Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка
The QSAR models previously created by the OCHEM web platform were used for the research and design of novel isoxazole derivatives as antimicrobial agents. Based on the created virtual set of promising isoxazole derivatives, a number of potential antibacterial agents were selected for synthesis and f...
Gespeichert in:
| Datum: | 2022 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2022
|
| Schlagworte: | |
| Online Zugang: | https://bioorganica.com.ua/index.php/journal/article/view/32 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Ukrainica Bioorganica Acta |
| Завантажити файл: |  |
Institution
Ukrainica Bioorganica Acta| _version_ | 1871193565844996096 |
|---|---|
| author | Hodyna, Diana M. Pavliuk, Oleksandr V. Baran, Maria M. Yevdokymenko, Vitaliy O. Kovalishyn, Vasyl V. Metelytsia, Larysa O. |
| author_facet | Hodyna, Diana M. Pavliuk, Oleksandr V. Baran, Maria M. Yevdokymenko, Vitaliy O. Kovalishyn, Vasyl V. Metelytsia, Larysa O. |
| author_institution_txt_mv | [
{
"author": "Diana M. Hodyna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr V. Pavliuk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maria M. Baran",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Vitaliy O. Yevdokymenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Vasyl V. Kovalishyn",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Larysa O. Metelytsia",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Hodyna, Diana M. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | The QSAR models previously created by the OCHEM web platform were used for the research and design of novel isoxazole derivatives as antimicrobial agents. Based on the created virtual set of promising isoxazole derivatives, a number of potential antibacterial agents were selected for synthesis and further research. A convenient synthetic sequence for obtaining initial isoxazole-containing sulfonylamides and preparative methods for the synthesis of target sulfonylamides of the isoxazole series, in particular, using ring-closing metathesis reactions, were worked out. The results of in vitro antimicrobial activity evaluation of synthesized compounds with predicted high activity showed that a series of isoxazole-containing sulfonylamides are promising antimicrobial agents with a wide spectrum of antibacterial action, especially against multidrug-resistant E. coli, A. baumannii and S. aureus bacterial pathogens. In vivo assessment of the acute toxicity of the studied compounds on the D. magna as a known biosensor proved that most of the studied isoxazole derivatives can be attributed to the class of slightly toxic substances according to the classification developed by Passino and Smith for hydrobionts |
| doi_str_mv | 10.15407/bioorganica2022.02.023 |
| first_indexed | 2025-07-17T12:19:36Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
UDC 547.7/.8, 579.22, 615.281: 577.1
DOI: https://doi.org/10.15407/bioorganica2022.02.023
23
RESEARCH ARTICLE
Isoxazole-containing sulfonylamides as new antibacterial agents: in silico
study, synthesis and in vitro evaluation
Diana M. Hodyna*, Oleksandr V. Pavliuk, Maria M. Baran, Vitaliy O. Yevdokymenko,
Vasyl V. Kovalishyn, Larysa O. Metelytsia
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: The QSAR models previously created by the OCHEM web platform were used for the research and design of novel isoxazole
derivatives as antimicrobial agents. Based on the created virtual set of promising isoxazole derivatives, a number of potential antibacterial
agents were selected for synthesis and further research. A convenient synthetic sequence for obtaining initial isoxazole-containing
sulfonylamides and preparative methods for the synthesis of target sulfonylamides of the isoxazole series, in particular, using ring-closing
metathesis reactions, were worked out. The results of in vitro antimicrobial activity evaluation of synthesized compounds with predicted
high activity showed that a series of isoxazole-containing sulfonylamides are promising antimicrobial agents with a wide spectrum of
antibacterial action, especially against multidrug-resistant E. coli, A. baumannii and S. aureus bacterial pathogens. In vivo assessment of
the acute toxicity of the studied compounds on the D. magna as a known biosensor proved that most of the studied isoxazole derivatives
can be attributed to the class of slightly toxic substances according to the classification developed by Passino and Smith for hydrobionts.
Keywords: QSAR; antibacterial activity; isoxazole; sulfonylamide; toxicity.
Introduction
The wide range of pharmacological activity of sulfo-
containing derivatives in organic chemistry makes them a
convenient option for inclusion in a significant number of
available drugs on the marketplace [1-2]. Sulfonylamides
are a well-known class of broad-spectrum synthetic
antibiotics. Thus, in particular, they are quite effective
against gram-positive and some gram-negative bacteria
such as Salmonella, Escherichia coli, and Enterobacter, but
are ineffective against Pseudomonas aeruginosa and
Serratia species [3-4]. It is known about the effectiveness of
the use of sulfonylamides in the treatment of tonsillitis,
hypoglycemia, thyroiditis, inflammation, glaucoma,
bacillary dysentery, septicemia, and urinary tract diseases
[5-6].
Received:
Revised:
Accepted:
Published online:
18.08.2021
13.09.2021
25.10.2021
30.12.2021
Corresponding author. Tel.: +380-44-296-0409;
e-mail: dianahodyna@gmail.com (D.M. Hodyna)
ORCID: 0000-0001-6161-9833
There is evidence of the effectiveness of sulfonylamides
against some fungal and bacterial infections caused by
Nocardia species, Staphylococcus aureus, and Escherichia
coli [7-9].
Isoxazole-containing derivatives are one of the
interesting, promising but little-studied representatives of
nitrogen-containing heterocycles with an Oxygen atom,
which, due to a number of practically useful properties, are
considered one of the most important classes of substances
for use in medical chemistry and are an important source of
valuable drugs with a diverse spectrum of action [10-12].
Sulfo-derivatives are one of the most intensively studied
derivatives among the numerous isoxazole derivatives, a
significant number of which are a variety of biologically
active substances and even commercially available drugs.
They are quite actively used in the development of synthetic
bacteriostatic antibiotics of various spectrums of action [13-
16]. In this study, we evaluated the use of isoxazole-
containing sulfonylamides as a broad spectrum of action
using in vitro studies and QSAR modeling as method for
studying the quantitative relationship between the
structure of substances and biological activity based on the
© Hodyna D.M. 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
https://orcid.org/0000-0001-6161-9833
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
24
description of the structure of a chemical compound using a
set of numerical descriptors and machine learning methods
[17-19].
Results and Discussion
In this study the antibacterial activity of isoxazole-
containing sulfonylamides as E. coli inhibitors was
predicted using previously developed and published on the
OCHEM server regression QSAR models [20]. The dataset
included 5143 compounds active against E. coli ATCC
25922 which was randomly divided into training (3780
compounds) and test (1363 compounds) sets. Three
regression QSAR models built by the Trans-CNN, ASNN,
and RFR methods and the consensus model as an average of
all three models were created using descriptor packages
such as E-state, ALOGPS and CDK2, with the best
performances. The results are summarized in Table 1 and
the consensus model performance is shown in Figure 1.
Table 1. Statistical coefficients calculated for QSAR models obtained from data with activity against E. coli
N MLM
Training Set Test Set
R2 q2 RMSE R2 q2 RMSE
1 Trans-CNN 0.80 ± 0.01 0.80 ± 0.01 0.48 ± 0.01 0.8 ± 0.02 0.8 ± 0.02 0.48 ± 0.02
2 ASNN 0.73 ± 0.01 0.72 ± 0.01 0.58 ± 0.01 0.74 ± 0.02 0.74 ± 0.02 0.57 ± 0.03
3 RFR 0.76 ± 0.01 0.75 ± 0.01 0.55 ± 0.01 0.78 ± 0.02 0.77 ± 0.02 0.53 ± 0.02
4 Consensus model 0.79 ± 0.01 0.79 ± 0.01 0.34 ± 0.01 0.80 ± 0.02 0.79 ± 0.01 0.33 ± 0.01
MLM – machine learning method; R2 – square of correlation coefficient; q2 – coefficient of determination; RMSE – Root Mean Squared Error.
CH3 OCH3
Ar =
, ,
N O
Ar
Br
N O
Ar
S
N O
Ar
S
Na2SO3 PCl5
O
O
ONa
O
O
Cl
.
1a-c 2a-c 3a-c
a b c
N O
Ar
S
O
O
N O
HN O
4a-c
Scheme 1. Synthesis of isoxazole-containing sulfonyl chlorides and corresponding sulfonylamides.
N O
Ar
S
O
O
N O
4a-c
Br
KOH
N O
Ar
S
O
O
N O
5a-c
- C2H2
Ru =
N O
Ar
S
O
O
N O
6a-b
Ru
CH3 OCH3
Ar =
, ,
a b c
Ru
PCy3
PCy3
Cl
Cl
Scheme 2. Synthesis of isoxazole-containing target sulfonylamides.
D.M. Hodyna, O.V. Pavliuk et al.
25
Figure 1. Plots of experimental versus predicted values for the
consensus QSAR model for E. coli inhibitors; minimum inhibitory
concentration (MIC) is the lowest concentration of a chemical
which prevents the visible growth of a bacteria. Please refer to
Table 1 for the goodness of fit parameters.
Figure 1 shows the regression line plotting the values
predicted by the consensus QSAR model for E. coli
inhibitors. Most predictions do not differ from the
experimental values by more than 1 log unit. Only 5.6% of
molecules in the training set have residuals between the
experimental and predicted - log(MIC) higher than one log
unit. In the test set, 5% of molecules have residuals between
the experimental and predicted - log(MIC) that are higher
than one log unit, but lower than two log units. This result
supports the robustness of the developed consensus model
(Figure 1, Table 1).
The antibacterial activity of virtual compounds was
predicted by the developed consensus QSAR model. In
order to select compounds for synthesis and biological
testing, attention was paid to the anti-E. coli inhibitors with
predicted activity (- log(MIC) as 100 µM including the
structural features of isoxazole-containing sulfonylamides
(Table 2).
As we previously reported, one of the convenient ways
of obtaining isoxazole-containing sulfonyl chlorides is the
interaction of sulfinic acid salts with phosphorus
pentachloride. Sulfonyl chlorides of the isoxazole series are
obtained by boiling water-alcohol solutions of the
corresponding halides with equimolar amounts of sodium
sulfite, followed by the interaction of thoroughly dried salts
of sulfinic acids with phosphorus pentachloride (Scheme 1)
[21].
As a result of the interaction of isoxazole-containing
sulfonyl chlorides with the corresponding amines in the
presence of triethylamine in the solutions of
dichloromethane at a temperature of about 5-10 ºC for
0.5-1 hours a series of isoxazole-containing sulfonylamides
were obtained (Scheme 1). Target products 3a-c were
obtained with 82-85% yields. The structure of obtained
compounds is confirmed by the data of chromatomas
spectra, 1H, 13C NMR spectra and elemental analysis.
Sulfonylamides 4a-c were alkylated on active methylene
group with 3 equivalents of allyl bromide (50% excess) in
DMF solutions at a temperature of 65-70 ºС for 4-5 hours in
the presence of 3 equivalents of potassium hydroxide (50%
excess) (Scheme 2). Diallyl containing sulfonylamides 5a-c
were isolated with 63-67% yields. Their structure is
confirmed by chromatomass spectra, elemental analysis and
data of 1H, 13C NMR spectra.
Ring-closing metathesis reactions of the diallyl
derivatives 5a-b were carried out in solutions of dry
degassed dichloromethane in the atmosphere of dry argon at
a temperature of 25-30 ºC for 10-12 hours using a
ruthenium-carbene catalyst ([Ru]) (Scheme 2). Cycloalkenil
products 6a-b were isolated after chromatographic
purification with 71-75% yields. Their structure is
confirmed by chromatomass spectra, elemental analysis and
data of 1H, 13C NMR spectra, elemental analysis.
The obtained results of antibacterial activity of
synthesized isoxazole-containing sulfonylamides with
predicted anti-E. coli activity against standard and MDR
bacterial strains are presented in Table 2.
The results presented in Table 2 demonstrated in vitro
high antibacterial potential of almost all studied isoxazole-
containing sulfonylamides (except compound 5b) against
Gram-negative E. coli ATCC strain, which confirmed the
results of QSAR prediction of anti-E. coli activity. Zones
diameters of growth inhibition of the indicated ATCC
culture strain were 15-25 mm for seven tested compounds.
It is also worth noting that all compounds except compound
5b showed activity in the range of 11 to 24 mm against the
E. coli HMR strain. The least sensitive strain of E. coli
MDR showed sensitivity only to compound 4b with an
activity of 14 mm by the diameter of the growth inhibition
zone. Thus, it was experimentally proven that the isoxazole-
containing sulfanilamide 4b is the most active against all
studied E. coli strains (zone diameters of growth inhibition
were in the range from 14 mm to 25 mm).
Considering the established high antibacterial potential
of the studied isoxazole-containing sulfonylamides against
E. coli strains, the futures studies were focusing on the
compounds activity against a wider range of standard and
antibiotic-resistant bacterial strains.
It was found that studied isoxazole-containing
sulfonylamides 4a-b and 6a-b possessed a high
antibacterial effect against all studied A. baumannii strains
(zones diameters of growth inhibition were in the range
from 8 mm to 22 mm). Also, сompounds 4a-b, 5b, and
6a-b were effective against the gram-positive S. aureus
ATCC 25923 strain with a range of zones diameter of
growth inhibition of 14-17 mm and against MDR S. aureus
strain with a range of zones diameter of growth inhibition of
12-15 mm.
The prospects of the studied isoxazole-containing
sulfonylamides as antibacterials were confirmed by the in
vivo results of their toxic profile.
0
1
2
3
4
5
6
7
8
9
0 2 4 6 8
P
re
d
ic
te
d
-
lo
g
(M
IC
)
Observed -log(MIC)
Training set
Test set
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
26
Table 2. In vitro antibacterial activity of isoxazole-containing sulfonylamides with predicted activity.
Compd
Zone diameter of growth inhibition of bacterial strains, mm
E. coli А. baumannii S. aureus
Predicted
activity
-log(MIC)
ATCC
25922
HMRа MDRb
MDR
1355
MDR
1536
MDR
871
MDR
725
ATCC
25923
MDRс
4a 3.7 ± 0.8 16 15 na* 11 14 13 8 14 12
4b 3.7 ± 0.8 25 24 14 22 15 12 11 17 13
4c 3.7 ± 0.8 15 11 na 11 9 8 na na na
5a 3.9 ± 0.8 15 14 na 11 na na na na na
5b 4.0 ± 1.2 na na na na na na na 15 15
5c 4.0 ± 1.2 18 12 na 10 8 12 na na na
6a 3.8 ± 0.8 16 13 na 16 12 11 10 15 12
6b 3.8 ± 0.8 17 11 na 15 12 10 9 15 13
na* - no activity.
aClinical isolate of hemolytic E. coli resistant to carbenicillin, ceftazidime, cefoxitin, oxacillin.
bClinical isolate of E. coli resistant to ampicillin, doxycycline, carbenicillin, cefoxitin, ceftazidime, ceftriaxone, kanamycin, oxacillin, ofloxacin,
tetracycline.
сClinical isolate of S. aureus resistant to ampicillin, carbenicillin, ceftazidime, oxacillin, tetracycline.
Table 3. Acute toxicity of isoxazole-containing sulfonylamides as potential antibacterial agents using biomarker D. magna.
Compd LC50 (mg/L) 95% confidence intervals
Toxicity level classification (by D.R.
Passino and S.B. Smith)*
4a > 100 - +
4b 45.33 ± 13.40 17.18-73.48 + +
4c 37.32 ± 10.59 15.69-58.95 + +
5a 25.69 ± 6.08 12.91-38.47 + +
5b 21.84 ± 5.12 10.36-32.13 + +
5c 33.23 ± 10.04 13.67-52.45 + +
6a 44.45 ± 14.36 18.25-74.49 + +
6b 41.08 ± 13.97 11.73-70.42 + +
«-» not determined. *Toxicity classification by LC50 range: « + » practically harmless (100-1000 mg/L); « + + » slightly toxic (10-100 mg/L);
« + + + » moderately toxic (1-10 mg/L); « + + + +» highly toxic (0.1-1 mg/L).
One of the most widely used international biological
tests for screening the toxicity of chemical substances is the
acute toxicity test using invertebrate hydrobionts such as
cyclops, amphipods, artemia and daphnia [22-23]. Daphnia
magna is one of the most common planktonic crustaceans
from the Cladocera suborder [24-25]. Due to the high
reproduction rate, sizes sufficient for visual observation,
availability in nature, laboratory maintenance and high
sensitivity to the toxicity of chemical compounds, D. magna
was used as a test organism in determining the acute
toxicity of the studied isoxazole-containing sulfonylamides
as antibacterials.
The results of the acute toxicity evaluation (48 h LC50
values) of the tested isoxazole-containing sulfonylamides as
potential antibacterial agents are presented in Table 3.
Presented in Table 3 the obtained results of in vivo
testing using the hydrobiont D. magna demonstrated two
levels of acute toxicity of the studied isoxazole-containing
sulfonylamides. In general, most of the investigated
isoxazole-containing derivatives 4b-c, 5a-c and 6a-b
according to the classification of Passino and Smith can be
attributed to the class of slightly toxic substances with a
range of LC50 values from 21.84 mg/L to 45.33 mg/L [26].
The least toxic compound 4a can be classified as practically
harmless with LC50 > 100 mg/L.
Conclusions
The antibacterial activity of new isoxazole derivatives
was predicted by a number of developed and published
earlier regression QSAR models using the OCHEM web
platform. Eight new isoxazole-containing sulfonylamides
were identified for biological testing, the anti-E. coli
activity of which was predicted up to 100 µM. Convenient
and effective strategies for obtaining the corresponding new
D.M. Hodyna, O.V. Pavliuk et al.
27
sulfonylamides of the isoxazole series with an active
methylene group were developed, which were subsequently
transformed into the corresponding dialkenyl derivatives.
Using ring-closing metathesis reactions, a number of new
cyclopentenyl-containing arylsulfonylamides of the
isoxazole series were synthesized. The obtained in silico
and in vitro studies results of the antibacterial activity of
synthesized isoxazole-containing sulfanilamides proved the
high antibacterial potential of a number of tested
compounds against both gram-positive and gram-negative
bacterial pathogens of E. coli, A. baumannii and S. aureus,
including multiresistant strains and their positive toxicity
profile (LC50 values from 41.08 mg/L to > 100 mg/L, which
corresponds to the class of practically harmless substances).
Experimental section
Chemistry
General information: 1H (500 MHz) and 13C (125 MHz)
NMR spectra were recorded on Bruker Avance DRX 500
spectrometer in CDCl3. Chromatomass spectra were
recorded using a liquid chromatography-mass spectrometric
system using an Agilent 1100 Series high- performance
liquid chromatograph equipped with a diode array with an
Agilent LC/MSD SL mass-selective detector (ionization
method - is the chemical ionization at atmospheric pressure,
APCI). Parameters of chromatography-mass analysis:
column-Zorbax SB-C18, 1.8 µm, 4.6 х 15 mm; solvents A)
MeCN-H2O 95 : 5, 0.1% aqueous CF3COOH, B) 0.1%
aqueous CF3COOH; flow eluent – 3 ml / min; Injection
volume – 1 µm; UV detectors – 215, 254, 285 nm; Cl at
atmospheric pressure. Elemental analysis was carried out in
the laboratory of analytical chemistry of the Institute of
Bioorganic Chemistry and Petrochemistry of the National
Academy of Sciences of Ukraine: the carbon and hydrogen
content was determined by the weight method of Pregle,
nitrogen by the Dumas gas meterind method, and chlorine
by the mercuric method. For column chromatography, was
used silica gel Merck Grade 9385, 60 A, 230-400. The
commercially available reagents and solvents were used for
this work, sulfonyl chloride of isoxazoles series (3a-c) were
synthesized from corresponding bromo derivatives by the
procedure [21].
General procedure for the synthesis of 4-(3-arylisoxazol-
5-yl-methyl) sulfonylamides
To a solution of 0,01 mol of the corresponding sulfonyl
chloride (3a-c) in dichloromethane in the presence of
0.01 mol of triethylamine, 0.01 mol of morpholine in 30 ml
of dichloromethane was added dropwise over 0,5-1 hour at
5-10 °C. After addition, the reaction mixture was stirred for
1 hour at room temperature. After completion of the
reaction, the mixture was filtered, the solvent was
evaporated in vacuo, and the residue was washed with water
(2 x 20 ml). Target products were purified by recrystalli-
zation from 96% ethanol.
4-(3-Phenyl-isoxazol-5-ylmethanesulfonyl)-morpholine
(4a).
Yield 82%; mp 135-136 °C. 1H NMR (500 MHz, CDCl3)
δ 7.87-7.79 (m, 2H), 7.53-7.45(m, 3H), 6.82(s, 1H), 4.49 (s,
2H), 3.70 (d, J 5.5 Hz, 4H), 3.25(d, J 5.5 Hz, 4H). 13C NMR
(125 MHz, CDCl3) δ 162.65, 160.94, 130.04, 128.61,
127.75, 126.38, 103.70, 66.10, 47.16, 45.41. MS (Cl): m/z
309 (MH+ 100). Anal. calcld. for C14H16N2O4S: C, 54.53;
H, 5.23; N, 9.08; S, 10.40. Found: C, 54.55; H, 5.20; N,
9.05; S, 10.37.
4-(3-p-Tolyl-isoxazol-5-ylmethanesulfonyl)-morpholine
(4b).
Yield 85%; mp 140-141 °C. 1H NMR (500 MHz, CDCl3)
δ 7.73-7.75 (m, 2H), 7.32-7.27 (m, 2H), 6.79 (s, 1H), 4.48
(s, 2H), 3.71(d, J 5.5 Hz, 4H), 3.26 (d, J 5.5 Hz, 4H), 2.42
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.55, 160.65,
140.22, 129.25, 126.22, 124.84, 103.60, 66.06, 47.15,
45.36, 20.95. MS (Cl): m/z 323 (MH+ 100). Anal. calcld. for
C15H18N2O4S: C, 55.88; H, 5.63; N, 8.69; S, 9.95. Found:
C, 55.85; H, 5.66; N, 8.71; S, 9.93.
4-[3-(4-Methoxy-phenyl)-isoxazol-5-ylmethanesulfonyl]-
morpholine (4c).
Yield 83%; mp 149-150 °C. 1H NMR (500 MHz, CDCl3)
δ 7.75 (d, J 10.0 Hz, 2H), 7.00(d, J 10.0 Hz, 2H), 6.76 (s,
1H), 4.47 (s, 2H), 3.87 (s, 3H), 3.69 (d, J 5.5 Hz, 4H),
3.2869 (d, J 5.5 Hz, 4H). 13C NMR (125 MHz, CDCl3) δ
162.19, 160.86, 160.56, 127.77, 120.15, 113.96, 103.44,
66.05, 54.91, 47.10, 45.35. MS (Cl): m/z 339 (MH+ 100).
Anal. calcld. for C15H18N2O5S: C, 53.24; H, 5.36; N, 8.28;
S, 9.48. Found: C, 53.20; H, 5.40; N, 8.25; S, 9.5
General procedure for the synthesis of for 4-(4-(3-Aryl-
isoxazol-5-yl))-hepta-1,6-diene-4- sulfonylamides
To a mixture of 0.005 mol of the corresponding
sulfonylamide (4a-c) and 0.015 mol potassium hydroxide in
20 ml of DMF, 0.015 mol of allyl bromide was added. The
reaction mixture was stirred at a temperature of 65-70 °C
for 4-5 hours. The solvent was removed in vacuo, the
residue was washed with water, and the product was
extracted with 2 x 15 ml of dichloromethane. The extract
was dried with anhydrous sodium sulfate and after
purification by chromatography (silica gel Merck Grade
9385, 60 A, 230-400, eluent dichloromethane) the product
was isolated by evaporation of the solvent and subsequent
recrystallization from 70% aqueous ethanol.
4-[4-(3-Phenyl-isoxazol-5-yl)-hepta-1,6-diene-4-
sulfonyl]-morpholine (5a).
Yield 67%; mp 87-88 °C. 1H NMR (500 MHz, CDCl3) δ
7.87-7.79 (m, 2H), 7.53-7.46 (m, 3H), 6.77 (s, 1H), 5.80-
5.93 (m, 2H), 5.18-5.31 (m, 4H), 3.64 (s, 4H), 3.16 (s, 4H),
3.08-3.14 (m, 2H), 2.98-3.07 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ 168.60, 162.18, 130.34, 130.01, 128.61, 127.84,
126.32, 120.06, 103.55, 68.56, 66.62, 46.58, 35.75. MS
(Cl): m/z 389 (MH+ 100). Anal. calcld. for C20H24N2O4S:
C, 61.83; H, 6.23; N, 7.21; S, 8.25. Found: C, 61.80;
H, 6.25; N, 7.18; S, 8.30.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
28
4-[4-(3-p-Tolyl-isoxazol-5-yl)-hepta-1,6-diene-4-
sulfonyl]-morpholine (5b).
Yield 63%; mp 99-100 °C. 1H NMR (500 MHz, CDCl3)
δ 7.72 (d, J 10.5 Hz, 2H ), 7.30 (d, J 10.5 Hz, 2H ), 6,74 (s,
1H), 5.80-5.94 (m, 2H), 5.17-5.30 (m, 4H), 3.64 (s, 4H),
3.13-3.23 (m, 4H), 3.10-3.12 (m, 2H), 2.99-3.05 (m, 2H),
2.43 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.35,
162.11, 140.25, 130.36, 129.27, 126.19, 124.97, 120.01,
68.52, 66.60, 45.54, 35.72, 29.22, 20.96. MS (Cl): m/z 403
(MH+ 100). Anal. calcld. for C21H26N2O4S: C, 62.66; H,
6.51; N, 6.96; S, 7.97. Found: C, 62.62; H, 6.55; N, 6.93; S,
8.00.
4-{4-[3-(4-Methoxy-phenyl)-isoxazol-5-yl]-hepta-1,6-
diene-4-sulfonyl}-morpholine (5c).
Yield 65%; light yellow oil. 1H NMR (500 MHz, CDCl3)
δ 7.75 (d, J 5.0 Hz, 2H ), 6.97 (d, J 5.0 Hz, 2H ), 6.69 (s,
1H), 5.90-5.79 (m, 2H), 5.27-5.16 (m, 4H), 3.86 (s, 3H),
3.62 (s, 4H), 3.22-3.11 (m, 4H), 3.12-3.06 (m, 2H), 3.04-
2.96 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 168.68,
162.19, 161.31, 130.80, 128.19, 120.71, 120.47, 114.43,
103.75, 68.94, 67.06, 55.39, 46.97, 36.17. MS (Cl): m/z 419
(MH+ 100). Anal. calcld. for C21H26N2O5S: C, 60.27;
H, 6.26; N, 6.69; S, 7.66. Found: C, 60.30; H, 6.23; N, 6.70;
S, 7.65.
General procedure for the synthesis of for 4-[1-(3-Aryl-
isoxazol-5-yl)-cyclopent-3-enyl]sulfonylamides
The [Ru] catalyst (0.028-0.03 mmol, 5% mol) was added
to a solution 0.6 mmol of the сorresponding diallyl
derivatives 5a-b in 15 ml of dry degassed dichloromethane
under a dry argon atmosphere. The mixture was kept at
room temperature for 10-12 hours. After completion of the
reaction, the target products were isolated from the reaction
mixture by column chromatography (Merck Grade 9385, 60
A, 230-400, dichloromethane) followed by evaporation and
recrystallization of the products from 70% aqueous ethanol.
4-[1-(3-Phenyl-isoxazol-5-yl)-cyclopent-3-enesulfonyl]-
morpholine (6a).
Yield 75%; mp 109-110 °C. 1H NMR (500 MHz, CDCl3)
δ 7.79-7.87 (m, 2H), 7.44-7.53 (m, 3H), 6.84 (s, 1H), 5.75
(s, 2H), 3.65 (t, J 6.0 Hz, 4H ), 3.46 (d, J 20.0 Hz, 2H ),
3.28 (d, J 20.0 Hz, 2H ), 3.19 (t, J 6.0 Hz, 4H ). 13C NMR
(125 MHz, CDCl3) δ 169.97, 162.42, 129.64, 128.57,
127.91, 127.13, 126.31, 103.03, 70.56, 66.48, 46.35,
40.77. MS (Cl): m/z 361 (MH+ 100). Anal. calcld. for
C18H20N2O4S: C, 59.98; H, 5.59; N, 7.77; S, 8.90. Found:
C, 59.95; H, 5.55; N, 7.75; S, 8.90.
4-[1-(3-p-Tolyl-isoxazol-5-yl)-cyclopent-3-enesulfonyl]-
morpholine (6b).
Yield 71%; mp 103-104 °C. 1H NMR (500 MHz, CDCl3)
δ 7.70 (d, J 8.0 Hz, 2H), 7.27 (d, J 8.0 Hz, 2H), 6.79 (s,
1H), 5.73 (s, 2H), 3.68-3.59 (m, 4H), 3.43 (d, J 15.5 Hz,
2H), 3.27 (d, J 15.5 Hz, 2H), 3.21-3.12 (m, 4H), 2.40 (s,
3H).13C NMR (125 MHz, CDCl3) δ 170.15, 162.79, 140.64,
129.70, 127.58, 126.64, 125.47, 103.42, 70.96, 66.93,
46.77, 41.21, 21.43. MS (Cl): m/z 375 (MH+ 100). Anal.
calcld. for C19H22N2O4S: C, 60.94; H, 5.92; N, 7.48; S, 8.56.
Found: C, 60.90; H, 5.95; N, 7.50; S, 8.54.
Antibacterial study
The antibacterial activity of the synthesized isoxazole-
containing sulfonylamides was determined by the disk-
diffusion method [27] using the Mueller-Hinton agar
against a number of standard (American Type Culture
Collection, ATCC) and multidrug-resistant strains of gram-
negative bacteria, such as E. coli and A. baumannii, and
gram-positive bacterial strains of S. aureus. All culture
strains were obtained from the collection of the Museum of
Microbial Culture Collection of the Shupyk National
Healthcare University of Ukraine. The microbial inoculum
concentration was 1 x 105 colony-forming units in 1 ml
(CFU/ml) of the culture liquid and was monitored by the
0.5 McFarland optical standard. The studied compounds
were applied to standard paper discs (6 mm in diameter) in
a volume of 0.02 ml. The inoculum was applied to Petri
dishes with the appropriate nutrient medium in a volume of
0.2 ml. Incubation was carried out for 24 hours at a
temperature of + 37 °C. The compound content on the
disc was 10 µM. All compounds were dissolved in
dimethylsulfoxide (DMSO). The studied microbial cultures
were not sensitive to this solvent. The antibacterial activity
of the studied compounds was determined by the diameters
of the growth inhibition zones of microorganisms in mm.
The experiment was repeated three times.
Acute toxicity study
The acute toxicity of the investigated compounds was
evaluated by the LC50 indicator (the lowest concentration of
compounds associated with a 50% death of test organisms
within 48 hours) on the freshwater D. magna model
according to OECD 202 for testing chemical compounds
[28]. D. magna was kept in ventilated aquariums
(pH=7.3 ± 0.3) at a temperature of 20-22 °С and a
concentration of dissolved oxygen > 6.0 mg/l. Cultivation
illumination was 400-600 lux with a light period of
16 ± 1 h, and 8 ± 1 h of darkness. Compounds
concentrations from 0.01 mg/L to 1000 mg/L were used to
determine the acute toxicity with D. magna neonates aged
< 24 hours obtained by cultivation. Five neonates were
placed in a 50 mL glass beaker containing 30 mL of the test
solution according to the corresponding concentration of the
studied compound. Two hours before the experiment, D.
magna was fed with Chlorella vulgaris or baker's yeast
suspension and was not fed during the experiment.
Mortality of individuals in each glass was assessed within
48 hours. The experiment was repeated three times and the
average value of LC50 was taken. Statistical analysis of the
obtained results was performed using the Statistica 7
program. The degree of toxicity of the compound was
determined according to the D.R. Passino and co-authors
classification [26]. In addition, the sensitivity of D. magna
to the reference model toxicant potassium dichromate
(K2Cr2O7) was determined.
D.M. Hodyna, O.V. Pavliuk et al.
29
Notes
The authors declare no conflict of interest.
Author contributions. D. M. H.: conceptualization,
supervision, bioactivity investigation, results analysis,
writing-original draft. O. V. P.: conceptualization, synthesis
of compounds, analysis. M. M. B: synthesis of compounds,
writing experimental section. V. O. Y: conceptualization,
analysis. V. V. K: analysis results, conceptualization,
writing and editing. L. O. M: supervision,
conceptualization, results analysis, editing.
References
1. Feng, M.; Tang, B.; Liang., S.H.; Jiang, X. Sulfur Containing
Scaffolds in Drugs: Synthesis and Application in Medicinal
Chemistry. Curr Top Med Chem. 2016, 16, 1200-16.
2. Gaba, M.; Mohan, C. Development of drugs based on imidazole and
benzimidazole bioactive heterocycles: recent advances and future
directions. Med Chem Res. 2016, 25, 173-210.
3. Badgujar, J.R.; More, D.H.; Meshram, J.S. Synthesis, Antimicrobial
and Antioxidant Activity of Pyrazole Based Sulfonamide
Derivatives. Indian J Microbiol. 2018, 58, 93-99.
4. Lavanya, R. Sulphonamides: a pharmaceutical review. International
Journal of Pharmaceutical Science Invention. 2017, 6, 1-3.
5. Wiedemann, B.; Heisig, A.; Heisig, P. Uncomplicated urinary tract
infections and antibiotic resistance-epidemiological and mechanistic
aspects. Antibiotics. 2014, 3, 341-352.
6. Ovung, A.; Bhattacharyya, J. Sulfonamide drugs: structure,
antibacterial property, toxicity, and biophysical interactions. Biophys
Rev. 2021, 13, 259-272.
7. Genç, Y.; Özkanca, R.; Bekdemir, Y. Antimicrobial activity of some
sulfonamide derivatives on clinical isolates of Staphylococus aureus.
Ann Clin Microbiol Antimicrob. 2008, 7, 1-6.
8. Tacic, A.; Nikolic, V.; Nikolic, L.; Savic, I. Antimicrobial
sulfonamide drugs. Advanced Technologies. 2017, 6, 58-71.
9. Isik, K.; Özdemir-Kocak, F. Antimicrobial activity screening of some
sulfonamide derivatives on some Nocardia species and isolates.
Microbiol Res. 2009, 164, 49-58.
10. Zimecki, M.; Bąchor, U.; Mączyński, M. Isoxazole Derivatives as
Regulators of Immune Functions. Molecules. 2018, 23, 2724.
11. Barmade, M.A.; Murumkar, P.R.; Sharma, M.K.; Yadav, M.R.
Medicinal Chemistry Perspective of Fused Isoxazole Derivatives.
Curr Top Med Chem. 2016, 16, 2863-2883.
12. Kapadiya, K.M.; Kavadia, K.M.; Manvar, P.A.; Khunt, R.C.
Synthesis of Nitrogen and Oxygen based Pyrazole Derivatives and Its
Antitubercular and Antimicrobial Activity. Anti-Infective Agents.
2015, 13, 1-10.
13. Nasr, T.; Bondock, S.; Eid, S. Design, synthesis, antimicrobial
evaluation and molecular docking studies of some new 2,3-
dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole.
Journal of Enzyme Inhibition and Medicinal Chemistry. 2015, 31,
236-246.
14. Solanki, P.V.; Uppelli, S.B.; Padaki, S.A.; Anekal, D.; Dahale, S.B.;
Bembalkar, S.R.; Mathad, V.T. A Facile Approach for the Synthesis
of Highly Pure Immunomodulator Drugs-Leflunomide and
Teriflunomide: A Robust Strategy to Control Impurities. World
Journal of Pharmaceutical Sciences. 2015, 13, 2265-2272.
15. Supuran, C.T. Special issue: Sulfonamides. Molecules. 2017, 22, 1-5.
16. Capasso, C.; Supuran, C.T. Sulfa and trimethoprim-like drugs-
antimetabolites acting as carbonic anhydrase, dihydropteroate
synthase and dihydrofolate reductase inhibitors. J. Enzym. Inhib.
Med. Chem. 2014, 29, 379-387.
17. Golbraikh, A.; Wang, X.S.; Zhu, H.; Tropsha, A. Predictive QSAR
Modeling: Methods and Applications in Drug Discovery and
Chemical Risk Assessment. In Handbook of Computational
Chemistry; Leszczynski, J., Kaczmarek-Kedziera, A., Puzyn, T.,
Papadopoulos, M., Reis, H., Shukla, M., Eds.; Springer, Cham. 2017,
pp 2303-2340.
18. Khan, A.U. Descriptors and their selection methods in QSAR
analysis: paradigm for drug design. Drug Discovery Today, 2016, 21,
1291-1302.
19. Huang, T.; Sun, G.; Zhao, L.; Zhang, N.; Zhong, R.; Peng, Y.
Quantitative Structure-ActivityRelationship (QSAR) Studies on
theToxic Effects of NitroaromaticCompounds (NACs): A Systematic
Review. Int. J. Mol. Sci. 2021, 22, 8557.
20. Hodyna, D.M.; Kovalishyn, V.V.; Blagodatnyi, V.M.; Bondarenko,
S.P.; Mrug, G.P.; Frasinyuk, M.S.; Metelytsia, L.O. Cytisine
derivatives as new anti-Escherichia coli agents: in silico and in vitro
studies. Ukr. Bioorg. Acta. 2021, 16, 29-37.
21. Pavliuk, O.V.; Holovatiuk, V.M.; Bezugly, Yu.V.; Kashkovsky, V.I.
Synthesis of new sulfonylamide derivatives of isoxazole via ring-
closing metathesis. Dopov. Nac. akad. nauk Ukr., 2015, 3, 127-134.
22. Marus, E.M.; Elphick, J.R.; Bailey, H.C. A New Toxicity Test Using
the Freshwater Copepod Cyclops vernalis. Bulletin of Environmental
Contamination and Toxicology. 2015, 95, 357-362.
23. Gustinasari, K.; Sługocki, Ł.; Czerniawski, R.; Pandebesie, E.S.;
Hermana, J. Acute toxicity and morphology alterations of
glyphosate-based herbicides to Daphnia magna and Cyclops vicinus.
Toxicol Res. 2020, 37, 197-207.
24. Baumann, J.; Sakka, Y.; Bertrand, C.; Köser, J.; Filser, J. Adaptation
of the Daphnia sp. acute toxicity test: miniaturization and
prolongation for the testing of nanomaterials. Environ Sci Pollut Res
Int. 2014, 21, 2201-2213.
25. Okamoto, A.; Yamamuro, M.; Tatarazako, N. Acute toxicity of 50
metals to Daphnia magna. Journal of Applied Toxicology. 2015, 35,
824-830.
26. Passino, D.R.; Smith, S. Acute bioassays and hazard evaluation of
representative contaminants detected in Great Lakes fish.
Enviromental Toxicology and Chemistry. 1987, 6, 901-907.
27. Bauer, A.W.; Kirby, W.M.; Sherris, J.C.; Turck, M. Antibiotic
susceptibility testing by a standardized single disk method. American
Journal of Clinical Pathology. 1966, 45, 493-496.
28. Organisation for Economic Co-operation and Development. 2004.
Test No. 202: Daphnia sp. acute toxicity test. OECD Guidelines for
the Testing of Chemicals. Paris, France.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 2
30
Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico
дослідження, синтез та in vitro оцінка
Д.М. Година*, О.В. Павлюк, М.М. Баран, В.О. Євдокименко, В.В. Ковалішин,
Л.О. Метелиця
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Розроблені за допомогою веб-платформи OCHEM та раніше опубліковані QSAR-моделі були використані для дослідження та розробки
нових похідних ізооксазолу як антимікробних агентів. На основі створеного віртуального набору перспективних похідних ізооксазолу відібрано
низку потенційних антибактеріальних агентів для синтезу та подальших досліджень. Розроблено зручну послідовність синтезу вихідних
ізооксазоловмісних сульфоніламідів та препаративні методи синтезу цільових сульфоніламідів ізоксазолового ряду, зокрема з використанням
реакцій метатезису із закриттям циклу. Результати in vitro оцінки антимікробної активності синтезованих сполук із прогнозованою високою
активністю показали, що ряд ізооксазоловмісних сульфоніламідів є перспективними антимікробними засобами з широким спектром
антибактеріальної дії, особливо проти мультирезистентних бактеріальних патогенів E. coli, A. baumannii та S. aureus. Дослідження in vivo гострої
токсичності синтезованих сполук на біомоделі D. magna як відомому біосенсорі засвідчили, що більшість ізооксазоловмісних сульфоніламідів
можна віднести до класу малотоксичних речовин згідно з класифікацією, розробленою Passino та Smith для гідробіонтів.
Ключові слова: QSAR; антибактеріальна активність; ізооксазол; сульфаніламід; токсичність.
|
| id | oai:ojs2.bioorganica.com.ua:article-32 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:44Z |
| publishDate | 2022 |
| 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/f9/9c6e32886445d68ecd8dbbc0a925aef9.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-322026-07-19T14:56:53Z Isoxazole-containing sulfanilamides as new antibacterial agents: in silico study, synthesis and in vitro evaluation Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка Hodyna, Diana M. Pavliuk, Oleksandr V. Baran, Maria M. Yevdokymenko, Vitaliy O. Kovalishyn, Vasyl V. Metelytsia, Larysa O. QSAR antibacterial activity isoxazole sulfanilamide QSAR антибактеріальна активність ізооксазол сульфаніламід токсичність The QSAR models previously created by the OCHEM web platform were used for the research and design of novel isoxazole derivatives as antimicrobial agents. Based on the created virtual set of promising isoxazole derivatives, a number of potential antibacterial agents were selected for synthesis and further research. A convenient synthetic sequence for obtaining initial isoxazole-containing sulfonylamides and preparative methods for the synthesis of target sulfonylamides of the isoxazole series, in particular, using ring-closing metathesis reactions, were worked out. The results of in vitro antimicrobial activity evaluation of synthesized compounds with predicted high activity showed that a series of isoxazole-containing sulfonylamides are promising antimicrobial agents with a wide spectrum of antibacterial action, especially against multidrug-resistant E. coli, A. baumannii and S. aureus bacterial pathogens. In vivo assessment of the acute toxicity of the studied compounds on the D. magna as a known biosensor proved that most of the studied isoxazole derivatives can be attributed to the class of slightly toxic substances according to the classification developed by Passino and Smith for hydrobionts Розроблені за допомогою веб-платформи OCHEM та раніше опубліковані QSAR-моделі були використані для дослідження та розробки нових похідних ізооксазолу як антимікробних агентів. На основі створеного віртуального набору перспективних похідних ізооксазолу відібрано низку потенційних антибактеріальних агентів для синтезу та подальших досліджень. Розроблено зручну послідовність синтезу вихідних ізооксазоловмісних сульфоніламідів та препаративні методи синтезу цільових сульфоніламідів ізоксазолового ряду, зокрема з використанням реакцій метатезису із закриттям циклу. Результати in vitro оцінки антимікробної активності синтезованих сполук із прогнозованою високою активністю показали, що ряд ізооксазоловмісних сульфоніламідів є перспективними антимікробними засобами з широким спектром антибактеріальної дії, особливо проти мультирезистентних бактеріальних патогенів E. coli, A. baumannii та S. aureus. Дослідження in vivo гострої токсичності синтезованих сполук на біомоделі D. magna як відомому біосенсорі засвідчили, що більшість ізооксазоловмісних сульфоніламідів можна віднести до класу малотоксичних речовин згідно з класифікацією, розробленою Passino та Smith для гідробіонтів. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/32 10.15407/bioorganica2022.02.023 Ukrainica Bioorganica Acta; Vol. 17 No. 2 (2022): Ukrainica Bioorganica Acta; 23-30 Ukrainica Bioorganica Acta; Том 17 № 2 (2022): Ukrainica Bioorganica Acta; 23-30 1814-9766 1814-9758 10.15407/bioorganica2022.02 en https://bioorganica.com.ua/index.php/journal/article/view/32/63 Copyright (c) 2022 Diana M. Hodyna, Oleksandr V. Pavliuk, Maria M. Baran, Vitaliy O. Yevdokymenko, Vasyl V. Kovalishyn, Larysa O. Metelytsia https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | QSAR антибактеріальна активність ізооксазол сульфаніламід токсичність Hodyna, Diana M. Pavliuk, Oleksandr V. Baran, Maria M. Yevdokymenko, Vitaliy O. Kovalishyn, Vasyl V. Metelytsia, Larysa O. Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title | Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title_alt | Isoxazole-containing sulfanilamides as new antibacterial agents: in silico study, synthesis and in vitro evaluation |
| title_full | Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title_fullStr | Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title_full_unstemmed | Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title_short | Ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| title_sort | ізооксазоловмісні сульфонаміди як нові антибактеріальні агенти: in silico дослідження, синтез та in vitro оцінка |
| topic | QSAR антибактеріальна активність ізооксазол сульфаніламід токсичність |
| topic_facet | QSAR antibacterial activity isoxazole sulfanilamide QSAR антибактеріальна активність ізооксазол сульфаніламід токсичність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/32 |
| work_keys_str_mv | AT hodynadianam isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT pavliukoleksandrv isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT baranmariam isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT yevdokymenkovitaliyo isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT kovalishynvasylv isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT metelytsialarysao isoxazolecontainingsulfanilamidesasnewantibacterialagentsinsilicostudysynthesisandinvitroevaluation AT hodynadianam ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka AT pavliukoleksandrv ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka AT baranmariam ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka AT yevdokymenkovitaliyo ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka AT kovalishynvasylv ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka AT metelytsialarysao ízooksazolovmísnísulʹfonamídiâknovíantibakteríalʹníagentiinsilicodoslídžennâsinteztainvitroocínka |