Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону
4-(5-Substituted furan-2-yl)benzoic acids with a pyrazolone moiety were evaluated in vitro as inhibitors of human cytosolic glutathione S-transferases A1-1 and P1-1, which are involved in cellular mechanisms of drug resistance and carcinogenesis. When inhibiting GSTA1-1, the compounds demonstrated m...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
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Ukrainica Bioorganica Acta| _version_ | 1871193534889984000 |
|---|---|
| author | Shulha, Yurii V. Kobzar, Oleksandr L. Pilyo, Stepan G. Vovk, Andriy I. |
| author_facet | Shulha, Yurii V. Kobzar, Oleksandr L. Pilyo, Stepan G. Vovk, Andriy I. |
| author_institution_txt_mv | [
{
"author": "Yurii V. Shulha",
"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": "Stepan G. Pilyo",
"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 | Shulha, Yurii V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:56Z |
| description | 4-(5-Substituted furan-2-yl)benzoic acids with a pyrazolone moiety were evaluated in vitro as inhibitors of human cytosolic glutathione S-transferases A1-1 and P1-1, which are involved in cellular mechanisms of drug resistance and carcinogenesis. When inhibiting GSTA1-1, the compounds demonstrated micromolar and nanomolar IC50 values depending on the nature of the substituent at position 3 of the pyrazolone ring. In particular, the inhibition was increased when the methyl group was replaced by a trifluoromethyl, phenyl, 4-fluorophenyl, thiophen-2-yl, or pyridin-4-yl substituent. The effect of the 4-(5-substituted furan-2-yl)benzoic acids on GSTP1-1 was approximately an order of magnitude lower than that on GSTA1-1. In both cases, the compound bearing a 1-phenyl-3-(4-nitrophenyl)-substituted pyrazolone moiety demonstrated the best inhibitory activity among the derivatives studied. Molecular docking results indicated that the inhibitors interact with GSTA1-1 mainly due to the participation of amino acid residues from the G-site, while in the case of GSTP1-1 the compounds bind to the H-site  |
| doi_str_mv | 10.15407/bioorganica2025.02.040 |
| first_indexed | 2026-02-08T07:59:48Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
UDC 547.775+547.722+577.152.2
DOI: https://doi.org/10.15407/bioorganica2025.02.040
40
Ukrainica Bioorganica Acta
www.bi oorgan ica . com.u a
RESEARCH ARTICLE
Inhibition of glutathione S-transferases A1-1 and P1-1
by pyrazolone-containing 4-(5-substituted furan-2-yl)benzoic acids
Yurii V. Shulha, Oleksandr L. Kobzar, Stepan G. Pilyo, Andriy I. Vovk*
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: 4-(5-Substituted furan-2-yl)benzoic acids with a pyrazolone moiety were evaluated in vitro as inhibitors of human cytosolic
glutathione S-transferases A1-1 and P1-1, which are involved in cellular mechanisms of drug resistance and carcinogenesis. When
inhibiting GSTA1-1, the compounds demonstrated micromolar and nanomolar IC50 values depending on the nature of the substituent at
position 3 of the pyrazolone ring. In particular, the inhibition was increased when the methyl group was replaced by a trifluoromethyl,
phenyl, 4-fluorophenyl, thiophen-2-yl, or pyridin-4-yl substituent. The effect of the 4-(5-substituted furan-2-yl)benzoic acids on GSTP1-1
was approximately an order of magnitude lower than that on GSTA1-1. In both cases, the compound bearing a 1-phenyl-3-(4-nitrophenyl)-
substituted pyrazolone moiety demonstrated the best inhibitory activity among the derivatives studied. Molecular docking results indicated
that the inhibitors interact with GSTA1-1 mainly due to the participation of amino acid residues from the G-site, while in the case of
GSTP1-1 the compounds bind to the H-site.
Keywords: 4-(furan-2-yl)benzoic acids; pyrazolones; glutathione S-transferases; inhibition.
Introduction
Glutathione S-transferases (GSTs; EC 2.5.1.18) represent
a superfamily of phase II detoxification enzymes that
catalyze the conjugation of reduced glutathione with
different endogenous and exogenous electrophilic
compounds [1, 2]. This reaction leads to glutathione
S-conjugated products, which have better water solubility
and lower cytotoxicity and can be further metabolized via
the mercapturic acid pathway [3]. The widely distributed
cytosolic GSTA1-1 (liver, intestine, kidney, adrenal gland,
and testis) and GSTP1-1 (brain, heart, lung, testis, skin,
kidney, pancreas, erythrocytes) [4, 5] play diverse biolo-
gical roles. In addition to the detoxification functions, these
enzymes are also involved in cellular signaling [5, 6]. The
regulation of signaling can occur through the mitogen-
activated protein (MAP) kinase pathway and includes
Received:
Revised:
Accepted:
Published online:
08.10.2025
10.11.2025
26.11.2025
30.12.2025
Corresponding author. Tel.: +380-44-558-5388;
e-mail: vovk@bpci.kiev.ua (A.I. Vovk)
ORCID: 0000-0001-6167-076X
inhibition of kinases JNK1, ASK1, and MEKK1 [7]. Thus,
the role of GSTP1-1 and GSTA1-1 makes these enzymes
promising targets for drug design to overcome resistance
mechanisms to anticancer agents as well as to influence
signaling pathways in cancer cells. In this connection, the
new bioactive compounds can be developed to be used
solely or together with chemotherapeutic drugs [8-10].
Various organic compounds such as derivatives of
glutathione [11], 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)-
hexanol [12, 13], coumarins [14, 15], benzisoselenazolones
[16] were studied as inhibitors of GSTs. Glutathione-based
ezatiostat (TLK199) and canfosfamide (TLK286) were
found to be useful as prodrugs targeting GSTP1-1 [17, 18].
Ethacrynic acid, used as a diuretic, as well as its derivatives
and structural analogues can exhibit inhibitory activity
towards GSTP1-1 [19, 20]. Recently, methyl
3-amino-4-nitrobenzoate [21], methyl 4-amino-2-nitro-
benzoate, and methyl 4-amino-3-bromo-5-fluorobenzoate
[22] were found to be effective inhibitors of GST isolated
from human erythrocytes. 3,4-Dihydroxyphenylacetic acid,
being a metabolite of dopamine, can in vitro inhibit the
glutathione S-transferase isolated from N27 dopaminergic
cells [23].
In the presented work, the objects of our research were
© Shulha Yu.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.
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/detoxication
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/signal-transduction
mailto:vovk@bpci.kiev.ua
https://orcid.org/0000-0001-6167-076X
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/drug-development
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/anticarcinogen
Yu.V. Shulha et al.
41
4-(5-substituted furan-2-yl)benzoic acids. Similar
compounds are known to be inhibitors of SARS-CoV and
MERS-CoV 3C-like proteases [24], heptosyltransferase
WaaC [25], and neuraminidase [26]. It was recently shown
that 4-(furan-2-yl)benzoic acids with a pyrazolone or
rhodanine part can inhibit xanthine oxidase [27, 28]. This
study aimed to evaluate 4-(5-substituted furan-2-yl)benzoic
acids with different substituents in position 3 of the
pyrazolone moiety (Figure 1) as inhibitors of human
glutathione S-transferases A1-1 and P1-1.
Figure 1. Pyrazolone-containing 4-(5-substituted furan-2-yl)ben-
zoic acids studied as GSTP1-1 and GSTA1-1 inhibitors.
Results and Discussion
According to the results obtained (Table 1), compounds
2-8 exhibited submicromolar and nanomolar IC50 values
against recombinant GSTA1-1 in vitro. Compound 1, which
contains a 3-methyl-5-phenylpyrazolone ring, was charac-
terrized by an IC50 value of 3.7 μM, while 4-(5-
formylfuran-2-yl)benzoic acid exhibited lower activity (IC50
value >25 μM). This indicates the involvement of the
pyrazolone moiety in the binding of the inhibitor to the
enzyme.
The inhibitory efficacy of compounds 1-8 against
GSTA1-1 increased when the methyl group at position 3 of
the pyrazolone moiety was replaced by trifluoromethyl,
phenyl, 4-fluorophenyl, thiophen-2-yl, or pyridin-4-yl
group, varying in the range from 0.45 to 0.18 μM. A further
decrease in IC50 values occurs when going from phenyl
(compounds 3) to 4-chlorophenyl or 4-nitrophenyl
substituents at position 3 of the pyrazolone ring
(compounds 5 and 6).
The inhibitory effects of 4-(5-substituted furan-2-
yl)benzoic acids 1-8 on GSTP1-1 were approximately an
order of magnitude worse than those on the A1-1 isoform.
Among the derivatives 1-8, the significant decrease in
inhibitory activity was observed for compound 5 with a
4-chlorophenyl substituent. As in the case of isoform A1-1,
the derivative 6 bearing 4-nitrophenyl substituents was the
most effective, showing IC50 values for GSTP1-1 inhibition
in the low micromolar range. The similar effect of
compound 6 was also observed in a system with the enzyme
isolated from human placenta, with activity significantly
exceeding that of ethacrynic acid used as a reference
compound [29] (IC50 value of 4.3 ± 0.6 μM). The inhibition
of GSTHP by compounds 2, 4, and 8 was found to be
almost the same as the effect of ethacrynic acid, while the
influence of derivatives 1, 3, 5, and 7 was noticeably
weaker.
Molecular docking by AutoVina was performed to assess
the possible interactions between the inhibitors and amino
acid residues at the active sites of GSTA1-1 and GSTP1-1.
According to the values of the docking scores (Table 1), the
binding energy between the ligand and enzyme for the most
effective inhibitor 6 was -9.3 kcal/mol (GSTA1-1) and
-9.7 kcal/mol (GSTP1-1). Compound 1, with low inhibitory
potential against GSTA1-1 and GSTP1-1, is characterized
by docking scores of -8.7 kcal/mol and -8.6 kcal/mol,
respectively. The data obtained suggest that inhibitor 6 has
stronger binding interactions within the active site as
compared to compound 1.
The GSTA1-1 is known to possess three possible ligand
binding sites. The conserved G-site for glutathione binding
is located in the N-terminal domain I. H-Site at the
C-terminal domain II binds the diverse electrophilic
substrates with participation of the amino acid residues of
the 1-1 loop, the C-terminal part of helix 4, and the
C-terminus. Non-catalytic site of the human GSTA1-1,
located at the dimer interface, can be involved in the
binding of various non-substrate ligands [30, 31]. The
results in Table 1 show that mainly amino acid resi-
Table 1 IC50 values (µM) of 4-(5-substituted furan-2-yl)benzoic acids as inhibitors of glutathione S-transferases a.
Compound GSTA1-1 GSTP1-1 GSTHPb
1 3.7 ± 1.1 >25 16.7 ± 1.4
2 0.45 ± 0.04 6.1 ± 0.4 2.4 ± 0.9
3 0.45 ± 0.15 6.7 ± 1.1 17.1± 4.0
4 0.29 ± 0.04 2.5 ± 0.4 5.5 ± 2.1
5 0.035 ± 0.021 2.4 ± 0.7 13.9 ± 4.0
6 0.018 ± 0.006 0.20 ± 0.05 0.38 ± 0.10
7 0.30 ± 0.11 1.6 ± 0.7 10.9 ± 3.8
8 0.18 ± 0.05 2.5 ± 0.9 4.3 ± 0.7
a IC50 values were determined from 2-3 series of experiments and shown as an average value ± standard deviation. b Glutathione S-transferase from human
placenta.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
42
Table 2. The docking scores and amino acid residues of GSTA1-1 and GSTP1-1 involved in binding the 4-(5-substituted
furan-2-yl)benzoic acids a.
Enzyme Inhibitor
Docking
score,
kcal/mol
Amino acid residues
Subunit A Subunit B
GSTA1-1 1 -8.7 Tyr9, Phe10, Gly14, Arg15, Gln54, Val55, Gln67, Thr68,
Glu104, Met208, Ala216, Phe220
Asp101
2 -9.1 Tyr9, Phe10, Gly14, Arg15, Gln54, Val55, Pro56, Gln67,
Thr68, Glu104, Met208, Ala216, Phe220
Asp101
3 -9.2 Arg15, Arg45, Gln54, Gln67, Thr68, Arg69, Val111, Phe220,
Phe222
Asp101, Arg131
4 -9.2 Tyr9, Phe10, Arg15, Arg45, Gln54, Val55, Ala216, Phe220,
Phe222
Asp101, Glu104, Arg131
5 -9.1 Tyr9, Phe10, Arg15, Arg45, Gln54, Val55, Arg69, Val111,
Ala216, Phe220, Phe222
Asp101
6 -9.3 Tyr9, Phe10, Arg15, Arg45, Gln54, Gln67, Thr68, Arg69,
Ala216, Phe220, Phe222
Glu97, Asp101, Lys127,
Arg131
7 -8.6 Tyr9, Phe10, Arg45, Gln54, Val55, Met208, Ala216, Phe220,
Arg221, Phe222
Asp101, Arg121
8 -9.3 Tyr9, Arg15, Arg45, Gln54, Val55, Gln67, Thr68, Arg69,
Val111, Phe220, Phe222
Leu123, Lys127, Arg131
GSTP1-1 1 -8.6 Tyr7, Phe8, Val10, Arg13, Val35, Gln51, Leu52, Gln64,
Ile104, Tyr108, Gly205
Asp98
2 -9.2 Tyr7, Phe8, Val10, Gly12, Arg13, Gln51, Leu52, Ile104,
Tyr108, Ile203, Asn204, Gly205
Asp98, Lys102
3 -9.1 Tyr7, Phe8, Pro9, Val10, Gly12, Arg13, Val35, Arg100,
Tyr103, Ile104, Tyr108, Ile161, Ile203, Asn204, Gly205,
Asn206
4 -9.3 Tyr7, Phe8, Pro9, Gly12, Arg13, Val33, Thr34, Val35,
Arg100, Tyr103, Ile104, Tyr108, Ile161, Ile203, Asn204,
Gly205, Asn206
5 -9.3 Tyr7, Phe8,Val10, Arg13, Gln51, Leu52, Gln64, Cys101,
Ile104, Ser105, Tyr108, Gly205
Asp98
6 -9.7 Tyr7, Phe8,Val10, Arg13, Val35, Gln51, Leu52, Gln64,
Ile104, Ser105, Tyr108, Thr109, Gly205, Asn206
Asp98
7 -9.0 Tyr7, Phe8, Val10, Arg13, Gln51, Leu52, Gln64, Ser65,
Cys101, Ile104, Tyr108, Gly205
8 -9.0 Tyr7, Phe8, Val10, Arg13, Gln51, Leu52, Gln64, Cys101,
Ile104, Tyr108, Gly205
Asp98
a There are shown the amino acid residues surrounding the ligand at a distance not more than 4.0 Å.
dues from the G-site of GSTA1-1 can provide the enzyme-
inhibitor complex formation. Among them, Arg15 is known
as a conserved residue stabilizing the thiolate anion of
substrate [32], and Arg131 from the other subunit
coordinates the carboxylate group of the glycine part of
glutathione [2]. In addition, the residues Phe220 and
Phe222 belonging to the H-site are involved in the
formation of a lid over the active site.
In contrast, the inhibitors of GSTP1-1 can bind to a
region close to the H-site. This site, consisting of both
hydrophobic and hydrophilic residues, is not such hydro-
phobic as in GSTA1-1 [30, 33]. Key amino acid residues
that determine the binding of pyrazolone-tethered 4-(5-sub-
stituted furan-2-yl)benzoic acids are also involved in the
mechanisms of ethacrynic acid binding [34].
In particular, Phe8 coordinates to the chlorine atoms of
ethacrynic acid, and Arg13 forms a hydrogen bond with its
carboxyl group [35]. There is also the G-site Tyr108 residue
nearby, which can participate in the interaction of
ethacrynic acid with glutathione [34].
As shown in Figure 1, compound 6 can occupy the
region of glutathione binding to GSTA1-1. The residue
Arg15, which plays an important role in the glutathione
binding and its ionization, can interact with the oxygen of
pyrazolone and the benzene ring of 4-(furan-2-yl)benzoic
acid fragment through a hydrogen bond and π-cationic
interactions. Gln54 possesses a hydrogen interaction with
the oxygen atom of the furan-2-yl linker. The residues
Thr68 and Arg69 can be crucial for the fixation of the
carboxylic group, while Arg45 as well as Lys127 and
Arg131 of the B subunit are involved in the hydrogen bonds
with the nitro group of compound 6. The 5-phenyl
substituent of the pyrazolone part of the inhibitor shows π-π
stacking interaction with Phe220 and hydrophobic contacts
with Phe10 and Phe222.
Y.V. Shulha et al.
43
a
b
c
d
Figure 1. Predicted binding modes of compound 6 in the active site of subunit A of GSTA1-1 (a, b) and GSTP1-1 (c, d). Amino acid
residues surrounding the compound are shown in panels b and d.
Compound 6 binds in the H-site of GSTP1-1 similarly to
binding ethacrynic acid. This binding shows the contacts of
Arg13 with the pyrazolone and phenyl substituent in
position 1 through π-cation interactions. The residue Tyr7
forms a hydrogen bond with the oxygen of pyrazolone,
while Phe8 participates in π-π stacking with the benzene
ring of the benzoic acid fragment. Tyr108 has a π-π
stacking interaction with the benzene ring of the 4-nitro-
phenyl substituent, and Thr109 possesses a hydrogen bond
with the nitro group. Van der Waals contacts and
hydrophobic interactions are also important for stabilizing
the position of inhibitor 6 at the H-site of GSTP1-1.
Conclusions
This study expands the possible biological functions of
4-(5-substituted furan-2-yl)benzoic acids with a pyrazolone
moiety as potent inhibitors of GSTA1-1 and GSTP1-1. The
structure and in vitro activity of a series of compounds with
different substituents at position 3 of the pyrazolone ring
were analyzed. Based on molecular docking modeling, the
distinct locations were suggested for the binding of the
inhibitors to GSTA1-1 and GSTP1-1. Thus, the compounds
of this class can be considered a basis for further
development of the pyrazolone-containing 4-(5-substituted
furan-2-yl)benzoic acids as inhibitors of GSTA1-1 and
GSTP1-1.
Experimental section
Synthesis of 4-(5-substituted furan-2-yl)benzoic acids
Compounds 1-8 were synthesized as previously
described [27]. Compounds 2 and 7 were obtained as
Z-isomers, and the E/Z ratio was 1/3 for compounds 1 and
5. This ratio was 1/5 for compounds 3, 4, 6, and 8.
In vitro inhibition assays
The human recombinant GSTA1-1 and GSTP1-1, as well
as GST from human placenta, were purchased from Sigma-
Aldrich. Before using in experiments, GST from human
placenta was diluted in bidistilled water. GSTA1-1 or
GSTP1-1 were diluted in 1 ml of a solution consisting of 50
mM Tris-HCl buffer (pH 7.5), 50 mM NaCl, 1 mM DTT,
5 mM EDTA, and 50 vol.% glycerol. The compounds tested
were dissolved in pure DMSO. The assay system containing
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
44
0.1 M sodium-phosphate buffer (pH 6.5), 0.1 mM EDTA,
2.5 vol.% DMSO, 20 μL of enzyme solution, and inhibitor
was incubated for 5 min at 25 ± 2 ºC, and then the
enzymatic reaction was started by the addition of GSH and
CDNB (concentrations of 1 mM in the reaction mixture).
The enzyme activity was monitored spectrophotometrically
by the accumulation of glutathione conjugate at 340 nm.
The IC50 values were determined from the dose-dependent
inhibition curves as the concentration of compounds at
which the rate of the enzymatic reaction decreased by 50%.
Molecular docking
The PDB crystals of human GSTA1-1(PDB code 6ATO)
and human GSTP1-1 (PDB code 6GSS) were downloaded
from the RCSB PDB server (https://www.rcsb.org) [36].
The ligands, water molecules, and amino acids conformers
were removed from these files before docking calculations
performed by the program AutoDock Vina 1.1.2 [37]. The
pdbqt files of the enzymes were saved from AutoDockTools
(version 1.5.6) software [38] after adding hydrogen atoms
and Gasteiger charges. The coordinates 82.939, 28.292, and
16.07 of the grid box center and box size of 20 Å × 20 Å ×
20 Å were used for docking the 4-(5-substituted furan-2-
yl)benzoic acids into the active site of subunit A of GSTA1-
1. The coordinates 10.412, 5.923, and 25.019 of the grid
box center and box size 20 Å × 20 Å × 20 Å were used for
molecular docking of the compounds into the active site of
subunit A of GSTP1-1.
The structures of pyrazolone-containing 4-(5-substituted
furan-2-yl)benzoic acids with a carboxylic group in ionized
form were drawn using the MarvinSketch program [39] and
optimized with the MMFF94s force field in Avogadro 1.2.0
[40]. The conversion of the obtained mol2 files to pdbqt
format, which is used by AutoDock Vina, was performed
using AutoDockTools software. Discovery Studio 3.5 vi-
sualizer (Accelrys Software Inc., San Diego, CA, USA) and
Visual Molecular Dynamics 1.9.3 [41] software were used
for analysis of binding modes of the compounds.
Notes
Acknowledgments and finances. This work was
supported by the National Academy of Sciences of Ukraine,
project 0122U000439.
The authors declare no conflict of interest.
Author contributions. Yu.V.S.: in vitro and in silico
experiments, preparation of data. O.L.K.: in silico studies,
data analysis, and writing the manuscript. S.G.P.: synthesis
of compounds. A.I.V.: conceptualization and writing the
manuscript.
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Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними
4-(5-заміщеними фуран-2-іл)бензойними кислотами
Ю.В. Шульга, О.Л. Кобзар, С.Г. Пільо, А.І. Вовк*
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: 4-(5-Заміщені фуран-2-іл)бензойні кислоти з піразолоновим фрагментом були оцінені in vitro як інгібітори цитозольних глутатіон
S-трансфераз людини A1-1 та P1-1, які беруть участь у клітинних механізмах лікарської стійкості та канцерогенезу. При інгібуванні GSTA1-1
сполуки демонстрували мікромолярні та наномолярні значення IC50, які залежали від природи замісника в положенні 3 піразолонового кільця.
Зокрема, ефективність інгібування GSTA1-1 зростала, коли метильна група в положенні 3 піразолонового циклу була замінена
трифлуорометильним, фенільним, 4-флуорофенільним, тіофен-2-ільним або піридин-4-ільним замісником. Вплив 4-(5-заміщених фуран-2-іл)бен-
зойних кислот на GSTP1-1 був приблизно на порядок нижчим, ніж на GSTA1-1. При цьому в обох випадках сполука, що містить 1-феніл-3-(4-
нітрофеніл)-заміщений піразолоновий фрагмент, демонструвала найкращу інгібувальну активність серед досліджених похідних. Результати
молекулярного докінгу вказують на те, що інгібітори можуть взаємодіяти з GSTA1-1 переважно за участю амінокислотних залишків з G-сайту,
тоді як у випадку GSTP1-1 сполуки зв’язуються в H-сайті.
Ключові слова: 4-(фуран-2-іл)бензойні кислоти; піразолони; глутатіон S-трансферази; інгібування.
https://onlinelibrary.wiley.com/authored-by/Morton/Craig+J.
https://onlinelibrary.wiley.com/authored-by/Paola+Mazzetti/Anna
https://onlinelibrary.wiley.com/authored-by/Lo+Bello/Mario
https://onlinelibrary.wiley.com/authored-by/Parker/Michael+W.
http://www.chemaxon.com/
|
| id | oai:ojs2.bioorganica.com.ua:article-122 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:15Z |
| publishDate | 2025 |
| 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/35/7e24c459d0793b21ea31c2c35d69bd35.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-1222026-07-19T14:56:56Z Inhibition of glutathione S-transferases A1-1 and P1-1 by pyrazolone-containing 4-(5-substituted furan-2-yl)benzoic acids Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону Shulha, Yurii V. Kobzar, Oleksandr L. Pilyo, Stepan G. Vovk, Andriy I. 4-(furan-2-yl)benzoic acids pyrazolones glutathione S-transferases inhibition 4-(фуран-2-іл)бензойні кислоти піразолони глутатіон S-трансферази інгібування 4-(5-Substituted furan-2-yl)benzoic acids with a pyrazolone moiety were evaluated in vitro as inhibitors of human cytosolic glutathione S-transferases A1-1 and P1-1, which are involved in cellular mechanisms of drug resistance and carcinogenesis. When inhibiting GSTA1-1, the compounds demonstrated micromolar and nanomolar IC50 values depending on the nature of the substituent at position 3 of the pyrazolone ring. In particular, the inhibition was increased when the methyl group was replaced by a trifluoromethyl, phenyl, 4-fluorophenyl, thiophen-2-yl, or pyridin-4-yl substituent. The effect of the 4-(5-substituted furan-2-yl)benzoic acids on GSTP1-1 was approximately an order of magnitude lower than that on GSTA1-1. In both cases, the compound bearing a 1-phenyl-3-(4-nitrophenyl)-substituted pyrazolone moiety demonstrated the best inhibitory activity among the derivatives studied. Molecular docking results indicated that the inhibitors interact with GSTA1-1 mainly due to the participation of amino acid residues from the G-site, while in the case of GSTP1-1 the compounds bind to the H-site  4-(5-Заміщені фуран-2-іл)бензойні кислоти з піразолоновим фрагментом були оцінені in vitro як інгібітори цитозольних глутатіон S-трансфераз людини A1-1 та P1-1, які беруть участь у клітинних механізмах лікарської стійкості та канцерогенезу. При інгібуванні GSTA1-1 сполуки демонстрували мікромолярні та наномолярні значення IC50, які залежали від природи замісника в положенні 3 піразолонового кільця. Зокрема, ефективність інгібування GSTA1-1 зростала, коли метильна група в положенні 3 піразолонового циклу була замінена трифлуорометильним, фенільним, 4-флуорофенільним, тіофен-2-ільним або піридин-4-ільним замісником. Вплив 4-(5-заміщених фуран-2-іл)бен-зойних кислот на GSTP1-1 був приблизно на порядок нижчим, ніж на GSTA1-1. При цьому в обох випадках сполука, що містить 1-феніл-3-(4-нітрофеніл)-заміщений піразолоновий фрагмент, демонструвала найкращу інгібувальну активність серед досліджених похідних. Результати молекулярного докінгу вказують на те, що інгібітори можуть взаємодіяти з GSTA1-1 переважно за участю амінокислотних залишків з G-сайту, тоді як у випадку GSTP1-1 сполуки зв’язуються в H-сайті  V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-12-31 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/122 10.15407/bioorganica2025.02.040 Ukrainica Bioorganica Acta; Vol. 20 No. 2 (2025): Ukrainica Bioorganica Acta; 40-45 Ukrainica Bioorganica Acta; Том 20 № 2 (2025): Ukrainica Bioorganica Acta; 40-45 1814-9766 1814-9758 10.15407/bioorganica2025.02 en https://bioorganica.com.ua/index.php/journal/article/view/122/106 Copyright (c) 2025 Yurii V. Shulha, Oleksandr L. Kobzar, Stepan G. Pilyo, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 4-(фуран-2-іл)бензойні кислоти піразолони глутатіон S-трансферази інгібування Shulha, Yurii V. Kobzar, Oleksandr L. Pilyo, Stepan G. Vovk, Andriy I. Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title | Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title_alt | Inhibition of glutathione S-transferases A1-1 and P1-1 by pyrazolone-containing 4-(5-substituted furan-2-yl)benzoic acids |
| title_full | Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title_fullStr | Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title_full_unstemmed | Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title_short | Інгібування глутатіон S-трансфераз A1-1 та P1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| title_sort | інгібування глутатіон s-трансфераз a1-1 та p1-1 піразолоновмісними 4-(5-заміщеними фуран-2-іл)бензойними кислотами, приєднаними до піразолону |
| topic | 4-(фуран-2-іл)бензойні кислоти піразолони глутатіон S-трансферази інгібування |
| topic_facet | 4-(furan-2-yl)benzoic acids pyrazolones glutathione S-transferases inhibition 4-(фуран-2-іл)бензойні кислоти піразолони глутатіон S-трансферази інгібування |
| url | https://bioorganica.com.ua/index.php/journal/article/view/122 |
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