Synthesis of 2-Organylchalcogenopheno[2,3-b]pyridines from Elemental Chalcogen and NaBH4/PEG-400 as a Reducing System: Antioxidant and Antinociceptive Properties

Article abstract of DOI:10.1002/cmdc.202000358

An alternative method to prepare 2-organylchalcogenopheno[2,3-b]pyridines was developed by the insertion of chalcogen species (selenium, sulfur or tellurium), generated in situ, into 2-chloro-3-(organylethynyl)pyridines by using the NaBH₄/PEG-4

Full text of DOI:10.1002/cmdc.202000358

Accepted Article
Title: Synthesis of 2-organylchalcogenopheno[2,3-b]pyridines from
elemental chalcogen and NaBH4/PEG-400 as reducing system:
antioxidant and antinociceptive properties
Authors: Thiago J. Peglow, Ricardo H. Bartz, Carolina C. Martins,
Andrei L. Belladona, Cristiane Luchese, Ethel A Wilhelm,
Ricardo Frederico Schumacher, and Gelson Perin
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.202000358
Link to VoR: https://doi.org/10.1002/cmdc.202000358
01/2020

10.1002/cmdc.202000358
ChemMedChem
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Synthesis of 2-organylchalcogenopheno[2,3-b]pyridines from
elemental chalcogen and NaBH4/PEG-400 as reducing system:
antioxidant and antinociceptive properties
Thiago J. Peglow,[a] Ricardo H. Bartz,[a] Carolina C. Martins,[b] Andrei L. Belladona,[c] Cristiane
Luchese,[b] Ethel A. Wilhelm,[b] Ricardo F. Schumacher,*[c] and Gelson Perin*[a]
[a]
[b]
[c]
T. J. Peglow, R. H. Bartz, Prof. G. Perin*
LASOL-CCQFA, Universidade Federal de Pelotas – UFPel
P.O. Box 354 - 96010-900, Pelotas, RS, Brazil.
E-mail: gelson_perin@ufpel.edu.br
C. C. Martins, Prof. C. Luchese, Prof. E. A. Wilhelm
LaFarBio-CCQFA, Universidade Federal de Pelotas – UFPel
96010-900, Pelotas, RS, Brazil
E-mail: ethelwilhelm@yahoo.com.br
A. L. Belladona, Prof. R. F. Schumacher*
CCNE, Universidade Federal de Santa Maria – UFSM
97105-900, Santa Maria, RS, Brazil
E-mail: ricardo.schumacher@ufsm.br
Supporting information for this article is given via a link at the end of the document.
compounds based on thieno[2,3-b]pyridine scaffolds have been
widely studied[44-49]. For example, Gao and co-workers reported
the preparation of the N-(thieno[2,3-b]pyridine)carboxamide I and
its evaluation as a target drug for the treatment of autoimmune
diseases (Figure 1)[44]. Pevet and co-workers synthesized
thieno[2,3-b]pyridine-3-amine based drugs II which presented
potent enzymatic and cellular c-Src inhibition activities[45]. In
addition, different thienopyridine derivatives have been described
as anticancer III[46] and anti-inflammatory agents IV[47], among
Abstract:
An
alternative
method
to
prepare
2-
organylchalcogenopheno[2,3-b]pyridines was developed by the
insertion of chalcogen species (selenium, sulfur or tellurium),
generated in situ, into 2-chloro-3-(organylethynyl)pyridines using the
NaBH4/PEG-400 reducing system, followed by an intramolecular
cyclization reaction. It was possible to obtain a series of compounds
with up to 93% yields in short reaction times. Among the synthesized
products, 2-organyltelluropheno[2,3-b]pyridines have not been
described in the literature so far. Moreover, the compounds 2-
phenylthieno[2,3-b]pyridine (3b) and 2-phenyltelluropheno[2,3-
b]pyridine (3c) exhibited significant antioxidant potential in different in
vitro assays. Further studies demonstrated that the compound 3b
exerted antinociceptive effect in acute inflammatory and non-
inflammatory pain models, indicating the involvement of the central
and peripheral nervous system on its pharmacological action. More
specifically, our results suggest that the intrinsic antioxidant property
of the compound 3b may contribute to attenuate the nociception and
the inflammatory process on the local injury induced by CFA.
others[48-49]
.
Introduction
Figure 1. Examples of thieno[2,3-b]pyridine-based drug candidates.
Chalcogen-containing heterocycles are an important class of
compounds that have been extensively exploited in medicinal
Despite the importance of chalcogenophenopyridines, synthetic
methodologies for their production remain limited, particularly in
the case of selenophene and tellurophene-based compounds. In
2012, Peixoto and co-workers[50] disclosed a method for the
synthesis of 2-(hetero)arylthieno[2,3-b]- or [3,2-b]pyridines by the
reaction of 2- or 3-chloro(hetero)arylethynylpyridines with Na2S
(Scheme 1-A). Cai and co-workers[51] described the synthesis of
thienopyridines by Pd-catalyzed cross-coupling reaction of ortho-
fluorinated iodopyridines with terminal alkynes, followed by a
thiolation and cyclization process (Scheme 1-B). Recently, our
chemistry[1-3], materials science[4-10] and organic synthesis[11-13]
.
Among them, chalcogenophenes have presented many
promising applications as new materials due to their properties as
organic semiconductors, which showed potential as organic field-
effect transistors (OFET)[14-19]
, organic light-emitting diode
(OLED)[20-24], and organic solar cells (OSC)[25-31]. In addition, these
compounds also have shown promising pharmacological
applications[32-37], being found in worldwide consumed drugs[38-42]
.
Still, chalcogenophenes when associated to another biological
active heterocycle, such as pyridine, usually makes the new
compound biologically more active[43-47]. Thus, the development
of new and efficient methodologies for the synthesis of
chalcogenophene-fused pyridine as promising drug candidates is
crucial in contemporary organic synthesis. In this sense, many
research group described
a
method to prepare 2-
organylselenopheno[2,3-b]pyridines starting from bis(3-amino-2-
pyridyl) diselenide and aryl- or alkylacetylenes in the presence of
tBuONO as a nitrosating agent[52]. This method was used to
synthesize selenopheno[2,3-b]pyridine derivatives (Scheme 1-C).
1
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10.1002/cmdc.202000358
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the synthetic methodology. When we focused on thiophenes 3e
and 3h, a significant increase in the products yield was observed
if compared to the non-substituted product 3b. On the other hand,
selenophenes 3d and 3g, or tellurophenes 3f and 3i, were
obtained in similar yields to 3a and 3c, respectively. Conversely,
we observed that the presence of an electron-withdrawing group
disfavored the formation of the chalcogenophene ring 3j and 3k.
Meanwhile, the tellurophene[2,3-b]pyridine 3l could be obtained
in good 66% yield.
Table 1. Reaction scope for synthesis of 2-organylchalcogenopheno[2,3-
b]pyridines 3a-r.a,b
Scheme 1. Previous works on the synthesis of 2-organylchalcogenopheno[2,3-
b]pyridines and our general protocol.
Due to our continued interest in the synthesis and
pharmacological evaluation of organochalcogen compounds, we
describe herein an efficient cyclization reaction using elemental
chalcogen 1a-c (selenium, sulfur or tellurium) and 2-chloro-3-
(organylethynyl)pyridines 2a-f in the presence of NaBH4/PEG-
400 as a reducing system for the preparation of new 2-
organylchalcogenopheno[2,3-b]pyridines 3a-r (Scheme 1-D).
Results and Discussion
Chemistry
Initially, we focused on the optimization of the reaction conditions
varying the amount of reagents, temperature and use of eco-
friendly solvents. For that, we chosen elemental selenium 1a, 2-
chloro-3-(phenylethynyl)pyridine 2a and NaBH4 as the standard
starting materials. After conducted many experiments, we
assumed that the optimal reaction condition to obtain the
selenopheno[2,3-b]pyridine 3a consists of two steps as follow: in
the first, selenium powder 1a (0.3 mmol) and NaBH4 (0.9 mmol)
are poured into a vessel containing PEG-400 (2.0 mL) under
argon atmosphere at 50 °C, and are maintained at this
temperature for approximately 0.5 hours. Then, as a second step,
2-chloro-3-(phenylethynyl)pyridine 2a (0.25 mmol) is added and
the temperature is raised to 100 °C stirring for additional 2 hours.
The complete optimization of the reaction conditions and their
results can be seen on Supporting Information (Table S1).
[a] The mixture of the chalcogen 1a-c (0.3 mmol), NaBH4 (0.9 mmol) and PEG-
400 (2.0 mL) was heated to 50 °C and stirred under argon for approximately 0.5
h. After that, the compound 2a-f (0.25 mmol) was added and the temperature
was raised to 100 °C stirring for additional 2 hours. [b] Isolated yield. [c] The
reaction remained for 1 hour. [d] Yield is given for 1H NMR analysis.
Furthermore, this protocol also enabled the synthesis of alkyl-
substituted chalcogenopheno[2,3-b]pyridines 3m-o starting from
2-chloro-3-(heptynyl)pyridine 2e. In these cases, the reactions
occured smoothly and gave the products in yields ranging from
56% to 81%. Finally, the 2-chloropyridine containing a propargyl
alcohol group at 3-position (compound 2f) was also reacted with
different elemental chalcogens (Se, S and Te) under the same
reaction conditions. The selenopheno[2,3-b]pyridin-2-ylmethanol
3p could be isolated in 31% yield. However, when elemental
sulfur was used as reagent a complex mixture of byproducts was
obtained and the compound 3q was observed only in traces
amount, while the telluropheno[2,3-b]pyridin-2-ylmethanol 3r was
only confirmed by 1H NMR analysis of a inseparable mixture with
3-(2-chloropyridin-3-yl)propanol. We believe that this byproduct
was obtained due to the reduction reaction of the starting material
2e promoted by NaBH4. The synthesis of 3p-r were conducted for
only 1 hour because we noticed that the prolonged reaction time
was involved in byproducts formation.
After completing the optimization tests, to demonstrate the
generality of this method, we turned our attention to synthesize a
series of 2-organylchalcogenopheno[2,3-b]pyridines 3a-r using
different elemental chalcogens (selenium, sulfur and tellurium)
1a-c and 2-chloro-3-(organylethynyl)pyridines 2a-f (Table 1).
When we conducted reactions using sulfur or tellurium powder,
the
2-phenylthieno[2,3-b]pyridine
3b
and
the
2-
phenyltelluropheno[2,3-b]pyridine 3c were obtained in 77% and
45% yield, respectively. It is important to mention that
telluropheno[2,3-b]pyridines remained unpublished until now.
In general, sulfur-containing compounds were obtained in higher
yields, followed by selenium and tellurium compounds. Still, both
electron-donating 3d-i and electron-withdrawing 3j-l groups can
be present on the aromatic ring without affecting the efficiency of
To complete our investigation and to understand the reaction
pathway of the new synthetic methodology, we performed a series
of control experiments which can be accessed through the
Supporting Information (Scheme S1). Based on these results and
2
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on information from the literature, we also proposed the reaction
mechanism outlined in Scheme S2.
Those
data
clearly
indicate
that
the
2-
organylchalcogenopheno[2,3-b]pyridine compounds 3a-3c play
as antioxidant agents through multiple mechanisms, mainly by
preventing the hepatic RS generation induced by sodium azide.
Although both compounds 3b and 3c exerted effects as ABTS+
and DPPH radical scavengers, it suggested that their antioxidant
activity involve different pathways. In this way, the compound 3c
was the most effective in the ABTS+ assay suggesting that the
introduction of the tellurium element enhanced its ability to
transfer a pair of electrons to free radicals. On the other hand, the
Biological evaluation
Different bio-assays were performed to assess the antioxidant
properties of the 2-organylchalcogenopheno[2,3-b]pyridine
compounds 3a-3c. One of them is based on the overproduction
of reactive species (RS), a marker of oxidative damage, by
inhibiting one of the electron transport chain enzymes[53]. In this
way, the results inserted in Table S2 demonstrated that all the 2-
organylchalcogenopheno[2,3-b]pyridines 3a-3c tested were able
to reduce the hepatic RS production induced by sodium azide in
mice. Despite the compound 3c exhibited the highest Imax (37.1
± 4.38) in this assay, it decreased the hepatic RS formation at
higher concentrations (100 µM) as well as the compound 3a (200
µM). On the other hand, the 2-organylchalcogenopheno[2,3-
b]pyridine 3b, at all concentrations tested (1 – 500 µM), reduced
the RS levels in the liver of mice. Also, the compound 3b showed
similar Imax (18.5 ± 1.04) in this assay than 3a (19.4 ± 3.22).
The spectrophotometric methods based on pair up the unpaired
2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+)
and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals are widely
employed to determine the antioxidant properties of new
compounds[54]. According to Table S3, the compounds 3b and 3c
demonstrated promising effects in scavenging the synthetic
radical ABTS+ because they showed similar Imax (86.9 ± 3.84 and
90.0 ± 3.12) to ascorbic acid (99.9 ± 0.05), a widely known
antioxidant agent. In special, the 2-organylchalcogenopheno[2,3-
b]pyridine 3c exhibited scavenging ABTS+ radical activity at
concentrations equal or higher of 10 µM whereas the compound
3b presented the same effect at higher concentrations (100 µM).
In this view, the compound 3c showed the lowest IC50 (31.2 µM ±
insertion
of
the
sulfur
element
in
the
2-
organylchalcogenopheno[2,3-b]pyridine 3b potentiated its ability
to donate an electron or hydrogen atom, as shown in the DPPH
assay. Regarding the toxicology of organoselenium, organosulfur
and organotellurium derivatives, consistent findings have
indicated that organotellurium are more toxic than
organoselenium compounds[57]. In accordance, a previous study
had shown that tellurium pseudopeptides exhibited significant
cytotoxic effect in human fibroblast cells when compared to both
sulfur and selenium derivatives[58]
.
Based on our findings and on the toxicology of organochalcogen
derivatives, the compound 3b was chosen to further studies of its
pharmacological properties in an acute inflammatory pain model
induced by CFA.
A single intraplantar injection of complete Freund’s adjuvant
(CFA) produces a local immune response which is characterized
by the paw edema, vasodilatation and hyperalgesic behavior.
Therefore, this animal model is well-recognized for screening
novel compounds to acute inflammatory pain[59]. In this view, the
Figure 2 illustrated that intraplantar injection of CFA induced a
mechanical hyperalgesia in mice. As expected,
a single
administration of the compound 3b, at all doses tested, attenuated
the mechanical hyperalgesia in CFA-treated mice, suggesting
that this 2-organylchalcogenopheno[2,3-b]pyridine exhibited an
antinociceptive effect. Also, this compound showed
pharmacological effect similar to meloxicam (50 mg/kg, ig), a
reference drug extensively prescribed in the clinic. However,
there is a significant difference on the antinociceptive responses
exerted by the 2-organylchalcogenopheno[2,3-b]pyridine 3b and
the meloxicam, at the same dose (50 mg/kg), in CFA-treated mice.
This finding suggests that the compound 3b may be more potent
than meloxicam.
0.18),
being
the
most
effective
among
the
2-
organylchalcogenopheno[2,3-b]pyridines tested in this assay
(Table 2). On the other hand, the compound 3b was able to
scavenge DPPH radicals at concentrations ranging from 100 µM
to 500 µM, as well as it showed the highest Imax (34.3 ± 2.18)
among the compounds tested, being the most promising in this
assay. The compound 3c was able to donate an electron or
hydrogen to stabilize the DPPH radical just at higher
concentrations (200 µM), as shown in Table S3. The 2-
organylchalcogenopheno[2,3-b]pyridine 3a, at all concentrations
tested, had no significant difference when compared to control in
both ABTS+ and DPPH assays.
Table 2. IC50 values of the chalcogenophene compounds 3a-3c on the ABTS+
radical scavenging.
Compounds
Ascorbic
3a
3b
3c
acid
IC50 (µM)
-
155.2 ± 0.03
31.2 ± 0.18
10.8 ± 71.70
Data are expressed as the mean ± SEM. IC50 = concentration (µM) to decrease
50% of ABTS+ radical formation.
Figure 2: Dose-response of antinociceptive effect of compound 3b in an acute
inflammatory pain model induced by CFA. Each column represents the mean ±
Furthermore, the pyrogallol autoxidation in an alkaline
environment stimulates the release of superoxide radicals in the
superoxide dismutase (SOD)-like assay[55]. SODs, superoxide-
scavenging enzyme, are already known as the first and most
S.E.M of 7 mice/group. Asterisks denote the significance levels when compared
****
with the vehicle-treated group:
(
) P < 0.0001. Hashtags denote the
significance levels when compared with the CFA-treated group: (####) P < 0.0001
and (###) P < 0.001. Arroba denotes the significance levels when compared with
compound 3b-treated group (50 mg/kg): (@) P < 0.05 (One-way ANOVA
followed by the Newman-Keuls test).
important line of antioxidant enzyme defense system in a cell[56]
.
In this view, antioxidant compounds that inhibit the pyrogallol
autoxidation mimic the SOD function within the cells. The results
inserted
in
Table
S4
demonstrated
that
the
had
2-
no
In relation to the time-course antinociceptive effect of the
compound 3b, the Figure 3 demonstrated that the intraplantar
injection of CFA triggered a mechanical hyperalgesia in mice
which persisted during all experimental period. Indeed, the
administration of compound 3b improved the mechanical stimulus
response in CFA-treated mice, that started at 0.5 h and long
organylchalcogenopheno[2,3-b]pyridines
superoxide-scavenging activity when compared to control.
Therefore, our findings suggest that these
chalcogenophenopyridines exerted in vitro antioxidant activity
throughout mechanisms that do not involve the SOD’s function as
superoxide scavenger.
3a-3c
3
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lasting up significant until 6 h after the treatment. In a different
time profile, meloxicam treatment (50 mg/kg, ig) also reduced the
mechanical
hyperalgesia
in
CFA-treated
mice.
The
antinociceptive effect of meloxicam also started at 0.5 h and
persisted significant for only 2 h after the administration. In this
context, there is an immediate need for new therapeutic
approaches as pain management due the low efficacy, the
limitations and the adverse effects associated to the analgesic
drugs commercially available, including the non-steroidal anti-
inflammatory drugs (NSAIDs), the cyclooxygenase-2 (COX-2)
selective inhibitors[60] and the opioid drugs[61]. Therefore, our
results suggest the compound 3b may be a promising prototype
for the management of acute inflammatory pain conditions.
Figure 5. Effect of the acute chalcogenophenopyridine 3b treatment on the RS
levels induced by intraplantar injection of CFA in mice. Data are expressed as
mean ± S.E.M of 7 animals/group. Asterisks denote the significance levels when
compared with the vehicle group: (**) P < 0.01. Hashtags denote the significance
levels when compared with CFA-treated group: (#) P < 0.05 (One-way ANOVA
followed by the Newman-Keuls test).
Figure 3. Time-response of antinociceptive effect of compound 3b in an acute
inflammatory pain model induced by CFA. Each column represents the mean ±
S.E.M of 7 mice/group. Asterisks denote the significance levels when compared
with the vehicle-treated group: (*) P < 0.05. Hashtags denote the significance
levels when compared with the CFA-treated group: (#) P < 0.05 (One-way
ANOVA followed by the Newman-Keuls test).
Figure 6: Effect of the acute chalcogenophenopyridine 3b treatment on the
TBARS levels induced by intraplantar injection of CFA in mice. Data are
It has been well-stablished that the exacerbated production of
oxidizing agents is a common feature of inflammatory and painful
conditions. Furthermore, the release of inflammatory mediators,
including the RS overproduction and the cytokines, sensitizes the
nociceptive nerve endings and thus, produces allodynia and
hyperalgesia[62]. In this way, we showed that an intraplantar
injection of CFA induced the edema formation (Figure 4), as well
as increased the RS (Figure 5) and the thiobarbituric acid reactive
substances (TBARS) levels in mice (Figure 6).
expressed as mean
± S.E.M of 7 animals/group. Asterisks denote the
significance levels when compared with the vehicle group: (***) P < 0.001.
Hashtags denote the significance levels when compared with CFA-treated
group: (####) P < 0.0001, (###) P < 0.001 and (##) P < 0.01 (One-way ANOVA
followed by the Newman-Keuls test).
A single administration of the compound 3b, at all doses tested,
reduced the lipidic peroxidation whereas only the highest dose (50
mg/kg, ig) decreased the inflammatory process and the RS levels
in the paw of CFA-treated mice. Although the meloxicam did not
reduce the edematogenic process, this NSAID drug was effective
in decrease the TBARS and RS levels in the paw of CFA-treated
mice. In agreement with our findings, previous studies also
demonstrated that the meloxicam (10 and 50 mg/kg, ig) was
ineffective in reduce the paw edema formation in the formalin and
glutamate tests in mice, respectively[63,64]. Despite the difficulties
in explain why meloxicam did not reduce the edema formation, it
is possible that the selected treatment time (0.5 h) may not be
appropriate for this NSAID to inhibit the prostaglandin
biosynthesis and thus, exhibits an anti-inflammatory action.
It has been reported that CFA triggers an inflammatory painful
condition mediated by the overproduction of free radicals and
oxidizing agents[65]. Taken together, these data reinforce the
antioxidant properties in vitro exerted by the 2-
organylchalcogenopheno[2,3-b]pyridine 3b. Moreover, such
findings lead us to believe that the compound 3b, through its free
radical-scavenging activity, modulated the oxidative damage and
may suppressed the subsequent signaling pathways of
inflammation in CFA-treated mice. Consequently, this 2-
organylchalcogenopheno[2,3-b]pyridine reduced the paw edema
as well as the hyperalgesic behavior in mice. Beyond the
inflammatory process, it is also known that the intraplantar
injection of CFA promotes a sensitization in the central nervous
regions related to the pain modulation[66]. Considering the
promising effects of the compound 3b on the CFA-induced
inflammatory pain model, we also investigated the involvement of
the central nervous system (CNS) on the antinociceptive behavior
Figure 4. Effect of the acute chalcogenophenopyridine 3b treatment on the
edema formation in mice. Data are expressed as mean ± S.E.M of 7
animals/group. Asterisks denote the significance levels when compared with the
vehicle group: (****) P < 0.0001. Hashtags denote the significance levels when
compared with CFA-treated group: (#) P < 0.05 (One-way ANOVA followed by
the Newman-Keuls test).
4
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exerted by this chalcogenophenopyridine in an acute non-
inflammatory nociceptive model, the hot-plate test.
b]pyridine 3b appears to have a considerable margin of safety
because it has a low toxicity profile in plasma and liver parameters
of mice.
The Figure 7 demonstrated that the compound 3b (50 mg/kg, ig)
enhanced response latency to thermal stimulus when compared
with the vehicle group, as well as morphine (50 mg/kg, sc). Indeed,
there is a tightly link between the noxious thermal stimulus and
the activation of the supraspinal structures sites[67]. In this way,
the current finding suggests that the thienopyridine 3b
antinociceptive action may be partially mediated by the CNS
signaling. Besides, it was also demonstrated that a single
administration of this compound did not alter the number of
crossings and rearings when compared to control group.
Table 4. Effect of a single administration of compound 3b on the serum and
liver toxicological parameters of mice.
Blood
Compound 3b
50 mg/kg
Compound 3b
300 mg/kg
Vehicle
AST
ALT
16.2 ± 3.39
10.4 ± 1.73
121.2 ± 8.02
16.9 ± 3.87
10.6 ± 2.62
112.8 ± 4.93
Liver
15.1 ± 0.81
10.2 ± 1.39
109.0 ± 2.46
Urea
Compound 3b
50 mg/kg
Compound 3b
300 mg/kg
Vehicle
TBARS
RS
44.9 ± 0.74
223.9 ± 2.31
12.9 ± 0.07
41.5 ± 0.73
216.4 ± 1.18
11.25 ± 1.48
42.1 ± 2.28
225.9 ± 4.10
13.3 ± 1.35
δ-ALA-D
The values of serum AST, ALT and urea levels were expressed as U/I and mg/dl
respectively, and the data are reported as mean ± S.E.M of 3 animals/group.
Also, the results of hepatic TBARS and RS levels as well as δ-ALA-D activity
were expressed as nmol MDA/mg protein, arbitrary fluorescence units and nmol
PBG/mg protein/h respectively. The statistical analysis was carried out by one-
way ANOVA followed by the Newman-Keuls test.
Figure 7. Antinociceptive effect exerted by compound 3b on the hot plate test.
Each column represents the mean ± S.E.M of 7 mice/group. Asterisks denote
the significance levels when compared with the control group: (****) P < 0.0001
and (**) P < 0.001 (One-way ANOVA followed by the Newman Keuls test).
On the other hand, morphine-treated mice increased the number
of crossings and decreased the number of rearings when
compared to the vehicle group (Table 3). A previous study also
showed that a single administration of morphine enhanced the
locomotor stimulation in rodents, an adverse effect known as
behavior sensitization[68]. The development of this phenomenon,
common in most drug of abuses, is highly related to the relapse
and drug seeking behavior[69]. Therefore, despite morphine
exhibited more potent antinociceptive effect than the compound
3b, this chalcogenopheno[2,3-b]pyridine did not alter the
locomotor and exploratory activities, as well as did not induce the
locomotor sensitization, a sign of addictive behavior, in mice.
Conclusion
Summarizing, we have developed a simple and efficient method
for the synthesis of 2-organylchalcogenopheno[2,3-b]pyridines
through
the
cyclization
reaction
of
2-chloro-3-
(organylethynyl)pyridines mediated by the insertion of
nucleophilic chalcogen species (selenium, sulfur and tellurium)
obtained by the NaBH4/PEG-400 reducing system. Through this
protocol it was possible to obtain seventeen compounds with
moderate to excellent yields in short reaction times. By this
method it was possible to obtain six tellurophene derivatives
which are unknown heterocycles in the literature until now.
In addition, the 2-organylchalcogenopheno[2,3-b]pyridines 3b
and 3c demonstrated promising antioxidant properties in vitro.
Regarding the toxicology of the chalcogens, the compound 3b
was selected to further studies in vivo. In this study, it has been
shown that the free radical-scavenging activity exerted by the
compound 3b may be involved in its antinociceptive and anti-
edematogenic effects at central and peripheral levels. Thus, our
results suggest that the compound 3b could be an efficient, potent
and safe prototype to treat acute painful conditions.
Table 3. Locomotor and exploratory activities of mice treated with thienopyridine
3b or morphine on the OFT.
OFT
Groups
Number of crossings
75.0 ± 3.09
Number of rearings
37.3 ± 3.82
Vehicle
Compound 3b
Morphine
74.5 ± 5.97
31.3 ± 3.45
202.5 ± 21.74****
0.5 ± 0.34****
Data are reported as mean ± S.E.M of 6 mice/group. Statistical analysis was
performed using the one-way ANOVA followed by the Newman-Keuls test.
Regarding the toxicity of the 2-phenylthieno[2,3-b]pyridine 3b, this
compound appeared to be well tolerated and did not elicit any
signs of abnormal behavior or even mortality. In this way, such
data were also substantially sustained by the fact that the
compound 3b (50 and 300 mg/kg, ig) did not change the key
biochemical parameters of hepatic (aspartate and alanine
aminotransferase activities) and renal (urea levels) functions in
the plasma of mice (Table 4). Besides, the δ-aminolevulinate
dehydratase (δ-ALA-D) activity, a marker sensitive to oxidative
stress, as well as RS and TBARS levels were evaluated to
determine whether the compound 3b metabolization deregulates
the redox cellular state and thus, the hepatic homeostasis.
According to Table 4, a single administration of the compound 3b
(50 and 300 mg/kg, ig) did not alter the oxidative damage
parameters in the liver of mice when compared to the vehicle
group. Taken together, these findings suggest that the thieno[2,3-
Experimental Section
General materials and methods: The reactions were monitored by TLC
carried out on Merk silica gel (60 F254) by using UV light as visualization
agent and the mixture between 5% of vanillin in 10% of H2SO4 under
heating conditions as developing agents. Merck silica gel (particle size
0.040-0.063 mm) was used to flash chromatography. Hydrogen nuclear
magnetic resonance spectra (1H NMR) were obtained on Bruker Avance
III HD 400 MHz employing a direct broadband probe at 400 MHz. The
spectra were recorded in CDCl3 solutions. The chemical shifts are reported
in ppm, referenced to tetramethylsilane (TMS) as the internal reference.
Coupling constants (J) are reported in Hertz. Abbreviations to denote the
multiplicity of a particular signal are brs (broad singlet) s (singlet), d
5
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10.1002/cmdc.202000358
ChemMedChem
FULL PAPER
(doublet), dd (doublet of doublet), dt (doublet of triplet) t (triplet), q (quartet),
quint (quintet) and m (multiplet). Carbon-13 nuclear magnetic resonance
spectra (13C NMR) were obtained on Bruker Avance III HD 400 MHz
employing a direct broadband probe at 100 MHz. The chemical shifts are
reported in ppm, referenced to the solvent peak of CDCl3 (δ 77.0 ppm).
Selenium-77 nuclear magnetic resonance spectra (77Se NMR) were
obtained on Bruker Avance III HD 400 MHz employing a direct broadband
probe at 76 MHz. The chemical shifts are reported in ppm, using as solvent
the CDCl3 and as an internal standard the diphenyl diselenide (δ 463 ppm).
Telurium-125 nuclear magnetic resonance spectra (125Te NMR) were
obtained on Bruker Avance III HD 400 MHz employing a direct broadband
probe at 126 MHz. The chemical shifts are reported in ppm, using as
solvent the CDCl3 and as an internal standard the diphenyl ditellurate (δ
422 ppm). The high-resolution electrospray ionization mass spectrometry
(ESI-QTOF) analysis were performed on a Bruker Daltonics micrOTOF-Q
II instrument in positive mode. The samples were solubilized in HPLC-
grade acetonitrile and injected into the APCI source by means of a syringe
pump at a flow rate of 5.0 µL min-1. The follow instrument parameters were
applied: capillary and cone voltages were set to +3500 V and -500 V,
139.4, 133.3, 129.0, 128.5, 127.8, 127.6, 120.4. DEPT-135 NMR (CDCl3,
100 MHz) δ (ppm) = 145.9 (CH), 133.4 (CH), 129.1 (2x CH), 128.6 (CH),
127.9 (CH), 127.7 (2x CH), 120.5 (CH). 125Te NMR (CDCl3, 126 MHz) δ
(ppm) = 725.5. MS (rel. int., %) m/z: 309 (80.3), 179 (100.0), 151 (40.8),
115 (1.7), 102 (15.0), 89 (7.2). HRMS (APCI-QTOF) calculated mass for
C13H9NTe [M+H]+: 309.9875, found: 309.9871.
2-(4-Tolyl)selenopheno[2,3-b]pyridine 3d[52]: Yield: 0.053 g (77%);
yellow solid, m.p: 108-109 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.34
(dd, J = 4.7 and 1.4 Hz, 1H); 7.85 (dd, J = 7.9 and 1.4 Hz, 1H); 7.44-7.42
(m, 3H); 7.19 (dd, J = 7.9 and 4.7 Hz, 1H); 7.12 (d, J = 8.0 Hz, 2H); 2.29
(s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 164.0, 149.4, 145.1,
139.0, 138.0, 132.8, 132.0, 129.7, 126.8, 120.0, 119.0, 21.2. DEPT-135
NMR (CDCl3, 100 MHz) δ (ppm) = 145.1 (CH), 132.0 (CH), 129.7 (2x CH),
126.8 (2x CH), 120.0 (CH), 119.0 (CH), 21.2 (CH3). 77Se NMR (CDCl3, 76
MHz) δ (ppm) = 533.6. MS (rel. int., %) m/z: 273 (100.0), 192 (26.1), 115
(12.6), 102 (3.7), 89 (7.3). HRMS (APCI-QTOF) calculated mass for
C14H11NSe [M+H]+: 274.0135, found: 274.0134.
respectively, with
a desolvation temperature of 180 °C. For data
2-(4-Tolyl)thieno[2,3-b]pyridine 3e: Yield: 0.052 g (93%); yellow solid,
m.p: 107-108 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.41 (dd, J = 4.7
and 1.4 Hz, 1H); 7.91 (dd, J = 8.0 and 1.4 Hz, 1H); 7.52 (d, J = 8.0 Hz,
2H); 7.31 (s, 1H); 7.19 (dd, J = 8.0 and 4.7 Hz, 1H); 7.15 (d, J = 8.0 Hz,
2H); 2.30 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 160.7, 145.4,
139.0, 134.6, 131.6, 130.8, 129.7, 129.2, 126.4, 119.7, 115.9, 21.2. DEPT-
135 NMR (CDCl3, 100 MHz) δ (ppm) = 145.4 (CH), 130.8 (CH), 129.7 (2x
CH), 126.4 (2x CH), 119.8 (CH), 115.9 (CH), 21.2 (CH3). MS (rel. int., %)
m/z: 225 (100.0), 191 (3.1), 115 (3.9), 102 (1.0), 89 (3.3). HRMS (APCI-
QTOF) calculated mass for C14H11NS [M+H]+: 226.0690, found: 226.0702.
acquisition and processing, Compass 1.3 for micrOTOF-Q II software
(Bruker daltonics, USA) was used. The data were collected in the m/z
range of 50-1200 at the speed of two scans per second. Low-resolution
mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass
spectrometer. Melting point (mp) values were measured in a Marte PFD III
instrument with a 0.1 °C precision.
General procedure for synthesis of 2-organylchalcogenophene[2,3-
b]pyridines 3a-r: In a 10.0 mL reaction vial containing Se, S or Te (0.3
mmol) in PEG-400 (2.0 mL) under argon atmosphere was added NaBH4
(0.9 mmol) and the mixture was slowly heated to 50 °C being stirred for 30
min. Then, 2-chloro-3-(organylethynyl)pyridine 2 (0.25 mmol) was added
and the temperature was raised to 100 °C. The reaction mixture remained
under magnetic stirring for 2 h. Then, water was added (25.0 mL) and the
reaction was extracted with ethyl acetate (3x 10.0 mL). The organic phase
was separated, dried over MgSO4, and the solvent was evaporated under
reduced pressure. The product 3 was isolated by column chromatography
using hexane/ethyl acetate (97/3) as eluent.
2-(4-Tolyl)telluropheno[2,3-b]pyridine 3f: Yield: 0.041 g (51%); yellow
solid, m.p: 129-130 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.39 (dd, J
= 4.7 and 1.6 Hz, 1H); 7.88 (dd, J = 7.9 and 1.6 Hz, 1H); 7.70 (s, 1H); 7.42
(d, J = 8.0 Hz, 2H); 7.27 (dd, J = 7.9 and 4.7 Hz, 1H); 7.19 (d, J = 8.0 Hz
2H); 2.37 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 160.5, 145.7,
145.6, 145.1, 138.7, 136.7, 133.1, 129.7, 127.5, 127.1, 120.5, 21.2. DEPT-
135 NMR (CDCl3, 100 MHz) δ (ppm) = 145.7 (CH), 133.1 (CH), 129.7 (2x
CH), 127.5 (2x CH), 127.1 (CH), 120.4 (CH), 21.2 (CH3). 125Te NMR
(CDCl3, 126 MHz) δ (ppm) = 720.8. MS (rel. int., %) m/z: 323 (94.8), 192
(100.0), 115 (28.8), 102 (4.7), 89 (13.1). HRMS (APCI-QTOF) calculated
mass for C14H11NTe [M+H]+: 324.0032, found: 324.0038.
Spectral data of the products
2-Phenylselenopheno[2,3-b]pyridine 3a[52]
: Yield: 0.050 g (77%);
slightly yellowish solid, m.p: 86-88 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm)
= 8.37 (dd, J = 4.7 and 1.6 Hz, 1H); 7.88 (dd, J = 8.0 and 1.6 Hz, 1H); 7.58-
7.55 (m, 2H); 7.49 (s, 1H); 7.37-7.28 (m, 3H); 7.20 (dd, J = 8.0 and 4.7 Hz,
1H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 164.8, 148.9, 146.0, 137.6,
135.8, 131.9, 129.0, 128.8, 126.9, 120.0, 119.9. DEPT-135 NMR (CDCl3,
100 MHz) δ (ppm) = 146.0 (CH), 131.9 (CH), 129.0 (2x CH), 128.8 (CH),
126.9 (2x CH), 120.0 (CH), 119.9 (CH). 77Se NMR (CDCl3, 76 MHz) δ
(ppm) = 533.4. MS (rel. int., %) m/z: 259 (100.0), 179 (33.2), 151 (20.6),
115 (5.9), 102 (6.6), 89 (8.0). HRMS (APCI-QTOF) calculated mass for
C13H9NSe [M+H]+: 259.9978, found: 259.9984.
2-(4-Ethylphenyl)selenopheno[2,3-b]pyridine 3g[52]
: Yield: 0.043 g
1
(60%); slightly yellow solid, m.p: 91-93 °C. H NMR (CDCl3, 400 MHz) δ
(ppm) = 8.44 (dd, J = 4.8 and 1.1 Hz, 1H); 7.94 (dd, J = 7.9 and 1.1 Hz,
1H); 7.56 (d, J = 8.1 Hz, 2H); 7.53 (s, 1H); 7.28-7.24 (m, 3H); 2.69 (q, J =
7.6 Hz, 2H); 1.27 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ
(ppm) = 164.6, 149.1, 145.7, 145.3, 137.8, 133.3, 131.7, 128.5, 126.9,
120.0, 119.2, 28.6, 15.4. DEPT-135 NMR (CDCl3, 100 MHz) δ (ppm) =
145.7 (CH), 131.7 (CH), 128.5 (2x CH), 126.9 (2x CH), 120.0 (CH), 119.2
(CH), 28.6 (CH2), 15.4 (CH3). 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 531.7.
MS (rel. int., %) m/z: 287 (74.8), 272 (100.0), 191 (17.7), 115 (8.9), 102
(8.0), 89 (9.2). HRMS (APCI-QTOF) calculated mass for C15H13NSe
[M+H]+: 288.0291, found: 288.0288.
2-Phenylthieno[2,3-b]pyridine (3b)[50]: Yield: 0.041 g (77%); yellow solid,
m.p: 94-95 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.50 (dd, J = 4.6 and
1.4 Hz, 1H); 7.97 (dd, J = 8.0 and 1.4 Hz, 1H); 7.71-7.69 (m, 2H); 7.44-
7.40 (m, 3H); 7.37-7.33 (m, 1H); 7.25 (dd, J = 8.0 and 4.6 Hz, 1H). 13C{1H}
NMR (CDCl3, 100 MHz) δ (ppm) = 161.4, 146.2, 144.4, 134.2, 133.8, 130.6,
129.0, 128.7, 126.5, 119.7, 116.6. DEPT-135 NMR (CDCl3, 100 MHz) δ
(ppm) = 146.2 (CH), 130.6 (CH), 129.0 (2x CH), 128.7 (CH), 126.5 (2x CH),
119.7 (CH), 116.6 (CH). MS (rel. int., %) m/z: 211 (100.0), 179 (4.7), 151
(2.3), 115 (1.3), 102 (1.7), 89 (1.7).
2-(4-Ethylphenyl)thieno[2,3-b]pyridine 3h[51]: Yield: 0.051 g (86%);
yellow solid, m.p: 112-113 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.49
(dd, J = 4.6 and 1.4 Hz, 1H); 7.96 (dd, J = 8.0 and 1.4 Hz, 1H); 7.63 (d, J
= 8.1 Hz, 2H); 7.39 (s, 1H); 7.27-7.23 (m, 3H); 2.68 (q, J = 7.6 Hz, 2H);
1.26 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 161.4,
146.0, 145.2, 144.7, 134.3, 131.2, 130.4, 128.5, 126.5, 119.7, 116.0, 28.6,
15.4. DEPT-135 NMR (CDCl3, 100 MHz) δ (ppm) = 146.0 (CH), 130.4 (CH),
128.5 (2x CH), 126.5 (2x CH), 119.7 (CH), 116.0 (CH), 28.8 (CH2), 15.4
(CH3). MS (rel. int., %) m/z: 239 (77.6), 224 (100.0), 115 (2.6), 102 (1.8),
89 (3.4). HRMS (APCI-QTOF) calculated mass for C15H13NS [M+H]+:
240.0841, found: 240.0839.
2-Phenyltelluropheno[2,3-b]pyridine 3c: Yield: 0.035 g (45%); slightly
yellowish solid, m.p: 111-112 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) =
8.40 (dd, J = 4.7 and 1.6 Hz, 1H); 7.89 (dd, J = 7.9 and 1.6 Hz, 1H); 7.73
(s, 1H); 7.53-7.50 (m, 2H); 7.40-7.31 (m, 3H); 7.27 (dd, J = 7.9 and 4.7 Hz,
1H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 160.7, 145.9, 145.4, 145.0,
6
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10.1002/cmdc.202000358
ChemMedChem
FULL PAPER
2-(4-Ethylphenyl)telluropheno[2,3-b]pyridine 3i: Yield: 0.036 g (43%);
slightly yellow solid, m.p: 95-96 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) =
8.39 (dd, J = 4.7 and 1.5 Hz, 1H); 7.88 (dd, J = 7.9 and 1.5 Hz, 1H); 7.70
(s, 1H); 7.44 (d, J = 8.1 Hz, 2H); 7.27 (dd, J = 7.9 and 4.7 Hz, 1H); 7.22 (d,
J = 8.1 Hz, 2H); 2.67 (q, J = 7.6 Hz, 2H); 1.26 (t, J = 7.6 Hz, 3H). 13C{1H}
NMR (CDCl3, 100 MHz) δ (ppm) = 160.5, 145.7, 145.6, 145.2, 145.1, 136.9,
133.1, 128.5, 127.6, 127.1, 120.4, 28.6, 15.4. DEPT-135 NMR (CDCl3, 100
MHz) δ (ppm) = 145.7 (CH), 133.1 (CH), 128.5 (2x CH), 127.6 (2x CH),
127.1 (CH), 120.4 (CH), 28.6 (CH2), 15.4 (CH3). 125Te NMR (CDCl3, 126
MHz) δ (ppm) = 721.5. MS (rel. int., %) m/z: 337 (100.0), 322 (89.4), 191
(61.8), 115 (21.7), 102 (13.6), 89 (20.3). HRMS (APCI-QTOF) calculated
mass for C15H13NTe [M+H]+: 338.0188, found: 338.0179.
129.7 (CH), 119.2 (CH), 117.7 (CH), 31.2 (2x CH2), 30.5 (CH2), 22.3 (CH2),
13.9 (CH3). MS (rel. int., %) m/z: 205 (35.9), 148 (100.0), 116 (1.6), 102
(2.8), 89 (2.9). HRMS (APCI-QTOF) calculated mass for C12H15NS [M+H]+:
206.1013, found: 206.1003.
2-Pentyltelluropheno[2,3-b]pyridine 3o: Yield: 0.042 g (56%); yellow oil.
1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.35 (dd, J = 4.7 and 1.7 Hz, 1H);
7.76 (dd, J = 7.9 and 1.7 Hz, 1H); 7.25 (t, J = 1.3 Hz, 1H); 7.22 (dd, J = 7.9
and 4.7 Hz, 1H); 2.92 (dt, J = 7.3 and 1.3 Hz, 2H); 1.69 (quint, J = 7.3 Hz,
2H); 1.44-1.33 (m, 4H); 0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (CDCl3, 100
MHz) δ (ppm) = 160.3, 150.1, 145.1, 144.0, 132.2, 128.6, 120.1, 37.7, 33.1,
31.2, 22.4, 13.9. DEPT-135 NMR (CDCl3, 100 MHz) δ (ppm) = 145.1 (CH),
132.2 (CH), 128.6 (CH), 120.1 (CH), 37.7 (CH2), 33.1 (CH2), 31.2 (CH2),
22.4 (CH2), 13.9 (CH3). 125Te NMR (CDCl3, 126 MHz) δ (ppm) = 721.9.
MS (rel. int., %) m/z: 303 (36.3), 246 (51.8), 116 (100.0), 102 (10.6), 89
(51.4). HRMS (APCI-QTOF) calculated mass for C12H15NTe [M+H]+:
304.0345, found: 304.0357.
2-(4-Chlorophenyl)selenopheno[2,3-b]pyridine 3j[52]: Yield: 0.040 g
(55%); slightly yellow solid, m.p: 91-92 °C. 1H NMR (CDCl3, 400 MHz) δ
(ppm) = 8.38 (dd, J = 4.7 and 1.5 Hz, 1H); 7.89 (dd, J = 7.9 and 1.5 Hz,
1H); 7.48-7.45 (m, 3H); 7.31-7.28 (m, 2H); 7.22 (dd, J = 7.9 and 4.7 Hz,
1H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 164.3, 147.7, 145.7, 137.7,
134.7, 134.2, 132.3, 129.2, 128.0, 120.3, 120.2. DEPT-135 NMR (CDCl3,
100 MHz) δ (ppm) = 145.7 (CH), 132.3 (CH), 129.2 (2x CH), 128.0 (2x CH),
120.3 (CH), 120.2 (CH). 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 536.7. MS
(rel. int., %) m/z: 295 (43.1), 293 (100.0), 258 (12.9), 213 (19.4), 115 (1.2),
102 (2.7), 89 (5.0). HRMS (APCI-QTOF) calculated mass for C13H8ClNSe
[M+H]+: 293.9589, found: 293.9579.
Selenopheno[2,3-b]pyridin-2-ylmethanol 3p: Yield: 0.017 g (31%);
yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.45 (dd, J = 4.7 and 1.6
Hz, 1H); 7.92 (dd, J = 7.9 and 1.6 Hz, 1H); 7.30-7.26 (m, 2H); 4.97 (s, 2H);
2.43 (brs, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 165.1, 151.0,
145.9, 136.3, 132.0, 120.9, 119.8, 63.1. DEPT-135 NMR (CDCl3, 100
MHz) δ (ppm) = 145.9 (CH), 132.0 (CH), 120.9 (CH), 119.8 (CH), 63.1
(CH2). 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 539.5. MS (rel. int., %) m/z:
213 (61.5), 196 (12.6), 184 (100.0), 116 (20.7), 102 (11.6), 89 (9.0). HRMS
(APCI-QTOF) calculated mass for C8H7NOSe [M+H]+: 213.9771, found:
213.9757.
2-(4-Chlorophenyl)thieno[2,3-b]pyridine 3k[51]: Yield: 0.046 g (75%);
yellow solid, m.p: 123-124 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.43
(dd, J = 4.7 and 1.5 Hz, 1H); 7.91 (dd, J = 8.0 and 1.5 Hz, 1H); 7.54-7.51
(m, 2H); 7.32-7.28 (m, 3H); 7.20 (dd, J = 8.0 and 4.7 Hz, 1H). 13C{1H} NMR
(CDCl3, 100 MHz) δ (ppm) = 161.1, 146.2, 143.2, 134.7, 134.2, 132.2,
130.9, 129.2, 127.6, 119.9, 117.0. DEPT-135 NMR (CDCl3, 100 MHz) δ
(ppm) = 146.2 (CH), 130.9 (CH), 129.2 (2x CH), 127.6 (2x CH), 119.9 (CH),
117.0 (CH). MS (rel. int., %) m/z: 245 (100.0), 213 (2.6), 113 (2.4), 101
(4.1), 89 (1.4). HRMS (APCI-QTOF) calculated mass for C13H8NS [M+H]+:
246.0139, found: 246.0158.
Telluropheno[2,3-b]pyridin-2-ylmethanol 3r: Yield by 1H NMR (20%);
yellowish oil. Mixture of compounds 3r and 3-(2-chloropyridin-3-
yl)propanol 3r’ (ratio 4:1, respectively). Asterisk denotes the chemical
shifts of the 3-(2-chloropyridin-3-yl)propanol 3r’. 1H NMR (CDCl3, 400
MHz) δ (ppm) = 8.35 (dd, J = 4.7 and 1.4 Hz, 1H); 8.23* (dd, J = 4.8 and
1.8 Hz, 1H) 7.81 (dd, J = 7.9 and 1,4 Hz, 1H); 7.57* (dd, J = 7.5 and 1.8
Hz, 1H) 7.27-7.24 (m, 1H); 7.16* (dd, J = 7.5 and 4.8 Hz, 1H) 4.92 (s, 2H);
3.71* (t, J = 6.3 Hz, 2H); 3.28 (brs, 1H); 3.28* (brs, 1H); 2.82* (t, J = 7.6
Hz, 2H); 1.94-1.87* (m, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) =
160.0, 151.5, 147.2*, 144.9, 144.3, 139.0*, 136.0*, 133.4, 126.3, 122.6*,
120.1, 65.5, 61.7*, 31.8*, 29.4*. DEPT-135 NMR (CDCl3, 100 MHz) δ
(ppm) = 147.2* (CH), 144.9 (CH), 139.0* (CH), 133.4 (CH), 126.3 (CH),
122.6* (CH), 120.1 (CH), 65.5 (CH2), 61.7* (CH2), 31.8* (CH2), 29.4* (CH2).
125Te NMR (CDCl3, 126 MHz) δ (ppm) = 741.8. MS (rel. int., %) m/z: 263
(83.2), 246 (2.9), 116 (43.3), 104 (100.0), 89 (28.6). HRMS (APCI-QTOF)
calculated mass for C8H7NOTe [M+H]+: 263.9668, found: 263.9653.
2-(4-Chlorophenyl)telluropheno[2,3-b]pyridine 3l: Yield: 0.057
g
(66%); yellow solid, m.p: 131-132 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm)
= 8.34 (dd, J = 4.7 and 1.6 Hz, 1H); 7.87 (dd, J = 7.9 and 1.6 Hz, 1H); 7.66
(s, 1H); 7.38-7.35 (m, 2H); 7.29-7.22 (m, 3H). 13C{1H} NMR (CDCl3, 100
MHz) δ (ppm) = 160.3, 145.4, 145.1, 144.6, 137.9, 134.5, 133.8, 129.2,
128.7, 128.1, 120.6. DEPT-135 NMR (CDCl3, 100 MHz) δ (ppm) = 145.4
(CH), 133.8 (CH), 129.2 (2x CH), 128.7 (2x CH), 128.1 (CH), 120.6 (CH).
125Te NMR (CDCl3, 126 MHz) δ (ppm) = 737.3. MS (rel. int., %) m/z: 343
(100.0), 213 (84.0), 178 (67.8), 115 (0.2), 102 (4.3), 89 (4.3). HRMS (APCI-
QTOF) calculated mass for C13H8ClNTe [M+H]+: 343.9486, found:
343.9488.
Animals
2-Pentylselenopheno[2,3-b]pyridine 3m[52]
: Yield: 0.038 g (60%);
Male Swiss mice (two months old, 25-35 g) were provided by the local
breeding colony. The animals were housed in groups with free access to
food and water. They were kept in a separate animal room, under a 12-
hour light/ 12-hour dark cycle (the lights were turned on at 07.00 a.m), in
an appropriate temperature environment (22 ± 2 °C). A commercial diet
and filtered water were available ad libittum. The experimental protocol
was approved by the Committee on Care and Use of Experimental Animal
Resources of the Federal University of Pelotas, Rio Grande do Sul, Brazil,
affiliated to the National Council for the Control of Animal Experimentation
and registered under the number 1877/2016 and 1287/2016. All
procedures were performed according to National Institutes of Health
Guide for the Care and Use of Laboratory Animals and every effort was
made to minimize both the suffering and the number of animals utilized.
orange oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.39 (dd, J = 4.7 and 1.6
Hz, 1H); 7.83 (dd, J = 7.9 and 1.6 Hz, 1H); 7.22 (dd, J = 7.9 and 4.7 Hz,
1H); 7.05 (t, J = 1.1 Hz, 1H); 2.94 (dt, J = 7.3 and 1.1 Hz, 2H); 1.75 (quint,
J = 7.3 Hz, 2H); 1.41-1.35 (m, 4H); 0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(CDCl3, 100 MHz) δ (ppm) = 164.8, 152.9, 145.1, 136.8, 130.9, 120.9,
119.6, 33.8, 31.3, 31.2, 22.4, 13.9. DEPT-135 NMR (CDCl3, 100 MHz) δ
(ppm) = 145.1 (CH), 130.9 (CH), 120.9 (CH), 119.6 (CH), 33.8 (CH2), 31.3
(CH2), 31.2 (CH2), 22.4 (CH2), 13.9 (CH3). 77Se NMR (CDCl3, 76 MHz) δ
(ppm) = 544.8. MS (rel. int., %) m/z: 253 (47.8), 196 (100.0), 116 (59.2),
102 (8.7), 89 (24.4). HRMS (APCI-QTOF) calculated mass for C12H15NSe
[M+H]+: 254.0448, found: 254.0448.
2-Pentylthieno[2,3-b]pyridine 3n: Yield: 0.042 g (81%); slightly yellow oil.
1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.44 (dd, J = 4.7 and 1.6 Hz, 1H);
7.87 (dd, J = 8.0 and 1.6 Hz, 1H); 7.21 (dd, J = 8.0 and 4.7 Hz, 1H); 6.90
(t, J = 1.0 Hz, 1H); 2.89 (dt, J = 7.4 and 1.0 Hz, 2H); 1.75 (quint, J = 7.4
Hz, 2H); 1.40-1.36 (m, 4H); 0.91 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (CDCl3,
100 MHz) δ (ppm) = 161.5, 147.5, 145.3, 133.6, 129.7, 119.2, 117.7, 31.2,
30.5, 22.3, 13.9. DEPT-135 NMR (CDCl3, 100 MHz) δ (ppm) = 145.3 (CH),
Preparation of tissue homogenate
Samples of paw and liver were homogenized (1:10, w/v) in 50 mM of Tris-
HCl at pH 7.4. The homogenates were then centrifuged at 2,500 x g for 10
min at 4ºC and the low-speed supernatant (S1) was used for in vitro and
ex vivo assays.
7
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000358
ChemMedChem
FULL PAPER
In vitro assays
SP, Brazil). For this purpose, the animals were randomly assigned to six
groups (n= 7 animals/group).
Reactive species (RS) assay: The sodium azide, a cytochrome oxidase
inhibitor, induces mitochondrial dysfunction and consequently promotes
the overproduction of RS levels[57]. The levels of RS were estimated in the
liver of mice. The 2-organylchalcogenopheno[2,3-b]pyridine compounds
were diluted in DMSO and then they were assayed at 1, 10, 100, 200 and
500 µM. In this method, the compounds 3a-3c were incubated with an
aliquot of the supernatant S1, 10 mM Tris-HCl buffer at pH 7.4 and 1 mM
dichloro-dihydro-fluorescein diacetate (DCFH-DA) in the presence or the
absence of the 10 mM sodium azide, a pro-oxidant substance, during 1
hour at room temperature (RT) in the dark. The oxidation of DCFH-DA to
fluorescent dichlorofluorescein (DCF) is measured for the detection of
intracellular RS[73]. The DCF fluorescence intensity was determined at 488
nm for excitation and 520 nm for emission and the results were expressed
as the percentage (%) of control.
In this experiment, the animals received a subcutaneous intraplantar CFA
injection (1 mg/ml of heat killed Mycobacterium tuberculosis in 85%
paraffin oil and 15% mannide monoleate, 20 µl) into the right hindpaw and
saline solution (0.9%, w/v, 20 µl) into the left hindpaw. Also, mice received
vehicle (canola oil, 10 ml/kg), compound 3b (1, 10 and 50 mg/kg) or
meloxicam (50 mg/kg), a positive control, by the ig route 24 h later the CFA
injection. The mechanical paw withdrawal threshold was measured before
(baseline values) and at 0.5 h after the last treatments administration to
evaluate the dose-response curve.
After the behavioral test, the animals were euthanized and both hindpaws
were cut at the ankle joint and weighed on an analytical balance. The paw
edema was measured by difference between right paw (CFA treatment)
and left paw (vehicle treatment) and the results were expressed in mg. The
samples of CFA-treated paw were quickly frozen at -20 °C for further
biochemical analyses (RS and lipid peroxidation assays).
2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical
scavenging activity assay: In this assay, the long-life radical cation
ABTS+ is generated by the oxidation of ABTS with the potassium
persulfate. The reduction in the intensity of greenish coloration
characteristic of this radical reflects the ability of the antioxidant
Time-response curve of compound 3b in an acute inflammatory pain
model: The treatment time-curve was conducted with compound 3b at the
dose of 50 mg/kg which was chosen based on the best antinociceptive
effect obtained in the dose-response curve. In this experiment, another set
of animals were randomly assigned into four groups (n= 7 animals/group).
Mice received a subcutaneous intraplantar CFA injection (1 mg/ml of heat
killed Mycobacterium tuberculosis in 85% paraffin oil and 15% mannide
monoleate, 20 µl) into the right hindpaw and saline solution (0.9%, w/v, 20
µl) into the left hindpaw. Also, mice received vehicle (canola oil, ig, 10
ml/kg), compound 3b (50 mg/kg, ig) or meloxicam (50 mg/kg, ig) 24 h later
the CFA injection. The mechanical paw withdrawal threshold was
measured before (baseline values) and at 0.5, 1, 2, 4, 6 and 8 h after the
last treatments administration to evaluate the time-response curve.
compounds to donate a hydrogen atom and scavenge the ABTS+ radical[70]
The 2-organylchalcogenopheno[2,3-b]pyridine compounds were diluted in
dimethyl sulfoxide (DMSO) and then they were assayed at 1, 10, 100, 200
and 500 µM. Briefly, an aliquot of the compounds 3a-3c was mixed with
the ABTS solution diluted in a phosphate buffer saline pH 7.4 during 30
minutes at RT in the dark. The ascorbic acid at 1, 10, 100, 200 and 500
µM was used as a positive control to determine the maximal decrease in
the ABTS+ absorbance. The color reaction was measured at 734 nm and
the results were expressed as percentage (%) of the control.
.
Diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity assay:
In this method, the stable free radical DPPH could accept an electron or
Hot-plate test: The hot-plate test, widely employed as a model of acute
non-inflammatory nociception, evaluates the possible central action of new
developed compounds with potential antinociceptive properties. In this test,
mice were individually placed in a glass cylinder on a heated metallic
surface that was maintained at a temperature of 55 ± 1 °C[75]. The time
between the animal placement on the hot plate and the reaction to a
noxious thermal stimulus (jumping off the surface, licking and shaking of
the hind paws) was recorded as the latency to nociceptive response
(seconds). It was established a cut-off time of 45 s in attempt to avoid any
injury on the animal paws. The thermal withdrawal latency (seconds) for
each animal was recorded 0.5 h after the treatment with the compound 3b
(50 mg/kg, ig), vehicle (canola oil, ig) or morphine (50 mg/kg), a positive
control, by the subcutaneous (sc) route (n= 6 animals/group). The
treatment time was defined in accordance to the best effect obtained in the
time-response curve, which was carried out with compound 3b at 50 mg/kg.
To discard any alterations that could be misinterpreted as nociception, the
locomotor and exploratory activities of mice were assessed before the hot
plate test.
hydrogen radical to become
a stable molecule. The free radical
scavenging activity of the antioxidant compounds was assessed by the
coloration change, from deep purple to yellow, of the DPPH ethanolic
solution[71]
. The 2-organylchalcogenopheno[2,3-b]pyridine compounds
were diluted in DMSO and then they were assayed at 1, 10, 100, 200 and
500 µM. Briefly, the DPPH ethanolic solution was mixed with an aliquot of
the compounds 3a-3c during 30 minutes at RT in the dark. The ascorbic
acid at 1, 10, 100, 200 and 500 µM was used as a reference standard to
determine the maximal decrease in the DPPH absorbance. The bleaching
of the purple colored ethanol solution of DPPH was measured at 517 nm
and the results were expressed as percentage (%) of the control.
Superoxide dismutase (SOD)-like activity assay: The pyrogallol
autoxidation at pH 8.5 generates superoxide radicals being responsible for
a time-dependent increase in the absorbance at 412 nm. The SOD-like
assay was performed to determine the ability of a superoxide radical
scavenger to inhibit the autoxidation of the pyrogallol which it is identified
as a SOD function[72]. The 2-organylchalcogenopheno[2,3-b]pyridine
compounds were diluted in DMSO and then they were assayed at 1, 10,
100, 200 and 500 µM. In this method, an aliquot of the compounds 3a-3c,
50 mM Tris-HCl buffer at pH 8.5 and pyrogallol were pre-incubated for 10
min at RT in the dark. Then it was incubated with 1N hydrochloric acid.
After 10 min under the same conditions, the color reaction was measured
at 412 nm and the results were expressed as the percentage (%) of control.
Open field test (OFT): This test evaluates the exploratory behaviors and
the general locomotor activity in mice. The apparatus was made of
plywood (30 H x 45 L x 45 W) in which the floor was divided into 9 squares
(3 rows of 3) by masking tape markers. Thirty minutes after the treatments,
each animal was placed at the center of the open field and observed for 4
min. The locomotor (number of segments crossed with the four paws) and
exploratory (number of rearings) activities were recorded during 4 min[76]
The arena was cleaned with 30% ethanol after each session.
.
In vivo experiments
Acute oral toxicity studies: In order to explore the toxicological effects
of the compound 3b, another group of mice (n= 3 animals/group) received
a single dose of the 2-phenylthieno[2,3-b]pyridine 3b (50 and 300 mg/kg,
ig) or vehicle (canola oil). Thus, these animals were observed for up to 72
h to determine the lethal potential of this compound. After this time of
exposure, mice were anesthetized to blood collection by heart puncture for
further biochemical markers analysis of liver and kidney functions. The
Dose-response curve of compound 3b in an acute inflammatory pain
model: In attempt to better elucidate the compound 3b antinociceptive
effect in vivo, the dose-response curve was carried out in an acute
inflammatory pain model induced by CFA. As described by Cunha et al.[74]
,
the mechanical hyperalgesia was defined as the behavioral parameter
measured using the electronic anesthesiometer (Insight, Ribeirão Preto,
8
This article is protected by copyright. All rights reserved.

10.1002/cmdc.202000358
ChemMedChem
FULL PAPER
aspartate (AST) and alanine aminotransferase (ALT) activities as well as
the urea levels in the plasma were determined by colorimetric tests. AST
and ALT activities were expressed as units (U)/I and urea levels were
expressed as mg/dl. The samples of liver were also collected to determine
TBARS and RS levels, as well as δ-ALA-D activity.
Keywords: antinociception
•
antioxidant
•
chalcogen
•
chalcogenophenopyridine • green solvent
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Acknowledgements
The authors thank the Fundação de Amparo à Pesquisa do
Estado do Rio Grande do Sul (FAPERGS) (PqG 19/2551-
0001867-3), Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) and Financiadora de Inovação e Pesquisa
(FINEP) for the financial support. CNPq is also acknowledged for
the fellowships to EAW and GP. This study was financed in part
by the Coordenação de Aperfeiçoamento de Pessoal de Nível
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10.1002/cmdc.202000358
ChemMedChem
FULL PAPER
Key Topic: 2-Organylchalcogenopheno[2,3-b]pyridines: Synthesis and Biological Evaluation
The synthesis of 2-organylchalcogenopheno[2,3-b]pyridines was promoted by chalcogen/NaBH4/PEG-400 system. These compounds
were obtained in moderated to good yields. Among the synthesized products, the compound 3b exhibited promising antinociceptive
effect in different animal models probably due to its intrinsic antioxidant property.
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