Electrocatalytic tandem assembly of aldehydes with 2-thiobarbituric acid into 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids) and evaluation of their interaction with catalases

Article abstract of DOI:10.1007/s10593-021-02904-8

[Figure not available: see fulltext.] Electrocatalytic transformation of aldehydes with two equivalents of 1,3-diethyl-2-thiobarbituric acid has been carried out in alcohols in an undivided cell in the presence of sodium halides with the selective formati

Full text of DOI:10.1007/s10593-021-02904-8

DOI 10.1007/s10593-021-02904-8
Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
Electrocatalytic tandem assembly of aldehydes with 2-thiobarbituric
acid into 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids)
and evaluation of their interaction with catalases
Michail N. Elinson1, Anatoly N. Vereshchagin1, Yuliya E. Ryzhkova1,
Kirill A. Karpenko1, Fedor V. Ryzhkov1*, Mikhail P. Egorov1
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; е-mail: ryzhkov.fe@ya.ru
Submitted October 7, 2020
Accepted after revision December 12, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(3), 274–283
Electrocatalytic transformation of aldehydes with two equivalents of 1,3-diethyl-2-thiobarbituric acid has been carried out in alcohols in an
undivided cell in the presence of sodium halides with the selective formation of the substituted 5,5'-(arylmethylene)bis(1,3-diethyl-
2-thiobarbituric acids) in 87–98% yields and with 870–980% current efficiency. This new one-pot electrochemically induced tandem
Knoevenagel–Michael process is a simple and efficient approach to substituted 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric
acids) containing two 1,3-diethyl-2-thiobarbituric acid fragments separated by C-aryl-substituted spacer, which are promising
compounds for different biomedical applications, including anticonvulsant, antiAIDS agents and anti-inflammatory remedies.
Theoretical studies were carried out to investigate the interaction of the synthesized compounds with beef and human catalases.
Keywords: aldehydes, 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids), 1,3-diethyl-2-thiobarbituric acid, docking studies,
electrocatalysis, electroorganic chemistry.
The continuously growing interest in convenient and
green reaction techniques encourages organic chemists to
elaborate new synthetic methodologies.1 Tandem reaction
is the combination of two or more reactions, which take
place in a specific order.2 These reactions are also one-pot
processes and, hence, such a method of synthesis is a very
powerful way to the rapid and efficient construction of
complex organic molecules.2 These reactions adhere to green
chemistry principles, as the stages of isolation and purifica-
tion of intermediates are omitted, which leads to diminished
pollution of the environment. In addition to the intrinsic
atom economy and selectivity, the tandem reaction strategy
offers significant advantages over conventional linear-type
synthesis due to its flexible and convergent nature.3
decade new types and applications of this methodology are
being intensively studied.4–13
The electroorganic synthesis is also attractive method,
especially taking into consideration ecological demands of
modern green chemistry.14,15 Although application of
electrolytic methods in organic synthesis is often limited
with equipment complicacy and long reaction time, the
utilization of electrogenerated base has become popular.
An electrogenerated base is an anion that is formed in situ
directly on a cathode. Electrogenerated base may be used
as a homogeneous catalyst under reaction conditions
instead of classic bases, such as alkaline or amine. Due to
its nature, it allows to regulate formation of the catalyst
during electrolysis and reduce the reaction of waste. Electro-
organic reactions of such type proceed smoothly with easy
workup and do not require the use of harsh conditions and
expensive reagents.16–21
Tandem Knoevenagel–Michael process is a special case
of both cascade and multicomponent reactions, in which
Knoevenagel condensation is directly followed by Michael
addition.2 This complex one-pot transformation is an
efficient method of organic synthesis,2 and in the last
During our research in the field of electroorganic syn-
thesis, we have found the electrochemical catalytic process,
0009-3122/21/57(3)-0274©2021 Springer Science+Business Media, LLC
274

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
induced by an electrogenerated base in an electrolyzer
Herein, we have attempted to connect two pharma-
cologycally active 1,3-diethyl-2-thiobarbituric moieties by
a C-aryl-substituted spacer, presuming that introduction of
two units of this medicinally privileged scaffold in one
molecule could enhance pharmacological activity. We have
already implemented some electrochemically induced
multicomponent transformations of carbonyl compounds
and different C–H acids.39–44 In continuation of our study,
now we report the data on the new selective and efficient
electrocatalytic cascade assembly of aldehydes and two
molecules of 1,3-diethyl-2-thiobarbituric acid in electro-
chemically induced tandem Knoevenagel–Michael reaction.
The electrolytic chain strategy is the simple and very
efficient way to "ideal synthesis".45 On this route, cascade
reactions have sufficient overlap with PASE (Pot, Atom,
and Step Economy) methodology.46,47 PASE syntheses
presuppose pot and step economy, but also introduce atom
economy (with the aim that the most atoms of the starting
compounds become part of the final product). In the case of
electrocatalytic reactions, such process is also energy-
economic due to high current efficiency (>100%).48
without diaphragm.22 We have already used this
electrolytic method for the synthesis of biologically active
2-amino-4H-chromenes.23–25 This convenient and efficient
electrocatalytic procedure utilizes cheap undivided cell. It
is useful also for the large-scale synthesis thanks to the use
of catalytic chain reaction and the application of
inexpensive and environmentally clean electricity instead
of chemical reagent. This catalytic methodology is very
important for the organic synthesis, as it combines the
efficiency of one-pot methods with the green chemistry
advantages of electrolytic processes.26, 27
Heterocycles are the key structural compounds in
medicinal chemistry, as they are found in many biolo-
gically important molecules such as enzyme, vitamins,
natural products, and pharmacologically active compounds
with antifungal, anti-inflammatory, antibacterial, anti-
oxidant, anticonvulsant, anti-allergic, antiHIV, and anti-
cancer activity.28 Among the nitrogen-containing hetero-
cycles, barbituric acid represents a type of a privileged
medicinal scaffold.29 Its 5-substituted derivatives are
known as barbiturates. Many barbiturates are drugs that act
on the central nervous system.30 The current interest in
barbiturates also arises from their pharmacological
potential as antiAIDS31 and anticancer agents.32,33
At the same time, the thiobarbituric acid derivatives also
showed a broad range of pharmacological action, including
diaminopimelate aminotransferase and tyrosinase inhibit-
ing,34 antituberculosis,35 and anticancer in combination
with anti-inflammatory activities.36,37 Moreover, thiobarbi-
turic acid was used in preparation of compounds, which
possess quadratic non-linear optical (NLO) properties for
optoelectronic and photonic technologies.38
At the beginning of our investigation, to evaluate the
synthetic potential of the electrocatalytic procedure and
optimize the electrolysis conditions, the electrocatalytic
cascade assembly of benzaldehyde 1a with 2 equiv of 1,3-di-
ethyl-2-thiobarbituric acid (2) was carefully studied under
conditions of electrolysis in alcohols in an undivided cell
(Table 1).
Data in Table 1 indicate, that the current density 5 mA/cm2
(I 25 mA, n-PrOH as a solvent, NaBr as electrolyte) and
the temperature near to the boiling point of n-PrOH were
the optimal conditions for the electrochemically induced
chain process and allowed for the highest isolated yield of
Table 1. Electrocatalytic coupling of benzaldehyde 1a with 2 equiv of 1,3-diethyl-2-thiobarbituric acid (2)*
O
O
O
OH
CHO
Electrolyte
Solvent
+
2
Et
Et
S
N
N
N
N
Et
Et
S
1a
S
N
Et
O
N
Et
OH
2
3a
Current density,
mA/cm2
Time,
min
Electricity passed,
Yield, %
(CE, %)**
Entry
Solvent
Electrolyte
Temperature, °C
I, mA
F/mol
1
2
MeOH
MeOH
EtOH
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaI
25
65
78
97
78
78
78
78
78
78
25
25
25
25
25
25
50
10
25
25
5
5
32
32
32
32
64
64
16
80
32
32
0.1
0.1
0.1
0.1
0.2
0.2
0.1
0.1
0.1
0.1
12*** (120)
75 (750)
85 (850)
93 (930)
88 (440)
91 (455)
80 (800)
87 (870)
89 (890)
87 (870)
3
5
4
n-PrOH
EtOH
5
5
5
6
n-PrOH
n-PrOH
n-PrOH
n-PrOH
n-PrOH
5
7
10
2
8
9
5
10
KBr
5
* Reaction conditions: benzaldehyde 1a (5 mmol), 1,3-diethyl-2-thiobarbituric acid (2) (10 mmol), NaBr (1 mmol) as electrolyte, solvent (20 ml), iron
cathode (5 cm2), graphite anode (5 cm2), undivided cell, electrode surface 5 cm2.
** Current efficiency CE = m·F/(Mr·I·t)·100%, where m – the real obtained mass of compound; F – Faraday constant, 9.649·104 s·A/mol; Mr – molar
mass of the product; I – electric current, A; t – reaction time, s.
*** 1H NMR data.
275

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
Scheme 1. Electrocatalytic assembly of compounds 3a–l (yields given in parentheses and current efficiency in brackets)
R3
R2
R1
CHO
R1
O
O
Electrolysis, I 25 mA
+
2
N
N
O
OH
R3
Et
Et
NaBr, n-PrOH, 97°C, 32 min
Et
Et
S
R2
S
N
N
1a–l
2
S
N
O
N
OH
3a–l
a R1 = R2 = R3 = H
f R1 = H, R2 = F, R3 = H
g R1 = R2 = H, R3 = Cl
h R1 = H, R2 = Br, R3 = H
i R1 = R2 = H, R3 = CO2Me
j R1 = R2 = H, R3 = NO2
CHO
Et
Et
b R1 = R2 = H, R3 = Me
c R1 = R2 = H, R3 = CF3
d R1 = OH, R2 = R3 = H
e R1 = R2 = H, R3 = OMe
CHO
N
1k
1l
Me
CF3
HO
O
O
OH
O
OH
O
OH
OH
Et
Et
S
Et
Et
S
Et
Et
Et
Et
S
N
N
N
N
N
N
N
N
S
N
O
N
S
N
O
N
S
N
O
N
S
S
N
O
N
OH
OH
OH
OH
Et
Et
Et
Et
Et
Et
Et
Et
3a (93%)
3b (96%)
3c (96%)
3d (87%)
[930%]
[960%]
[960%]
[870%]
OMe
Cl
F
Br
O
O
OH
O
OH
O
N
OH
OH
Et
Et
S
Et
Et
S
Et
Et
Et
Et
N
N
N
N
N
N
N
N
S
N
O
N
S
N
O
N
S
O
N
S
S
N
O
N
S
OH
OH
OH
OH
Et
Et
Et
Et
Et
Et
Et
Et
3e (89%)
3f (95%)
[950%]
NO2
3g (90%)
3h (92%)
[890%]
[900%]
[920%]
CO2Me
N
O
OH
O
OH
O
OH
O
OH
Et
Et
S
Et
Et
S
Et
Et
S
Et
Et
S
N
N
N
N
N
N
N
N
S
N
O
N
S
N
O
N
S
N
O
N
S
N
O
N
OH
OH
OH
OH
Et
Et
Et
Et
Et
Et
Et
Et
3i (94%)
3j (91%)
3k (98%)
3l (88%)
[940%]
[910%]
[980%]
[880%]
5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acid)
(3a) (entry 4). When the current density 10 mA/cm2 was
used, both decrease of the substance yields and current
efficiency have been observed (Table 1, entry 7). The
current density 2 mA/cm2 resulted in diminution of the
substance yields and current efficiency (entry 8) as well. In
the last case, this could be a result of inefficient induction
of the electrolytic chain process.
On the whole, the elevated temperature favors the
formation of phenylbisthiobarbiturate 3a. n-PrOH appears
to be the most suitable for the electrocatalytic process
anion at cathode, which explains that reaction in propanol
media proceeded with the highest yields. On the other
hand, the longer reaction proceeds, the lower the current
efficiency is, as the quantity of electricity passed increases.
This way a simple and effective method was found for
electrolytic transformation of aromatic aldehydes and
double excess of 1,3-diethyl-2-thiobarbituric acid (2) into
5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids)
in the electrolyzer without diaphragm. Under the optimal
conditions (Table 1, entry 4), the electrolysis of aldehydes
1a–l and 2 equiv of 1,3-diethyl-2-thiobarbituric acid (2) led
to 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids)
3a–l in 87–98% yields (current efficiency 870–980%)
(Scheme 1). After the end of the electrolytic cascade
process, the solution was evaporated to volume of 4 ml. The
product crystallized from the concentrated reaction mixture
and was isolated by filtration and washed on filter with
chilled EtOH–H2O, 4:1. The structures of all new com-
1
pounds 3b–d,f–i,k,l were confirmed by H, 13C NMR and
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Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
Scheme 2. The mechanism of electrocatalytic reaction of aldehydes 1 with 2 equiv of 1,3-diethyl-2-thiobarbituric acid (2)
IR spectroscopy, mass spectrometry, and elemental
analysis.
(binding mode) for a ligand in the binding pocket and to
assess binding energy for those poses.
Earlier 5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric
acids) 3a,e,j were obtained in 42–65% yields by the
reaction of aldehydes 1a,e,j with 4 equiv of 1,3-diethyl-
2-thiobarbituric acid (2) in EtOH with reaction time of
8 h.49 In comparison with the electrocatalytic method
proposed above, this method uses a significant excess of
1,3-diethyl-2-thiobarbituric acid.
With the above-mentioned results and taking into consi-
deration the mechanistic data on tandem Knoevenagel–
Michael reactions,50,51 the following mechanism for the
electrocatalytic assembly of aldehydes with 2 equiv of
1,3-diethyl-2-thiobarbituric acid (2) forming 5,5'-(aryl-
methylene)bis(1,3-diethyl-2-thiobarbituric acids) 3a–l was
proposed (Scheme 2).
The first step of this electrochemically induced process
is the deprotonation of alcoholic solvent at the cathode,
which leads to the formation of an alkoxide anion. Then,
interaction of the latter with 1,3-diethyl-2-thiobarbituric
acid (2) results in the conjugate thiobarbiturate anion A
formation (Scheme 2). The following process in the bulk of
solution is reaction of anion A and aldehyde 1 with the
elimination of a hydroxide anion and formation of
Knoevenagel adduct 4.52 The hydroxide anion promoted
Michael addition of the next molecule of 1,3-diethyl-2-thio-
barbituric acid (2) to the electron-deficient Knoevenagel
adduct 4 affords the end product of the electrocatalytic
chain process, namely, substituted 5,5'-(arylmethylene)bis-
(1,3-diethyl-2-thiobarbituric acid) 3 with the regeneration
of the alkoxide anion as the last step of the catalytic cycle.
Then, the catalytic chain process continues by the
interaction of the alkoxide anion with the next molecule of
1,3-diethyl-2-thiobarbituric acid (2) (Scheme 2).
Catalases play important role in oxidation processes,54
inflammation,55 apoptosis,56 and tumor stimulation.57
Catalases take part in EtOH metabolism58 and decrease
voluntary EtOH consumption.59 Therefore, we were prompted
to carry out a docking study of the synthesized compounds
3a–l and catalases and identify modes of their interaction.
To begin the investigation, the NAPDH binding site of
beef liver catalase was chosen for docking studies, namely,
structure 7CAT from the RCSB Protein Data Bank.60 The
protein structure was proposed by the CSD-CrossMiner
software.61 This software allows mapping a pharmacophore
for a given structure. Unsubstituted compound 3a was
chosen for mapping as a reference structure. The most
distant donors and acceptors of compound 3a were selected
(mapped) as pharmacophore features (Fig. 1a). To reduce
the amount of results, ring fragment was mapped as well
and Tanimoto index was selected as 0.9. The search was
carried out in "pdb_crossminer" feature database.
As a result, three similar protein-ligand complexes from
protein data bank were proposed: 7CAT (root-mean-square
deviation of atomic positions (RMSD) 0.815), 5OYD63
(RMSD 0.832), 6BF464 (RMSD 0.867). The structure 7CAT
Figure 1. The pharmacophore of compound 3a. a) The reference
structure 3a, b) the result of pharmacophore search – NADPH,
c) the superposition of the reference and resulted structures. Blue
mesh sphere represents a donor, translucent sphere is a donor
projection, red sphere represents an acceptor, and green sphere
represents a ring fragment.
Molecular docking studies. Molecular docking has
become a powerful approach for structure-based drug
discovery, as docking programs are able to provide correct
predictions.53 Docking aims to predict a correct pose
277

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
was chosen as it had the lowest RMSD value. The
As it follows from distribution of binding energy
(Fig. 3a), binding of compounds 3a–l to 7CAT is even
more beneficial than the binding of NADPH from thermo-
dynamic point of view. The calculated binding values are
broadly distributed, the binding energies for compounds
3a–l are below –7÷–6 kcal/mol. In the 4thand 5th modes
the difference in the energy between synthesized com-
pounds and reference compound is the greatest: the best
values for synthesized compounds are close to –10 kcal/mol,
while the values for NADPH are above –4 kcal/mol.
Ligand efficiency (LE) of synthesized compounds is
also beneficial due to the lower molecular mass and higher
values of binding energies (see the Supplementary information
file). The form of LE distribution is the same as binding
energy distribution, and the values have the same tendency:
the binding efficiency per atom of synthesized compounds
3a–l is in the range of –0.3÷–0.2 kcal/mol·atom and the LE
of NADPH is close to 0.1 kcal/mol·atom.
conformation of NADPH in the binding site of beef liver
catalase and its relation to pharmacophore are presented in
Figure 1b, the superposition of reference compound 3a, the
pharmacophore, and NADPH are shown in Figure 1c.
The choices having been made, docking studies were
carried out. The calculation process was performed with
the Lead Finder tool in Flare software.64 The protein
structure was prepared with Buildmodel (a part of the Flare
software). NADPH was used as a reference compound in
docking studies. Several binding modes were calculated for
each compound. Figure 2 shows that the first modes are the
most favorable for each compound, and the results of the
docking for the most favorable modes are presented in
Table 2 (the rank score values for each compound are given
in the Supplementary information file).
One should note that pharmacophore search with CSD-
CrossMiner has provided a good target protein: the
calculated binding energy (ΔG) is below –10 kcal/mol for
compounds 3b,c,e–i. The binding energy of compound 2g
(–11.25 kcal/mol) is almost twice as big as calculated
energy for the reference compound NADPH (–5.91 kcal/mol).
Compounds 3a–c,e–k superimposed into binding pocket
of 7CAT are demonstrated in Figure 4. The most favorable
modes of compounds 3a–c and 3e–k are almost the same.
In most cases, the aromatic fragment is exposed to hydro-
phobic surroundings or exposed to solvent.
Generally, the synthesized compounds and 7CAT form
π–π stacking with Phe197. An atom of oxygen of barbituric
fragment is tended to form hydrogen bond to Arg202, the
adjacent atom of hydrogen is able to form bond to Tyr214
(compounds 3h,k,l, and compounds 3c,d through H2O
molecule), or Phe197 (compounds 3a,e,i,j). Generally,
barbituric fragments are exposed to positively charged or
hydrophobic surroundings. Compound 3l has slightly
rotated position (counterclockwise, ~30°), while in the
Figure 2. Ranking of binding modes to 7CAT. Six binding modes
with rank score are given, rank score is dimensionless, the values
for selected compounds are presented in Table 2.
Table 2. The results of the docking studies of compounds 3a–l
and NADPH to 7CAT or 1DGB*
7CAT
1DGB
Structures
ΔG,**
LE,***
ΔG,
LE,
kcal/mol kcal/mol·atom kcal/mol
kcal/mol·atom
–8.98
–10.80
–10.47
–8.63
–0.27
–0.32
–0.28
–0.25
–0.29
–0.29
–0.33
–0.30
–0.29
–0.27
–0.27
–0.22
–0.12
–8.35
–9.20
–8.07
–8.15
–8.58
–8.25
–8.16
–9.31
–9.14
–8.84
–9.41
–7.06
–7.38
–0.25
3a
3b
–0.27
–0.22
3c
–0.24
3d
–10.05
–10.00
–11.25
–10.20
–10.63
–9.71
–0.25
3e
–0.24
3f
–0.24
3g
–0.27
3h
–0.25
3i
–0.25
3j
–8.93
–0.29
3k
–8.15
–0.19
3l
NADPH
–5.91
–0.15
* The data given for the best poses, the remaining data are given in the
Supplementary information file.
** The energy of interaction between ligand and protein.
*** Ligand efficiency which is equal to ΔG per number of heavy (non-
hydrogen) atoms in ligand molecule.
Figure 3. The distribution of binding energy of compounds 3a–l
to a) 7CAT and b) 1DGB. The horizontal axis line represents
index of pose (binding mode). The calculated values for the first
modes are given in Table 2.
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Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
Figure 4. Position of docked compounds in binding pocket of 7CAT: superimposed compounds 3a–c,e–k, compound 3d, compound 3l,
and exemplary interactions of compounds 3k,d,l inside the binding pocket.
position of compound 3d the barbituric fragment and the
aromatic fragment are interchanged (Fig. 4). Modes of
compound 3d,l are characterized by the lowest values of
Gibbs free energy and ligand efficiency, but compound 3d
interacts with His304, while many compounds form
interactions with Arg202, Phe197, and Tyr214 (Fig. 4).
Compound 3d forms hydrogen bond to Arg202, but 3l
forms a π–cation interaction. The aromatic fragment of
compound 3d is surrounded by hydrophobic chains, while
aromatic fragment of compound 3l is exposed to solvent.
Barbituric fragments of compound 3d are exposed to polar
and positively charged surroundings, in contrast, barbituric
fragments of compound 3l are surrounded by hydrophobic
and negatively charged surroundings (Fig. 4).
Encouraged by the results of docking compounds 3a–l to
7CAT, we were prompted to investigate the relation of
these compounds with human catalase. The structure
1DGB54,65 of human erythrocyte catalase was selected for
further investigation. The results of docking procedure are
also presented in Table 2.
and the values of binding energy below –9 kcal/mol are
featured only by compounds 3b,h,i,k (considering the first
modes, Fig. 3b).
The LE follows the distribution of binding energy
(Table 2) and due to the lower molecular mass and higher
values of binding energies, the synthesized compounds have
more beneficial LE distribution.
Best modes of compounds 3a–c,g–k have similar
positions in binding pocket of 1DGB. These compounds
interact with Tyr215 and Arg203 (Fig. 5). Generally,
aromatic fragments are surrounded by hydrophobic or
positively charged chains, they are also exposed to solvent
in case of compounds 3b,c,h,j.
Best mode of compound 3e has slightly rotated
(counterclockwise ~30°C) and mirrored position (Fig. 5).
Its aromatic fragment is exposed to polar and positively
charged surroundings, while the barbituric fragment is
surrounded by hydrophobic chains and slightly exposed to
solvent. Compound 3e has the most unusual mode and
forms hydrogen bond with Trp303 and His305.
The distribution of binding energy has similar
tendencies to the results mentioned above: the values of
binding energy of synthesized compounds 3a–l are below
–6 kcal/mol, and the values of binding energy of NADPH
are mostly above –6 kcal/mol (Fig. 3b). Nevertheless, the
binding energy of the first mode of NADPH is –7.38 kcal/mol,
Interesting, that compounds 3f,l have very close
conformations to each other and similar surroundings, but
different hydrogen bonding: compound 3l forms π–cation
interaction with Arg203 and there is an additional π–cation
interaction with His305, while compound 3f also forms a
π–cation interaction with Arg203, and also forms the same
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Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
Figure 5. The position of synthesized compounds in binding site of 1DGB.
hydrogen bonds as compounds 3a–c,g–k. At the same time,
the position of compound 3l is the least beneficial from
thermodynamic point of view (binding energy is
–7.06 kcal/mol, Table 2). Both compounds 3f,l are surrounded
by hydrophobic chains, but the aromatic fragments are
among positively charged chains of 1DGB structure.
Thus, a new electrochemically induced fast and highly
efficient reaction of aromatic aldehydes with 2 equiv of
1,3-diethyl-2-thiobarbituric acid in alcohols carried out in
an undivided cell results in formation of the substituted
5,5'-(arylmethylene)bis(1,3-diethyl-2-thiobarbituric acids)
in 87–98% yields and current efficiency of 870–980%.
This new electrochemically induced tandem Knoevenagel–
Michael process is simple, one-pot, and efficient approach
to molecules containing two 1,3-diethyl-2-thiobarbituric
acid fragments separated by C-aryl-substituted spacer,
which are promising compounds for different biomedical
applications, including anticonvulsant, antiAIDS agents,
and anti-inflammatory remedies.
Instead of divided cells which are applied in many
electroorganic syntheses, this efficient electrocatalytic
procedure utilizes simple equipment, an undivided cell that
is similar to common multineck flask. Commercially
available, mostly stable starting compounds which need no
preparation for the reaction, high yields of end compounds,
simple procedures of synthesis and product isolation are
also among the advantages of this method. Taking into
consideration the short reaction time and tenfold current
efficiency as well as low amount of waste, the proposed
electrocatalytic method is promising as an environmentally
benign scalable batch process.
The docking studies of synthesized compounds with
some catalases were carried out. The investigations of
proposed binding modes revealed the interactions with
280

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
3
3
different parts of NADPH binding site. The values of
calculated binding energy and ligand efficiency of
synthesized compounds are more beneficial than the
calculated values for original ligand. Therefore, synthesized
compounds are relevant for the further investigation of
their activity as potent ligands of beef liver and human
erythrocyte catalases.
1.32 (6H, t, J = 6.9, 2CH3); 1.40 (6H, t, J = 6.9, 2CH3);
4.53–4.75 (8H, m, 4CH2); 5.69 (1H, s, CH); 7.24–7.33 (2H,
3
m, H Ar); 7.60 (2H, d, J = 8.3, H Ar); 8.60 (1H, br. s,
OH); 13.91 (1H, br. s, OH). 13С NMR spectrum (126 MHz,
CDCl3), δ, ppm (J, Hz): 11.4 (2C); 11.5 (2C); 34.5; 44.1 (2C);
1
44.6 (2C); 96.3 (2C); 123.5 (q, JCF = 271.9; СF3); 124.8
3
2
(q, JCF = 3.7, 2C); 126.2 (2C); 128.6 (q, JCF = 32.6, CСF3);
139.4; 161.7 (2C); 163.2 (2C); 174.0 (2C). Mass spectrum,
m/z (Irel, %): 556 [M]+ (100), 356 [M–C8H11N2O2S]+ (74),
323 (44), 200 (41). Found, %: C 51.65; H 4.82; F 10.11;
N 10.01; S 11.38. C24H27F3N4O4S2. Calculated, %: C 51.79;
H 4.89; F 10.24; N 10.07; S 11.52.
5,5'-[(2-Hydroxyphenyl)methylene]bis(1,3-diethyl-
6-hydroxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3d).
Yield 2.26 g (87%), yellow solid, mp 141–143°C.
IR spectrum, ν, cm–1: 3376 (O–H), 2981, 2935 (C=S),
2526, 1631 (C=O), 1423 (C=C Ar), 1264, 1109, 896, 747.
1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz):
1.25 –145 (12H, m, 4CH3); 4.51–4.76 (8H, m, 4CH2); 5.69
Experimental
IR spectra were registered on a Bruker ALPHA-T FT-IR
spectrometer in KBr pellets. 1H and 13C NMR spectra were
recorded on Bruker Avance II-300 (300 and 75 MHz,
respectively) and Bruker XWIND (500 and 126 MHz,
respectively) spectrometers at ambient temperature with
TMS as internal standard. Mass spectra (EI, 70 eV) were
obtained directly with a Finningan MAT INCOS 50
spectrometer. For elemental analysis, PerkinElmer 2400
SERIES II and multi EA 5000 instruments were used. All
melting points were measured with a Gallenkamp melting
point apparatus and are uncorrected.
3
(1H, s, CH); 6.71 (1H, d, J = 8.0, H Ar); 6.89–6.96 (1H,
Synthesis of 5,5'-(arylmethylene)bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones) 3a–l
(General method). A solution of aldehyde 1a–l (5 mmol),
1,3-diethyl-2-thiobarbituric acid (2) (10 mmol), and NaBr
(0.1 g, 1 mmol) in n-PrOH (20 ml) was electrolyzed in an
undivided cell equipped with a magnetic stirrer, a graphite
anode, and an iron cathode at 97°C under a constant current
density of 5 mA/cm2 (I 25 mA, electrode surface size
5 cm2) until the catalytic quantity of 0.1 F/mol of electricity
was passed (32 min). After the electrolysis was finished,
the reaction mixture was concentrated to one fifth of its
initial volume (ca. 4 ml) and cooled to 0°C to crystallize
the solid product, which was then filtered off, twice rinsed
with an ice-cold EtOH–H2O, 4:1 mixture (4 ml), and dried
under reduced pressure.
m, CH Ar); 7.07–7.21 (2H, m, CH Ar); 9.46 (3H, br. s, 3OH).
13С NMR spectrum (75 MHz, CDCl3), δ, ppm: 12.4 (2C);
12.5 (2C); 32.2; 44.6 (2C); 45.2 (2C); 98.3 (2C); 115.9;
120.6; 128.3; 128.8; 135.8; 153.8; 162.4 (2C); 163.1 (2C);
174.5 (2C). Mass spectrum, m/z (Irel, %): 504 [M]+ (4), 304
[M–C8H11N2O2S]+ (83), 200 (69), 173 (87), 29 (100).
Found, %: C 54.61; H 5.54; N 11.02; S 12.57. C23H28N4O5S2.
Calculated, %: C 54.74; H 5.59; N 11.10; S 12.71.
5,5'-[(4-Methoxyphenyl)methylene]bis(1,3-diethyl-
6-hydroxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3e).
Yield 2.31 g, (89%), white solid, mp 135–137°C (mp 133–
136°C49).
5,5'-[(3-Fluorophenyl)methylene]bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3f). Yield
2.41 g (95%), white solid, mp 196–197°C. IR spectrum,
ν, cm–1: 2981, 2935, 2876 (C=S), 2523, 1622 (C=O), 1424
(C=C Ar), 1380, 1266, 1108, 788. 1H NMR spectrum
5,5'-(Phenylmethylene)bis(1,3-diethyl-6-hydroxy-2-thi-
oxo-2,3-dihydropyrimidin-4(1H)-one) (3a). Yield 2.27 g
(93%), white solid, mp 174–175°C (mp 174–176°C49).
5,5'-[(4-Methylphenyl)methylene]bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3b). Yield
2.57 g (96%), white solid, mp 164–166°C. IR spectrum,
ν, cm–1: 3435 (O–H), 2978, 2933, 2874 (C=S), 1620 (C=O),
3
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.32 (6H, t, J = 6.9,
3
2CH3); 1.40 (6H, t, J = 6.9, 2CH3); 4.55–4.77 (8H, m,
4CH2); 5.66 (1H, s, CH); 6.82–6.89 (3H, m, H Ar); 6.91–7.01
(1H, m, H Ar); 7.82 (1H, br. s, OH); 13.96 (1H, br. s, OH).
13С NMR spectrum (75 MHz, CDCl3), δ, ppm (J, Hz):
12.1 (4C); 34.9; 44.7 (2C); 45.2 (2C); 97.1 (2C); 113.8
1
1435 (C=C Ar), 1383, 1267, 1110, 786. H NMR spectrum
3
2
2
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.31 (6H, t, J = 6.9,
(d, JCF = 23.9, C Ar); 113.9 (d, JCF = 23.9); 122.1 (d,
2CH3); 1.39 (6H, t, 3J = 6.9, 2CH3); 2.36 (3H, s, CH3); 4.55–
4JCF = 3.2); 129.9 (d, JCF1 = 8.4); 138.5 (d, JCF = 8.4);
162.3 (2C); 163.2 (d, JCF = 245.5); 163.8 (2C);
174.7 (2C). Mass spectrum, m/z (Irel, %): 506 [M]+ (18),
306 [M–C8H11N2O2S]+ (35), 273 (27), 200 (39), 29 (100).
Found, %: C 54.42; H 5.33; F 3.62; N 10.97; S 12.54.
C23H27FN4O4S2. Calculated, %: C 54.53; H 5.37; F 3.75;
N 11.06; S 12.66.
3
3
4.77 (8H, m, 4CH2); 5.65 (1H, s, CH); 6.88 (1H, br. s, OH);
3
3
7.02 (2H, d, J = 7.7, H Ar); 7.14 (2H, d, J = 7.7, H Ar);
13.85 (1H, br. s, OH). 13С NMR spectrum (75 MHz,
CDCl3), δ, ppm: 12.0 (2C); 12.1 (2C); 21.0; 34.7; 44.6
(2C); 45.2 (2C); 97.6 (2C); 126.3 (2C); 129.2 (2C); 132.4;
136.4; 162.3 (2C); 163.8 (2C); 174.6 (2C). Mass spectrum, m/z
(Irel, %): 502 [M]+ (38), 302 [M–C8H12N2O2S]+ (83), 269
(82), 243 (13), 200 (53), 29 (100). Found, %: C 57.28;
H 5.98; N 10.92; S 12.69. C24H30N4O4S2. Calculated, %:
C 57.35; H 6.02; N 11.15; S 12.76.
5,5'-[(4-Chlorophenyl)methylene]bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3g). Yield
2.35 g (90%), white solid, mp 183–184°C. IR spectrum,
ν, cm–1: 3426 (O–H), 2977, 2932, 2874 (C=S), 1622
1
5,5'-{[4-(Trifluoromethyl)phenyl]methylene}bis(1,3-di-
ethyl-6-hydroxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-
one) (3c). Yield 2.67 g (96%), white solid, mp 193–194°C.
IR spectrum, ν, cm–1: 3430 (O–H), 2987, 2938, 2878 (C=S),
1624 (C=O), 1438 (C=C Ar), 1379, 1266, 1111, 782.
1H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz):
(C=O), 1438 (C=C Ar), 1383, 1268, 1109, 779. H NMR
spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.31 (6H, t,
3
3J = 7.0, 2CH3); 1.39 (6H, t, J = 7.0, 2CH3); 4.54–4.77
(8H, m, 4CH2); 5.63 (1H, s, CH); 7.08 (2H, d, 3J = 8.2, H Ar);
3
7.30 (2H, d, J = 8.2, H Ar); 9.78 (1H, br. s, OH); 13.94
(1H, br. s, OH). 13С NMR spectrum (75 MHz, CDCl3), δ, ppm:
281

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
12.1 (4C); 34.7; 44.7 (2C); 45.2 (2C); 97.2 (2C); 127.9 (2C);
N 14.18; S 13.01. C22H27N5O4S2. Calculated, %: C 53.97;
128.7 (2C); 132.7; 134.3; 162.3 (2C); 163.8 (2C); 174.7 (2C).
Mass spectrum, m/z (Irel, %): 524 [M(37Cl)]+ (38), 522
[M(35Cl)]+ (79), 324 [M(37Cl)–C8H11N2O2S]+ (54), 322
[M(35Cl)–C8H11N2O2S]+ (100), 289 (56), 200 (28). Found, %:
C 52.73; H 5.23; Cl 6.65; N 10.59; S 12.13. C23H27ClN4O4S2.
Calculated, %: C 52.81; H 5.20; Cl 6.78; N 10.71; S 12.26.
5,5'-[(3-Bromophenyl)methylene]bis(1,3-diethyl-
6-hydroxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3h).
Yield 2.61 g (92%), white solid, mp 198–200°C. IR spectrum,
ν, cm–1: 3427 (O–H), 3043, 2981 (C=S), 2523, 1620
H 5.56; N 14.30; S 13.10.
5,5'-(1-Naphthylmethylene)bis(1,3-diethyl-6-hydroxy-
2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3l). Yield
2.37 g (88%), white solid, mp 130–132°C. IR spectrum,
ν, cm–1: 3435 (O–H), 2980, 2934, 2874 (C=S), 1615
1
(C=O), 1428 (C=C Ar), 1381, 1267, 1109, 781. H NMR
spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 1.21
(6H, t, 3J = 6.9, 2CH3); 1.44 (6H, t, 3J = 6.9, 2CH3); 4.54
(4H, q, 3J = 6.5, 2CH2); 4.74 (4H, q, 3J = 6.5, 2CH2); 6.21 (1H,
s, CH); 6.44 (1H, br. s, OH); 7.32–7.51 (4H, m, H Ar); 7.55–
7.61 (1H, m, H Ar); 7.82 (1H, d, 3J = 7.9, H Ar); 7.88 (1H,
1
(C=O), 1430 (C=C Ar), 1379, 1267, 1108, 781. H NMR
3
spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 1.32 (6H, t,
d, J = 7.9, H Ar); 13.89 (1H, br. s, OH). 13С NMR
3
3J = 6.9, 2CH3); 1.40 (6H, t, J = 6.9, 2CH3); 4.54–4.77
spectrum (75 MHz, DMSO-d6), δ, ppm: 11.9 (2C); 12.2
(2C); 34.0; 44.6 (2C); 45.3 (2C); 99.5 (2C); 122.8; 124.8;
125.5; 125.8 (2C); 126.1; 128.5; 129.5; 134.4; 154.8; 162.6
(2C); 163.3 (2C); 174.5 (2C). Mass spectrum, m/z (Irel, %):
538 [M]+ (7), 338 [M+–C8H11N2O2S]+ (100), 305 (50),
200 (36). Found, %: C 60.09; H 5.59; N 10.27; S 11.78.
C27H30N4O4S2: C 60.20; H 5.61; N 10.40; S 11.91.
(8H, m, 4CH2); 5.64 (1H, s, CH); 7.09 (1H, d, 3J = 7.8, H Ar);
3
3
7.22 (1H, dd, J = 8.0, J = 7.6, H Ar); 7.27 (1H, s, H Ar);
3
7.42 (1H, d, J = 7.8, H Ar); 8.19 (1H, br. s, OH); 13.94
(1H, br. s, OH). 13С NMR spectrum (75 MHz, CDCl3), δ, ppm:
12.1 (4C); 34.8; 44.7 (2C); 45.3 (2C); 97.0 (2C); 122.8;
125.2; 129.7; 129.9; 130.0; 138.2; 162.3 (2C); 163.8 (2C);
174.7 (2C). Mass spectrum, m/z (Irel, %): 568 [M(81Br)]+
(10), 566 [M(79Br)]+ (8), 368 [M(81Br)–C8H11N2O2S]+ (59),
366 [M(79Br)–C8H11N2O2S]+ (49), 335 (31), 333 (31), 200
(55), 29 (100). Found, %: C 48.54; H 4.77; Br 14.01;
N 9.73; S 11.23. C23H27BrN4O4S2. Calculated, %: C 48.68;
H 4.80; Br 14.08; N 9.87; S 11.30.
Supplementary information file containing H and 13C
NMR spectra for the new compounds and docking results is
available at the journal website at http://link.springer.com/
journal/10593.
1
Methyl 4-[bis(1,3-diethyl-6-hydroxy-4-oxo-2-thioxo-
1,2,3,4-tetrahydropyrimidin-5-yl)methyl]benzoate (3i).
Yield 2.57 g (94%), white solid, mp 195–197°C. IR spectrum,
ν, cm–1: 3443 (O–H), 2981, 2833 (C=S), 1717 (C=O), 1616,
1433 (C=C Ar), 1378, 1270, 1109, 779. 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.31 (6H, t, 3J = 7.0, 2CH3);
1.40 (6H, t, 3J = 7.0, 2CH3); 3.93 (3H, s, OCH3); 4.53–4.77
(8H, m, 4CH2); 5.69 (1H, s, CH); 7.23 (2H, d, 3J = 8.0, H Ar);
The reported study was funded by the Russian
Foundation for Basic Research (project 19-29-08013).
References
1. Cioc, R. C.; Ruijter, F.; Orru, R. V. A. Green Chem. 2014, 16, 2958.
2. Ho, T.-L. Tandem Organic Reactions; John Wiley & Sons:
New York, 1992.
3. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 2000.
4. Moosavi-Zare, A. R.; Afshar-Hezarkhani, H.; Rezaei, M. M.
Polycyclic Aromat. Compd. 2020, 40, 150.
5. Zeynizadeh, B.; Rahmani, S.; Ilkhanizadeh, S. Polyhedron
2019, 168, 48.
6. Liu, M.; Liu, C.-F.; Zhang, J.; Xu, Y.-J.; Dong, L. Org. Chem.
Front. 2019, 6, 664.
7. Moosavi-Zare, A. R.; Goudarziafshar, H.; Jalilian, Z. Prog.
Chem. Biochem. Res. 2019, 2, 59.
8. Maleki, R.; Koukabi, N.; Kolvari, E. Appl. Organomet. Chem.
2018, 32, e3905.
9. Elinson, M. N.; Sokolova, O. O.; Nasybullin, R. F. Heterocycl.
Commun. 2015, 21, 97.
10. Khazaei, A.; Abbasi, F.; Moosavi-Zare, A. R. New J. Chem.
2014, 38, 5287.
3
7.42 (2H, d, J = 8.0, H Ar); 8.83 (1H, br. s, OH); 13.91
(1H, br. s, OH). 13С NMR spectrum (75 MHz, CDCl3), δ, ppm:
12.1 (4C); 35.3; 44.7 (2C); 45.3 (2C); 52.3; 97.2 (2C);
126.6 (2C); 128.9; 129.8 (2C); 141.3; 162.4 (2C); 163.8
(2C); 166.8; 174.7 (2C). Mass spectrum, m/z (Irel, %):
546 [M]+ (11), 346 [M–C8H11N2O2S]+ (50), 313 (44),
200 (58), 29 (100). Found, %: C 54.86; H 5.46; N 10.20;
S 11.61. C25H30N4O6S2. Calculated, %: C 54.93; H 5.53;
N 10.25; S 11.73.
5,5'-[(4-Nitrophenyl)methylene]bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3j). Yield
2.43 g (91%), white solid, mp 198–200°C (mp 198–199°C49).
5,5'-[(Pyridin-3-yl)methylene]bis(1,3-diethyl-6-hydr-
oxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one) (3k). Yield
2.40 g (98%), white solid, mp 267–269°C. IR spectrum,
ν, cm–1: 3610, 3443 (O–H), 2975 (C=S), 1610 (C=O), 1432
11. Elinson, M. N.; Nasybullin, R. F.; Nikishin, G. I. C. R. Chimie
2013, 16, 789.
1
12. Moosavi-Zare, A. R.; Zolfigol, M. A.; Zarei, M.; Zare, A.;
Khakyzadeh, V.; Hasaninejad, A. Appl. Catal., A 2013, 467, 61.
13. Safaei-Ghomi, J.; Khojastehbakht-Koopaei, B.; Zahedi, S.
Chem. Heterocycl. Compd. 2015, 51, 34. [Khim. Geterotsikl.
Soedin. 2015, 51, 34.]
14. Organic Electrochemistry: Revised and Expanded;
Hammerich, O.; Speicer, B., Eds.; CRS Press: Boca Raton,
2016, 5th ed.
15. Yan, M.; Kawamata, Y.; Baran, P. S. Angew. Chem., Int. Ed.
2018, 57, 4149.
16. Nikishin, G. I.; Elinson, M. N.; Makhova, I. V. Angew.
Chem., Int. Ed. 1988, 27, 1716.
(C=C Ar), 1382, 1270, 1108, 1013, 786. H NMR spectrum
(300 MHz, DMSO-d6), δ, ppm (J, Hz): 1.17 (12H, t,
3
3J = 6.9, 4CH3); 4.44 (8H, q, J = 6.2, 4CH2); 6.43 (1H, s,
3
CH); 7.93 (dd, J = 8.1, 3J = 5.7, 1H, CH Ar); 8.28 (1H, d,
3
3J = 7.1, CH Ar); 8.58 (1H, s, H Ar); 8.69 (1H, d, J = 5.7,
H Ar); 9.05 (1H, br. s, OH); 16.98 (1H, br. s, OH).
13С NMR spectrum (75 MHz, DMSO-d6), δ, ppm: 12.2
(4C); 32.2; 43.0 (4C); 94.1 (2C); 126.6; 139.1; 140.0;
143.1; 144.6; 161.0 (4C); 174.6 (2C). Mass spectrum, m/z
(Irel, %): 489 [M]+ (4), 289 [M–C8H11N2O2S]+ (65), 256
(29), 200 (40), 29 (100). Found, %: C 53.85; H 5.53;
282

Chemistry of Heterocyclic Compounds 2021, 57(3), 274–283
17. Ogibin, Yu. N.; Elinson, M. N.; Nikishin, G. I. Russ. Chem.
45. Wender, P. A. Nat. Prod. Rep. 2014, 31, 433.
46. Zang, W.; Yi, W.-B. Pot, Atom, and Step Economy (PASE)
Synthesis; Springer: Cham, 2019.
47. Vereshchagin, A. N.; Elinson, M. N.; Zaimovskaya, T. A.;
Nikishin, G. I. Tetrahedron 2008, 64, 9766.
Rev. 2009, 78, 89. [Usp. Khim. 2009, 78, 99.]
18. Kashimura, S.; Matsumoto, K. In Encyclopedia of Applied
Electrochemistry; Kreysa, G.; Ota, K.; Savinell, R. F., Eds;
Springer: New York, 2014, p. 706.
19. Utley, J. H. P. Top. Curr. Chem. 1987, 142, 131.
20. Fotouhi, L.; Heravi, M. M.; Fatehi, A.; Bakhtiari, K.
Tetrahedron Lett. 2007, 48, 5379.
48. Elinson, M. N.; Merkulova, V. M.; Ilovaisky, A. I.;
Demchuk, D. V.; Belyakov, P. A.; Nikishin, G. I. Mol. Diversity
2010, 14, 833.
21. Chiarotto, I.; Mattiello, L.; Feroci, M. Acc. Chem. Res. 2019,
52, 3297.
22. Elinson, M. N.; Feducovich, S. K.; Lizunova, T. L.; Nikishin, G. I.
Tetrahedron 2000, 56, 3063.
23. Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.;
Gorbunov, S. V.; Nasybullin, R. F.; Miloserdov, F. M.;
Nikishin, G. I. Eur. J. Org. Chem. 2006, 4335.
24. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky A. I.;
Feducovich, S. K.; Belyakov, P. A.; Nikishin, G. I. Adv.
Synth. Catal. 2008, 350, 591.
25. Elinson, M. N.; Vereshchagin, A. N.; Ryzhkov, F. V. Chem.
Rec. 2016, 16, 1950.
26. Ilovaisky, A. I.; Merkulova, V. M.; Elinson, M. N.; Nikishin, G. I.
Russ. Chem. Rev. 2012, 81, 381. [Usp. Khim. 2012, 81, 381.]
27. Elinson, M. N.; Vereshchagin, A. N.; Ryzhkov, F. V. Curr.
Org. Synth. 2017, 21, 1427.
28. Arora, P.; Arora, V.; Lamba, H. S.; Wadhwa, D. Int. J. Pharm.
Res. 2012, 3, 2947.
29. Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.;
Jones, L. H.; Fadeyi, O. Org. Biomol. Chem. 2016, 14, 6611.
30. Johns, M. W. Drugs 1975, 9, 448.
31. Naguib, F. N. M.; Levesque, D. L.; Wang, E.-C.; Panzica. R. P.;
El Kouni, M. H. Biochem. Pharmacol. 1993, 46, 1273.
32. Grams, F.; Brandstetter, H.; D'Alo, S.; Geppert, D.; Krell, H.-W.;
Leinert, H.; Livi, V.; Menta, E.; Oliva, A.; Zimmermann, A. G.
Biol. Chem. 2001, 382, 1277.
33. Maquoi, E.; Sounni, N. E.; Devy, L.; Olivier, F.; Frankenne, F.;
Krell, H.-W.; Grams, F.; Foidart, J.-M.; Noël, A. Clin. Cancer
Res. 2004, 10, 4038.
34. Fan, C.; Clay, M. D.; Deyholos, M. K.; Vederas, D. C.
Bioorg. Med. Chem. 2010, 18, 2141.
35. Laxmi, S. V.; Reddy, Y. T.; Kuarm, B. S.; Reddy, P. N.;
Crooks, P. A.; Rajitha, B. Bioorg. Med. Chem. Lett. 2011, 21, 4329.
36. Reddy, P. N.; Ponogoti, R. P.; Kasam, V.; Crooks, P. A.
Bioorg. Med. Chem. Lett. 2013, 23, 1442.
49. Adamson, J.; Coe, B. J.; Grassam, H. L.; Jeffery, J. C.; Coles, S. J.;
Hursthouse, M. B. J. Chem. Soc., Perkin Trans. 1 1999,
2483.
50. Elinson, M. N.; Dorofeev, A. S.; Nasybullin, R. F.;
Feducovich, S. K.; Nikishin, G. I. Electrochim. Acta 2008, 53,
5033.
51. Elinson, M. N.; Dorofeev, A. S.; Nasybullin, R. F.; Nikishin, G. I.
Synthesis 2008, 1933.
52. Patai, S.; Israeli, Y. J. Chem. Soc. 1960, 2025.
53. Torres, P. H. M.; Sodero, A. C. R.; Jofily, P.; Silva-Jr, F. P.
Int. J. Mol. Sci. 2019, 20, 4574.
54. Putnam, C. D.; Arvai, A. S.; Bourne, Y.; Tainer, J. A. J. Mol.
Biol. 2000, 296, 295.
55. Halliwell, B.; Gutteridge, J. M. C. Biochem. J. 1984, 219, 1.
56. Yabuki, M.; Kariya, S.; Ishisaka, R.; Yasuda, T.;
Yoshioka. T.; Horton, A. A.; Utsumi, K. Free Radical. Biol.
Med. 1999, 26, 325.
57. Miyamoto, T.; Hayashi, M.; Takeuchi, A.; Okamoto, T.;
Kawashima, S.; Takii, T.; Hayashi, H.; Onozaki, K.
J. Biochem. 1996, 120, 725.
58. Zimatkin, S. M.; Liopo, A. V.; Deitrich, R. A. Alcohol.: Clin.
Exp. Res. 1998, 22, 1623.
59. Aragon, C. M. G.; Amit, Z. Neuropharmacology 1992,
31, 709.
60. (a) Murthy, M. R. N.; Reid, T. J., III; Sicignano, A.; Tanaka, N.;
Fita, I.; Rossmann, M. G. PDB ID: 7CAT. DOI: 10.2210/
pdb7CAT/pdb. (b) Fita, I.; Rossman, M. G. Proc. Natl. Acad.
Sci. U. S. A. 1985, 82, 1604.
61. CSD-CrossMiner 1.4.1. Cambridge Crystallographic Data
Centre. https://www.ccdc.cam.ac.uk/whitepapers/csd-crossminer-
versatile-pharmacophore-query-tool-successful-modern-drug-
discovery/. Accessed July 22, 2020.
62. (a) Attia, M. A.; Nelson, C. E.; Offen, W. A.; Jain, N.;
Davies, G. J.; Gardner, J. G.; Brumer, H. PDB ID: 5OYD.
https://doi.org/10.2210/pdb5OYD/pdb. (b) Attia, M. A.;
Nelson, C. E.; Offen, W. A.; Jain, N.; Davies, G. J.; Gardner, J. G.;
Brumer, H. Biotechnol. Biofuels 2018, 11, 45.
37. Rayburn, E. R.; Ezell, S. J.; Zang R. Mol. Cell Pharmacol.
2009, 1, 29.
38. Marder, S. R.; Cheng, L.-T.; Tiemann, B. J.; Friedly, A. C.;
Blanchard-Desce, M.; Perry, J. W.; Skindhøj, J. Science 1994,
263, 511.
39. Elinson, M. N.; Dorofeeva, E. O.; Vereshchagin, A. N.;
Nasybullin, R. F.; Egorov, M. P. Catal. Sci. Technol. 2015, 5, 2384.
40. Elinson, M. N.; Dorofeeva, E. O.; Vereshchagin, A. N.;
Nikishin, G. I. Russ. Chem. Rev. 2015, 84, 485. [Usp. Khim.
2015, 84, 485.]
41. Elinson, M. N.; Merkulova, V. M.; Ilovaisky, A. I.;
Chizhov, A. O.; Barba, F.; Batanero, B. J. Electrochem. Soc.
2014, 161, G48.
42. Vereshchagin, A. N.; Elinson, M. N.; Dorofeeva, E. O.;
Stepanov, N. O.; Zaimovskaya, T. A.; Nikishin, G. I.
Tetrahedron 2013, 69, 1945.
63. (a) Zhou, T.; Kwong, P. D.; PDB ID: 6BF4. https://doi.org/
10.2210/pdb6BF4/pdb. (b) Zhou, T.; Zheng, A.; Baxa, U.;
Chuang, G.-Y.; Georgiev, I. S.; Kong, R.; O'Dell, S.; Shahzad-Ul-
Hussan, S.; Shen, C.-H.; Tsybovsky, Y.; Bailer, R. T.; Gift, S. K.;
Louder, M. K.; McKee, K.; Rawi, R.; Stevenson, C. H.;
Stewart-Jones, G. B. E.; Taft, J. D.; Waltari, E.; Yang, Y.;
Zhang, B.; Shivatare, S. S.; Shivatare, V. S.; Lee, C. D.; Wu, C.-Y.;
Mullikin, J. C.; Bewley, C. A.; Burton, D. R.; Polonis, V. R.;
Shapiro, L.; Wong, C. H.; Mascola, J. R.; Kwong, P. D.; Wu, X.
Immunity 2018, 48, 500.
64. (a) Flare, 3.0.0, Cresset Software: Litlington, 2019. http://
www.cresset-group.com/flare/. Accessed July 22, 2020.
(b) Cheeseright, T.; Mackey, M.; Rose, S.; Vinter, A.
J. Chem. Inf. Model. 2006, 46, 665. (c) Bauer, M. R.;
Mackey, M. D. J. Med. Chem. 2006, 62, 3036. (d) Kuhn, M.;
Firth-Clark, S.; Tosco, P.; Mey, A. S. J. S.; Mackey, M.;
Michel, J. J. Chem. Inf. Model 2020, 60, 3120.
43. Elinson, M. N.; Merkulova, V. M.; Ilovaisky, A. I.; Barba, F.;
Batanero, B. Electrochim. Acta 2011, 56, 8219.
44. Elinson, M. N.; Feducovich, S. K.; Bushuev, S. G.;
Zakharenkov, A. A.; Pashchenko, D. V.; Nikishin, G. I.
Mendeleev Commun. 1998, 8, 15.
65. Putnam, C. D.; Arvai, A. S.; Bourne, Y.; Tainer, J. A. PDB ID:
1DGB. https://doi.org/10.2210/pdb1DGB/pdb.
283