A simple method for the synthesis of 4-arylselanyl-7-chloroquinolines used as in vitro acetylcholinesterase inhibitors and in vivo memory improvement

Article abstract of DOI:10.1016/j.tetlet.2017.07.039

We described here an alternative method for the synthesis of 4-arylselanyl-7-chloroquinolines through reactions of 4,7-dichloroquinoline with organylselenols, generated in situ by the reaction of diorganyl diselenides with H₃PO₂ (50?wt% in H₂O). These reactions proceeded efficiently at 60?°C under N₂ atmosphere and are suitable to a range of diorganyl diselenides containing electron-donating and electron-withdrawing groups, affording the corresponding 4-aryl-7-chloroquinolines in high yields. The synthesized compounds were screened for their in vitro acetylcholinesterase (AChE) activity and our results demonstrated that the 7-chloro-4-[(4-fluorophenyl)selanyl]quinoline inhibited the AChE activity and improved memory in mice, making this compound is a potential therapeutic agent for the treatment of Alzheimer disease and other neurodegenerative disorders.

Full text of DOI:10.1016/j.tetlet.2017.07.039

Accepted Manuscript
A simple method for the synthesis of 4-arylselanyl-7-chloroquinolines used as
in vitro acetylcholinesterase inhibitors and in vivo memory improvement
Luis Fernando B. Duarte, Eduardo S. Barbosa, Renata L. Oliveira, Mikaela P.
Pinz, Benhur Godoi, Ricardo F. Schumacher, Cristiane Luchese, Ethel A.
Wilhelm, Diego Alves
PII:
S0040-4039(17)30885-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.039
TETL 49121
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 May 2017
6 July 2017
10 July 2017
Please cite this article as: Duarte, L.F.B., Barbosa, E.S., Oliveira, R.L., Pinz, M.P., Godoi, B., Schumacher, R.F.,
Luchese, C., Wilhelm, E.A., Alves, D., A simple method for the synthesis of 4-arylselanyl-7-chloroquinolines used
as in vitro acetylcholinesterase inhibitors and in vivo memory improvement, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.039
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A simple method for the synthesis of 4-arylselanyl-7-
chloroquinolines used as in vitro acetylcholinesterase
inhibitors and in vivo memory improvement
Luis Fernando B. Duarte, Eduardo S. Barbosa, Renata L. Oliveira, Mikaela P. Pinz, Benhur Godoi, Ricardo
F. Schumacher, Cristiane Luchese, Ethel A. Wilhelm* and Diego Alves*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A simple method for the synthesis of 4-arylselanyl-7-chloroquinolines used as in
vitro acetylcholinesterase inhibitors and in vivo memory improvement
Luis Fernando B. Duartea, Eduardo S. Barbosaa, Renata L. Oliveirab, Mikaela P. Pinzb, Benhur Godoic,
Ricardo F. Schumachera, Cristiane Lucheseb, Ethel A. Wilhelmb* and Diego Alvesa*
a Laboratório de Síntese Orgânica Limpa - LASOL - CCQFA - Universidade Federal de Pelotas - UFPel - P.O. Box 354 - 96010-900, Pelotas, RS, Brazil,
b Programa de Pós-Graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica, Grupo de Pesquisa em
Neurobiotecnologia - GPN, CCQFA Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brasil.
c Núcleo de Síntese, Aplicação e Análise de Compostos Orgânicos e Inorgânicos, Universidade Federal da Fronteira Sul - UFFS, Cerro Largo - RS - Brasil.
ARTICLE INFO
ABSTRACT
Article history:
Received
We described here an alternative method for the synthesis of 4-arylselanyl-7-chloroquinolines
through reactions of 4,7-dichloroquinoline with organylselenols, generated in situ by the
reaction of diorganyl diselenides with H3PO2 (50 wt% in H2O). These reactions proceeded
efficiently at 60 °C under N2 atmosphere and are suitable to a range of diorganyl diselenides
containing electron-donating and electron-withdrawing groups, affording the corresponding 4-
aryl-7-chloroquinolines in high yields. The synthesized compounds were screened for their in
vitro acetylcholinesterase (AChE) activity and our results demonstrated that the7-chloro-4-[(4-
fluorophenyl)selanyl]quinoline inhibited the AChE activity and improved memory in mice,
making this compound is a potential therapeutic agent for the treatment of Alzheimer disease
and other neurodegenerative disorders.
Received in revised form
Accepted
Available online
Keywords:
Nitrogen Heterocycles
Quinolines
Selenium
Acetylcholinesterase
Memory
2017 Elsevier Ltd. All rights reserved
.
H
1
Quinolines are an important class of heterocyclic compounds
and their structural entities are common in therapeutics, alkaloids
and synthetic analogues with interesting biological activities.1 A
great variety of quinoline derivatives have been used as antiviral,
anticancer, antibacterial, antifungal, antiplatelet, antiobesity and
anti-inflammatory agents (Figure 1).2 Particularly, molecules
containing the nucleus 7-chloroquinoline are biologically active
units and display a wide range of pharmacological properties,
such as antimalarial and antitubercular properties.3 Because of
their presence in a wide diversity of synthetic and natural
CO2Na
H
N
HO
OH
S
O
N
Cl
N
Quinine
Montelukast
O
N
N
HN
products, significant efforts have been dedicated to the design
and the synthesis of new molecules containing quinoline nucleus.
N
O
HO
Camptothecin
In this context, there are a large number of methodologies in
the literature for the synthesis of chalcogen-containing
quinolines, especially selenium derivatives.4 Organoselenium
compounds are valuable scaffolds in organic synthesis because
their pharmacological activities,5 and also as versatile building
blocks participating in regio-, chemio-, and stereoselective
reactions.6 Thus, the synthesis of selenium-containing quinolines
have great significance and their applicability range from
antioxidant, antifungal, and antibacterial agents, to selective
DNA binding and photocleaving agents.4
Cl
N
O
Chloroquine
Figure 1. Selected examples of bioactive quinolines.
Recently, a significant increase in the number of alternative
procedures for the synthesis of organoselenium compounds has
appeared, especially involving the use of non-volatile and
renewable solvents, and alternative energy sources.7 In this sense,
the use of aqueous solution of hypophosphorous acid (H3PO2)
have been described as an efficient and cheap way to synthesize
organoselenium compounds.8 This acid is air-stable and can be
used efficiently in aqueous solution while the expected
———
*Corresponding author. Tel./fax: +55 5332757533, email:
ethelwilhelm@yahoo.com.br (E.A. Wilhelm) and diego.alves@ufpel.edu.br
(D. Alves).
organylselenol is easily generated in situ after cleavage of
diorganyl diselenide under nitrogen atmosphere, avoiding the bad
smell of this selenating agent, and the incompatibility of boron

2
Tetrahedron Letters
hidrides or alkali metals with sensitive groups. In recent years,
benzeneselenol, followed by the addition of 4,7-
our group published some methodologies using H3PO2 to the
generation of organylselenols in situ from diorganyl diselenides,
with application in the synthesis of mono- or bis-selanyl alkenes,
benzoselenazoles or benzoselenazolines, unsymmetrical diaryl
selenides, organylselanyl pyridines and selanylesters.8d-h
dichloroquinoline 2 (0.5 mmol) and stirring for additional 1 h at
60 °C. Our results indicates that this reaction of diphenyl
diselenide 1a with H3PO2 (50 wt% in H2O) produce in situ two
portions of benzeneselenol, and subsequent reaction with 4,7-
dichloroquinoline 2 is able to use both benzeneselenol groups,
highlighting the atom economy of this process.
In continuation to our efforts devoted to the development of
new efficient protocols correlated to the nitrogen-functionalized
organoselenium compounds, we report an alternative method for
the synthesis of 4-arylselanyl-7-chloroquinolines. This method
involves reactions of 4,7-dichloroquinoline with organylselenols,
generated in situ by the reaction of diorganyl diselenides with
H3PO2 (50 wt% in H2O). In addition, the obtained products were
screened for their in vitro acetylcholinesterase (AChE) activity,
and the best inhibitor was assessed on the in vivo memory
improvement (Scheme 1).
Once defined the ideal reaction parameters, we have focused on
the study of the generality and limitations of the synthetic
method. Therefore, several experiments were carried out by
employing the 4,7-dichloroquinoline 2 and diaryl diselenides 1a-
h bearing different substituents bonded to the aromatic rings, as
substrates (Table 1). The reaction system showed to be no
sensitive to electronic effects from donating and electron-
withdrawing groups present in the structure of the diaryl
diselenides affording the desired 4-arylselanyl-7-chloro-
quinolines 3a-g in good to excellent yields (Table 1, entries 1-7).
In order to test the influence of steric effects in the efficiency of
the synthetic approach, the substrate 2 was submitted to the
reaction conditions in the presence of the sterically hindered
dimesityl diselenide 1h. Through this reaction the expected 4-
arylselanyl-quinoline derivative 3h was isolated in 86% yield
(Table 1, entry 8). It is important to note that the synthetic
methodology proved to be highly regioselective once all
experiments furnished the desired quinolines 3 only by
replacement of chlorine atom at C-4 position of the heterocyclic
nucleus. These results must be highlighted since the preservation
of the chlorine atom at C-7 position enables the further
functionalization of the heterocyclic unit.
Scheme 1. General scheme of the present work.
Initially, we choose diphenyl diselenide 1a (0.25 mmol) and
4,7-dichloroquinoline 2 (0.5 mmol) as model substrates to
establish the best conditions for the reaction using H3PO2 (50
wt% in H2O) as the reducing agent and some experiments were
performed to synthesize the 7-chloro-4-(phenylselanyl)quinoline
3a (Scheme 2). All the reactions were carried out in a Schlenk
tube and monitored by TLC until total disappearance of starting
materials. Thus, a mixture of diphenyl diselenide 1a (0.25 mmol)
and H3PO2 (50 wt% in H2O, 0.5 mL) was stirred at 90 °C under
N2 atmosphere for 1 h. Then, 4,7-dicloroquinoline 2 (0.5 mmol)
was added and the mixture was stirred for additional 1 h at 90
°C.8h Under these reaction conditions, the estimated product 3a
was obtained in 69% yield (Condition A, Scheme 2).
After these studies, we turned our attention to the in vitro
AChE activity and in vivo memory improvement of the
synthesized compounds. Progressive loss of memory is a major
feature of Alzheimer’s disease. In recent years, therapy of
Alzheimer’s disease using AChE inhibitors has been extensively
studied.9 Nowadays, the Food and Drug Administration (FDA)
approved five drugs for the treatment of Alzheimer’s disease,
including four AChE inhibitors (tacrine, donepezil, galanthamine
and rivastigmine). Unfortunately, these drugs have low
bioavailability and undesirable side effects, such as
hepatotoxicity. Indeed, no new treatment has been approved for
the Alzheimer’s disease since 2003 and several new candidates
have not succeeded in clinical trials. Therefore, in a first step, we
investigated the inhibitory effect of synthesized quinolines 3 on
the cerebral AChE activity in vitro.
Interestingly, the yield of 7-chloro-4-(phenylselanyl)quinoline 3a
was increased to 93% and 97% when the reaction temperature
was maintained at 60 °C after the addition of 4,7-
dicloroquinoline 2 (Conditions B and C, Scheme 2).
Unfortunately, when the reaction temperature was maintained at
room temperature after the addition of substrate 2, a decrease in
the yield of product 3a was observed, even after 24 h (Condition
D, Scheme 2).
AChE is an enzyme that presents a key role in cholinergic
neurotransmission by hydrolyzing the acetylcholine to acetate
and choline in the synaptic cleft.10 Acetylcholine is the major
neurotransmitter involved in learning and memory, and in the
regulation of cognitive functions.11 Consequently, AChE
inhibitors, which enhance the availability of acetylcholine in the
synaptic cleft, are a potential treatment strategy to enhance the
cholinergic function.12 Thus, this study reported inhibitory effect
of quinoline derivatives 3a, 3b, 3c, 3e and 3g on cerebral AChE
activity, since cholinergic system is important to cognitive
process. Compounds 3d, 3f and 3h were not used in the assay
because of their low solubility in DMSO.
Table 2 shows the effect of 4-arylselanyl-7-chloroquinolines
3a, 3b, 3c, 3e and 3g on AChE activity in cerebral cortex of
mice. Compound 3e significantly inhibited the cerebral cortex
AChE activity at concentrations equal to or greater than 1 µM,
being that the Imax was 36.5%. 7-Chloroquinoline derivatives 3a,
3b, 3c and 3g had no effect in inhibiting AChE activity in
cerebral cortex of mice.
Scheme 2. Optimization of the reaction.
Analyzing the results shown in Scheme 2, we judged that the
best reaction conditions to afford 7-chloro-4-
(phenylselanyl)quinoline 3a are those in Condition C. This
condition involves the preliminary reaction of diphenyl
diselenide 1a (0.25 mmol) with H3PO2 50 wt% in H2O (0.5 mL)
at 60 °C under N2 for 1 h (for the formation in situ of

3
Data are reported as mean S.D. of 3 independent experiments. AChE
activity was expressed as µmol acetylthiocholine/h/mg protein. * p < 0.05
as compared with the vehicle group (one-way ANOVA/Newman-Keuls).
Table 1. Variability in the synthesis of 4-arylselanyl-7-
chloroquinolines.a
Considering the results obtained in vitro, we extend our
studies to investigate the effect of the best inhibitor on the three
stages of memory, acquisition, consolidation and retrieval, in
mice. Memory can be defined as the record of information
representation acquired through experiences, and it is a process
that has several stages.14 Moreover, there are multiple
mechanisms and neurotransmitters involved in the memory, but
cholinergic system has a key function in this process.11 Thus,
based on in vitro results of quinoline derivatives on the AChE
activity, compound 3e was used to investigate its effect in
improving memory in mice.
Product
(Yield)b
Product
(Yield)b
Entry
Entry
F
Se
N
1
5
Cl
3a (97%)c
3b (87%)
3c (81%)
3d (71%)
3e (67%)
2
3
4
6
7
8
3f (75%)
3g (75%)
3h (86%)
a Reactions are performed using diorganyl diselenide 1a-h (0.25 mmol), 0.5
mL of H3PO2 (50 wt% in H2O) at 60 °C under N2 atmosphere for 1 hour.
After the generation of the organylselenol, 4,7-dichloroquinoline 2a (0.5
mmol) was added and the mixture was stirred at 60 °C for additional 1 hour.
Yields are given for isolated products. c One reaction was performed using
diphenyl diselenide 1a (5 mmol), 5 mL of H3PO2 (50 wt% in H2O) and 2-
b
chloropyridine 2a (10 mmol) and the desired product 3a was obtained in 87%
yield.
Therefore, it can suggest that the fluorine in the chemical
structure of quinoline derivative 3e contributes to the inhibitory
effect on cerebral AChE activity. In accordance, Liu and co-
workers demonstrated that insertion of fluorine atom markedly
influenced the activity and the selectivity of chalcone derivatives
in inhibiting AChE.13 Moreover, so far hundreds of fluorine-
containing drugs had been applied in clinical practice, such as
Fluoxetine (antidepressant), Ofloxacin (antibacterial), 5-
Fluorouracil (anti-cancer agent), among others.
Figure 2. Effect of compound 3e on the step-down inhibitory
avoidance task in mice. Compound, at the dose of 10 mg/kg, was
administered, intragastrically, 30 min before training session
(acquisition) (A), immediately post-training (consolidation) (B) and
30 min before test (retrieval) (C). Each column represents mean
Table 2 - Effect of 4-arylselanyl-7-chloroquinolines 3a, 3b,
3c, 3e and 3g on AChE activity in cerebral cortex of mice.
S.E.M. for 7 to 8 animals per group. Data were analyzed using a non-
paired t-test. (*) p < 0.05 when compared to the control group.
4-arylselanyl-7-chloroquinolines
Figure 2 shows the effect of quinoline derivative 3e on the
step-down inhibitory avoidance task in mice. During the training
session in the step-down inhibitory avoidance task, there was no
difference in the step-through latency time among groups.
Administration of compound 3e 30 min before the training
(acquisition) and immediately after the training session
(consolidation) did not alter the step-through latency time in
these stages of memory (Figures 2A and 2B, respectively).
3a
3b
3c
3e
3g
Vehicle
1 µM
9.6 0.5
10.2 3.9
9.1 1.2
7.6 1.7
7.8 1.5
9.6 0.5
10.2 0.9
9.4 0.7
8.1 1.6
8.7 1.6
9.6 0.5
8.5 0.8
8.3 2.6
8.5 1.7
9.4 1.9
9.6 0.5
9.6 0.5
8.2 1.7
8.4 2.2
7.4 1.7
9.0 1.2
6.9 1.6*
6.0 0.7*
6.2 1.9*
6.1 0.7*
10 µM
100 µM
200 µM

4
Tetrahedron Letters
Paris, J. L.; Pinney, B. B.; Reizes, O.; Hu, X. E. Bioorg. Med.
Chem. Lett. 2006, 16, 5207.
However, administration of the compound 3e 30 min before the
test session (retrieval) increased (around 44 %) the step-through
latency in comparison to the control group (Figure 2C).
Acquisition, consolidation and retrieval are stages of memory.14
The present study established a cognitive enhancement in the
memory phase of retrieval after administration of quinoline
derivative 3e in the step-down inhibitory avoidance task.
3. Recent examples: (a) Macedo, B.; Kaschula, C. H.; Hunter, R.;
Chaves, J. A. P.; van der Merwe, J. D.; Silva, J. L.; Egan, T. J.;
Cordeiro, Y. Eur. J. Med. Chem. 2010, 45, 5468. (b) Carmo, A.
M. L.; Silva, A. M. C.; Machado, P. A.; Fontes, A. P. S.; Pavan, F.
R.; Leite, C. Q. F.; Leite, S. R. A.; Coimbra, E. S.; Silva, A. D.
Biomed. Pharmacother. 2011, 65, 204. (c) Singh, P.; Singh, P.;
Kumar, M.; Gut, J.; Rosenthal, P. J.; Kumar, K.; Kumar, V.;
Mahajan, M. P.; Bisetty, K. Bioorg. Med. Chem. Lett. 2012, 22,
57. (d) Souza, N. B.; Carvalhaes, R.; Carmo, A. M. L.; Alves, M.
J. M.; Coimbra, E. S.; Cupolilo, S. M. N.; Abramo, C.; Silva, A.
D. Lett. Drug. Des. Discov. 2012, 9, 361. (e) Bueno, J.; Ruiz, F. A.
R.; Etupinan, S. V.; Kouznetsov, V. V. Lett. Drug. Des. Discov.
2012, 9, 126.
4. For recent examples of selenium-containing quinolines see: (a)
Abdel-Hafez, S. H. Phosphorus, Sulfur Silicon Relat. Elem. 2010,
185, 2543. (b) Naik, H. R. P.; Naik, H. S. B.; Naik, T. R. R.;
Lamani, D. S.; Aravinda, T. Phosphorus, Sulfur Silicon Relat.
Elem. 2010, 185, 355. (c) Abdel-Hafez, S. H. Russ. J. Bioorg.
Chem. 2010, 36, 370. (d) Bhasin, K. K.; Arora, E.; Kwak, C.;
Mehta, S. K. J. Organomet. Chem. 2010, 695, 1065. (e)
Savegnago, L.; Vieira, A. I.; Seus, N.; Goldani, B. S.; Castro, M.
R.; Lenardão, E. J.; Alves, D. Tetrahedron Lett. 2013, 54, 40. (f)
Pinz, M.; Reis, A. S.; Duarte, V.; Rocha, M. J.; Goldani, B. S.;
Alves, D.; Savegnago, L.; Luchese, C.; Wilhelm, E. A. Eur. J.
Pharmacol. 2016, 780, 122. (g) Reis, A. S.; Pinz, M.; Duarte, L. F.
B.; Roehrs, J. A.; Alves, D.; Luchese, C.; Wilhelm, E. A. J.
Psychiatric Res. 2017, 84, 191.
Administration of compound 3e pre-training, immediately
post-training and before test did not change the number of
crossings and rearing in the open-field test in mice (data not
shown). Therefore, compound 3e did not cause impairment in the
locomotor activity and exploratory behavior of mice assessed by
the open-field test.
In summary, we have developed an alternative methodology
for the synthesis of 4-aryl-7-chloroquinolines. This method
involves the reaction of 4,7-dichloroquinoline with
organylselenols, generated in situ by the reaction of diorganyl
diselenides with aqueous H3PO2. Reactions are suitable to a range
of diorganyl diselenides and proceeded efficiently at 60 °C under
N2 atmosphere. In addition, the synthesized compounds were
screened for their in vitro AChE activity. Our results
demonstrated that quinoline derivative 3e inhibited AChE
activity in vitro. Moreover, this quinoline derivative
administrated in mice caused cognitive enhancement in the
memory phase of retrieval in the step-down inhibitory avoidance
task in mice. Given that quinoline derivative 3e inhibited the
AChE activity and improved cognitive enhancement, this
compound is a potential therapeutic agent for the treatment of
Alzheimer disease and other neurodegenerative disorders.
5. (a) Mugesh, G.; du Mont, W. W.; Sies, H. Chem. Rev. 2001, 101,
2125. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev.
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Chemistry - From Small Molecules to Biomolecules and
Materials; Derek, W. J.; Risto, L., eds.; Springer-Verlag: Berlin,
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Menezes, P. H.; Zeni, G. In Patai’s Chemistry of Functional
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Acknowledgments
We are grateful for the financial support and scholarships
from the Brazilian agencies CNPq (400150/2014-0 and
447595/2014-8), FAPERGS (PRONEM 16/2551-0000240-1 and
PRONUPEQ 16/2551-0000526-5), FINEP and CAPES. CNPq is
also acknowledged for the fellowship to D. A. and C. L..
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6
Tetrahedron Letters
• Arylselenation of quinolines using aqueous
solution of hypophosphorous acid.
• Selenium-functionalized 7-chloroquinolines
in good to excellent yields.
• Synthetized compounds are a potential
therapeutic agents for the Alzheimer
disease.