In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans
The previously established in vitro high antimicrobial activity of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of actio...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2021
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| author | Semenyuta, Ivan V. Trush, Maria M. Hodyna, Diana M. Kachaeva, Maryna V. Metelytsia, Larysa O. Brovarets, Volodymyr S. |
| author_facet | Semenyuta, Ivan V. Trush, Maria M. Hodyna, Diana M. Kachaeva, Maryna V. Metelytsia, Larysa O. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Ivan V. Semenyuta",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Maria M. Trush",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Diana M. Hodyna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Larysa O. Metelytsia",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Semenyuta, Ivan V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | The previously established in vitro high antimicrobial activity of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG C. albicans is optimal in terms of quality indicators such as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot analysis (90% amino acid residues in the favored regions). The modeling of molecular docking of the most active ligands 1a-d, 3c into the active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with calculated binding energies from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C. albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3c are the perspective objects for further study as antimicrobials against infectious MDR pathogens |
| doi_str_mv | 10.15407/bioorganica2021.01.025 |
| first_indexed | 2025-07-17T12:19:45Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
UDC 547.78 + 577.152.24
DOI: https://doi.org/10.15407/bioorganica2021.01.025
25
RESEARCH ARTICLE
In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts
as potential inhibitors of Candida albicans transglycosylase
Ivan V. Semenyuta*, Maria M. Trush, Diana M. Hodyna, Maryna V. Kachaeva,
Larysa O. Metelytsia, Volodymyr S. Brovarets
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
Abstract: The previously established in vitro high antimicrobial activity of triphenylphosphonium salts (TPPs) against bacterial
(Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains
made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The
hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG
C. albicans is optimal in terms of quality indicators such as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot
analysis (90% amino acid residues in the favored regions). The modeling of molecular docking of the most active ligands 1a-d, 3c into the
active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with
calculated binding energies from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation
belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C.
albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-
yltriphenylphosphonium salts 1a-d, 3c are the perspective objects for further study as antimicrobials against infectious MDR pathogens.
Keywords: transglycosylase; triphenylphosphonium salts; 1,3-oxazole; Candida albicans; Staphylococcus aureus.
Introduction
Hospital infections, which often lead to systemic damage
and mortality in patients with various types of diseases, are
an important problem in the modern healthcare system [1].
The increase in the number of hospital infections is directly
related to patients with reduced immunity of various
etiologies. The rapid development of multidrug resistance in
most microbial pathogens is the main motivation for the
rapid development and creation of drugs with new
alternative molecular mechanisms of action [2]. It is known
that bacterial TG are used as a promising target for the
development of new antimicrobial drugs [3-4]. On the other
hand, such antifungal agents as caspofungin, anidulafungin
Received:
Revised:
Accepted:
Published online:
16.04.2021
23.04.2021
17.05.2021
30.06.2021
Corresponding author. Tel.: +380-44-573-2595;
e-mail: ivan@bpci.kiev.ua (I. V. Semenyuta)
ORCID: 0000-0001-8464-3692
and micafungin are inhibitors of 1,3-beta-glucan synthase
(EC 2.4.1.34) from the transglycosylase family and
participate in the formation of the main component of the
fungal cell wall - beta-1,3-glucan polymer [5-6].
Many transglycosylases inhibitors are known as drugs or
antibiotics. There is evidence about echinocandins as
inhibitors of fungal β-1,3-glucan synthases [6], ethambutol
as an inhibitor of mycobacterial arabinotransferases [7],
moenomycin as an inhibitor of peptidoglycan
glycosyltransferases [8] and niccomycins as inhibitors of
chitin synthases [9]. Phosphonium salts have also
demonstrated transglycosylase activity as antimicrobial
agents against methicillin-resistant S. aureus [10]. Analysis
of the structure-activity relationship of salts in the online
chemical database ChEMBL confirmed this fact as well
[11]. As pharmacological agents, a number of phosphonium
salts have shown high activity against parasites of the genus
Leishmania [12], Trypanosoma brucei [13], Trypanosoma
cruzi [14] and Schistosoma mansoni [15]. Particular interest
in the TPPs is due to a number of other unique properties.
They can act as intracellular antioxidants [16],
acetylcholinesterase inhibitors [17], chemotherapeutic
© Semenyuta I. 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
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mailto:ivan@bpci.kiev.ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
26
agents [18], some studies have demonstrated the
antiglycemic properties and antiproliferative activity of
phosphonium salts [19, 20].
In our work, the results of in silico and in vitro studies of
a number of 1,3-oxazol-4-yltriphenylphosphonium salts are
presented as effective antimicrobial agents with a high
activity potential against bacterial and fungal strains with a
special type of molecular action.
Results and discussion
The synthesis of 5-amino- and 5-sulfanyl-1,3-oxazol-4-
yl(triphenyl)phosphonium salts 1-4 was based on
convenient approaches developed by B. S. Drach and
coworkers [21-23]. 5-Alkylsulfanyl-1,3-oxazol-4-
yl(triphenyl)phosphonium iodides 1a-d were synthesized
from available 1-acylamino-2,2-dichloroethenyl
(triphenyl)phosphonium chlorides A of the general formula
Cl2C=C(NHC(O)Ar)P+Ph3Cl- [21] by the reaction with
sodium hydrosulfide followed by alkyl iodide treatment
[21] (Scheme 1).
Scheme 1. Synthesis of 5-аlkylsulfanyl-1,3-oxazol-4-
yl(triphenyl)phosphonium iodides 1a-d.
For the synthesis of 5-(4-chlorophenylsulfanyl)-2-(4-
methylphenyl)-1,3-oxazol-4-yl(triphenyl)phosphonium
perchlorate (2) 2,2-dichloro-1-((4-methylbenzoyl)amino)
ethenyl(triphenyl)phosphonium chloride A was converted
into the corresponding ylide betaine B. The reaction of
compound B with methyl iodide with subsequent hydrogen
peroxide oxidation and sodium perchlorate treatment leads
to 5-mesyl-substituted 1,3-oxazol-4-yl(triphenyl)-
phosphonium chloride C. By the substitution of mesyl
group with sodium 4-chlorobenzenethiolate we obtained
compound 2 [22] (Scheme 2).
Interaction of the 1-acylamino-2,2-dichloroethenyl-
(triphenyl)phosphonium chlorides A with amines leads to
formation of 5-amino-1,3-oxazol-4-yl(triphenyl)-
phosphonium chlorides converted to the corresponding
phosphonium iodides or perchlorates 3a-e [21, 24]
(Scheme 3). Cyclization of urea derivatives D with
morpholine leads to 2-anilino-5-morpholino-1,3-oxazol-4-
yl(triphenyl) phosphornium perchlorate (4) [23] (Scheme
4).
Scheme 2. Synthesis of 5-(4-chlorophenylsulfanyl)-2-(4-
methylphenyl)-1,3-oxazol-4-yl(triphenyl)phosphonium
perchlorate (2).
Scheme 3. Synthesis of 5-aminosubstituted 2-aryl-1,3-oxazol-4-
yl(triphenyl)phosphonium iodides or perchlorates 3a-e.
Scheme 4. Synthesis of 2-anilino-5-morpholino-1,3-oxazol-4-
yl(triphenyl)phosphonium perchlorate (4).
Earlier, we have obtained and published the results of in
silico and in vitro studies of a number of TPPs as effective
antimicrobial agents against S. aureus and C. albicans,
including against their clinical drug-resistant isolates [25,
26], presented in Table 1.
Table 1 demonstrates that salts 1a-d, 3с are the most
active against both bacterial S. aureus and fungal C.
albicans strains. It is important to note the high
antimicrobial potential of these compounds against clinical
drug-resistant strains. Many authors associate the anti-
staphylococcal potential of TPPs with their transglycosylase
activity [10]. A similarly high potential was noted in our
I. V. Semenyuta, M. M. Trush, D. M. Hodyna et al.
27
Table 1. Antimicrobial activity of TPPs.
Compound
Antibacterial activity* Antifungal activity*
S. aureus
ATCC 25923
S. aureus
MDR
C. albicans
ATCC 10231
C. albicans
MDR
1 38,7±0,3 32,3±0,3 36,0 ± 0,3 30,3 ± 0,3
2 34,3±0,9 31,0±0,9 35,3 ± 0,9 30,0 ± 0,6
3 34,7±0,6 34,7±0,6 36,7 ± 0,3 37,3 ± 0,6
4 37,3±0,6 34,7±0,6 29,3 ± 0,6 31,3 ± 0,3
5 20,3 ± 0,3 34,3±0,6 22,0 ± 0,3 17,0 ± 0,6
6 32,3±0,6 24,3±0,3 14,3 ± 0,3 15,3 ± 0,3
7 30.3±0.6 28.3±0.3 22,3 ± 0,3 21,0 ± 0,3
8 35.0±0.6 31.3±0.3 38,0 ± 0,9 34,7 ± 0,3
9 36.3±0.9 32.0±0.3 25,7 ± 0,3 27,0 ± 0,6
10 20,7±0,3 19,3±0,3 21,3 ± 0,3 16,0 ± 0,3
11 27,5±0,3 22,0±0,6 18,0 ± 0,3 14,0 ± 0,6
Fluconazole - - 21,6±0,3 n/a
Ampicillin 29,0±0,6 n/a - -
Oxacillin 30,3±0,3 n/a - -
Ceftriaxone 11,3±0,6 n/a - -
work against the fungi (Table 1). Hence, it was possible to
assume a similar target-oriented molecular mechanism of
TPPs action. Based on this hypothesis, we conducted in
silico studies including the creation of a homology model
C. albicans TG.
A preliminary search of amino acid sequences associated
with C. albicans TGs was conducted by the SWISS-
MODEL template library. 1726 templates were created,
from which the 5oa6.1.A template with 48.65% sequence
identity was selected and a homology model was built. The
created model (Figure 1) is the most optimal considering
the resolution (1.94Å) and the estimation quality QMEAN
(-1.75), GMQE (0.61).
At the next stage, the quality of the homology model was
assessed using the online resources ERRAT and
PROCHECK-web server data analysis has been also
confirmed the 3D model structure TG good quality using
Ramachandran plot analysis (Figure 2). Ramachandran plot
results indicated that 90.0 % of the amino acid residues
were distributed in the favored regions, 9.5 % – in the
additionally allowed regions, 0.3 % – in the generously
allowed regions and only 0.3 % – in the disallowed regions.
Thus, the created 3D structure of TG С. albicans has
good stereochemically quality and was used for molecular
docking. Molecular docking of ligands 1a-d and 3c, as the
most active antimicrobials, was carried out into the active
site of the created homology C. albicans TG model (Figure
3, 4). Ligand-protein complex formation of the studied
TPPs was provided by various types of interactions (Table
2).
Thus, the formation of ligand-protein complexes is
accompanied by estimated binding energies in a certain
range from -8.9 to -9.7 kcal/mol (Table 2). The ligand-
protein complexes were stabilized through strong hydrogen
bonds (2.59-2.75 Ǻ), electrostatic (3.38-4.55 Ǻ) and
hydrophobic (3.94-5.26 Ǻ) interactions. The amino acid
residues TYR307, TYR107, GLU275, ALA108 and
PRO136 play a key role in this complexation.
Conclusions
Thus, we have experimentally established the presence
of high antibacterial and antifungal activity of TPPs 1a-d,
3с, including the activity against drug-resistant clinical
isolates obtained from biomaterial. The formation of stable
ligand-protein complexes is provided by strong hydrogen
bonds between amino acid residues and the oxazole ring of
the ligands. The triphenylphosphonium group also plays a
special role in the stabilization of the complexes. Other
substituents in the structure of salts also form a number of
electrostatic (3.38-4.55 Ǻ) and hydrophobic interactions
(3.94-5.26 Ǻ).
Thus, a qualitative homology model of C. albicans TG
can be used as a tool for the successful construction of new
agents with the double antimicrobial action mechanism.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
28
Figure 1. Quality assessment of the created homology model TG C. albicans. a) QMEAN quality plot of the homology model; b) the 3D
profile of subunit A TG verified by using ERRAT server.
Table 2. Docking results of ligands 1a-d, 3c into TG С. albicans active sites.
Compound ∆G,
kcal/mol
Hydrogen bonds Electrostatic interaction Hydrophobic interactions
1a ̶ 9.2 TYR307 (2.59Ǻ)
GLU275 (3.61Å),
GLU275 (3.38Å),
GLU176 (4.12Å)
TYR307 (5.20Ǻ), TYR107 (4.41Ǻ),
TYR244 (4.92Ǻ), TYR307 (5.18Ǻ),
TYR107 (5.18Ǻ), TYR107 (3.94Ǻ),
ALA108 (5.27Ǻ), PRO136 (4.45Ǻ),
PRO136 (4.60Ǻ)
1b ̶ 9.3 TYR307 (2.65Ǻ)
TYR307 (3.60Ǻ),
TYR307 (3.38Ǻ),
GLU275 (4.12Ǻ),
TYR107 (4.08Ǻ)
GLU275 (5.20Ǻ), TYR107 (4.41Ǻ),
TYR107 (3.96Ǻ), ALA108 (5.22Ǻ),
PRO136 (4.35Ǻ), PRO136 (4.53Ǻ)
1c ̶ 8.9 TYR307 (2.75Ǻ)
GLU275 (3.64Ǻ),
TYR107 (3.94Ǻ)
TYR244 (4.89Ǻ), TYR307 (5.26Ǻ),
TYR107 (4.41Ǻ), TYR107 (3.97Ǻ),
ALA108 (5.26Ǻ), PRO136 (4.32Ǻ),
PRO136 (4.55Ǻ)
1d ̶ 9.1 TYR307 (2.76Ǻ)
GLU275 (3.58Ǻ),
TYR107 (4.00Ǻ)
TYR307 (5.25Ǻ), TYR107 (4.39Ǻ),
ALA108 (5.22Ǻ), PRO136 (4.29Ǻ),
PRO136 (4.54Ǻ)
3с ̶ 9.7 TYR307 (2.74Ǻ)
GLU275 (3.70Ǻ),
GLU275 (4.99Ǻ),
ARG142 (4.55Ǻ)
TYR307 (5.05Ǻ), TYR107 (4.88Ǻ),
TYR107 (5.10Ǻ), PRO136 (5.21Ǻ),
PRO136 (5.16Ǻ)
I. V. Semenyuta, M. M. Trush, D. M. Hodyna et al.
29
Figure 2. Quality assessment of the created homology model TG C. albicans. Ramachandran plot analysis of the stereochemical quality of
TG model generated by PROCHECK validation server.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
30
Figure 3. Molecular docking of the ligands 1a-d into the active site of TG C. albicans.
Figure 4. Molecular docking of the ligand 3с into the active site of TG C. albicans.
I. V. Semenyuta, M. M. Trush, D. M. Hodyna et al.
31
1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3с are
promising candidates for the development of new
antimicrobials against infectious pathogens MDR S. aureus
and C. albicans.
Experimental section
General chemistry methods
Melting points were determined on a Fisher-Johns
apparatus. IR spectra were recorded on a Vertex-70
spectrometer from KBr pellets. 1H and 13C NMR spectra
were recorded on Varian Mercury 400 (400 MHz) and
Bruker Avance DRX 500 (500 and 125 MHz, respectively)
spectrometers in (CD3)2SO or CDCl3 taking its residual
protons signal as a standard. LCMS analysis was performed
on an Agilent 1200 Series system equipped with a diode
array and a G6130A mass-spectrometer (atmospheric
pressure electrospray ionization). Combustion elemental
analysis was performed in the V.P. Kukhar Institute of
Bioorganic Chemistry and Petrochemistry of the NAS of
Ukraine analytical laboratory.
The structure of investigated 1,3-oxazole derivatives 1a-
d [26, 27], 2 [27, 22], 4 [28], 3a [29, 30], 3b,c [21], 3d [26]
and 3e [24] have been confirmed by NMR (1H and
13C NMR), IR spectroscopy, chromato-mass and elemental
analysis and corresponded to previously described.
Biology
The antimicrobial activity of the studied
triphenylphosphonium salts (TPPs) was estimated against
C. albicans (ATCC 10231 and fluconazole-resistant clinical
isolate) and S. aureus (ATCC 25923 and multi-drug (MDR)
resistant clinical isolate) received from the Museum of
Microbial Culture Collection of the P.L. Shupyk National
Medical Academy of Postgraduate Education.
Antimicrobial properties were determined by the disc
diffusion method in Mueller-Hinton and Sabouraud agar
[31]. A final inoculum concentration of 1•105 colony-
forming unit (CFU) per mL was established using a
0.5 McFarland turbidity standard and subsequent dilution of
0.02 ml of the tested compounds was applied on standard
paper disks (6 mm) which were placed on the agar plate.
The compound content on a disk was 0.3 µM. The known
antifungal Fluconazole and antibacterial Ampicilline,
Oxacilline and Ceftriaxone were used as positive controls.
The activity of tested compounds was identified by
measuring the zone diameter of the growth inhibition,
which indicates the degree of susceptibility or resistance of
all microbial pathogens against the test compounds. The
compounds, which formed zones > 15 mm of growth
inhibition of microorganisms, were selected as active.
Homology modeling
Homology modeling of the aminoacid sequence of C.
albicans TG (UniProt: C4YFM5) [32] was performed using
web server SWISS-MODEL [33]. First, a preliminary
search for evolutionarily related aminoacids sequences was
performed using the SWISS-MODEL template library.
Search and analysis of structures homologous to C. albicans
TG were performed using the methods of BLAST [34] and
HHBlits [35]. Templates for building a homology model
were selected based on the overall rating of the created
templates. The quality of the created homology model of
C. albicans TG was estimated using internal methods of
testing the web server SWISS-MODEL [36] and web
servers ERRAT [37] and PROCHECK [38].
Molecular docking
The created homology model of C. albicans TG was
used for docking studies. AutoDock Tools (ADT) 1.5.6 [39]
was used to prepare the protein and ligands. All polar
hydrogens were added to the protein molecules by ADT.
The renumbering of all atoms with included new hydrogen
atoms were performed by the noBondOrder method. The
Gasteiger method was applied for the calculation and
addition of partial charges. The made protein and ligands
were saved in PDBQT format. The ChemAxon Marvin
Sketch 5.3.735 program [40] was used to create, optimize
and save the ligand structures in Mol2 format. The ligands
optimization and energy minimization were performed by
Avogadro v1.1.1 [41] using an auto-optimization tool by
applying MMFF94s force field with the steepest descent
algorithm. The partial charges and torsion angles of the
ligands were altered by ADT and saved in PDBQT format.
Docking was performed by AutoDock Vina 1.1.2 program
[42]. The grid map (30*30*30 points) with a grid spacing of
1Å was used. The analysis and visualization of protein-
ligand interactions were conducted by Accelrys DS 4.0
[43].
Notes
Acknowledgments and finances. We thank the National
Research Foundation of Ukraine (NRFU competition
"Science for the Security of Human and Society"
№2020.01/0075) for financial support.
The authors declare no conflict of interest.
Author contributions. I. V. S: molecular docking,
homology modeling, analysis results, conceptualization,
writing and editing. M. M. T., D. M. H. the investigation of
bioactivity. M. V. K: synthesis of compounds, writing
experimental section. V. S. B: synthesis of compounds,
conceptualization. L. O. M: the investigation of bioactivity,
conceptualization, results analysis, writing and editing.
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14. Long, T. E.; Lu, X.; Galizzi, M.; Docampo, R.; Gut, J.; Rosenthal,
P.J. Phosphonium lipocations as antiparasitic agents. Bioorg. Med.
Chem. Lett. 2012, 8, 2976-2979.
15. McAllister, P. R.; Dotson, M. J.; Grim, S. O.; Hillman, G. R. Effects
of phosphonium compounds on Schistosoma mansoni. J. Med. Chem.
1980, 8, 862-865.
16. Korshunova, G. A.; Shishkina, A. V.; Skulachev, M. V. Design,
synthesis, and some aspects of the biological activity of
mitochondria-targeted antioxidants. Biochemistry (Moscow). 2017,
82, 760-777.
17. Levi-Schaffer, F.; Tarrab-Hazdai, R.; Meshulam, H.; Arnon, R.;
Effect of phosphonium salts and phosphoranes on the
acetylcholinesterase activity and on the viability of Schistosoma
mansoni parasites. Int. Immunopharmacol. 1984, 6, 619-627.
18. Bergeron, K. L.; Murphy, E. L.; Majofodun, O.; Muñoz, L. D.;
Williams, J. C.; Almeida, K. H. Arylphosphonium salts interact with
DNA to modulate cytotoxicity. Mutat. Res. 2009, 2, 141-148.
19. Blank, B.; DiTullio, N. W.; Deviney, L.; Roberts, J. T.; Saunders, H.
L. Synthesis and hypoglycemic activity of phenacyl-
triphenylphosphoranes and phosphonium salts. J. Med. Chem. 1975,
9, 952-954.
20. Rideout, D. C.; Calogeropoulou, T.; Jaworski, J. S.; Dagnino, R.;
McCarthy, M. R. Phosphonium salts exhibiting selective anti-
carcinoma activity in vitro. Anticancer Drug Des. 1989, 4, 265-280.
21. Lobanov, O. P.; Martyn'yuk, A. P.; Drach, B. S. Reactions of (2,2-
dichloro-1-acylaminovinyl)triphenylphosphonium chlorides with
nucleophiles. Zh. Obshch. Khim. 1980, 50, 2248-2257.
22. Golovchenko, A. V.; Brovarets, V. S.; Drach, B. S. A Convenient
Procedure for Introducing Arylsulfanyl and Heterylsulfanyl Groups
into the 5 Position of the Oxazole Ring. Rus. J. Gen. Chem. 2004, 74,
1414-1417.
23. Martynyuk, A. P.; Brovarets, V. S.; Lobanov, O. P.; Drach, B. S.
Phosphorus-containing derivatives of N-2,2-dichlorovinylurea. Zh.
Obshch. Khim. 1984, 54, 2186-2200.
24. Abdurakhmanova, E. R.; Pil’o, S. G.; Kondratyuk, K. M.;
Golovchenko, A. V.; Brovarets, V. S. 1,3-Oxazole derived cytisines.
Russ. J. Gen. Chem., 2017, 87, 244-251.
25. Trush, M. M.; Kovalishyn, V.; Ocheretniuk, A. D.; Kovalishyn, V.;
Ocheretniuk, A. D.;Kachaeva, M. V.; Brovarets, V. S.; Metelytsia, L.
O. QSAR Study of Some 1,3-Oxazolylphosphonium Derivatives as
New Potent Anti-Candida Agents and Their Toxicity Evaluation.
Curr. Drug Discov. Technol. 2019, 16, 204-209.
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E.; Prokopenko, V. M.; Holovchenko, O. V.; Kobzar, O. L.;
Brovarets V. S.; Metelytsia, L. O. New 1,3-oxazolylphosphonium
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Chumachenko, S.; Tetko, I. V.; Brovarets, V. S.; Metelytsia, L. In
silico and in vitro studies of a number PILs as new antibacterials
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metallic salt and a surfactant / Tessier, D.; Filteau, M.; Radu I. Patent
appl. No PCT/CA2006/000543 07.04.2006. Publ. 12.10.2006.
29. Brovarets, V. S.; Lobanov, O. P.; Drach, B. S. Syntheses of 2,5-
substituted azoles from (2,2-dichloro-1-acylaminovinyl)
triphenylphosphonium chlorides. Zh. Obshch. Khim. 1983, 53, 2015-
2020.
30. Drach, B. S.; Sviridov, E. P.; Kirsanov, A. V. Reaction of 1,2,2,2-
tetrachloroethylamides of acids with the ethyl ester of
diphenylphosphinous acid and with triphenylphosphene. Zh. Obshch.
Khim. 1975, 45, 12-16.
31. A. W. Bauer, W. M. Kirby, J. C. Sherris, M. Turck. Am. J. Clin.
Pathol. 1966, 45, 493-496.
32. The UniProt Consortium, UniProt: the universal protein
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on April 16, 2021).
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Gumienny, R.; Heer, F. T.; de Beer, T. A. P.; Rempfer, C.; Bordoli,
L.; Lepore, R.; Schwede, T. SWISS-MODEL: homology modelling
of protein structures and complexes. Nucleic Acids Res. 2018, 46,
296-303.
34. Camacho, C.; Coulouris, G.; Avagyan, V.; Ma, N.; Papadopoulos, J.;
Bealer, K.; Madden, T.L. BLAST+: architecture and applications.
BMC Bioinformatics, 2009, 10, 421-430.
35. Steinegger, M.; Meier, M.; Mirdita, M.; Vöhringer, H.; Haunsberger,
S. J.; Söding, J. HH-suite3 for fast remote homology detection and
deep protein annotation. BMC Bioinformatics. 2019, 20, 473.
36. Benkert, P.; Biasini, M.; Schwede, T. Toward the estimation of the
absolute quality of individual protein structure models.
Bioinformatic. 2011, 27, 343-350.
37. Colovos, C.; Yeates, T. O. Verification of protein structures: patterns
of nonbonded atomic interactions. Protein Sci. 1993, 2, 1511-1519.
38. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M.;
PROCHECK - a program to check the stereochemical quality of
protein structures. J. App. Cryst. 1993, 26, 283-291.
39. Sanner, M. F. Python: A programming language for software
integration and development. J. Mol. Graph. Model. 1999, 17, 57-61.
40. Marvin Sketch was used for drawing, displaying and optimization
chemical structures; MarvinSketch 5.3.735, 2017, ChemAxon
website [Internet]. Available from: http://www.chemaxon.com
(accessed on April 16, 2021).
41. Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.;
Zurek, T.; Hutchison, G. R. Avogadro: an advanced semantic
chemical editor, visualization, and analysis platform. J. Cheminform.
2012, 4, 17.
42. Trott, O.; Olson, A. J. AutoDock Vina: improving the speed and
accuracy of docking with a new scoring function, efficient
optimization, and multithreading. J. Comput. Chem. 2010, 31, 455-
461.
43. Dassault Systèmes BIOVIA, Discovery Studio Visualizer,
v4.0.100.13345. Dassault Systèmes; San Diego: Dassault Systèmes,
2020.
https://www.ebi.ac.uk/chembl/assay_report_card/CHEMBL1640432/
https://www.uniprot.org/uniprot/C4YFM5
http://www.chemaxon.com/
I. V. Semenyuta, M. M. Trush, D. M. Hodyna et al.
33
In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як
потенційних інгібіторів трансглікозилази Candida albicans
І. В. Семенюта*, М. М. Труш, Д. М. Година, М. В. Качаєва, Л. О. Метелиця, В. С. Броварець
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
Резюме: У роботі запропоновано новий потенційний молекулярний механізм дії 1,3-оксазол-4-ілтрифенілфосфонієвих солей як інгібіторів
трансглікозилази. За результатами біологічних досліджень встановлено високий антимікробний потенціал досліджених солей трифенілфосфонію
як проти бактеріальних (Staphylococcus aureus ATCC 25923 та мультирезистентний), так і проти грибкових (Candida albicans ATCC 10231 та
мультирезистентний) штамів. Отримані експериментальні дані щодо їх антимікробної активності дозволили запропонувати молекулярний
механізм дії цих сполук, пов'язаний з трансглікозилазною активністю. В основу гіпотези було покладено результати аналізу «структура-
активність» солей трифосфонію в онлайн хімічній базі ChEMBL, а також за відомими літературниими джерелами щодо антимікробної активності
солей як інгібіторів трансглікозилази S. aureus. Створена гомологічна модель трансглікозилази C. albicans продемонструвала високі показники
якості та була використана для молекулярного докінгу. Молекулярний докінг найбільш активних лігандів 1a-d, 3с в активний центр створеної
гомологічної моделі C. albicans засвідчив утворення стабільних ліганд-білкових комплексів з ∆G в діапазоні від -8,9 до -9,7 ккал/моль шляхом
формування різних типів взаємодій. Представлена якісна гомологічна модель трансглікозилази C. albicans може бути використана для пошуку та
створення нових агентів з подвійним механізмом антимікробної дії. Солі 1,3-оксазол-4-ілтріфенілфосфонію 1a-d, 3с є перспективними об’єктами
для подальшого вивчення в якості антимікробних засобів проти мультирезистентних інфекційних збудників.
Ключові слова: трансглікозилаза; трифенілфосфонієві солі; 1,3-оксазол; Candida albicans; Staphylococcus aureus.
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| id | oai:ojs2.bioorganica.com.ua:article-45 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:02Z |
| publishDate | 2021 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
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| spelling | oai:ojs2.bioorganica.com.ua:article-452026-07-19T14:56:54Z In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts as potential inhibitors of Candida albicans transglycosylase In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans Semenyuta, Ivan V. Trush, Maria M. Hodyna, Diana M. Kachaeva, Maryna V. Metelytsia, Larysa O. Brovarets, Volodymyr S. transglycosylase triphenylphosphonium salts 1,3-oxazole Candida albicans Staphylococcus aureus трансглікозилаза трифенілфосфонієві солі 1,3-оксазол Candida albicans Staphylococcus aureus The previously established in vitro high antimicrobial activity of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG C. albicans is optimal in terms of quality indicators such as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot analysis (90% amino acid residues in the favored regions). The modeling of molecular docking of the most active ligands 1a-d, 3c into the active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with calculated binding energies from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C. albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3c are the perspective objects for further study as antimicrobials against infectious MDR pathogens У роботі запропоновано новий потенційний молекулярний механізм дії 1,3-оксазол-4-ілтрифенілфосфонієвих солей як інгібіторів трансглікозилази. За результатами біологічних досліджень встановлено високий антимікробний потенціал досліджених солей трифенілфосфонію як проти бактеріальних (Staphylococcus aureus ATCC 25923 та мультирезистентний), так і проти грибкових (Candida albicans ATCC 10231 та мультирезистентний) штамів. Отримані експериментальні дані щодо їх антимікробної активності дозволили запропонувати молекулярний механізм дії цих сполук, пов'язаний з трансглікозилазною активністю. В основу гіпотези було покладено результати аналізу «структура-активність» солей трифосфонію в онлайн хімічній базі ChEMBL, а також за відомими літературниими джерелами щодо антимікробної активності солей як інгібіторів трансглікозилази S. aureus. Створена гомологічна модель трансглікозилази C. albicans продемонструвала високі показники якості та була використана для молекулярного докінгу. Молекулярний докінг найбільш активних лігандів 1a-d, 3с в активний центр створеної гомологічної моделі C. albicans засвідчив утворення стабільних ліганд-білкових комплексів з ∆G в діапазоні від -8,9 до -9,7 ккал/моль шляхом формування різних типів взаємодій. Представлена якісна гомологічна модель трансглікозилази C. albicans може бути використана для пошуку та створення нових агентів з подвійним механізмом антимікробної дії. Солі 1,3-оксазол-4-ілтріфенілфосфонію 1a-d, 3с є перспективними об’єктами для подальшого вивчення в якості антимікробних засобів проти мультирезистентних інфекційних збудників V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2021-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/45 10.15407/bioorganica2021.01.025 Ukrainica Bioorganica Acta; Vol. 16 No. 1 (2021): Ukrainica Bioorganica Acta; 25-33 Ukrainica Bioorganica Acta; Том 16 № 1 (2021): Ukrainica Bioorganica Acta; 25-33 1814-9766 1814-9758 10.15407/bioorganica2021.01 en https://bioorganica.com.ua/index.php/journal/article/view/45/45 Copyright (c) 2021 Ivan V. Semenyuta, Maria M. Trush, Diana M. Hodyna, Maryna V. Kachaeva, Larysa O. Metelytsia, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | трансглікозилаза трифенілфосфонієві солі 1,3-оксазол Candida albicans Staphylococcus aureus Semenyuta, Ivan V. Trush, Maria M. Hodyna, Diana M. Kachaeva, Maryna V. Metelytsia, Larysa O. Brovarets, Volodymyr S. In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title | In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title_alt | In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts as potential inhibitors of Candida albicans transglycosylase |
| title_full | In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title_fullStr | In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title_full_unstemmed | In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title_short | In vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази Candida albicans |
| title_sort | in vitro та in silico дослідження 1,3-оксазол-4- ілтрифенілфосфонієвих солей як потенційних інгібіторів трансглікозилази candida albicans |
| topic | трансглікозилаза трифенілфосфонієві солі 1,3-оксазол Candida albicans Staphylococcus aureus |
| topic_facet | transglycosylase triphenylphosphonium salts 1,3-oxazole Candida albicans Staphylococcus aureus трансглікозилаза трифенілфосфонієві солі 1,3-оксазол Candida albicans Staphylococcus aureus |
| url | https://bioorganica.com.ua/index.php/journal/article/view/45 |
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