eur. J. Med. Chem. 2020, 208, 112864.
[CrossRef] [PubMed]
13. He, X.; Nie, Y.; Zong, M.; Li, S.; Li, X.; Guo, Y.; Liu, Z.; Gao, Y.; Ding, F.; Wen, D.; et al. New organoselenides (NSAIDs-Se
derivatives) as potential anticancer agents: Synthesis, biological evaluation and in silico calculations. Eur. J. Med. Chem. 2021, 218,
113384. [CrossRef]
14. Sabir, S.; Yu, T.T.; Kuppusamy Almohaywi, B.; Iskander, G.; Das, T.; Willcox MD, P.; Black, D.S.; Kumar, N. Novel seleno- and
thio-urea containing dihydropyrrol-2-one analogues as antibacterial agents. Antibiotics 2021, 10, 321. [CrossRef] [PubMed]
15. Ali, W.; Benedetti, R.; Handzlik, J.; Zwergel Battisetlli, C. The innovative potential of selenium-containing agents for fighting
cancer and viral infections. Drug Discov. Today 2021, 26, 256–263. [CrossRef] [PubMed]
16. Almeida, G.M.; Rafique, J.; Saba, S.; Siminski, T.; Mota NS, R.S.; Filho, D.W.; Braga, A.L.; Pedrosa, R.C.; Ourique, F. Novel
selenylated imidazo[1,2-a]pyridines for breast cancer chemotherapy: Inhibition of cell proliferation by Akt-mediated regulation,
DNA cleavage and apoptosis. Biochem. Biophys. Res. Commun. 2018, 503, 1291–1297. [CrossRef] [PubMed]
17. Chen, Z.; Lai, H.; Hou, L.; Chen, T. Rational design and action mechanisms of chemically innovative organoselenium in cancer
therapy. Chem. Commun. 2020, 56, 179–196. [CrossRef]
18. Santos, D.C.; Rafique, J.; Saba, S.; Almeida, G.M.; Siminski, T.; Padua, C.; Filho, D.W.; Zamoner, A.; Braga, A.L.; Pedrosa, R.C.;
et al. Apoptosis oxidative damage-mediated and antiproliferative effect of selenylated imidazo[1,2-a]pyridines on hepatocellular
carcinoma HepG2 cells and in vivo. J. Biochem. Mol. Toxicol. 2021, 35, e22663. [CrossRef]
19. Spengler, G.; Gjdacs, M.; Marc, M.A.; Dominguez-Alvarez, E.; Sanmartin, C. Organoselenium compounds as novel adjuvants of
chemotherapy drugs—A promising approach to fight cancer drug resistance. Molecules 2019, 24, 336. [CrossRef]
20. Kumawat, A.; Raheem, S.; Ali, F.; Dar, T.A.; Chakrabarty, S.; Rizvi, M.A. Organoselenium compounds as acetylcholinesterase
inhibitors: Evidence and mechanism of mixed inhibition. J. Phys. Chem. B 2021, 125, 1531–1541. [CrossRef]
21. Rodrigures, J.; Saba, S.; Joussef, A.C.; Rafique, J.; Braga, A.L. KIO3-catalyzed C(sp2)-H bond selenylation/sulfenylation of
(hetero)arenes: Synthesis of chalcogenated (hetero)arenes and their evaluation for anti-Alzheimer activity. Asian J. Org. Chem.
2018, 7, 1819–1824. [CrossRef]
22. Kepp, K.P. Bioinorganic chemistry of Alzheimer’s disease. Chem. Rev. 2012, 112, 5193–5239. [CrossRef] [PubMed]
23. Scheide, M.R.; Schneider, A.R.; Jardin GA, M.; Martins, G.M.; Durigon, D.C.; Saba, S.; Rafique, J.; Braga, A.L. Electrochemical
synthesis of selenyl-dihydrofurans via anodic selenofunctionalization of allyl-naphthol/phenol derivatives and their anti-
Alzheimer activity. Org. Biomol. Chem. 2020, 18, 4916–4921. [CrossRef]
24. Wang, B.; Wang, Z.; Chen, H.; Lu, C.-J.; Li, X. Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with
(benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced A
2016, 24, 4741–4749. [CrossRef]
β aggregation and antioxidant. Bioorg. Med. Chem.
25. Veloso, I.C.; Delangara, E.; Machado, A.E.; Braga, S.P.; Rosa, G.K.; Bem, A.F.; Rafique, J.; Saba, S.; Trindade, R.N.; Galetto, F.Z.;
et al. A selanylimidazopyridine (3-SePh-IP) reverses the prodepressant- and anxiogenic-like effects of a high-fat/high-fructose
diet in mice. J. Pharm. Pharmacol. 2021, 73, 673–681. [CrossRef]
26. Gülçin, I.; Trofimov, B.; Kaya, R.; Taslimi, P.; Sobenina, L.; Schmidt, E.; Petrova, O.; Malysheva, S.; Gusarova, N.; Farzaliyev,
V.; et al. Synthesis of nitrogen, phosphorus, selenium and sulfur-containing heterocyclic compounds—Determination of their
carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase and
104171. [CrossRef]
α-glycosidase inhibition properties. Bioorg. Chem. 2021, 103,
27. Martín-Escolano, R.; Etxebeste-Mitxeltorena, M.; Martín-Escolano, J.; Plano, D.; Rosales, M.J.; Espuelas, S.; Moreno, E.; Sánchez-
Moreno, M.; Sanmartín, C.; Marín, C. Selenium Derivatives as Promising Therapy for Chagas Disease: In Vitro and In Vivo
Studies. ACS Infect. Dis. 2021. [CrossRef]
28. Galant, L.S.; Rafique, J.; Braga, A.L.; Braga, F.C.; Saba, S.; Radi, R.; Rocha JB, T.; Santi CMonsalve, M.; Farina, M.; Bem, A.F. The
thiol-modifier effects of organoselenium compounds and their cytoprotective actions in neuronal cells. Neurochem. Res. 2021, 46,
120–130. [CrossRef]
29. Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; et al. Structure of Mpro from COVID-19
virus and discovery of its inhibitors. Nature 2020, 582, 289–293. [CrossRef] [PubMed]
30. Sies, H.; Parnham, M.J. Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections. Free Radic. Biol.
Med. 2020, 156, 107–112. [CrossRef]

Molecules 2021, 26, 4446
10 of 11
31. Sun, L.-Y.; Chen, C.; Su, J.; Li, J.-Q.; Jiang, Z.; Gao, H.; Ching, J.-Z.; Ding, H.-H.; Zhai, L.; Yang, K.-W. Ebsulfur and Ebselen as
highly potent scaffolds for the development of potential SARS-CoV-2 antivirals. Bioorg. Chem. 2021, 112, 104889. [CrossRef]
[PubMed]
32. Masuda, R.; Kimura, R.; Karasaki, T.; Sase, S.; Goto, K. Modeling the catalytic cycle of glutathione peroxidase by nuclear magnetic
resonance spectroscopic analysis of selenocysteine selenenic acids. J. Am. Chem. Soc. 2021, 143, 6345–6350. [CrossRef]
33. Bortoli, M.; Madabeni, A.; Nogara, P.A.; Omage, F.B.; Ribaudo, G.; Zeppliil, D.; Rocha JB, T.; Orian, L. Chalcogen-nitrogen bond:
Insights into a key chemical motif. Catalysts 2020, 11, 114. [CrossRef]
34. Sudati, J.H.; Nogara, P.A.; Saraiva, R.A.; Wagner, C.; Alberto, A.E.; Braga, A.L.; Fachinetto, R.; Piquini, P.C.; Rocha, J.B.T.
Diselenoamino acid derivatives as GPx mimics and as substrates of TrxR: In vitro and in silico studies. Org. Biomol. Chem. 2018,
16, 3777–3787. [CrossRef] [PubMed]
35. Rafique, J.; Saba, S.; Canto RF, S.; Frizon TE, A.; Hassan, W.; Waczuk, E.P.; Jan, M.; Back, D.F.; Rocha JB, T.; Braga, A.L. Synthesis
and biological evaluation of 2-picolylamide-based diselenides with non-bonded interactions. Molecules 2015, 20, 10095–10109.
[CrossRef] [PubMed]
36. Collins, C.A.; Fry, F.H.; Holme, A.L.; Yiakouvaki, A.; Al-Qenaei, A.; Pourzand, C.; Jacob, C. Towards multifunctional antioxidants:
Synthesis, electrochemistry, in vitro and cell culture evaluation of compounds with ligand/catalytic properties. Org. Biomol.
Chem. 2005, 3, 1541–1546. [CrossRef]
37. Nowak, P.; Saluk-Juszczak, J.; Olas, B.; Kolodziejczyk, J.; Wachowics, B. The protective effects of selenoorganic compounds
against peroxynitrite-induced changes in plasma proteins and lipids. Cell. Mol. Biol. Lett. 2006, 11, 1–11. [CrossRef] [PubMed]
38. Saluk, J.; Bijak, M.; Nowak, P.; Wachowicz, B. Evaluating the antioxidative activity of diselenide containing compounds in human
blood. Bioorg. Chem. 2013, 50, 26–33. [CrossRef] [PubMed]
39. Kloc, K.; Mlochowski, L.; Osajda, K.; Sypeer, L.; Wójtowics, H. New heterocyclic selenenamides: 1,2,4-benzoselenadiazin-3(4H)-
ones and 1,3,2-benzodiselenazoles. Tetrahedron Lett. 2002, 43, 4071–4074. [CrossRef]
40. Viglianisi, C.; Simone, L.; Menichetti, S. Copper-Mediated One-Pot Transformation of 2-N-Sulfonyl- aminoaryl Diselenides into
Benzo[b][1,4]selenazines. Adv. Synth. Catal. 2012, 354, 77–82. [CrossRef]
41. Radatz, C.S.; Alves, D.; Schneider, P.H. Direct synthesis of 2-aryl-1,3-benzoselenazoles by reaction of bis(2-aminophenyl)
diselenides with aryl aldehydes using sodium metabisulfite. Tetrahedron 2013, 69, 1316–1321. [CrossRef]
42. Deobald, A.M.; Camargo LR, S.; Hörner, M.; Rodrigues OE, D.; Alves, D.; Braga, A.L. Synthesis of arylseleno-1,2,3-triazoles via
copper-catalyzed 1,3-dipolar cycloaddition of azido arylselenides with alkynes. Synthesis 2011, 15, 2397–2406.
43. Frizon TE, A.; Cararo, J.H.; Saba, S.; Dal-Pont, G.C.; Michels, M.; Braga, H.C.; Pimentel, T.; Dal-Pizzol, F.; Valvassori, S.S.; Rafique,
J. Synthesis of novel selenocyanates and evaluation of their effect in cultured mouse neurons submitted to oxidative stress. Oxid.
Med. Cell. Longev. 2020, 5417024. [CrossRef]
44. Scheide, M.R.; Peterle, M.M.; Saba, S.; Neto JS, S.; Lenz, G.F.; Cezar, R.D.; Felix, J.F.; Botteselle, G.V.; Schneider, R.; Rafique, J.; et al.
Borophosphate glass as an active media for CuO nanoparticle growth: An efficient catalyst for selenylation of oxadiazoles and
application in redox reactions. Sci. Rep. 2020, 10, 15233. [CrossRef]
45. Rafique, J.; Farias, G.; Saba, S.; Zapp, E.; Bellettini, I.C.; Salla, C.A.M.; Bechtold, I.H.; Scheide, M.R.; Neto JS, S.; Souza, D.M., Jr.;
et al. Selenylated-oxadiazoles as promising DNA intercalators: Synthesis, electronic structure, DNA interaction and cleavage.
Dyes Pigm. 2020, 180, 108519. [CrossRef]
46. Peterle, M.M.; Scheide, M.R.; Silva, L.T.; Saba, S.; Rafique, J.; Braga, A.L. Copper-catalyzed three-component reaction of
oxadiazoles, elemental Se/S and aryl iodides: Synthesis of chalcogenyl (Se/S)-oxadiazoles. Chemitryselect 2018, 3, 13191–13196.
[CrossRef]
47. Silva, L.T.; Azerefo, J.B.; Saba, S.; Rafique, J.; Bortoluzzi, A.J.; Braga, A.L. Solvent- and metal-free chalcogenation of bicyclic arenes
Using I2/DMSO as non-metallic catalytic system. Eur. J. Org. Chem. 2017, 32, 4740–4748. [CrossRef]
48. Rafique, J.; Saba, S.; Frizon TE, A.; Braga, A.L. Fe3O4 nanoparticles: A robust and magnetically recoverable catalyst for direct C-H
bond selenylation and sulfenylation of benzothiazoles. Chemsitryselect 2018, 3, 328–334. [CrossRef]
49. Rocah MS, T.; Rafique, J.; Saba Azerdo, J.B.; Back, D.; Godoi, M.; Braga, A.L. Regioselective hydrothiolation of terminal acetylene
catalyzed by magnetite (Fe3O4) nanoparticles. Synth. Commun. 2017, 47, 291–298. [CrossRef]
50. Rafique, J.; Saba, S.; Rosario, A.R.; Zeni, G.; Braga, A.L. K2CO3-mediated, direct C–H bond selenation and thiolation of
1,3,4-oxadiazoles in the absence of metal catalyst: An eco-friendly approach. RSC Adv. 2014, 4, 51648–51652. [CrossRef]
51. Menichetti, S.; Capperucci Tanini, D.; Braga ALBotteselle, G.V.; Viglianisi, C. A one-pot access to benzo[b][1,4]selenazines from
2-aminoaryl diselenides. Euro. J. Org. Chem. 2016, 18, 3097–3102. [CrossRef]
52. Sharma, U.; Verma, P.K.; Kumar, N.; Kumar, V.; Bala, M.; Singh, B. Phosphane-free green protocol for selective nitro reduction
with an iron-based catalyst. Chem. Eur. J. 2011, 17, 5903–5907. [CrossRef]
53. Iwaoka, M.; Tomoda, S. A model study on the effect of an amino group on the antioxidant activity of glutathione peroxidase. J.
Am. Chem. Soc. 1994, 116, 2557–2561. [CrossRef]
54. Neese, F. Software update: The ORCA program system, version 4.0. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2017, 8, e1327.
[CrossRef]

Molecules 2021, 26, 4446
11 of 11
55. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion
correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104. [CrossRef] [PubMed]
56. Glendening, E.D.; Badenhoop, J.K.; Reed, A.E.; Carpenter, J.E.; Bohmann, J.A.; Morales, C.M.; Landis, C.R.; Weinhold, F. NBO 6.0;
Theoretical Chemistry Institute, University of Wisconsin: Madison, WI, USA, 2013; Available online: http://nbo6.chem.wisc.edu/
(accessed on 12 July 2021).