4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази
A series of rhodanine derivatives bearing 4-(furan-2-yl)benzoic acid moiety were synthesized and studied as inhibitors of xanthine oxidase. This enzyme is a known target for allopurinol and febuxostat used in the treatment of hyperuricemia, gout, and other diseases. The synthesized compounds with di...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
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| author | Beiko, Alona V. Kobzar, Oleksandr L. Kachaeva, Maryna V. Pilyo, Stepan G. Kozachenko, Olexandr P. Vovk, Andriy I. |
| author_facet | Beiko, Alona V. Kobzar, Oleksandr L. Kachaeva, Maryna V. Pilyo, Stepan G. Kozachenko, Olexandr P. Vovk, Andriy I. |
| author_institution_txt_mv | [
{
"author": "Alona V. Beiko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr L. Kobzar",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Olexandr P. Kozachenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Andriy I. Vovk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Beiko, Alona V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | A series of rhodanine derivatives bearing 4-(furan-2-yl)benzoic acid moiety were synthesized and studied as inhibitors of xanthine oxidase. This enzyme is a known target for allopurinol and febuxostat used in the treatment of hyperuricemia, gout, and other diseases. The synthesized compounds with different substituents in position 3 of the rhodanine ring showed in vitro inhibitory activities towards xanthine oxidase in a low micromolar concentration range. The 4-(furan-2-yl)benzoic acid derivative with a fragment of N-unsubstituted rhodanine was found to have the lowest IC50 value which does not depend on the presence of albumin or Tween-80 under the assay conditions. According to kinetic data, the rhodanine-based 4-(furan-2-yl)benzoic acid was a mixed-type inhibitor with the same affinity for the free enzyme and the enzyme-substrate complex. Molecular docking and molecular dynamic studies were performed to elucidate the binding mode of this compound in the active site of xanthine oxidase  |
| doi_str_mv | 10.15407/bioorganica2023.02.031 |
| first_indexed | 2025-07-17T12:19:57Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
UDC 547.789.13+547.722+577.152.1
DOI: https://doi.org/10.15407/bioorganica2023.02.031
31
RESEARCH ARTICLE
Rhodanine-based 4-(furan-2-yl)benzoic acids as inhibitors
of xanthine oxidase
Alona V. Beiko, Oleksandr L. Kobzar, Maryna V. Kachaeva, Stepan G. Pilyo,
Olexandr P. Kozachenko, Andriy I. Vovk*
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A series of rhodanine derivatives bearing 4-(furan-2-yl)benzoic acid moiety were synthesized and studied as inhibitors of
xanthine oxidase. This enzyme is a known target for allopurinol and febuxostat used in the treatment of hyperuricemia, gout, and other
diseases. The synthesized compounds with different substituents in position 3 of the rhodanine ring showed in vitro inhibitory activities
towards xanthine oxidase in a low micromolar concentration range. The 4-(furan-2-yl)benzoic acid derivative with a fragment of N-
unsubstituted rhodanine was found to have the lowest IC50 value which does not depend on the presence of albumin or Tween-80 under the
assay conditions. According to kinetic data, the rhodanine-based 4-(furan-2-yl)benzoic acid was a mixed-type inhibitor with the same
affinity for the free enzyme and the enzyme-substrate complex. Molecular docking and molecular dynamic studies were performed to
elucidate the binding mode of this compound in the active site of xanthine oxidase.
Keywords: rhodanine; 4-(furan-2-yl)benzoic acid; xanthine oxidase; inhibition; molecular docking; molecular dynamic.
Introduction
Rhodanine fragment is considered one of the key
structural motifs for the development of bioactive
heterocyclic compounds and drug discovery [1]. Rhodanine
derivatives exhibit antibacterial, antiviral, and other
activities [2, 3]. Many studies have confirmed the potential
of rhodanines in the treatment of various types of cancer [4,
5]. The compounds of this class are known inhibitors of
cyclooxygenases [6], α-amylase [7], aldose reductase [8],
glutathione S-transferases [9], and other enzymes. Despite
belonging to pan-assay interference structures (PAINS)
[10], the bioactivity of rhodanines and their 5-ylidene
derivatives can be exploited in a useful way for certain
targets [11]. The undesirable activity of such compounds
can depend on how PAINS fragments are incorporated in
larger designed molecules [12].
Received:
Revised:
Accepted:
Published online:
04.09.2023
20.09.2023
31.10.2023
30.12.2023
Corresponding author. Tel.: +380-44-558-5388;
e-mail: vovk@bpci.kiev.ua (A.I. Vovk)
ORCID: 0000-0001-6167-076X
Xanthine oxidase (EC 1.17.3.2; XO) is an iron-sulfur-
molybdenum flavoprotein, widely distributed in human
tissues. This enzyme catalyzes the oxidative conversion of
hypoxanthine and xanthine to uric acid with a reduction of
molecular oxygen to superoxide. The excessive formation
of uric acid and reactive oxygen species can lead to
hyperuricemia, gout, inflammation, and other diseases. In
this connection, XO is a therapeutic target for allopurinol
and febuxostat which are used as drugs to prevent unwanted
effects caused by the production of uric acid. There is also
significant interest in searching for new potent and safer
XO inhibitors such as non-purine heterocyclic and
other compounds [13]. Among them, the derivatives of
1,3-selenazole, 1,3-thiazole, imidazole, pyrazole, isoxazole,
pyrimidine, and quinolone have been tested as XO
inhibitors [14, 15].
Previously, the compounds with the furanyl methylidene
rhodanine fragment were demonstrated to be potential
antiviral and antibacterial agents [16, 17, 18]. Besides this,
they also act as inhibitors of apoptosis signal-regulating
kinase 1 [19], anthrax lethal factor [20], bacterial RNA
polymerase [21], and tau protein aggregation [22]. In the
present study, the rhodanine derivatives bearing 4-(furan-2-
yl)benzoic acid moiety were studied in vitro and in silico as
inhibitors of xanthine oxidase. It is known that the presence
of a carboxylic acid functional group or its mimetic in the
© Beiko A.V. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
32
structure of an XO inhibitor can significantly increase its
affinity to the enzyme [14, 23, 24].
Results and Discussion
Compounds 3a-m, 4a,b (Scheme 1) were synthesized via
a Knoevenagel condensation of rhodanines 1 with 4-(5-
formylfuran-2-yl)benzoic acid (2a) or 5-phenylfuran-2-
carbaldehyde (2b). For the synthesis of compounds 3a-i, a
solution of rhodanine or its derivative in acetic acid in the
presence of 2-aminoethanol was added to a solution of
aldehyde 2a or 2b. In the case of compounds 3j-m, sodium
acetate was added instead of 2-aminoethanol. The products
were obtained in moderate to good yield. The structures of
the synthesized compounds were confirmed by data of 1H-
and 13C-NMR spectroscopy and mass spectrometry.
According to chemical shifts of the methine proton which
were observed as singlets in the range of 7.46 to 7.86 ppm,
the obtained compounds appeared to be in the form of
Z-isomer [25]. In addition, the Knoevenagel reaction of
aromatic aldehydes and 4-thiazolidinones is characterized
by the formation of 5-Z-arylidene derivatives [26, 27].
The inhibition studies were carried out in sodium-
phosphate buffer (pH 7.4) using xanthine oxidase from
bovine milk, which has 90% amino acid sequence identity
to the enzyme from the human liver. The IC50 values shown
S
N
O
S
R
O
OHO
O
O
HO
O
S
N
S
O
R
O
S
N
S
O
R
1
2a
2b
3a-m
4a,b
3a R = H
3b R = Me
3c R = Et
3d R = i-Pr
3e R =
Me
OMe
OMe
H
N
O OH3f R =
3g R =
3h R =
3i R =
3j R =
4a R = Me
4b R = Et
3k R = (CH2)2COOH
3l R = (CH2)3COOH
3m R = (CH2)5COOHOMe
O
O
a
b
Scheme 1. Synthesis of rhodanine derivatives 3a-m and 4a,b. Reagents and conditions: a) i, NH2(CH2)2OH or CH3COOK, CH3COOH, ii,
reflux, 2-5 h; b) i, NH2(CH2)2OH, CH3COOH, ii, reflux, 2 h.
Table 1. Rhodanine-based 4-(furan-2-yl)benzoic acids as xanthine oxidase inhibitors.*
Compounds IC50, µM
IC50, µM
(in the presence of BSA)
IC50, µM
(in the presence of Tween-80)
3a 0.025 ± 0.002 0.028 ± 0.005 0.025 ± 0.007
3b 0.41 ± 0.05 0.83 ± 0.26 0.76 ± 0.13
3c 0.33 ± 0.08 0.47 ± 0.10 0.62 ± 0.06
3d 0.075 ± 0.02 0.66 ± 0.17 0.79 ± 0.18
3e 0.13 ± 0.02 2.82 ± 0.56 2.25 ± 0.51
3f 0.097 ± 0.03 2.16 ± 0.50 2.59 ± 0.006
3g 0.067 ± 0.007 1.92 ± 0.38 1.55 ± 0.10
3h 0.49 ± 0.08 5.96 ± 1.63 8.87 ± 0.41
3i 0.6 ± 0.16 2.93 ± 0.63 2.03 ± 0.04
3j 0.54 ± 0.13 1.60 ± 0.23 0.89 ± 0.07
3k 0.37 ± 0.04 0.50 ± 0.09 0.38 ± 0.08
3l 0.39 ± 0.07 0.61 ± 0.08 0.52 ± 0.06
3m 0.09 ± 0.02 0.35 ± 0.04 0.06 ± 0.01
Febuxostat 0.0062 ± 0.0007 0.0075 ± 0.0001 0.0056 ± 0.0005
Allopurinol 3.5 ± 0.2 Not determined Not determined
*
IC50 values are averages of 2-3 experiments with standard deviation. The concentrations of the BSA and Tween-80 in experiments were 2 µM and 0.025
vol. %, respectively.
A.V. Beiko, O.L. Kobzar et al.
33
in Table 1 (i.e. the compound concentration that decreases
the activity of xanthine oxidase by 50%) were determined
from the dose-dependent curves.
According to the data obtained, the carboxylated
compounds 3a-m are low micromolar xanthine oxidase
inhibitors with IC50 values up to 0.60 µM. The comparison
of IC50 value of 4.5 µM for 4-(5-formylfuran-2-yl)benzoic
acid (2a) with IC50 values of compounds 3a-m indicates the
importance of the rhodanine scaffold in the structure of the
inhibitors. Control experiments demonstrated also the role
of a carboxyl group of the benzene ring in the inhibition of
xanthine oxidase. As an example, compounds 3b and 3c
have IC50 values of 0.41 μM and 0.33 μM, while
compounds 4a and 4b at a concentration of 10 μM inhibit
the enzyme activity by only 25% and 21%, respectively.
Among the rhodanine-containing derivatives of 4-(furan-
2yl)benzoic acid, compound 3a with N-unsubstituted
rhodanine part was found to have the best affinity to
xanthine oxidase with an IC50 value of 0.025 µM (Table 1,
Figure 1). Under the assay conditions, the inhibitory effect
of this compound was approximately 4 times less potent
and 140 times stronger as compared to febuxostat and
allopurinol, respectively. It should be noted that some
derivatives of the N-unsubstituted rhodanines possessed
inhibitory effects against Pim kinases [28], PI3Kγ [29], and
PRL-3 [30]. The 2-iminothiazolidin-4-one-based 4-(furan-
2-yl)benzoic acid, being structurally related to compound
3a, was previously described as a micromolar inhibitor of
CDK2 [31].
In the group of N-alkyl substituted derivatives, inhibitor
3d demonstrated a better effect towards xanthine oxidase
(IC50 of 0.075 µM) in comparison with compounds 3b and
3c. A similar result was observed for N-carboxyalkyl
substituted compounds 3k-m. However, N-benzyl
substituted derivatives 3e-g were found to be more effective
than N-phenylethyl or N-benzamide substituted rhodanine
derivatives 3h-j.
Figure 1. The dose-dependent curve of xanthine oxidase inhibition
by compound 3a.
To assess the other properties of designed compounds, an
in vitro study was conducted with bovine serum albumin
(BSA) or Tween-80. According to the obtained results
(Table 1), compounds 3a, 3k, and 3l turned out to bind
selectively to xanthine oxidase, showing IC50 values
practically the same as in the absence of BSA or Tween-80.
Along with this the compounds 3b, 3c, 3i, 3j, and 3m have
reduced inhibitory capacity at least two times compared to
control data without BSA, and compounds 3d-h showed
activities, which were lower by an order of magnitude or
more.
Lineweaver-Burk double reciprocal plots (Figure 2)
represent the kinetics of xanthine oxidase inhibition by most
active rhodanine derivative 3a. The changes of Km and Vmax
values in the presence of the compound are consistent with
a mixed type of inhibition. The calculated competitive (Ki)
and non-competitive (Ki') inhibition constants are 22.5 ± 3.8
nM and 25.7 ± 4.4 nM, respectively. This indicates that the
binding affinity of the inhibitor to the free enzyme is the
same as that to the enzyme-substrate complex.
Figure 2. Lineweaver-Burk plots of XO inhibition by compound
3a. Inhibitor concentrations were 0 (○), 10 nM (□), and 25 nM (∆).
To find out the molecular mechanism of the enzyme-
inhibitor complex formation, the most active compound 3a
was docked into the active site of xanthine oxidase by
AutoDock Vina software [32]. The possible ligand position
(Figure 3A) was characterized by the presence of salt bridge
interaction and several hydrogen bonds between the
carboxyl group and amino acid residues of Arg880,
Thr1010, and Glu1261 (via the HOH1457 water molecule).
Benzene ring provides π-π stacking interactions with
Phe914 and Phe1009. The furan moiety has π-alkyl
interactions with Leu648, Leu873, Leu1014, and Pro1076,
while the rhodanine part is surrounded by Leu648, Lys771,
and Phe1013.
The stability of the enzyme-inhibitor complex was
verified using molecular dynamic simulation. Analysis of
root mean square deviation (RMSD) of the protein
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
34
Figure 3. Binding modes of the compound 3a in the active site of XO suggested by molecular docking (A) and molecular dynamic (B)
studies. The red spheres represent the oxygen atoms of water molecules.
backbone is considered one of the approaches for the
examination of MD results. As can be seen from Figure 4A,
the RMSD of the model systems of XO-molybdopterin
cofactor (XO-Moco) and XO-Moco-3a are very similar
(average values ± standard deviation were 1.213 ± 0.141 Å
and 1.247 ± 0.155 Å, respectively), and both reached the
equilibration approximately after 10 ns of the simulation.
The root mean square fluctuation (RMSF) showed that the
bound ligand only slightly reduces the fluctuation of the
acid residues close to it (Figure 4B). In general, the RMSD
and RMSF analyses suggest that the compound does not
affect the secondary structure of the enzyme. Minor changes
in the presence of the ligand were observed in the radius of
gyration and the solvent-accessible surface area.
The binding mode of the compound at the active site of
XO obtained from the last frame of MD simulation is
shown in Figure 3B. The positions of the ligand and the
surrounding amino acid residues have been slightly changed
compared to the docking model (Figure 3A). The compound
became more open to solvent, and its rhodanine moiety was
turned away from the enzyme and can form a few hydrogen
bonds with water molecules. Although the rhodanine part is
located between Phe649 and Phe1013, the furan ring
remains sandwiched between Leu873 and Leu1014 as
revealed by the docking result. In addition, the carboxylic
group of the ligand possesses the salt bridge interaction
with Arg880 and hydrogen bonds with Thr1010.
The MMPBSA method was applied to determine the free
binding energy and enzyme-ligand interactions from
snapshots of conformations. The calculated values (± SD)
were -24.46 ± 3.35 kcal/mol (van der Waals energy),
-115.76 ± 8.66 kcal/mol (electrostatic energy), 103.10 ±
7.40 kcal/mol (electrostatic contribution to the solvation
free energy), -22.21 ± 1.44 kcal/mol (non-polar contribution
to the solvation free energy), 38.56 ± 2.07 kcal/mol
(dispersion energy), and -20.76 ± 6.26 kcal/mol (free
binding energy). As can be noted by considering these
results, the electrostatic energy contributes significantly to
the enzyme-ligand complex stabilization, while the
electrostatic contribution to the solvation free energy is
unfavorable.
The free energy was decomposed into residues located
within 4 Å of the ligand to understand their relative
contribution to the interactions with compound 3a. Unlike
the van der Waals, electrostatic and polar solvation
energies, the non-polar solvation component currently
cannot be decomposed by the MMPBSA method. As can be
seen from Table 2, the total energies of the ligand binding
with amino acid residues of Arg880, Phe1009, and Thr1010
Figure 4. Root mean square deviation (RMSD) of the enzyme backbone and root mean square fluctuation (RMSF) of Cα atoms of the
amino acid residues of the enzyme-Moco and enzyme-Moco-3a complexes obtained during production MD simulation.
A.V. Beiko, O.L. Kobzar et al.
35
Table 2. Per-residue free energy decomposition by MMPBSA method.
Residue
Value ± Std. dev., kcal/mol
van der Waals Electrostatic Polar Solvation TOTAL
Leu648 -1.06 ± 0.48 0.29 ± 0.36 0.51 ± 0.73 -0.26 ± 0.57
Phe649 -1.17 ± 0.6 -0.42 ± 0.23 0.87 ± 0.49 -0.73 ± 0.40
Leu873 -0.62 ± 0.19 1.18 ± 0.17 -0.92 ± 0.14 -0.36 ± 0.19
Ser876 -1.50 ± 0.24 -0.03 ± 1.10 2.39 ± 1.13 0.85 ± 0.66
Arg880 0.74 ± 0.82 -48.94 ± 1.94 33.53 ± 1.82 -14.67 ± 2.34
Phe914 -0.50 ± 0.26 -0.33 ± 0.79 0.27 ± 0.57 -0.56 ± 0.40
Phe1009 -1.85 ± 0.24 -4.71 ± 0.43 3.55 ± 0.33 -3.01 ± 0.51
Thr1010 0.77 ± 0.95 -12.41 ± 2.40 5.66 ± 1.00 -5.98 ± 1.16
Val1011 -1.17 ± 0.39 0.32 ± 0.36 0.10 ± 0.45 -0.74 ± 0.36
Phe1013 -0.50 ± 0.33 -0.43 ± 0.17 0.50± 0.22 -0.43 ± 0.25
Leu1014 -1.35 ± 0.38 -0.77 ± 0.18 0.84 ± 0.18 -1.28 ± 0.36
Ala1078 -0.40 ± 0.17 -1.07 ± 0.24 1.30 ± 0.27 -0.16 ± 0.20
Ala1079 -0.83 ± 0.34 -1.36 ± 0.66 1.29 ± 0.42 -0.90 ± 0.56
may be a key in stabilizing the enzyme-inhibitor complex.
Electrostatic interactions occurring between the amino acid
residues and benzoic acid moiety of the ligand make the
main contribution to these energies. At the same time, the
polar solvation energies were found to be unfavorable.
Conclusions
Rhodanine-based 4-(furan-2-yl)benzoic acids were
synthesized and studied as inhibitors of xanthine oxidase.
The dependence of the inhibitory activity on the structure of
the synthesized compounds was analyzed. Among the
compounds with low micromolar values of IC50, the most
active inhibitor was found to be 4-(furan-2-yl)benzoic acid
bearing N-unsubstituted rhodanine scaffold. The results of
kinetic studies suggested a mixed-type inhibition
mechanism. The molecular docking calculations indicated
the probable interactions responsible for the inhibitor
binding to the enzyme active site. The following molecular
dynamics simulation showed a slight change in the ligand
position, namely the rhodanine part, which became more
open to interacting with water molecules through hydrogen
bonds. The salt bridge between the carboxyl group and
Arg880 as well as hydrogen bonds with Thr1010 can
provide a major contribution to the enzyme-inhibitor
complex stabilization.
Experimental section
Synthesis
Commercially available chemical reagents and solvents
were purchased and used without purification. The TCL
method was applied to monitor the reaction progress. 1H
and 13C NMR spectra were recorded in DMSO-d6 on a
Varian Mercury spectrometer using the signal of residual
solvent protons as an internal standard. IR spectra were
recorded on a Vertex-70 spectrometer in KBr tablets. LC-
MS spectra were obtained using an Agilent 1200 Series
high-performance liquid chromatograph. Fisher-Johns
apparatus was used for the melting point determination.
Rhodanines (1) were synthesized using a known
procedure [33]. 4-(5-Formylfuran-2-yl)benzoic acid (2a)
was synthesized by the method described previously [34].
5-Phenylfuran-2-carbaldehyde (2b) was obtained as
described previously [35].
General method for the synthesis of compounds 3a-i
The solution of 0.005 mol of corresponding rhodanine 1
in 15-20 ml of acetic acid with 0.005 mol of ethanol-
amine was added to a hot solution of 0.005 mol of
4-(5-formylfuran-2-yl)benzoic acid 2a in 20-30 ml of acetic
acid. The reaction mixture was boiled for 2 h, then left at
20-25 oC for 12 h. The resulting precipitate was filtered,
washed with ethanol, and dried to give products 3a-i.
4-(5-Formyl-2-furyl)benzoic acid (2a)
Yield 88%, white solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1676, 1609, 1526, 1420, 1290, 1259, 1045, 963, 805,
768, 696, 549. 1H NMR (400 MHz, DMSO-d6) δ 13.02 (br
s, 1Н, COОH), 9.64 (s, 1Н, Ar), 8.04 (d, J = 8.4 Hz, 2Н,
Ar), 7.41-7.95 (m, 4Н, Ar, CH). 13C NMR (126 MHz,
DMSO-d6) 179.5, 170.6, 155.5, 153.0, 134.7, 132.2, 128.1,
127.8, 120.3, 107.5. LC-MS m/z 217 [M+H]+. Anal. calcd
for C12H8O4: C, 66.67; H, 3.73. Found: C, 66.61; H, 3.81.
4-{5-[(4-Oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-
2-furyl}benzoic acid (3a)
Yield 89%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 3132, 3024, 2845, 1681, 1603, 1550, 1421, 1312,
1281, 1209, 1190, 1071, 921, 793, 769, 673, 570, 547. 1H
NMR (400 MHz, DMSO-d6) δ 13.7 (br s, 1Н, NH), 12.91
(br s, 1Н, COОH), 8.04 (d, J = 8.4 Hz, 2Н, Ar), 7.87 (d, J =
8.4 Hz, 2Н, Ar), 7.46 (s, 1Н, CH), 7.39 (d, J = 3.6 Hz, 1Н,
Ar), 7.28 (d, J = 3.6 Hz, 1Н, Ar). 13C NMR (126 MHz,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
36
DMSO-d6) 191.6, 170.6, 164.1, 151.9, 147.7, 134.3, 130.6,
128.3, 125.8, 122.6, 122.3, 113.4, 109.7. LC-MS m/z 332
[M+H]+. Anal. calcd for C15H9NO4S2: C, 54.37; H, 2.74; N,
4.23. Found: C, 54.41; H, 2.69; N, 4.28.
4-{5-[(3-Methyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylide-
ne)methyl]-2-furyl}benzoic acid (3b)
Yield 87%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1710, 1609, 1424, 1287, 1127, 925, 850, 791, 768,
649, 551, 500. 1H NMR (400 MHz, DMSO-d6) δ 13.1 (br s,
1H, COOH ), 8.04 (d, J = 8 Hz, 2Н, Ar), 7.88 (d, J = 8 Hz,
2Н, Ar), 7.61 (s, 1H, CH), 7.41 (d, J = 3.6 Hz, 1Н, Ar), 7.32
(d, J = 3.6 Hz, 1Н, Ar), 2.50 (s, 3Н, СН3). 13C NMR (126
MHz, DMSO-d6) 188.2, 170.6, 161.5, 151.9, 147.2, 134.3,
130.6, 128.3, 125.8, 123.1, 122.3, 113.1, 109.8, 34.9. LC-
MS m/z 346 [M+H]+. Anal. calcd for C16H11NO4S2: C,
55.64; H, 3.21; N, 4.06. Found: C, 55.69; H, 3.71; N, 4.02.
4-{5-[(3-Ethyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylide-
ne)methyl]-2-furyl}benzoic acid (3c)
Yield 86%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1713, 1686, 1606, 1423, 1377, 1343, 1319, 1288,
1233, 1128, 769, 645, 514. 1H NMR (400 MHz, DMSO-d6)
δ 12.95 (br s, 1H, COOH), 8.08 (d, J = 8.4 Hz, 2Н, Ar),
7.93 (d, J = 8.4 Hz, 2Н, Ar), 7.67 (s, 1H, CH), 7.46 (d, J =
3.6 Hz, 1Н, Ar), 7.37 (d, J = 3.6 Hz, 1Н, Ar), 4.06 (q, J =
7.2 Hz, 2Н, СН2), 1.19 (t, J = 7.2 Hz, 3Н, СН3). 13C NMR
(126 MHz, DMSO-d6) 191.1, 170.6, 161.8, 151.9, 145.9,
134.3, 130.6, 128.3, 125.8, 124.7, 120.1, 113.0, 109.8, 43.0,
13.7. LC-MS m/z 360 [M+H]+. Anal. calcd for
C17H13NO4S2: C, 56.81; H, 3.65; N, 3.90. Found: C, 56.87;
H, 3.65; N, 3.97.
4-{5-[(3-Isopropyl-4-oxo-2-thioxo-1,3-thiazolidin-5-yli-
dene)methyl]-2-furyl}benzoic acid (3d)
Yield 89%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1709, 1676, 1610, 1287, 1261, 1232, 1114, 791, 768,
648. 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H,
COOH), 8.07 (d, J = 8 Hz, 2Н, Ar), 7.91 (d, J = 8 Hz, 2Н,
Ar), 7.57 (s, 1H, CH), 7.43 (d, J = 3.6 Hz, 1Н, Ar), 7.35 (d,
J = 3.6 Hz, 1Н, Ar), 5.26 (sep, J = 4 Hz, 1Н, СН), 1.48 (d, J
= 4 Hz, 6Н, 2СН3). 13C NMR (126 MHz, DMSO-d6) 188.9,
170.6, 162.0, 151.9, 149.5, 134.3, 130.6, 128.3, 125.8,
123.1, 118.8, 114.6, 109.7, 43.3, 20.1. LC-MS m/z 374
[M+H]+. Anal. calcd for C18H15NO4S2: C, 57.89; H, 4.05;
N, 3.75. Found: C, 57.82; H, 4.01; N, 3.77.
4-{5-[(3-Benzyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylide-
ne)methyl]-2-furyl}benzoic acid (3e)
Yield 86%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1714, 1675, 1610, 1424, 1345, 1321, 1293, 1279,
1182, 1036, 922, 788, 768, 693, 533. 1H NMR (400 MHz,
DMSO-d6) δ 13.1 (br s, 1H, COOH), 8.09 (d, J = 8 Hz, 2Н,
Ar), 7.95 (d, J = 8 Hz, 2Н, Ar), 7.73 (s, 1H, CH), 7.48 (d, J
= 3.6 Hz, 1Н, Ar), 7.41 (d, J = 3.6 Hz, 1Н, Ar), 7.23-7.33
(m, 5Н, Ar), 5.25 (s, 2H, CH2). 13C NMR (126 MHz,
DMSO-d6) 189,8, 170.6, 161.4, 151.9, 151.2, 140.2, 134.3,
131.8, 130.6, 130.2, 128.3, 127.8, 125.8, 123.1, 122.8,
112.9, 109.7, 52.3. LC-MS m/z 422 [M+H]+. Anal. calcd for
C22H15NO4S2: C, 62.69; H, 3.59; N, 3.32. Found: C, 62.61;
H, 3.52; N, 3.37.
4-(5-{[3-(4-Methylbenzyl)-4-oxo-2-thioxo-1,3-thiazoli-
din-5-ylidene]methyl}-2-furyl)benzoic acid (3f)
Yield 91%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1715, 1675, 1611, 1345, 1278, 1182, 1038, 920, 769,
586, 544. 1H NMR (400 MHz, DMSO-d6) δ 13.1 (br s, 1H,
COOH), 8.09 (d, J = 8.4 Hz, 2Н, Ar), 7.94 (d, J = 8.4 Hz,
2Н, Ar), 7.72 (s, 1H, CH), 7.47 (d, J = 4 Hz, 1Н, Ar), 7.40
(d, J = 4 Hz, 1Н, Ar), 7.22 (d, J = 7.6 Hz, 2Н, Ar), 7.14 (d,
J = 7.6 Hz, 2Н, Ar), 5.19 (s, 2H, CH2), 2.26 (s, 3H, CH3).
13C NMR (126 MHz, DMSO-d6) 189.8, 170.6, 161.4, 151.9,
151.2, 137.3, 134.3, 131.0, 130.6, 130.3, 128.3, 125.8,
123.1, 122.8, 112.3, 109.7, 52.3, 21.2. LC-MS m/z 436
[M+H]+. Anal. calcd for C23H17NO4S2: C, 63.43; H, 3.93;
N, 3.22. Found: C, 63.47; H, 3.96; N, 3.26.
4-(5-{[3-(4-Methoxybenzyl)-4-oxo-2-thioxo-1,3-thiazoli-
din-5-ylidene]methyl}-2-furyl)benzoic acid (3g)
Yield 86%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1689, 1604, 1512, 1423, 1287, 1250, 1191, 1032,
799, 770, 545, 525. 1H NMR (400 MHz, DMSO-d6) δ 13.08
(br s, 1H, COOH), 8.07 (d, J = 8 Hz, 2Н, Ar), 7.91 (d, J = 8
Hz, 2Н, Ar), 7.68 (s, 1H, CH), 7.44 (d, J = 3.6 Hz, 1Н, Ar),
7.37 (d, J = 3.6 Hz, 1Н, Ar), 7.29 (d, J = 8 Hz, 2Н, Ar),
6.89 (d, J = 8 Hz, 2Н, Ar), 5.15 (s, 2H, CH2), 3.71 (s, 3H,
OCH3). 13C NMR (126 MHz, DMSO-d6) 189.7, 170.6,
161.4, 159.7, 151.9, 151.2, 134.3, 133.2, 130.6, 128.3,
125.8, 123.1, 122.8, 115.8, 112.9, 109.8, 55.2, 52.3. LC-MS
m/z 452 [M+H]+. Anal. calcd for C23H17NO5S2: C, 61.18; H,
3.79; N, 3.10. Found: C, 61.12; H, 3.71; N, 3.15
4-(5-{[4-Oxo-3-(2-phenylethyl)-2-thioxo-1,3-thiazolidin-
5-ylidene]methyl}-2-furyl)benzoic acid (3h)
Yield 86%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1704, 1674, 1609, 1425, 1323, 1286, 1252, 1161,
769, 695. 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H,
COOH), 8.07 (d, J = 8 Hz, 2Н, Ar), 7.91 (d, J = 8 Hz, 2Н,
Ar), 7.62 (s, 1H, CH), 7.35 (d, J = 3.2 Hz, 1Н, Ar), 7.44 (d,
J = 3.2 Hz, 1Н, Ar), 7.28-7.31 (m, 2Н, Ar), 7.21-7.23 (m,
3Н, Ar), 4.21 (t, J = 7.2 Hz 2H, CH2), 2.95 (t, J = 7.2 Hz,
2H, CH2). 13C NMR (126 MHz, DMSO-d6) 183.2, 170.6,
161.4, 151.9, 148.3, 142.8, 134.3, 130.6, 130.4, 129.1,
128.3, 126.1, 125.8, 123.1, 119.7, 113.8, 109.7, 49.9, 32.4.
LC-MS m/z 436 [M+H]+. Anal. calcd for C23H17NO4S2: C,
63.43; H, 3.93; N, 3.22. Found: C, 63.48; H, 3.91; N, 3.26.
4-[5-({3-[2-(3,4-Dimethoxyphenyl)ethyl]-4-oxo-2-thioxo-
1,3-thiazolidin-5-ylidene}methyl)-2-furyl]benzoic acid (3i)
Yield 90%, yellow solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1709, 1683, 1607, 1515, 1424, 1352, 1325, 1284,
1262, 1161, 1031, 855, 767, 525. 1H NMR (400 MHz,
DMSO-d6) δ 13.05 (br s, 1H, COOH), 8.07 (d, J = 6.4 Hz,
2Н, Ar), 7.92 (d, J = 6.4 Hz, 2Н, Ar), 7.64 (s, 1H, CH), 7.45
(d, J = 3.2 Hz, 1Н, Ar), 7.37 (d, J = 3.2 Hz, 1Н, Ar), 6.84-
6.86 (m, 2Н, Ar), 6.79 (s, 1Н, Ar), 6.69-6.71 (m, 2Н, Ar),
4.22 (t, J = 6 Hz, 2H, CH2), 3.72 (s, 3Н, OCH3), 3.70 (s,
3Н, OCH3), 2.89 (t, J = 6 Hz, 2H, CH2). 13C NMR (126
MHz, DMSO-d6) 183.2, 170.6, 161.4, 151.9, 149.5, 148.3,
A.V. Beiko, O.L. Kobzar et al.
37
148.0, 136.1, 134.3, 130.6, 128.3, 125.8, 123.1, 122.2,
119.7, 113.8, 113.4, 111.3, 109.7, 49.9, 32.7, 55.9. LC-MS
m/z 496 [M+H]+. Anal. calcd for C25H21NO6S2: C, 60.59; H,
4.27; N, 2.83. Found: C, 60.52; H, 4.22; N, 2.87.
General method for the synthesis of compounds 3j-m
The solution of 0.005 mol of corresponding rhodanine 1
in 15-20 ml of acetic acid and 0.005 mol of sodium acetate
was added to a hot solution of 0.005 mol of 4-(5-
formylfuran-2-yl)benzoic acid 2a in 20-30 ml of acetic acid.
The reaction mixture was boiled for 5 h and then left at 20-
25 ºC for 12 h. The resulting precipitate was filtered,
washed with ethanol, and dried to give products 3j-m.
4-[5-({3-[(2-Hydroxybenzoyl)amino]-4-oxo-2-thioxo-
1,3-thiazolidin-5-ylidene}methyl)-2-furyl]benzoic acid (3j)
Yield 88%, orange solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 3306, 3034, 1733, 1699, 1605, 1549, 1422, 1297,
1238, 1036, 802, 773, 754, 693, 653, 577, 542. 1H NMR
(400 MHz, DMSO-d6) δ 12.9 (br s, 1H, COOH), 11.25 (br
s, 2H, NH, OH), 8.11 (d, J = 8 Hz, 2Н, Ar), 7.99 (d, J = 8
Hz, 2Н, Ar), 7.92 (d, J = 4 Hz, 1Н, Ar), 7.86 (s, 1Н, CH),
7.52-7.53 (m, 2Н, Ar), 7.46-7.49 (m, 1Н, Ar), 7.05 (d, J = 4
Hz, 1H, Ar), 6.98-7.02 (m, 1Н, Ar). 13C NMR (126 MHz,
DMSO-d6) 179.5, 170.6, 166.9, 160.1, 158.1, 151.9, 150.0,
134.3, 133.9, 130.6, 130.3, 128.3, 126.0, 124.4, 121.9,
109.7, 120.5, 119.8, 118.9. LC-MS m/z 467 [M+H]+. Anal.
calcd for C22H14N2O6S2: C, 56.64; H, 3.02; N, 6.01. Found:
C, 56.68; H, 3.06; N, 6.07.
4-(5-{[3-(2-Carboxyethyl)-4-oxo-2-thioxo-1,3-thiazoli-
din-5-ylidene]methyl}-2-furyl)benzoic acid (3k)
Yield 91%, orange solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1681, 1608, 1423, 1318, 1289, 1260, 1174, 1043,
963, 922, 806, 768, 695, 549. 1H NMR (400 MHz, DMSO-
d6) δ 12.8 (br s, 2H, 2COOH), 8.05 (d, J = 8.4 Hz, 2Н, Ar),
7.88 (d, J = 8.4 Hz, 2Н, Ar), 7.62 (s, 1H, CH), 7.42 (d, J = 4
Hz, 1Н, Ar), 7.34 (d, J = 4 Hz, 1Н, Ar), 4.21 (t, J = 7.2 Hz,
2Н, СН2), 2.63 (t, J = 7.2 Hz, 2Н, СН2). 13C NMR (126
MHz, DMSO-d6) 190.1, 173.5, 170.6, 161.1, 151.9, 148.3,
134.3, 130.6, 128.3, 125.8, 124.6, 123.1, 109.7, 109.1,
45.0, 33.2. LC-MS m/z 404 [M+H]+. Anal. calcd for
C18H13NO6S2: C, 53.59; H, 3.25; N, 3.47. Found: C, 53.64;
H, 3.31; N, 3.41.
4-(5-{[3-(3-Carboxypropyl)-4-oxo-2-thioxo-1,3-thiazoli-
din-5-ylidene]methyl}-2-furyl)benzoic acid (3l)
Yield 90%, orange solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1706, 1694, 1610, 1427, 1310, 1288, 1211, 1166,
924, 770, 695. 1H NMR (400 MHz, DMSO-d6) δ 12.91 (br
s, 2H, 2COOH), 8.05 (d, J = 8.2 Hz, 2Н, Ar), 7.89 (d, J =
8.2 Hz, 2Н, Ar), 7.64 (s, 1H, CH), 7.45 (d, J = 4 Hz, 1Н,
Ar), 7.36 (d, J = 4 Hz, 1Н, Ar), 4.09 (t, J = 6.8 Hz, 2Н,
СН2), 2.27 (t, J = 6.8 Hz, 2Н, СН2), 1.91 (t, J = 6.8 Hz, 2Н,
СН2). 13C NMR (126 MHz, DMSO-d6) 190.1, 180.9, 170.6,
161.6, 151.9, 148.3, 134.3, 130.6, 128.3, 125.8, 123.1,
121.1, 110.9, 109.7, 49.0, 35.9, 23.4. LC-MS m/z 418
[M+H]+. Anal. calcd for C19H15NO6S2: C, 54.67; H, 3.62;
N, 3.36. Found: C, 54.61; H, 3.68; N, 3.32.
4-(5-{[3-(5-Carboxypentyl)-4-oxo-2-thioxo-1,3-thiazoli-
din-5-ylidene]methyl}-2-furyl)benzoic acid (3m)
Yield 88%, orange solid. Mp > 250 °С. IR (KBr, νmax,
cm−1) 1711, 1695, 1610, 1426, 1336, 1315, 1288, 1209,
1150, 1105, 922, 788, 768, 729, 692, 642, 541. 1H NMR
(400 MHz, DMSO-d6) δ 12.52 (br s, 2H, 2COOH), 8.04 (d,
J = 8.4 Hz, 2Н, Ar), 7.88 (d, J = 8.4 Hz, 2Н, Ar), 7.60 (s,
1H, CH), 7.41 (d, J = 4 Hz, 1Н, Ar), 7.33 (d, J = 4 Hz, 1Н,
Ar), 3.97 (t, J = 7.6 Hz, 2Н, СН2), 2.20 (t, J = 7.6 Hz, 2Н,
СН2), 1.62 (t, J = 7.6 Hz, 2Н, СН2), 1.52 (t, J = 7.6 Hz, 2Н,
СН2), 1.29 (t, J = 7.6 Hz, 2Н, СН2). 13C NMR (126 MHz,
DMSO-d6) 190.1, 175.2, 170.6, 161.6, 151.9, 148.3, 134.3,
130.6, 128.3, 125.8, 123.1, 121.1, 114.4, 109.7, 49.0, 33.5,
23.9, 27.3, 26.4. LC-MS m/z 446 [M+H]+. Anal. calcd for
C21H19NO6S2: C, 56.61; H, 4.30; N, 3.14. Found: C, 56.68;
H, 4.35; N, 3.19.
General method for the synthesis of compounds 4a,b
Using 5-phenylfuran-2-carbaldehyde (2b) as starting
material, the products 4a,b were synthesized by the method
described previously for compounds 3a-i.
3-Methyl-5-[(5-phenyl-2-furyl)methylene]-2-thioxo-1,3-
thiazolidin-4-one (4a)
Yield 87%, yellowish solid. Mp 210-212 °С. IR (KBr,
νmax, cm−1) 1702, 1610, 1550, 1423, 1281, 1252, 1120,
1034, 760, 648, 493. 1H NMR (400 MHz, DMSO-d6) δ
7.84-7.86 (m, 2Н, Ar), 7.68 (s, 1H, CH), 7.54-7.58 (m, 2Н,
Ar), 7.43-7.46 (m, 1Н, Ar), 7.36 (d, J = 3.6 Hz, 1Н, Ar),
7.33 (d, J = 3.6 Hz, 1Н, Ar), 3.39 (s, 3Н, СН3). 13C NMR
(126 MHz, DMSO-d6) 188.2, 161.5, 151.9, 147.2, 132.2,
128.7, 127.3, 124.0, 123.1, 122.3, 113.1, 105.8, 34.9. LC-
MS m/z 302 [M+H]+. Anal. calcd for C15H11NO2S2: C,
59.78; H, 3.68; N, 4.65. Found: C, 59.81; H, 3.73; N, 4.61.
3-Ethyl-5-[(5-phenyl-2-furyl)methylene]-2-thioxo-1,3-
thiazolidin-4-one (4b)
Yield 88%, yellowish solid. Mp 162-164 С. IR (KBr,
νmax, cm−1) 1701, 1603, 1546, 1434, 1349, 1327, 1231,
1122, 1034, 760, 645, 511. 1H NMR (400 MHz, DMSO-d6)
δ 7.83-7.85 (m, 2Н, Ar), 7.64-7.66 (m, 1Н, Ar), 7.42-7.55
(m, 3Н, Ar, CH), 7.32-7.35 (m, 2Н, Ar), 4.06 (q, J = 7.2 Hz,
2Н, СН2), 1.18 (t, J = 7.2 Hz, 3Н, СН3). 13C NMR (126
MHz, DMSO-d6) 191.7, 161.8, 151.9, 145.9, 132.2, 128.7,
127.3, 124.7, 124.0, 120.1, 113.0, 105.8, 43.0, 13.7. LC-MS
m/z 316 [M+H]+. Anal. calcd for C16H13NO2S2: C, 60.93; H,
4.15; N, 4.44. Found: C, 60.98; H, 4.19; N, 4.48.
In vitro study of compounds as xanthine oxidase
inhibitors
The xanthine oxidase from bovine milk and xanthine as
substrate were purchased from Sigma-Aldrich. The reaction
mixture contained sodium-phosphate buffer (50 mM, pH
7.4), xanthine (50 µM), EDTA (0.1 mM), DMSO (1%), and
inhibitor. The enzymatic substrate transformations were
initiated by the addition of XO after incubation of the
mixture for 5 min. The enzyme activity was detected
spectrophotometrically at 293 nm. The molar extinction
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
38
coefficient of uric acid (12.2 mM-1 cm-1) was used for the
calculations. The value of Km calculated from the
Lineweaver-Burk plots was 4.6 µM.
Molecular docking modeling
The protein structure of xanthine oxidase was
downloaded from the RCSB Protein Data Bank
(http://www.rcsb.org). Molecular docking was carried out
in the region of the active site of the C chain of xanthine
oxidase (PDB code 1FIQ [36]). During preparation for
docking, ligands and water molecules were removed from
the enzyme crystal. The water molecule HOH1457 was not
removed due to participation in the enzyme catalysis [36,
37]. The catalytically important oxygen atom of the
molybdopterin cofactor was replaced by a water molecule.
The structures of ligands (carboxylic group in ionized form)
were prepared by the MarvinSketch program [38] and
optimized using MMFF94s force field in Avogadro
software [39]. AutoDockTools 1.5.6 [40] was used for the
preparation of docking files. Visual analysis of the resulting
complexes was performed by Discovery Studio 3.5
visualizer (Accelrys, San Diego, USA).
Molecular dynamic
Model system preparation
A molecular dynamic simulation was used to study the
binding mode of Z-isomer of compound 3a at the active site
of XO. Using the PROPKA method [41] implemented in
PDB2PQR software [42] the protonation states of the amino
acid residues were verified and corrected according to the
pH 7.4. It was found that amino acid residue Glu802, which
is placed near compound 3a according to docking results
(Figure 3A), is protonated and represented in the MD result
as Glh802. This is in agreement with the available crystal
structures of the enzyme-substrate and enzyme-inhibitor
complexes, as well as with QM/MM studies [43, 44, 45].
The enzyme structure parameterization was carried out by
Amber ff14SB force field [46], while parameterization of
the pyranopterin part of the molybdopterin cofactor (Moco)
was performed by ACPYPE software [47] using AMBER
force field (GAFF) [48] with AM1-BCC charge method.
The parameter of dioxothiomolybdenum of the cofactor and
the vdW parameter of the molybdenum atom were obtained
from references [49] and [50], respectively. The enzyme-
Moco and enzyme-Moco-3a model systems were prepared
by the LEaP module of AmberTools22. The complexes
were solvated in the box with size 116 Å × 96 Å × 97 Å
using TIP3P water model. The minimal distance from
amino acids to the water box edge was set to 12 Å. The
model systems were neutralized by adding sodium ions.
Minimization, heating, equilibration, and production MD
simulation
Before production MD simulation the minimization,
heating, and equilibration of the model systems were
performed. First, each system was minimized during 100 ps
with the position of the heavy atoms fixed, allowing water
molecules to be distributed throughout the system. The
periodic boundary condition and particle mesh Ewald
method with PMEGridSpacing and PMETolerance of 1 Å
and 10-6, respectively, were applied to the calculation. The
time step was 1 fs. In the second stage, minimization was
performed for 100 ps without fixing atoms. Then, the model
system was heated to 298.15 K for 50 ps with an increment
of 0.007 K using the NVT ensemble. The heated model
system was equilibrated for 100 ps and 1 ns using NVT and
NPT ensembles, respectively. The Langevin thermostat and
Langevin barostat methods were applied to maintain
constant temperature and pressure at 298.15 K and 1 bar.
The Langevin damping, Langevin piston period, and
Langevin piston decay were set to 1 ps-1, 50 fs, and 25 fs,
respectively. The productive MD with NVT ensemble was
carried out for 20 ns. Every 250 fs was saved to the
trajectory file, which contained 80,000 frames in the end.
The trajectory files of productive MD simulation were
reduced by VMD software version 1.9.3 [51] to 2,000
frames and used for analysis of the root mean square
deviation (RMSD), root mean square fluctuation (RMSF),
radius of gyration, and solvent-accessible surface area.
MMPBSA calculation
The binding free energy of compound 3a to the XO was
calculated using MMPBSA.py [52] implemented in
AmberTools22. This Python script was also used to
decompose binding free energy per residue. The last 1,000
frames of the 2,000-frame trajectory file with an interval of
5 were used for the calculation. Since the systems were only
neutralized, the ionic strength was set to 0. Other
parameters were set to default.
Notes
Acknowledgments and finances. This work was
supported by the National Academy of Science of Ukraine.
The authors declare no conflict of interest.
Author contributions. A.V.B.: investigation of
bioactivity, molecular docking simulation, writing of the
manuscript. O.L.K.: formal analysis, molecular dynamic
simulation, and writing of the manuscript. M.V.K.:
synthesis of compound. S.G.P.: conceptualization, synthesis
of compound. O.P.K.: synthesis of the compound, writing
of the manuscript. A.I.V.: conceptualization, supervision,
and editing.
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4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази
А.В. Бейко, О.Л. Кобзар, М.В. Качаєва, С.Г. Пільо, О.П. Козаченко, А.І. Вовк
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Синтезовано і вивчено інгібувальну здатність щодо ксантиноксидази низки похідних роданіну, що містять фрагмент 4-(фуран-2-
іл)бензойної кислоти. Ксантиноксидаза є відомою мішенню для алопуринолу і фебуксостату, що застосовуються при лікуванні гіперурикемії,
подагри та інших захворювань. Cинтезовані сполуки з різними замісниками в положенні 3 кільця роданіну продемонстрували in vitro
інгібувальну здатність щодо ксантиноксидази в діапазоні низьких мікромолярних концентрацій. Встановлено, що похідна 4 -(фуран-2-
іл)бензойної кислоти, яка містить фрагмент N-незаміщеного роданіну, характеризується найнижчим значенням ІС50, що не залежить від наявності
альбуміну або Твіну-80 за умов експериментів. Згідно з кінетичними даними, 4-(фуран-2-іл)бензойна кислота з роданіновим скафолдом є
інгібітором змішаного типу з однаковою спорідненістю до вільного ензиму і комплексу ензим-субстрат. Дослідження методами молекулярного
докінгу і молекулярної динаміки були проведені для з’ясування способів зв’язування похідних роданіну в активному центрі ксантиноксидази.
Ключові слова: роданін; 4-(фуран-2-іл)бензойна кислота; ксантиноксидаза; інгібування; молекулярний докінг; молекулярна динаміка.
4. Yin, L.J.; Bin Ahmad Kamar, A.K.D.; Fung, G.T.; Liang, C.T.; Avupati, V.R. Review of anticancer potentials and structure-activity relationships (SAR) of rhodanine derivatives. Biomed. Pharmacother. 2022, 145, 112406.
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40. Sanner, M.F. Python: a programming language for software integration and development. J. Mol. Graph. Model. 1999, 17, 57-61.
41. Li H.; Robertson A.D.; Jensen J.H. Very fast empirical prediction and rationalization of protein pKa values. Proteins. 2005, 61, 704-721.
42. Dolinsky T.; Czodrowski P.; Li H.; Nielsen J.E.; Jensen J.H.; Klebe G.; Baker N.A. PDB2PQR: expanding and upgrading automated preparation of biomolecular structures from molecular simulation. Nucleic. Acids Res. 2007, 35, W522-W525.
43. Okamoto, K.; Eger, B.T.; Nishino, T.; Kondo, S.; Pai, E.F.; Nishino, T. An extremely potent inhibitor of xanthine oxidoreductase. J. Biol. Chem. 2002, 278, 1848-1855.
44. Metz, S.; Thiel, W. A combined QM/MM study on the reductive half-reaction of xanthine oxidase: substrate orientation and mechanism. J. Am. Chem. Soc. 2009, 131, 14885-14902.
45. Ribeiro, P.M.; Fernandes, H.S.; Maia, L.B.; Sousa, S.; Moura, J.J.G. J.; Cerqueira, N.M.F.S.A. The complete catalytic mechanism of xanthine oxidase: a computational study. Inorg. Chem. Front. 2021, 8, 405-416.
46. Maier J.A.; Martinez C.; Kasavajhala K.; Wickstrom L.; Hauser K.E.; Simmerling C. f14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 2015, 11, 3696-3713.
|
| id | oai:ojs2.bioorganica.com.ua:article-75 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:18Z |
| publishDate | 2023 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/75/65114a7e0b988a63984679d644c4f375.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-752026-07-19T14:56:54Z Rhodanine-based 4-(furan-2-yl)benzoic acids as inhibitors of xanthine oxidase 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази Beiko, Alona V. Kobzar, Oleksandr L. Kachaeva, Maryna V. Pilyo, Stepan G. Kozachenko, Olexandr P. Vovk, Andriy I. rhodanine 4-(furan-2-yl)benzoic acid xanthine oxidase inhibition molecular docking molecular dynamic роданін 4-(фуран-2-іл)бензойна кислота ксантиноксидаза інгібування молекулярний докінг молекулярна динаміка A series of rhodanine derivatives bearing 4-(furan-2-yl)benzoic acid moiety were synthesized and studied as inhibitors of xanthine oxidase. This enzyme is a known target for allopurinol and febuxostat used in the treatment of hyperuricemia, gout, and other diseases. The synthesized compounds with different substituents in position 3 of the rhodanine ring showed in vitro inhibitory activities towards xanthine oxidase in a low micromolar concentration range. The 4-(furan-2-yl)benzoic acid derivative with a fragment of N-unsubstituted rhodanine was found to have the lowest IC50 value which does not depend on the presence of albumin or Tween-80 under the assay conditions. According to kinetic data, the rhodanine-based 4-(furan-2-yl)benzoic acid was a mixed-type inhibitor with the same affinity for the free enzyme and the enzyme-substrate complex. Molecular docking and molecular dynamic studies were performed to elucidate the binding mode of this compound in the active site of xanthine oxidase  Синтезовано і вивчено інгібувальну здатність щодо ксантиноксидази низки похідних роданіну, що містять фрагмент 4-(фуран-2-іл)бензойної кислоти. Ксантиноксидаза є відомою мішенню для алопуринолу і фебуксостату, що застосовуються при лікуванні гіперурикемії, подагри та інших захворювань. Cинтезовані сполуки з різними замісниками в положенні 3 кільця роданіну продемонстрували in vitro інгібувальну здатність щодо ксантиноксидази в діапазоні низьких мікромолярних концентрацій. Встановлено, що похідна 4-(фуран-2-іл)бензойної кислоти, яка містить фрагмент N-незаміщеного роданіну, характеризується найнижчим значенням ІС50, що не залежить від наявності альбуміну або Твіну-80 за умов експериментів. Згідно з кінетичними даними, 4-(фуран-2-іл)бензойна кислота з роданіновим скафолдом є інгібітором змішаного типу з однаковою спорідненістю до вільного ензиму і комплексу ензим-субстрат. Дослідження методами молекулярного докінгу і молекулярної динаміки були проведені для з’ясування способів зв’язування похідних роданіну в активному центрі ксантиноксидази  V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/75 10.15407/bioorganica2023.02.031 Ukrainica Bioorganica Acta; Vol. 18 No. 2 (2023): Ukrainica Bioorganica Acta; 31-40 Ukrainica Bioorganica Acta; Том 18 № 2 (2023): Ukrainica Bioorganica Acta; 31-40 1814-9766 1814-9758 10.15407/bioorganica2023.02 en https://bioorganica.com.ua/index.php/journal/article/view/75/76 Copyright (c) 2023 Alona V. Beiko, Oleksandr L. Kobzar, Maryna V. Kachaeva, Stepan G. Pilyo, Olexandr P. Kozachenko, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | роданін 4-(фуран-2-іл)бензойна кислота ксантиноксидаза інгібування молекулярний докінг молекулярна динаміка Beiko, Alona V. Kobzar, Oleksandr L. Kachaeva, Maryna V. Pilyo, Stepan G. Kozachenko, Olexandr P. Vovk, Andriy I. 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title | 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title_alt | Rhodanine-based 4-(furan-2-yl)benzoic acids as inhibitors of xanthine oxidase |
| title_full | 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title_fullStr | 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title_full_unstemmed | 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title_short | 4-(Фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| title_sort | 4-(фуран-2-іл)бензойні кислоти на основі роданіну як інгібітори ксантиноксидази |
| topic | роданін 4-(фуран-2-іл)бензойна кислота ксантиноксидаза інгібування молекулярний докінг молекулярна динаміка |
| topic_facet | rhodanine 4-(furan-2-yl)benzoic acid xanthine oxidase inhibition molecular docking molecular dynamic роданін 4-(фуран-2-іл)бензойна кислота ксантиноксидаза інгібування молекулярний докінг молекулярна динаміка |
| url | https://bioorganica.com.ua/index.php/journal/article/view/75 |
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