ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ)
To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile, (3S/4R)-3-[(3R/4S)-9-chloroacr...
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| Datum: | 2021 |
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2021
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Ukrainian Chemistry Journal| _version_ | 1871465712572170240 |
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| author | Smetanin , Nikolay Tokarieva, Sofia Varenichenko , Svetlana Farat , Oleg Markov, Victor |
| author_facet | Smetanin , Nikolay Tokarieva, Sofia Varenichenko , Svetlana Farat , Oleg Markov, Victor |
| author_institution_txt_mv | [
{
"author": "Nikolay Smetanin ",
"institution": "Ukrainian State University of Chemical Technology, Postgraduate student of the Department of Pharmacy and Technology of Organic Compounds"
},
{
"author": "Sofia Tokarieva",
"institution": "Ukrainian State University of Chemical Technology, Master of the Department of Pharmacy and Technology of Organic Compounds"
},
{
"author": "Svetlana Varenichenko ",
"institution": "Ukrainian State University of Chemical Technology, Associate Professor of the Department of Pharmacy and Technology of Organic Compounds"
},
{
"author": "Oleg Farat ",
"institution": "Ukrainian State University of Chemical Technology, Associate Professor of the Department of Pharmacy and Technology of Organic Compounds"
},
{
"author": "Victor Markov",
"institution": "Ukrainian State University of Chemical Technology, Professor of the Department of Pharmacy and Technology of Organic Compounds"
}
] |
| author_sort | Smetanin , Nikolay |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:46Z |
| description | To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile, (3S/4R)-3-[(3R/4S)-9-chloroacridine(quinoline)-4-yl]-1-N-aryl)pyrrolidine-2,5-diones. Methods: Organic synthesis, spectral methods, and molecular docking. We investigated by molecular docking the potential biological activity of previously synthesized compounds containing acridine and pyrrolidine-2,5-diones fragments in their structure, as well as synthesized in this work N’-hydroxy-1,2,3,4,5,6,7,8-octahydroacridine-4-carboximidamide. Based on the literature data, 3 directions of searching for the biological activity of the synthesized compounds have been chosen: cholinesterase inhibitors, anti-inflammatory, and anticonvulsant agents. As inhibitors of acetylcholinesterase and butylcholinesterase, substances with good binding free energy and hydrogen bonds with the desired amino acid residues of the Glu-His-Ser triad have been found among the tested compounds. The indicators of synthesized products have exceeded the literature data. The docking data for anti-inflammatory activity has revealed compounds with values above the docking data of the reference drugs - celecoxib and indomethacin. The compounds tested have shown moderate activity as anticonvulsant agents. 3-(7-bromo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-1-(3-nitrophenyl)pyrrolidine-2,5-dione is potentially promising as an acetylcholinesterase inhibitor due to its high binding free energy (-13.7 kcal/mol) and hydrogen bonds with two amino acid residues Ser200, His440. Compound (4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile has proved to be the best as an anti-inflammatory agent. The presence of a pyrrolidine-2,5-diones fragment increases the indicators of the biological activity of the synthesized compounds in comparison with just acridine derivatives. |
| doi_str_mv | 10.33609/2708-129X.87.05.2021.38-52 |
| first_indexed | 2025-09-24T17:43:39Z |
| format | Article |
| fulltext |
38 ISSN 2708-129X. Укр. хім. журн., 2020
УДК 547.835: 547.831. doi: 10.33609/2708-129X.87.05.2021.38-52
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF
BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko*, O.K. Farat, V.I. Markov
Ukrainian State University of Chemical Technology, 49005 Dnipro, Ukraine
*е-mail: svetlanavarenichenko@gmail.com
To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-
hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-
1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile,
(3S/4R)-3-[(3R/4S)-9-chloroacridine(quinoline)-4-yl]-1-N-aryl)pyrrolidine-2,5-diones.
Methods: Organic synthesis, spectral methods, and molecular docking. We investigated by
molecular docking the potential biological activity of previously synthesized compounds
containing acridine and pyrrolidine-2,5-diones fragments in their structure, as well as syn-
thesized in this work N’-hydroxy-1,2,3,4,5,6,7,8-octahydroacridine-4-carboximidamide.
Based on the literature data, 3 directions of searching for the biological activity of the synthe-
sized compounds have been chosen: cholinesterase inhibitors, anti-inflammatory, and anti-
convulsant agents. As inhibitors of acetylcholinesterase and butylcholinesterase, substances
with good binding free energy and hydrogen bonds with the desired amino acid residues
of the Glu-His-Ser triad have been found among the tested compounds. The indicators of
synthesized products have exceeded the literature data. The docking data for anti-inflam-
matory activity has revealed compounds with values above the docking data of the reference
drugs - celecoxib and indomethacin. The compounds tested have shown moderate activity as
anticonvulsant agents. 3-(7-bromo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-1-(3-nitrophe-
nyl)pyrrolidine-2,5-dione is potentially promising as an acetylcholinesterase inhibitor due
to its high binding free energy (-13.7 kcal/mol) and hydrogen bonds with two amino acid
residues Ser200, His440. Compound (4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-dioxopyrro-
lidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile has proved to be the best as an
anti-inflammatory agent. The presence of a pyrrolidine-2,5-diones fragment increases the
indicators of the biological activity of the synthesized compounds in comparison with just
acridine derivatives.
Keywords: 9-chloroacridine(quinoline)-N-aryl)pyrrolidine-2,5-diones, docking studies,
cholinesterase inhibitors, anti-inflammatory activity, anticonvulsant activity.
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
39https://ucj.org.ua
UCJ № 5 / Vol. 87
INTRODUCTION. In recent years, more
and more information has appeared on the syn-
thesis, structure, pharmacological properties,
and use in the medical practice of compounds
containing an acridine (quinoline) fragment in
their structure [1–2]. Such derivatives have a
wide spectrum of therapeutic action causing
an increased interest in such structures.
Derivatives of 2,5-pyrolidin-ones are also
known for their biological activity, anti-can-
cer [3], antinociceptive [4], antibacterial [5],
anti-tubercular [6], anti-inflammatory [7], and
neuroprotective agents [8]. Pyrrolidine-2,5-di-
one and its 1,3 substituted derivatives have ap-
peared as the predecessor for pharmacological
activity [9]. In this regard, an urgent task in the
field of chemistry of heterocyclic compounds
is the development of methods for the synthe-
sis of new substances containing the acridine
ring and pyrrolidine-2,5-dione in their com-
position, in order to search for new biological-
ly active substances on their basis.
Previously, we developed a new method
for the synthesis of hydroacridine derivatives
as a result of rearrangement of geminal azines
and oxazines under the action of the Vilsmei-
er-Haack reagent [10, 11] and studied the reac-
tivity of the rearrangement products [12, 13].
Chloracridines are obtained in one stage with
a quantitative yield under the action of a three-
fold excess of the formylating agent [11]. To
obtain bromderivatives of acridines 2b,c, the
excess must be doubled. Under the action of
an equimolar amount of PBr3 / DMF complex,
acridone derivatives 3a,b (Scheme 1).
During the functionalization of tetrahy-
droacridine by N-arylmaleimides under
non-catalytic conditions, succinimides 1–6
have been obtained [13] containing acridine
and pyrrolidine fragments in their structure.
Considering both the practical importance of
hydroacridines 2a-c and the new method of
direct transformation of the sp3 С–Н bond of
these compounds, the number of examples of
effective functionalization has been expanded,
and products 7–12 have been synthesized [14]
(Scheme 2).
To compare the indicators of biological ac-
tivity, acridine derivative 13 without a pyrroli-
dine fragment has been also synthesized by the
interaction of 1,2,3,4,5,6,7,8-octahydroacri-
dine-4-carbonitrile with hydroxylamine
(Scheme 3).
Scheme 1: 1: а – R = H; b – R = CH3; 2: a – R = CH3, X = Cl; b – R = H, X = Br, c – R = CH3, X = Br;
3: a – R = H, b – R = CH3
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
40 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
Scheme 2
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
41https://ucj.org.ua
UCJ № 5 / Vol. 87
Scheme 3
EXPERIMENT AND DISCUSSION OF THE
RESULTS. Molecular Docking Studies Acetyl-
cholinesterase (AChE). For acetylcholinester-
ase inhibitors, binding to certain amino acids
is important. Important amino acid residues
in the esterase site are glutamate (Glu), histi-
dine (His), and serine (Ser). According to [15],
the aromatic cluster Trp286, Tyr72, Tyr124,
Phe338 enhances the binding of ligands to
AChE. Phenolic side residues Tyr341, Tyr124,
and Tyr337 are directly involved in controlling
the movement of substrates and inhibitors to
the active site [16]. All the synthesized com-
pounds 1–13 were subjected to docking study.
For the receptor-oriented flexible screening,
we used the Autodock 4 and the AutoDock
Vina software packages [17]. Additionally, mo-
lecular modeling studies were performed in
order to rationalize the biological activities of
the proposed compounds. Test data for com-
pounds 1–13 as acetylcholinesterase inhibitors
are shown in Table 1.
Binding to only one of the three required
amino acid residues has been found for com-
pounds 4 (His440) and 8 (Ser122). Com-
pounds 5, 7, 10 and 12 have already demon-
strated the blocking of two amino acid residues
Ser200 (122) and His440. However, compound
10 has a higher binding free energy (-13.7 kcal/
mol) (Fig. 1).
T a b l e 1
Binding free energy calculation results for synthesized compounds 1-13 bound with 1acl
Compound
Binding
free energy
(kcal/mol)
H-bonds
Amide-Pi
Stacked,Pi-Pi
Stacked, Pi-Pi
T-shaped
Compound
Binding
free energy
(kcal/mol)
H-bonds
Amide-Pi
Stacked,Pi-Pi
Stacked, Pi-Pi
T-shaped
1 -12.2 - Trp84 8 -13.1 Ser122 Tyr334,
Tyr121
2 -11.8 Tyr334 Trp84,
Phe331 9 -13.5 Tyr121 Tyr279
3 -12.9
Tyr121,
Phe288,
Arg289
Trp84 10 -13.7
Gly123,
Tyr121,
His440,
Ser200
Tyr121,
Trp279
4 -11.2
Gly119,
His440,
Tyr121
Tyr121,
Trp279 11 -13.4 Tyr121
Tyr121,
Tyr334,
Trp279
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
42 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
Compound
Binding
free energy
(kcal/mol)
H-bonds
Amide-Pi
Stacked,Pi-Pi
Stacked, Pi-Pi
T-shaped
Compound
Binding
free energy
(kcal/mol)
H-bonds
Amide-Pi
Stacked,Pi-Pi
Stacked, Pi-Pi
T-shaped
5 -12.4
His440,
Tyr121,
Ser200
Trp84,
Trp279 12 -12.0
Gly119,
Tyr121,
His440,
Ser200
-
6 -12.4 Tyr121
Phe331,
Tyr334,
Phe330,
Tyr121
13 -9.7 Asp72 Trp84,
Phe330
7 -12.8
Tyr121,
Ser122,
His440
Trp84,
Tyr334,
Gly117
Fig. 1. Binding model of compound 10 for the best docked pose in the active site of AChE (model of
the complex obtained by molecular docking, hydrogen bonds are shown in green dashed lines).
T a b l e 1
Based on the results obtained, the presence
of a pyrrolidine-2,5-dione fragment in com-
pounds 1–12 promotes an increase in activity
in comparison with acridine derivative 13.
Molecular Docking Studies butyrylcholineste
rase (BChE). Butylcholinesterase, like other me
tabolic serine hydrolases, belongs to the family
of α/β-hydrolases, and binding to the amino acid
residues of the Glu-His-Ser triad is important
for their inhibitors. Amino acid residues Asp70,
Tyr332, especially Asp70, play an essential role
in the binding and transport of substrates and
inhibitors to the active site of BChE [18]. Table 2
shows the binding free energy and the presence
of hydrogen bonds of compounds 1–13 with the
active site of butylcholinesterase.
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
43https://ucj.org.ua
UCJ № 5 / Vol. 87
The best binding free energy has been
demonstrated by compound 8 as well as the
presence of interaction with the amino acid
residue His438 (Fig. 2). Compound 3, with
lower binding free energy but with the pre
sence of interaction with two amino acid res-
idues Clu197, Ser287, or compound 5, with
good binding free energy and the presence
of a hydrogen bond with Asp70, may also be
promising (Fig. 3).
T a b l e 2
Binding free energy calculation results for synthesized compounds 1-13 bound with 1p0p
Compound
Binding
free energy
(kcal/mol)
H-bonds π-anion/
π-cation Compound
Binding
free energy
(kcal/mol)
H-bonds π-anion/
π-cation
1 -10.7 - 8 -12.4 His438,
Gly116,
2 -10.9 Tyr128,
Pro285 Asp70 9 -10.4 His438
3 -11.4 Glu197,
Ser287 His438, Asp70 10 -11.2 Tyr128
4 -12.3 - Asp70 11 -10.6 - Asp70,His438
5 -12.3 Asp70 Glu197,His438 12 -12.6 Tyr82,
Tyr440
6 -12.6 - Asp70 13 -8.8 -
7 -10.3 -
Fig. 2. Binding model of compound 8 for the best docked pose in the active site of BChE (model of the
complex obtained by molecular docking, hydrogen bonds are shown in green dashed lines).
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
44 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
Fig. 3. Binding model of compound 5 for the best docked pose in the active site of BChE (model of the
complex obtained by molecular docking, hydrogen bonds are shown in green dashed lines).
Our results exceeded the literature data [19],
for which the binding free energy was within
(-4.43696)-(-6.67689) kcal/mol, and there was
an interaction with the side chain and back-
bone donor of residues Gly118, Ser122.
Molecular Docking Studies of compounds
1–13 as anti-inflammatory agents.
Inflammation is a defense mechanism in the
body that is triggered by various stimulatory
factors including radiation, heat, microbial in-
fections and is often associated with tissue dam-
age. Arachidonic acid metabolism plays a vital
role in the mechanism of inflammation. Ara-
chidonic acid is metabolized to thromboxane
A2 and prostaglandins by the cyclooxygenase-2
(COX-2) cascade or by the 5-lipoxygenase (5-
LOX) pathway with suitable stimulation of the
neutrophil. Inhibition of proteases can help fight
several diseases, including inflammation. This is
more relevant than ever during the fight against
COVID-19, since overcoming inflammatory
processes plays a key role in its treatment. Some
ketoester derivatives of succinimides and acri-
dines [20] exhibit strong anti-inflammatory ac-
tivity. The good test results for such succinim-
ides have prompted us to test the succinimide
derivatives we synthesized for the presence of
anti-inflammatory activity. The results of mo-
lecular docking of compounds 1–13 as anti-in-
flammatory agents are presented in Table 3.
The results obtained agree with the litera-
ture data of similar compounds, which were
tested in vitro showing binding free energy of
-6.60-(-6.95) kcal/mol [9].
All synthesized compounds are docked in
the COX-2 binding pockets. In COX-2, an ad-
ditional secondary side pocket contains an
Arg120/Tyr355 residue. This additional pocket
is bordered by a small Val523 residue. In ad-
dition, COX-2 also contains the conservative
Arg513. Other residues important for COX-2
selectivity are His90, Gln192, Leu352, and
Ser353. The docking data have been compared
with the docking data of the reference drugs –
celecoxib and indomethacin. Interaction analy-
sis of celecoxib, a COX-2 selective inhibitor, has
shown that it interacts with amino acid residues
(His90, Leu352, Ser353, and Arg513) present in
the COX-2 additional pocket. Likewise, indo-
methacin interacts with Ser353 and Tyr355.
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
45https://ucj.org.ua
UCJ № 5 / Vol. 87
T a b l e 3
Binding free energy calculation results for synthesized compounds 1–13 bound with 1CX2
Compound
Binding
free energy
(kcal/mol)
H-bonds Amide-Pi
Stacked Compound
Binding
free energy
(kcal/mol)
H-bonds Amide-Pi
Stacked
1 -7.6 Asn581 - 8 -9.0 Gln192,
Asp515 Gln350
2 -7.8 - Asp515 9 -8.4 - -
3 -7.9 His351,
Gln192 - 10 -9.5 Gln192,
Asp515 Gln350
4 -9.0 Asn581 - 11 -9.0 Gln192 Asp515
5 -9.7 Gln192 - 12 -8.1 Tyr355,
Asn581 -
6 -8.5 Gln192 - 13 -7.5 Met522 -
7 -8.3 Gln192,
Asn581 -
Compounds 3, 5, 6, 7, 8, 10–12 have exhibited binding free energy in the range of -7.9 to -9.7
kcal/mol; and they bind to the amino acid residue Gln192. The energy index is better for com-
pound 5, and it has a hydrogen bond with the amino acid Gln192 as well (Fig. 4). Compound 10
with good binding free energy and a hydrogen bond with the amino acid residue Gln192 is also
promising (Fig. 5).
Fig. 4. Binding model of the most active compound 5 with 1CX2 (model of the complex obtained by
molecular docking, hydrogen bonds are shown in green dashed lines).
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
46 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
Fig. 5. Binding model of compound 10 for the best docked pose in the active site of 1CX2 (model of the
complex obtained by molecular docking, hydrogen bonds are shown in green dashed lines).
Molecular Docking Studies of compounds
1–13 as anticonvulsant agents.
Many succinimide derivatives exhibit high
anticonvulsant activity [21]. Phenytoin, which
forms hydrogen bonds with amino acid resi-
dues Asp415 and Ser403, has been chosen as
a reference drug for testing antiepileptic ac-
tivity. Of the nine compounds tested, six have
formed a hydrogen bond with the Ser403 ami-
no acid residue of the active site 1OHY (Ta-
ble 4). However, according to the binding free
energy, compound 3 will be the most promi
sing for further testing (Fig. 6).
T a b l e 4
Binding free energy calculation results for synthesized compounds 1–3, 7–12 bound with
1OHY
Compound 1 2 3 7 8 9 10 11 12
Binding
free energy
(kcal/mol)
-5.2 -4.0 -5.9 -3.4 -4.5 -4.6 -2.4 -5.5 -2.8
H-bonds Ser403 Arg404 Pro399,
Ser403
Arg222,
Ser403
Lys442,
Arg404 Ser403 Lys442,
Ser403
Arg404,
Ser403 -
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
47https://ucj.org.ua
UCJ № 5 / Vol. 87
Fig. 6. Binding model of compound 3 for the best docked pose in the active site 1OHY (model of the
complex obtained by molecular docking, hydrogen bonds are shown in green dashed lines).
Ligand and Receptor Structure Preparation.
Ligand structures were prepared using MGL
Tools 1.5.6 software (MGL Tools 1.5.6 (Scrips
Research Institute) http://mgltools.scripps.
edu/) and Vega ZZ [22]. Receptor-based vir-
tual screening was used to analyze the binding
of the compound collection. Docking was per-
formed at ATP-binding sites of protein data-
bank AChe (database code PDB: 1acl – 2.80Å),
BChE (database code PDB: 1p0p – 2.30Å),
COX-2 (database code PDB: 1CX2 – 3.00Å),
anticonvulsant activity (database code PDB:
1OHY – 2.80Å), using Autodock 4.2.6. The
structures taken for docking were kinase do-
mains in an active state. Water molecules, ions
and ligands were removed from the PDB file.
The receptor structures were prepared using
MGL Tools and AutoGrid. Hydrogen atoms
were removed from nonpolar atoms. The in-
coming formats of receptor and ligands data
were converted into PDBQT-format with
Vega ZZ in AUTODOCK force field.
Flexible docking. Autodock 4.2.6 programs
package was used for the receptor-based flexi-
ble docking [17].
Visual analysis.
A visual analysis of the molecular docking
results (interaction of compounds with the
amino acid residues of AChE, BChE, COX-2
and GABA transaminase active-binding site)
was carried out using Discovery Studio Vi
sualizer 4.0 (http://accelrys.com/).
Chemical synthesis.
1Н and 13C NMR spectrum was record-
ed on a Bruker Avance II 400 spectrometer
(400 MHz,) in DMSO-d6 using TMS as an in-
ternal standard. Mass spectra (EI ionization,
70 eV) was recorded on a МХ1321 apparatus
with direct sample injection at 200 °С ioniza-
tion chamber temperature. Elemental anal-
ysis was performed on a LECO CHN-900
Elemental analyzer. Melting points were de-
termined on an Electrothermal 9100 Digital
apparatus. The reaction progress and purity of
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
48 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
compounds were monitored by TLC on Sili-
cagel gel 60 F254 (Merck) plates, eluent CHCl3−
i-PrOH (10:1), visualization in the iodine
chamber. Compound 1а was obtained accord-
ing to the literature method [23].
4’-Methylspiro[3,1-benzoxazine-2,1’-cy-
clohexan]-4(1H)-one (1b): The compound is
obtained by literary methods [23]. The 1H and
13C NMR spectra for compound are presented
for the predominant isomer. Yield: 70 %. M. p.:
150–152 °C. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 7.46 (1Н, s, NH), 7.29-7.37 (2H, m,
H-Ar), 6.70-6.73 (2H, m, H-Ar), 2.13-2.16 (1H,
m, CH2), 2.04-2.06 (1H, m, CH2), 1.64-1.66
(1H, m, CH), 1.47-1.54 (4H, m, 2CH2), 1.24-
1.27 (2H, m, CH2), 0.90 (3H, m, CH3).
13C NMR
(100 MHz, DMSO-d6), δ, ppm: 162.5, 147.1,
135.4, 129.1, 128.2, 117.7, 115.1, 89.0, 34.6, 30.8,
29.5, 21.6. MS (EI), m/z (Iотн, %): 231 [M]+ (16).
Anal. calcd. for C14H17NO2: C, 72.70; H, 7.41; N,
6.06. Found: C, 72.83; H, 7.65; N, 6.26.
9-Chloro-2-methyl-1,2,3,4-tetrahydroacri-
dine (2a): Compound 1b (2.17 g, 0.01 mol) was
added to DMF (1 mL). The suspension formed
was treated with the ice-cold Vilsmeier reagent
obtained from DMF (6 mL) and POCl3 (2.75
mL, 0.03 mol) under ice-cooling. A yellow sol-
id precipitated abundantly within 10-15 min.
After 0.5 h, the reaction mixture was poured on
ice and treated with aq ammonia, the obtained
solid was filtered off and dried to give acridine
2a. Yield: 75 %. M. p.: 58–60 °C. 1H NMR (400
MHz, DMSO-d6), δ, ppm: 8.07-8.05 (1Н, d,
J=8.3 Hz, H-Ar), 7.89-7.91 (1H, d, J=8.3 Hz,
H-Ar), 7.69-7.73 (1H, t, J=7.3 Hz, H-Ar), 7.57-
7.61 (1H, t, J=7.3 Hz, H-Ar), 2.99-3.07 (3H, m,
CH2+CH), 2.32-2.39 (1H, m, CH2), 1.89-1.92
(2H, m, CH2), 1.42-1.46 (1H, m, CH), 1.06-
1.08 (3H, d, J=6.4 Hz, CH3). 13C NMR (100
MHz, DMSO-d6), δ, ppm: 158.9, 146.0, 139.7,
129.4, 128.4, 128.1, 126.8, 124.3, 123.0, 35.2,
33.0, 29.9, 28.1, 21.4. MS (EI), m/z (Iотн, %): 233
[М(37Cl)+H]+ (32), 231 [М(35Cl)+Н]+ (100).
Anal. calcd. for C14H14ClN: C, 72.57; H, 6.09;
N, 6.04. Found: C, 72.39; H, 6.15; N, 6.26.
9-Bromo-1,2,3,4-tetrahydroacridine (2b):
The Vilsmeier reagent was prepared from PBr3
(5.7 mL, 0.06 mol) and DMF (4,6 mL, 0.06 mol)
with ice cooling. Chloroform in a volume of 15
ml is used as a solvent. Compound 1a (2.17 g,
0.01 mol) was added to the Vilsmeier reagent.
After 2 h, the reaction mixture was poured on
ice and treated with aq ammonia, the obtained
solid was filtered off and dried to give acri-
dine 2b. Yield: 60 %. M. p.: 62–64 °C. 1H NMR
(400 MHz, DMSO-d6), δ, ppm: 8.11-8.08 (1Н,
d, J=8.3 Hz, H-Ar), 7.90-7.92 (1H, d, J=8.3,
H-Ar), 7.75-7.77 (1H, t, J=7.3 Hz, H-Ar), 7.59-
7.61 (1H, t, J=7.3 Hz, H-Ar), 3.10-3.12 (2H, m,
CH2), 2.39-2.41 (2H, m, CH2), 1.89-1.96 (4H,
m, 2CH2). MS (FAB), m/z (Iотн, %): 262 [М+Н
(81Br)]+ (90), 264 [М+Н (79Br)]+ (100). Anal.
calcd. for C13H12BrN: C, 59.56; H, 4.61; N, 5.34.
Found: C, 59.69; H, 4.55; N, 5.46.
9-Bromo-2-methyl-1,2,3,4-tetrahydroacri-
dine (2c): The synthesis procedure from com-
pound 1b is similar to the preparation of 2b.
Yield: 58 %. M. p.: 65–67 °C. 1H NMR (400
MHz, DMSO-d6), δ, ppm: 8.10-8.07 (1Н,
d, J=8.3 Hz, H-Ar), 7.92-7.90 (1H, d, J=8.3,
H-Ar), 7.71-7.75 (1H, t, J=7.3 Hz, H-Ar), 7.61-
7.65 (1H, t, J=7.3 Hz, H-Ar), 3.07-3.10 (2H, m,
CH2), 2.41-2.45 (2H, m, CH2), 1.93-1.96 (2H,
m, CH2), 1.46-1.51 (1H, m, CH), 1.11-1.13
(3H, d, J=6.6 Hz, CH3). MS (FAB), m/z (Iотн,
%): 275 [М+Н (81Br)]+ (90), 277 [М+Н (79Br)]+
(100). Anal. calcd. for C14H14BrN: C, 60.89; H,
5.11; N, 5.07. Found: C, 60.67; H, 5.25; N, 5.26.
1,3,4,10-Tetrahydroacridin-9(2H)-one (3a):
The Vilsmeier reagent was prepared from PBr3
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
49https://ucj.org.ua
UCJ № 5 / Vol. 87
(2.9 mL, 0.03 mol) and DMF (4,6 mL, 0.06
mol) with ice cooling. Chloroform in a volume
of 15 ml is used as a solvent. Compound 1a
(2.17 g, 0.01 mol) was added to the Vilsmei-
er reagent. After 2 h, the reaction mixture was
poured on ice and treated with aq ammonia,
the obtained solid was filtered off and dried to
give acridine 3а, as colorless crystals, mp 358–
360 C (Ref. [24]: mp 355–358 C). Spectral data
for 3а (FTIR, NMR) were identical to the re-
ported data [25].
2-Methyl-1,3,4,10-tetrahydroacridin-9(2H)-
one (3b): The synthesis procedure from com-
pound 1b is similar to the preparation of 3a.
Yield: 64 %. M. p.: 352–354 °C. 1H NMR (400
MHz, DMSO-d6), δ, ppm: 11.24 (1Н, s, NH),
8.05-8.03 (1H, d, J=7.8 Hz, H-Ar), 7.52-7.56
(1H, t, J=7.8, H-Ar), 7.43-7.45 (1H, t, J=8.3
Hz, H-Ar), 7.18-7.22 (1H, t, J=7.3 Hz, CH-Ar),
2.69-2.73 (3H, m, CH2+CH), 1.85-1.89 (2H, m,
CH2), 1.70-1.73 (1H, m, CH2), 1.34-1.37 (1H,
m, CH), 1.04-1.06 (3H, d, J=6.4 Hz, CH3). 13C
NMR (100 MHz, DMSO-d6), δ, ppm: 175.9,
146.5, 139.2, 130.9, 124.8, 123.2, 121.9, 117.3,
115.1, 30.2, 29.5, 28.0, 27.1 21.6. MS (EI),
m/z (Iотн, %): 213 [M]+ (35). Anal. calcd. for
C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found:
C, 78.58; H, 6.35; N, 7.26.
N’-Hydroxy-1,2,3,4,5,6,7,8-octahydroacri-
dine-4-carboximidamide (13): A portion of
1,2,3,4,5,6,7,8-octahydroacridine-4-carboni-
trile [10] (1 g, 4.7 mmol) and hydroxylamine
гидрохлорид (0.66 g, 10.2 mmol) was dis-
solved in 5 ml of DMSO. An equimolar amount
of alcoholic solution of sodium methylate rel-
ative to hydroxylamine hydrochloride is then
added to the solution as a catalyst. The reaction
mixture was heated at 130 °C for 5 hours. Then
the solution is poured into 20 ml of water. The
precipitate formed is filtered off and purified by
crystallization from isopropyl alcohol. Yield:
64 %. M. p.: 162–164 °C. 1H NMR (400 MHz,
DMSO-d6), δ, ppm: 8.89 (1Н, s, OH), 7.08 (1H,
s, H-Ar), 5.27 (2H, s, NH2), 3.48 (1H, t, J=4.9
Hz, CH), 2.69-2.63 (6H, m, 3CH2), 1.77-1.70
(8H, m, 4CH2). MS (EI), m/z (Iотн, %): 245 [M]+
(100). Anal. calcd. for C14H19N3O: C, 68.54;
H, 7.81; N, 17.13. Found: C, 68.29; H, 7.65; N,
17.26.
CONCLUSIONS.
Using molecular docking of the synthesized
compounds, products with high performance
have been found during the study. 3-(7-Bro-
mo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-
1-(3-nitrophenyl)pyrrolidine-2,5-dione (10) is
potentially promising as an acetylcholinester-
ase inhibitor due to its high binding free energy
(-13.7 kcal/mol) and hydrogen bonds with two
amino acid residues Ser200, His440. Compound
(4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-di-
oxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahy-
droacridine-4-carbonitrile (5) has proved to
be the best as an anti-inflammatory agent.
This allows them to be recommended for fur-
ther research as potential acetylcholinester-
ase inhibitors and anti-inflammatory agents.
N’-Hydroxy-1,2,3,4,5,6,7,8-octahydroacri-
dine-4-carboximidamide do not form hydro-
gen bonds with amino acid residues while re-
vealing moderate binding energies. Compound
13 differs from compounds 1–12 in that it does
not contain a pyrrolidine-2,5-dione hetero-
cycle and a nitrobenzene nucleus, which are
involved in the formation of additional hydro-
gen bonds with fragments of the correspond-
ing enzymes, as proved by molecular docking.
The data obtained lead us to the conclusion
that the presence of the pyrrolidine-2,5-diones
fragment enhances the biological activity of
acridine derivatives.
IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE(QUINOLINE) DERIVATIVES
50 ISSN 2708-129X. Укр. хім. журн., 2021
ORGANIC CHEMISTRY
The authors are grateful to the grant
for Young Scientists of Dnepropet
rovsk region 2020.
ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ
АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ
ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ)
М. В. Сметанін, С. В. Токарєва,
С. А. Варениченко*, О. К. Фарат,
В. І. Марков
Український державний хіміко-технологіч-
ний університет, Дніпро 49005, Україна
*е-mail: svetlanavarenichenko@gmail.com
Мета: Знайти біологічну активність се-
ред легкодоступних 2-[(4S,4’S/4R,4’R)-2’,5’-
діоксо-2,3,5,6,7,8-гексагідро-1H-спіро
[акридин-4,3’-пірролідин]-4’-іл]-N-арил-
ацетамідів, (4S/4R)-4-[(3R/3S)-1-(2-арил)-
2,5-діоксопірролідин-3-іл]-1,2,3,4,5,6, 7,8- ок-
тагідроакридин-4-карбонітрилів, (3S/4R)-
3-[(3R/4S)-9-хлоракридин(хінолін)-4-іл]-
1N-арил)піролідин-2,5-діонів. Методи: Ор
ганічний синтез, спектральні методи та
молекулярний докінг. Результати: За допо-
могою молекулярного докінгу ми досліди-
ли потенційну біологічну активність рані-
ше синтезованих сполук, що містять у своїй
структурі акридиновий та піролідин-2,5-ді-
оновий фрагменти, та синтезованого у цій
роботі N’-гідрокси-1,2,3,4,5,6,7,8-октагідро
акридин-4-карбоксаміду. На основі літера-
турних даних обрано 3 напрямки пошуку
біологічної активності серед синтезованих
сполук: інгібітори холінестераз, протиза-
пальні та протисудомні засоби. Як інгібітори
ацетилхолінестерази та бутилхолінестерази
серед досліджуваних сполук були знайдені
речовини з хорошими показниками енергії
зв’язування та водневих зв’язків із бажани-
ми амінокислотними залишками тріади Glu-
His-Ser. Показники синтезованих продуктів
перевищили літературні дані. Дані докінгу
протизапальної активності виявили сполу-
ки, показники яких перевищували дані до-
кінгу референтних препаратів – целекокси-
бу та індометацину. Випробувані сполуки
показали помірну активність як протисудо-
мні засоби. 3-(7-бром-9-хлор-1,2,3,4-тетра-
гідроакридин-4-іл)-1-(3-нітрофеніл)піролі-
дин-2,5-діон потенційно перспективний як
інгібітор ацетилхолінестерази завдяки його
показникам енергії зв’язування (-13,7 ккал/
моль) та водневим зв’язкам із двома залиш-
ками амінокислот Ser200, His440 Сполука
(4S/4R)-4-[(3R/3S)-1-(3-нітрофеніл)-2,5-ді-
оксопіролідин-3-іл]-1,2,3,4,5,6,7,8-октагід-
роакридин-4-карбонітрил виявилася кра-
щою у ролі протизапального засобу. Отри-
мані дані підводять нас до висновку, що при-
сутність піролідин-2,5-діонового фрагменту
посилює біологічну активність похідних
акридину.
Ключові слова: 9-хлоракридин(хінолін)-
N-арил)піролідин-2,5-діони, дослідження
стикування, інгібітори холінестерази, про-
тизапальна активність, протисудомна ак-
тивність.
N.V. Smetanin, S.V. Tokarieva, S.A. Varenichenko, O.K. Farat, V.I. Markov
51https://ucj.org.ua
UCJ № 5 / Vol. 87
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Стаття надійшла 30.06.2021.
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| language | English |
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| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-3122026-07-22T08:23:46Z IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) Smetanin , Nikolay Tokarieva, Sofia Varenichenko , Svetlana Farat , Oleg Markov, Victor 9-chloroacridine(quinoline)-N-aryl)pyrrolidine-2,5-diones, docking studies, cholinesterase inhibitors, anti-inflammatory activity, anticonvulsant activity. To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile, (3S/4R)-3-[(3R/4S)-9-chloroacridine(quinoline)-4-yl]-1-N-aryl)pyrrolidine-2,5-diones. Methods: Organic synthesis, spectral methods, and molecular docking. We investigated by molecular docking the potential biological activity of previously synthesized compounds containing acridine and pyrrolidine-2,5-diones fragments in their structure, as well as synthesized in this work N’-hydroxy-1,2,3,4,5,6,7,8-octahydroacridine-4-carboximidamide. Based on the literature data, 3 directions of searching for the biological activity of the synthesized compounds have been chosen: cholinesterase inhibitors, anti-inflammatory, and anticonvulsant agents. As inhibitors of acetylcholinesterase and butylcholinesterase, substances with good binding free energy and hydrogen bonds with the desired amino acid residues of the Glu-His-Ser triad have been found among the tested compounds. The indicators of synthesized products have exceeded the literature data. The docking data for anti-inflammatory activity has revealed compounds with values above the docking data of the reference drugs - celecoxib and indomethacin. The compounds tested have shown moderate activity as anticonvulsant agents. 3-(7-bromo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-1-(3-nitrophenyl)pyrrolidine-2,5-dione is potentially promising as an acetylcholinesterase inhibitor due to its high binding free energy (-13.7 kcal/mol) and hydrogen bonds with two amino acid residues Ser200, His440. Compound (4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile has proved to be the best as an anti-inflammatory agent. The presence of a pyrrolidine-2,5-diones fragment increases the indicators of the biological activity of the synthesized compounds in comparison with just acridine derivatives. V.I.Vernadsky Institute of General and Inorganic Chemistry 2021-06-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/312 10.33609/2708-129X.87.05.2021.38-52 Ukrainian Chemistry Journal; Vol. 87 No. 5 (2021): Ukrainian Chemistry Journal; 38-52 Украинский химический журнал; ##issue.vol## 87 ##issue.no## 5 (2021): Ukrainian Chemistry Journal; 38-52 Український хімічний журнал; Том 87 № 5 (2021): Український хімічний журнал; 38-52 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/312/171 Copyright (c) 2021 Nikolay Smetanin , Sofia Tokarieva, Svetlana Varenichenko , Oleg Farat , Victor Markov https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Smetanin , Nikolay Tokarieva, Sofia Varenichenko , Svetlana Farat , Oleg Markov, Victor ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title | ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title_alt | IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES |
| title_full | ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title_fullStr | ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title_full_unstemmed | ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title_short | ПРОГНОЗУВАННЯ IN SILICO БІОЛОГІЧНОЇ АКТИВНОСТІ ТА МОЛЕКУЛЯРНИЙ ДОКІНГ ПОХІДНИХ ГІДРОАКРИДИНІВ (ХІНОЛІНІВ) |
| title_sort | прогнозування in silico біологічної активності та молекулярний докінг похідних гідроакридинів (хінолінів) |
| topic_facet | 9-chloroacridine(quinoline)-N-aryl)pyrrolidine-2,5-diones docking studies cholinesterase inhibitors anti-inflammatory activity anticonvulsant activity. |
| url | https://ucj.org.ua/index.php/journal/article/view/312 |
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