Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю
A number of sulfamides were obtained by reaction interaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with primary and secondary amino group. The antiviral and antica...
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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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Ukrainica Bioorganica Acta| _version_ | 1871193581600899072 |
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| author | Kornii, Yurii Eu. Shablykin, Oleh V. Shablykina, Olga V. Brovarets, Volodymyr S. |
| author_facet | Kornii, Yurii Eu. Shablykin, Oleh V. Shablykina, Olga V. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Yurii Eu. Kornii",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Oleh V. Shablykin",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Olga V. Shablykina",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine; Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, 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 | Kornii, Yurii Eu. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | A number of sulfamides were obtained by reaction interaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with primary and secondary amino group. The antiviral and anticancer activity of new derivatives was evaluated. The most effective compounds against Human cytomegalovirus were sulfamides based on anisidine (1b), N-Boc-piperazine (1h), and the derivatives 1n, o with fragments of nipecotic and azetidine-3-carboxylic acids, respectively. Anticancer activity was most significant for sulfamides based on p-methoxybenzylamine (compound 1d), benzylmethylamine (compound 1f), and allylmethylamine (compound 1g). |
| doi_str_mv | 10.15407/bioorganica2021.01.010 |
| first_indexed | 2025-07-17T12:19:44Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2021, Vol. 16, N 1
UDC 547.783 + 615.281.8 + 615.277.3
DOI: https://doi.org/10.15407/bioorganica2021.01.010
10
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
New 4-iminohydantoin sulfamide derivatives with antiviral and
anticancer activity
Yurii Eu. Kornii1, Oleh V. Shablykin1, Olga V. Shablykina1,2*, Volodymyr S. Brovarets1
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine
Abstract: A number of sulfamides were obtained by reaction interaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-
ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with
primary and secondary amino group. The antiviral and anticancer activity of new derivatives was evaluated. The most effective
compounds against Human cytomegalovirus were sulfamides based on anisidine (1b), N-Boc-piperazine (1h), and the derivatives 1n, o
with fragments of nipecotic and azetidine-3-carboxylic acids, respectively. Anticancer activity was most significant for sulfamides based
on p-methoxybenzylamine (compound 1d), benzylmethylamine (compound 1f), and allylmethylamine (compound 1g).
Keywords: hydantoins; sulfamides; antiviral activity; anticancer activity.
Introduction
The hydantoin motif often appears in bioactive
molecules of both natural and synthetic origin (Figure 1)
[1-2]. This heterocyclic system, due to its low aromaticity,
can be consider as a cyclic combination of an α-amino acid
and urea with all the resultant consequences, such as the
possibility of assembly with a variation of substituents [3],
the relative ease of combinatorial libraries creation [4], the
possibility of further modification, as well as bioavailability
and environmental friendliness [5]. These factors make
hydantoin derivatives very attractive objects for medicinal
chemistry, and a brief overview of the achievements in this
area over the past decade can be found in the work [6]. At
the same time, the possibility disagreeable side effects of a
number of hydantoin drugs cannot be ignored [7-9].
However, it is also obvious that the main reason for the
toxicity of some derivatives is not the hydantoin fragment
(for example, Allantoin exhibits almost no undesirable
Received:
Revised:
Accepted:
Published online:
15.04.2021
29.04.2021
13.05.2021
30.06.2021
Corresponding author. Tel.: +380-66-167-9812;
e-mail: shablykina@ukr.net (O. V. Shablykina)
ORCID: 0000-0002-5362-0831
effects), but the effect of substituents. Consequently, the
creation of new substances with a hydantoin fragment and
Figure 1. Practically used natural and synthetic hydantoin
derivatives [1-2].
© Kornii Yu. Eu. 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://orcid.org/0000-0001-5556-9147
Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
11
the study of possible areas of their practical application is a
crucial task.
Earlier, we established a convenient way to synthesize
the novel sulfamides with a hydantoin fragment and found
anticancer [10] and antiviral [11] activity for some of these
compounds (Figure 2, general structure 1). The results of
studies of the anticancer activity of hydantoin sulfonamides
were quite optimistic in terms of further prospects for this
class of substances: for example, all of the first six
synthesized derivatives were selected for single-dose assay,
and five-dose assay were led for two compounds [10, 12].
Data on antiviral activity were less demonstrative [11], but
also showed a significant dependence of the level of activity
on the nature of the substituents R1 and R2.
Figure 2. Bioactive (5-(dichloromethylene)-2-oxoimidazolidin-4-
ylidene)sulfamides [10-12].
This has become a weighty reason for us to keep this
research course; therefore, the aim of this work was to
create new derivatives of general formula 1 (Figure 2), and
study their antiviral and anticancer effects. This course is
also supported by the data summarized in the review [13]
concerning the anticancer and antiviral activity of
sulfonamides: the varying the substituents can stimulate the
displaying one or another type of activity.
Results and Discussion
Chemistry
The starting sulfamoyl chloride 2 is formed by the
reaction of chlorosulfonylisocyanate (3) with 2-amino-3,3-
dichloroacrylonitrile (ADAN, 4) through the steps of
acylation of the ADAN amino group with isocyanate,
heterocyclization with the ADAN CN-group and the
nitrogen atom of the newly formed urea, and, at last,
recyclization [10]. Despite the presence of a several active
functional fragments, compound 2 is relatively stable and
suitable for long-term storage (at low temperature),
therefore, it is a convenient "building block".
Compared with previous works, we have significantly
expanded the list of amines that were involved in the
interaction with sulfamoyl chloride 2 to obtain the target
sulfamides 1a-o. Substituted anilines, benzylamines, Boc-
protected piperazine, methylalylamine, and amino acids
methyl esters with primary and secondary amino group
were used. The focus on a series of amino acid derivatives
obtaining was due to previous results: a sulfamide of similar
structure with a residue of ester nipecotic acid showed
strong anticancer activity [10], and the corresponding acid
exhibited antiviral action [11]. The formation of compounds
1 occurred under the action of 5-6 eq. amine on chloride 2
in THF solution, and the nature of the amine didn't have
much effect on the yield of the product. Removal of Boc-
protection of compound 1h was applied in organic solvent
with dry HCl.
Biological Assay
To establish antiviral activity in vivo against some strains
of cytomegalovirus compounds 1b-h, k, l, n, o were selec-
ted. Unfortunately, a number of investigated substances
revealed low activity and insufficient chemotherapeutic
index; namely Human cytomegalovirus was not suppressed
by sulfamides 1c-g, k, l. Compounds 1b, h couldn't effecti-
vely suppress the growth of H. cytomegalovirus strain
GDGr K17, but proved to be quite effective against
H. cytomegalovirus strain AD169 (see Table 1). The
derivatives 1n, o with a fragment of nipecotic and azetidine-
3-carboxylic acids, respectively, also acted selectively only
on certain species and strains of cytomegaloviruses and
weren't active against the others ones. In particular the
sulfamides 1n, o weren't effective against Guinea pig
cytomegalovirus (22122), Murine cytomegalovirus (Smith),
but active against H. cytomegalovirus (see Table 1). The
indexes of antiviral activity also depended on the detection
method. For example, when determining the EC50 value of
the compounds 1n, o to H. cytomegalovirus (AD169) by
quantitative polymerase chain reaction these substances
were classified as inefficient, while when determining EC50
by the method of CellTiter-Glo the value were nearby to the
comparison drugs (Table 1). Therefore, four substances
showed worthy of interest antiviral activity; these data are
shown in Table 1, where the EC50 – compound
concentration that reduces viral replication by 50%, EC90 –
concentration that reduces viral replication by 90%, CC50 –
concentration that reduces cell viability by 50%, SI50 –
CC50 / EC50, SI90 – CC50 / EC90. The EC50 value of the
sulfamides 1b, h, n, o were comparable to the Ganciclovir
and Cidofovir. But they have an unremarkable
chemotherapy index, especially SI90
The possible anticancer effect was investigated not only
for the sulfamides 1a-o synthetized in this work, but also
for the isopropylamine and tryptamine derivatives 1r, s,
described in the article [11]. As a result of the primary
analysis, a number of biological screening substances were
selected (see Table 2).
According to single-dose assay, not all of the studied
derivatives had significant anticancer activity. The average
percentage inhibition of cancer cell growth, the range of
values, as well as the number of lines (from 60 studying
ones) that experienced a growth inhibition of more than
50%, and the number of cell lines for which the test compo-
Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
12
Scheme 1. Synthesis of new (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamides.
unds were lethal are shown in Table 2. In the latter case, the
record values of mortality rates are also reported.
Even in a such small list of compounds, the following
tendency can be observed: sulfamides based on aliphatic
and aromatic amines show, on average, low anticancer
activity, and, on the other hand, the derivatives of
benzylamines, allylmethylamine and tryptamine very
effectively inhibit the growth of numerous cancer cell lines.
It is noteworthy that two compounds – 1f and 1g, which
were obtained from similar amines (benzylmethylamine and
allylmethylamine, respectively), showed the highest
anticancer activity against the same cancer cell lines
(Table 2) with very similar values.
Table 1. The antiviral activity data of sulfamides 1b, h, n, o
against H. cytomegalovirus.*
Virus
Strain Cоmpd EC50 EC90 CC50 SI50 SI90
AD169
Ganciclovir 0.39 1.13 >150.00 >383 >133
1b 0.21 >6.00 14.42 69 <2
1h 0.95 >6.00 15.87 17 <3
1n 0.15 >6.00 14.34 96 <2
1o 0.19 >30.00 68.08 353 <2
GDGr
K17
Ganciclovir 13.44 >150.00 >150.00 >11 1
Cidofovir 0.11 >30.00 117.81 1061 <4
1n 0.13 >6.00 15.99 119 <3
1o 0.54 >30.00 70.90 131 <2
* Cell Line: HFF; control assay: CellTiter-Glo (cytopathic
effect/toxicity).
It is also interesting that the values of the activity of
sulfamides 1f and 1g activity are in a plenty wide range.
These compounds have shown very selective cytotoxicity
against various cancer lines. As shown in Table 3, the
growth inhibition rates of 8 melanoma lines were observed.
It is easy to see that the compounds 1f, g only slightly
inhibit the growth of some lines, but a high percentage of
lethality was recorded for LOX IMVI cells. Similar strong
differences in the activity of compounds 1f, g can be
observed to different cell lines of colorectal, renal and
ovarian cancers. But these substances were found to be
highly effective against all studied lines of leukemia (Table
3) – from almost discontinuing of growth to significant
lethality.
For substances 1d, f, g, a five-dose assay of their anti-
cancer activity were performed. In the Table 4 the average
concentrations of GI50, TGI, LC50 and the corresponding
values for cancer lines that were inhibited most effectively
in a single-dose experiment are shown (compare with
Table 2; Melanoma LOX IMVI for compounds 1f, g wasn't
investigate), as well as values for the lines with the highest
inhibition (marked in a color).
In average values, compound 1f exhibits the highest
anticancer activity, and the effect of sulfonamide 1g is
slightly less. Substance 1f was able to inhibit growth by
50% at a concentration of less than 10–6 M (respectively,
lg GI50 < -6) of 5 lines out of 59 tested in a five-dose
experiment, including Colon Cancer KM12 (see Table 3),
Leukemia RPMI-8226 and SR, Breast Cancer MCF7 and
MDA-MB-468; and the substance 1g in less than 10–6 M
concentration inhibited the growth by 50% the same 5 lines.
Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
13
Substance 1d in less than micromolar concentrations
inhibited by 50% the growth of 11 lines from 59, but TGI
and LC50 values wasn’t so conductive.
Table 2. The effect of compounds 1a-h, p-s on the
growth of cancer cells, determined by single-dose assay
(C = 10–5 M); GP – Growth Percent, %; N50 – number of
lines with GP 50%; N0 – number of lines with GP 0%.
Compd
(NCS code)
GP,
Mean
GP,
Range
N50 N0
The most significant
inhibition, GP
1a
(827223)
100.8 58.9 – – 69.7 SNB-75 (CNS Cancer)
1b
(827225)
93.8 108.7 4 –
15.4 MDA-MB-468
(Breast Cancer)
1c
(827227)
52.9 121.6 29 3
-8.7 BT-549 (Breast Cancer)
-3.0 SNB-75 (CNS Cancer)
-1.1 HOP-92 (Non-Small
Cell Lung Cancer)
1d
(827226)
26.8 106.4 47 7
-23.2 SNB-75 (CNS Cancer)
-22.9 SF-295 (CNS Cancer)
-11.1 HL-60(TB)
(Leukemia)
1e
(827224)
98.7 82.7 1 –
44.1 MDA-MB-468
(Breast Cancer)
1f
(828790)
36.0 201.2 30 13
-90.8 ACHN (Renal Cancer)
-84.5 LOX IMVI
(Melanoma)
-81.7 OVCAR-3 (Ovarian
Cancer)
1g
(828791)
20.88 200.41 35 21
-96.7 ACHN (Renal Cancer)
-88.3 LOX IMVI
(Melanoma)
-84.3 OVCAR-3
(Ovarian Cancer)
1h
(827229)
83.9 176.1 7 1
-52.4 NCI-H522 (Non-Small
Cell Lung Cancer)
1p
(827228)
102.0 48.3 – – 72.5 SNB-75 (CNS Cancer)
1r
(812426)
95.5 102.6 1 – 19.7 SR (Leukemia)
1s
(812428)
56.4 135.9 23 3
-3.3 MDA-MB-468 (Breast
Cancer)
-4.6 KM12 (Colon Cancer)
-25.8 OVCAR-3 (Ovarian
Cancer)
Conclusions
Thus, the diversity of the sulfamides obtained on the
base of (5-(dichloromethylene)-2-oxoimidazolidin-4-
ylidene)sulfamoyl chloride was significantly supplemented
by us, and the antiviral and anticancer activity of new
derivatives was determined. It was found that the antiviral
activity against H. cytomegalovirus is inherent for esters of
nipecotic and azetidine-3-carboxylic acids 1n and 1o,
respectively, as well as for anisidine 1b and Boc-piperazine
1h sulfamides, but, unfortunately, these compounds have a
low chemotherapy index. Most of the tested compounds can
effectively inhibit the growth of tumor cells, and strongest
inhibition was observed for sulfamides based on p-
methoxybenzylamine (compo-und 1d), benzylmethylamine
(compound 1f), and allyl-methylamine (compound 1g). The
substances 1f, g also have high selectivity for certain cancer
cells lines. So, using various amines in the synthesis of N-
[5-(dichloro-methylene)-2-oxoimidazolidin-4-
ylidene]sulfami-des, it has been indeed possible to obtain
compounds with either antiviral or anticancer activity.
Table 3. The effect of compounds 1f, g on the growth of
Melanoma and Leukemia cells.
Growth Percent, %
1f
(NSC 828790)
1g
(NSC 828791)
Melanoma
LOX IMVI -84.5 -88.3
MALME-3M -19.9 -69.4
MDA-MB-435 79.6 34.4
SK-MEL-2 87.8 90.0
SK-MEL-28 11.2 -83.6
SK-MEL-5 95.7 91.6
UACC-257 68.2 57.4
UACC-62 62.2 32.9
Leukemia
CCRF-CEM -12.9 -27.1
HL-60(TB) -29.8 -51.7
K-562 1.1 -3.5
MOLT-4 10.3 -19.7
RPMI-8226 -1.1 5.2
SR -0.4 -18.7
Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
14
Table 4. The effect of compounds 1d, f, g on the growth of
cancer cells, determined by five-dose assay (the
concentrations GI50, TGI and LC50
*, mol/l, given as lg).
Compd
(NCS code)
Cell line
Value of cancer cell lines'
growth inhibition
lg GI50 lg TGI lg LC50
1d
(827226)
Mean value -5.75 -4.46 -4.07
SNB-75 (CNS Cancer) -5.87 > -4.00 > -4.00
SF-295 (CNS Cancer) -5.54 > -4.00 > -4.00
HL-60(TB) (Leukemia) -6.12 -5.25 > -4.00
MDA-MB-468 (Breast
Cancer)
-6.74 -6.19 -4.11
1f
(828790)
Mean value -5.74 -5.26 -4.69
ACHN (Renal Cancer) -5.75 -5.50 -5.24
OVCAR-3 (Ovarian
Cancer)
-5.75 -5.47 -5.18
KM12 (Colon Cancer) -6.57 -6.13 -4.44
1g
(828791)
Mean value -5.66 -5.14 -4.61
ACHN (Renal Cancer) -5.75 -5.50 -5.24
LOX IMVI
(Melanoma)
- - -
OVCAR-3 (Ovarian
Cancer)
-5.72 - 5.42 -
MCF7 (Breast Cancer) -6.41 > -4.00 > -4.00
RPMI-8226 (Leukemia) -6.39 -5.01 > -4.00
KM12 (Colon Cancer) -6.36 -4.59 > -4.00
* GI50 (growth inhibitory activity) – concentration of the compound causing
50 % decrease in net cell growth; TGI (cytostatic activity) – concentration
of the compound resulting in total growth inhibition; LC50 (cytotoxic
activity) – concentration of the compound causing net 50 % loss of initial
cells at the end of the incubation period of 48 h.
Experimental section
Chemistry
The solvents were purified according to the standard
procedures. All materials were purchased from commercial
sources and used without further purification. The success
rate was calculated as the number of successful experiments
divided by the total number of experiments. NMR spectra
were recorded on Varian Union Plus spectrometer
(400 MHz for 1H and 100 MHz for 13C) in DMSO-d6
solution. Chemical shifts are reported in ppm downfield
from TMS as internal standards. Mass spectra were
recorded on an LC-MS instrument with chemical ionization
(CI). LC-MS data were acquired on an Agilent 1200 HPLC
system equipped with DAD/ELSD/LCMS-6120 diode
matrix and mass-selective detector. Melting points were
measured on a MPA100 OptiMelt automated melting point
system. Elemental analyses were performed at the
Analytical Laboratory of the V.P. Kukhar Institute of
Bioorganic Chemistry and Petrochemistry of the NAS of
Ukraine, their results were found to be in good agreement
(±0.4%) with the calculated values.
The method of sulfamoyl chloride 2 synthesis and
general method of sulfamides 1a-o synthesis from 1 g
(3.59 mmol) sulfamoyl chloride 2 were given in publication
[10]. The synthesis and the data of sulfamides 1r, s see at
[11].
(Z)-N-[5-(Dichloromethylene)-2-oxoimidazolidin-4-yl-
idene]-N-(4-fluorophenyl)sulfamide (1a).
Yield: 0.36 g, 28%; mp 220-221 °C. 1H NMR δ 11.47
(br s, 1H, NH), 11.15 (br s, 1H, NH), 9.92 (s, 1H, SO2NH),
7.05-7.28 (m, 4H, Ar). 13C NMR δ 158.91 (d, JCF 240.1 Hz,
C-F), 152.2 (C=N or C=О), 151.1 (C=N or C=О), 134.4
(d, JCF 1.6 Hz, NH-S), 129.7 (С=CCl2), 122.85 2 (d, JCF
8.2 Hz, CHCHCF), 115.56 2 (d, JCF 22.5 Hz, CHCF),
107.3 (CCl2). HPLC (CI) m/z (Irel, %) 353.0 [M+1]+ (100).
(Z)-N-[5-(Dichloromethylene)-2-oxoimidazolidin-4-yl-
idene]-N-(4-methoxyphenyl)sulfamide (1b).
Yield: 0.97 g, 74%; mp 195 °С (decomp.). 1H NMR δ
11.38 (br s, 1H, NH), 11.13 (s, 1H, NH), 9.60 (s, 1H,
SO2NH), 7.13 (d, J 8.6 Hz, 2Н, Ar), 6.87 (d, J 8.6 Hz, 2Н,
Ar), 3.70 (s, 3H, CH3O). 13C NMR δ 156.5 (CArO), 152.2
(C=N or C=О), 150.9 (C=N or C=О), 130.6 (Ar), 129.7
(С=CCl2), 123.8 2 (Ar), 114.1 2 (Ar), 107.2 (CCl2),
55.2 (CH3O). HPLC (CI) m/z (Irel, %) 363.0 [M-1]– (100).
(Z)-N-[5-(Dichloromethylene)-2-oxoimidazolidin-4-yl-
idene]-N-(4-methylbenzyl)sulfamide (1c).
Yield: 0.91 g, 70%; mp 165-166 °C. 1H NMR δ 11.02
(m, 2H, 2NH), 7.80 (t, J 6.6 Hz, 1H, NHСН2), 7.19 (d,
J 6.8 Hz 2H, Ar), 7.08 (d, J 6.8 Hz, 2H, Ar), 4.12 (d,
J 6.6 Hz, 2H, NHСН2), 2.26 (s, 3H, СН3). 13C NMR δ 152.2
(C=N or C=О), 150.2 (C=N or C=О), 136.3 (Ar), 134.4
(Ar), 129.5 (С=CCl2), 128.5 2 (Ar), 127.8 2 (Ar), 106.9
(CCl2), 46.3 (CH2), 20.7 (CH3). HPLC (CI) m/z (Irel, %)
361.0 [M-1]– (100).
(Z)-N-[5-(Dichloromethylene)-2-oxoimidazolidin-4-yl-
idene]-N-(4-methoxybenzyl)sulfamide (1d).
Yield: 1.22 g, 90%; mp 190-191 °C. 1H NMR δ 11.03
(br s, 2H, NH), 7.76 (t, J 5.6 Hz, 1H, NHCH2), 7.22 (d,
J 7.9 Hz, 2H, Ar), 6.83 (d, J 7.9 Hz, 2H, Ar), 4.09 (d,
J 5.6 Hz, 2H, NHCH2), 3.72 (s, 3H, CH3O). 13C NMR δ
158.5 (CAr–O), 152.2 (C=N or C=О), 150.1 (C=N or C=О),
129.6 (С=CCl2), 129.4 (Ar), 129.2 2 (Ar), 113.4 2 (Ar),
106.9 (CCl2), 55.1 (CH3O), 46.0 (CH2). HPLC (CI) m/z (Irel,
%) 379.0 [M-1]– (100).
(Z)-N-(4-Chlorobenzyl)-N-[5-(dichloromethylene)-2-oxo-
imidazolidin-4-ylidene]sulfamide (1e).
Yield: 1.13 g, 82%; mp 202-203 °C. 1H NMR δ 11.12
(br s, 1H, NH), 11.06 (s, 1H, NH), 7.93 (t, J 5.7 Hz, 1H,
NHCH2), 7.29-7.41 (m, 4H, Ar), 4.16 (d, J 5.7 Hz, 2H,
Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
15
NHCH2). 13C NMR δ 152.2 (C=N or C=О), 150.3 (C=N or C=О), 136.8 (Ar), 131.8 (Ar), 129.6 2 (Ar), 129.5
(С=CCl2), 128.0 2 (Ar), 107.0 (CCl2), 45.7 (CH2). HPLC
(CI) m/z (Irel, %) 383.0 [M+1]+ (100).
(Z)-N-Benzyl-N-[5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene]-N-methylsulfamide (1f).
Yield: 1.15 g, 88%; mp 180-181 °C. 1H NMR δ 11.41
(br s, 1H, NH), 11.13 (br s, 1H, NH), 7.22-7.46 (m, 5H, Ph),
4.19 (s, 2H, CH2), 2.63 (s, 3H, CH3). 13C NMR δ 152.4
(C=N or C=О), 151.5 (C=N or C=О), 136.0 (Ph), 129.8
(С=CCl2), 128.4 4 (Ph), 127.6 (Ph), 107.2 (CCl2), 54.2
(CH3N), 35.1. HPLC (CI) m/z (Irel, %) 363.0 [M+1]+ (100).
(Z)-N-Allyl-N-[5-(dichloromethylene)-2-oxoimidazolidin-
4-ylidene)-N-methylsulfamide (1g).
Yield: 0.78 g, 69%; mp 102-103 °C. 1H NMR δ 11.52
(br s, 1H, NH), 11.12 (br s, 1H, NH), 5.77-5.93 (m, 1H,
–СН=), 5.28 (d, Jtrans 17.1 Hz, 1H, =СН2), 5.21 (d, Jcis
10.1 Hz, 1H, =СН2), 3.66 (d, J 5.7 Hz, 2H, NCH2), 2.67 (s,
3H, СН3). 13C NMR δ 152.4, 151.5, 132.8, 129.8, 118.9,
107.1 (CCl2), 53.2, 34.8. HPLC (CI) m/z (Irel, %) 313.0
[M+1]+ (100).
tert-Butyl (Z)-4-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)piperazine-1-carboxylate (1h).
Yield: 1.02 g, 66%; mp 198-199 °C. 1H NMR δ 11.64
(br s, 1H, NH), 11.13 (br s, 1H, NH), 3.37-3.50 (m,
4H, N(CH2)2), 2.96-3.09 (m, 4H, N(CH2)2), 1.39 (s,
9H, C(CH3)3). 13C NMR δ 153.8 (СО2), 152.5 (C=N or
C=О), 152.3 (C=N or C=О), 130.0 (С=CCl2), 107.1 (CCl2),
79.3 (O–C), 46.1 4 (2 N(CH2)2), 28.0 3 (C(CH3)3).
HPLC (CI) m/z (Irel, %) 426.0 [M-1]– (100).
Methyl (Z)-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)glycinate (1i).
Yield: 0.83 g, 70%; mp 179-180 °C. 1H NMR δ 11.16
(m, 2H, 2NH), 7.79 (t, J 5.8 Hz, 1H, NHCH2), 3.84 (d, J
5.8 Hz, 2H, NHCH2), 3.62 (s, 3H, CH3O). 13C NMR δ
169.7 (СО2), 152.4 (C=N or C=О), 151.2 (C=N or C=О),
129.8 (С=CCl2), 107.3 (CCl2), 51.9 (CH3O), 44.0 (CH2).
HPLC (CI) m/z (Irel, %) 331.0 [M+1]+ (100).
Methyl (Z)-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)phenylalaninate (1j).
Yield: 1.24 g, 82%; mp 174-175 °C. 1H NMR δ 10.82-
11.18 (m, 2H, 2NH), 7.96 (d, J 9.0 Hz, 1H, NHCH), 7.13-
7.30 (m, 5H, Ph), 4.10-4.23 (m, 1H, NHCH,), 2.99 (dd, Jhem
13.6 Hz, Jvic 5.8 Hz, 1H, CH2), 2.87 (dd, Jhem 13.6 Hz, Jvic
8.8 Hz, 1H, CH2). 13C NMR δ 171.6 (СО2), 152.3 (C=N or
C=О), 151.1 (C=N or C=О), 136.2 (Ph), 129.6 (С=CCl2),
129.1 2 (Ph), 128.1 2 (Ph), 126.6 (Ph), 107.4 (CCl2),
57.3 (NHCH), 51.9 (CH3O), 38.0 (CH2). HPLC (CI) m/z
(Irel, %) 421.0 [M+1]+ (100).
Dimethyl (Z)-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)aspartate (1k).
Yield: 1.11 g, 77%; mp 168-169 °C. 1H NMR δ 11.27
(br s, 1H, NH), 11.20 (br s, 1H, NH), 7.98 (d, J 7.9 Hz, 1H,
CHNH), 4.23-4.38 (m, 1H, CHNH), 3.62 (s, 3H, CH3O),
3.59 (s, 3H, CH3O), 2.83 (d, J 4.9 Hz, 2H, СНСН2).
13C NMR δ 170.5 (СО2), 170.1 (СО2), 152.3 (C=N
or C=О), 151.3 (C=N or C=О), 129.7 (C=CCl2), 107.4
(CCl2), 52.4 (CH3O), 52.3 (CH3O), 51.7 (CHNH). HPLC
36.8 (СН2), (CI) m/z (Irel, %) 403.0 [M+1]+ (100).
Dimethyl (Z)-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)glutamate (1l).
Yield: 1.17 g, 78%; mp 175-176 °C. 1H NMR δ 11.07-
11.25 (m, 2H, 2NH), 7.97 (d, J 9.0 Hz, 1H, SO2NH), 3.91-
4.03 (m, 1H, СН), 3.61 (s, 3H, CH3O), 3.58 (s, 3H, CH3O),
2.34-2.46 (m, 2H, СН2СН2СО2Ме), 1.90-2.02 (m, 1H,
СНСН2), 1.75-1.88 (m, 1H, СНСН2). 13C NMR δ 172.4
(СО2), 171.6 (СО2), 152.2 (C=N or C=О), 151.0 (C=N or
C=О), 129.7 (C=CCl2), 107.3 (CCl2), 54.8 (NHCH), 52.1
(CH3O), 51.4 (CH3O), 29.2 (CH2), 27.2 (CH2). HPLC (CI)
m/z (Irel, %) 415.0 [M-1]– (100).
Methyl (Z)-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)prolinate (1m).
Yield: 0.84 g, 63%; mp 142-143 °C. 1H NMR δ 11.52
(br s, 1H, NH), 11.12 (br s, 1H, NH), 4.15-4.25 (m, 1H,
NCH), 3.65 (s, 3H, CH3O), 3.30 (m, 2H, NCH2, with Н2О
signal), 2.12-2.27 (m, 1H, HPyr), 1.78-1.98 (m, 3H, HPyr).
13C NMR δ 172.3 (СО2), 152.4 (C=N or C=О), 152.2 (C=N
or C=О), 130.0 (C=CCl2), 107.2 (CCl2), 60.9 (NCH), 52.1
(CH3O), 49.7 (NCH2), 30.6 (CH2), 24.5 (CH2). HPLC (CI)
m/z (Irel, %) 371.2 [M+1]+ (100).
Methyl (Z)-1-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)piperidine-3-carboxylate (1n).
Yield: 0.77 g, 56%; mp 151-152 °C. 1H NMR δ 10.39-
11.98 (br s, 2H, 2NH), 3.45-3.65 (m, 4H, CH3O, HPip), 2.78-
2.96 (m, 1H, HPip), 2.62-2.78 (m, 1H, HPip), 1.80-1.99 (m,
1H, HPip), 1.63-1.80 (m, 1H, HPip), 1.29-1.63 (m, 4H, HPip).
13C NMR δ 173.0, 152.7, 152.1, 130.2, 107.6, 51.9, 48.2,
46.7, 26.0, 23.3. HPLC (CI) m/z (Irel, %) 385.0 [M+1]+
(100).
Methyl (Z)-1-(N-(5-(dichloromethylene)-2-oxoimidazoli-
din-4-ylidene)sulfamoyl)azetidine-3-carboxylate (1o).
Yield: 0.74 g, 58%; mp 211-212 °C. 1H NMR δ 11.74
(br s, 1H, NH), 11.17 (br s, 1H, NH), 4.06-3.92 (m,
4H, N(CH2)2), 3.65 (s, 3H, ОСН3), 3.59-3.49 (m, 1H,
СНСО2Ме). 13C NMR δ 171.9 (СО2Ме), 152.9 (C=N or
C=О), 152.4 (C=N or C=О), 130.0 (C=CCl2), 107.5 (CCl2),
53.2 (ОСН3), 52.1 2 (N(CH2)2), 30.8 (СНСО2Ме). HPLC
(CI) m/z (Irel, %) 355.0 [M-1]– (100).
Hydrochloride of (Z)-N-(5-(dichloromethylene)-2-oxo-
imidazolidin-4-ylidene)piperazine-1-sulfonamide (1p).
The substance 1h (0.50 g, 1.17 mmol) was dissolved in
10 mL of dry CH2Cl2, and the 1.5 mL (5 eq.) of 4 M HCl in
1,4-dioxane was added. The reaction mixture was stirred for
8 h, than was evaporated, and the dry residue was triturated
in 15 ml of MTBE, filtered and washed with MTBE
(2 10 ml). Yield: 0.36 mg, 85%; mp 218-219 °C. 1H NMR
δ 11.94 (br s, 1H, NH), 11.19 (br s, 1H, NH), 9.50 (br s, 2H,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 16, N 1
16
NH2
+), 3.30-3.38 (m, 4H, N(CH2)2), 3.13-3.25 (m, 4H,
N(CH2)2). 13C NMR δ 152.6 (C=N or C=О), 152.3 (C=N or
C=О), 129.6 (C=CCl2), 108.2 (CCl2), 43.4 2 (N(CH2)2),
41.7 2 (N(CH2)2). HPLC (CI) m/z (Irel, %) 328.0 [M+1]+
(100).
Biological Assay
The antiviral activity of synthesized compounds was
tested in the Department of Pediatrics, University of
Alabama, Birmingham; description of the technique see in
[11].
The anticancer activity of synthesized compounds was
tested according to the International Program of the
National Institutes of Health – DTP (Developmental
Therapeutic Program) of the National Cancer Institute
(NCI, Bethesda, Maryland, USA) on 60 cancer cell lines
[14]; a description of the technique is also given in [15].
Notes
Acknowledgments and finances. The study of antiviral
activity was performed according to the contract
HHSN2722011000191 from Virology Branch DMID,
NIAID, NIH (USA). We would like to thank US Public
Health Service and National Cancer Institute, USA, for in
vitro evaluation of anticancer activity (providing the NCI-
60 cell testing) within the framework of Developmental
Therapeutic Program (http://dtp.cancer.gov), and
ENAMINE Ltd. for the material and technical support for
this work.
Disclaimer. This material should not be interpreted as
representing the viewpoint of the U.S. National Institutes of
Health, or the National Cancer Institute.
The authors declare that there is no conflict of
interest.
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Yu. Eu. Kornii, O. V. Shablykina, V. S. Brovarets
17
Нові сульфамідні похідні 4-іміногідантоїну з противірусною та
протираковою активністю
Ю. Є. Корній1, О. В. Шабликін1, О. В. Шабликіна1,2*, В. С. Броварець1
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
2 Київський національний університет імені Тараса Шевченка, вул. Володимирська, 60, Київ, 01601, Україна
Резюме: Взаємодією (5-(дихлорометилен)-2-оксоімідазолідін-4-іліден)сульфамоїлхлоріду з анілінами, бензиламінами, Boc-захищеним
піперазином, метилаліламіном та метиловими естерами амінокислот з первинною та вторинною аміногрупами отримано ряд сульфамідів. Для
встановлення противірусної активності in vivo щодо окремих штамів цитомегаловірусу сполук було відібрано 11 сполук. На жаль, низьку
противірусну активність та хіміотерапевтичний індекс виявили похідні на основі пара-заміщених бензиламінів, бензилметил- та алілметиламіну,
а також естерів аспарагінової та глутамінової кислоти. Сульфаміди, отримані за участю естерів ніпекотинової та азетидин-3-карбонової кислот,
діяли селективно лише на певні види та штами цитомегаловірусів і не були активними щодо інших: зокрема, були неефективними проти
цитомегаловірусу морської свинки (22122), цитомегаловірусу миші (Сміт), але активні щодо цитомегаловірусу людини. Показники противірусної
активності також залежали від методу виявлення. Значення EC50 сульфамідів естерів ніпекотинової та азетидин-3-карбонової кислот, а також
сульфамідів пара-анізидину та N-Boc-піперазину були близькі до показників препаратів порівняння Ганцикловіру та Цидофовіру, хоча
досліджувані сполуки мали невисокі хіміотерапевтичні індекси, особливо SI90. При аналізі протиракової активності синтезованих сульфамідів за
результатами однодозових випробувань була встановлена висока активність похідних на основі заміщених бензиламінів, бензилметил- та
алілметиламіну, N-Boc-піперазину та раніше синтезованого сульфаміду з фрагментом триптаміну. Найбільш перспективними у якості
протиракових агентів виявились похідні бензилметил- та алілметиламіну, оскільки окрім активності в цілому вони виявляють високу
селективність по відношенню до окремих ліній ракових клітин. У порівнянні із цими двома речовинами сульфамід на основі пара-
метоксибензиламіну здатен до ефективного інгібування меншої кількості ліній ракових клітин; хоча середні показники EC50, отримані внаслідок
п'ятидозових випробувань, для усіх трьох похідних були близькі.
Ключові слова: гідантоїни; сульфаміди; противірусна активність; протипухлинна активність.
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| id | oai:ojs2.bioorganica.com.ua:article-43 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:59Z |
| publishDate | 2021 |
| 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/54/bd36bacdd7467d5b6eeb22a2310f8354.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-432026-07-19T14:56:54Z New 4-iminohydantoin sulfamide derivatives with antiviral and anticancer activity Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю Kornii, Yurii Eu. Shablykin, Oleh V. Shablykina, Olga V. Brovarets, Volodymyr S. hydantoins sulfamides antiviral activity anticancer activity гідантоїни сульфаміди противірусна активність протипухлинна активність A number of sulfamides were obtained by reaction interaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with primary and secondary amino group. The antiviral and anticancer activity of new derivatives was evaluated. The most effective compounds against Human cytomegalovirus were sulfamides based on anisidine (1b), N-Boc-piperazine (1h), and the derivatives 1n, o with fragments of nipecotic and azetidine-3-carboxylic acids, respectively. Anticancer activity was most significant for sulfamides based on p-methoxybenzylamine (compound 1d), benzylmethylamine (compound 1f), and allylmethylamine (compound 1g). Взаємодією (5-(дихлорометилен)-2-оксоімідазолідін-4-іліден)сульфамоїлхлоріду з анілінами, бензиламінами, Boc-захищеним піперазином, метилаліламіном та метиловими естерами амінокислот з первинною та вторинною аміногрупами отримано ряд сульфамідів. Для встановлення противірусної активності in&nbsp;vivo щодо окремих штамів цитомегаловірусу сполук було відібрано 11 сполук. На жаль, низьку противірусну активність та хіміотерапевтичний індекс виявили похідні на основі пара-заміщених бензиламінів, бензилметил- та алілметиламіну, а також естерів аспарагінової та глутамінової кислоти. Сульфаміди, отримані за участю естерів ніпекотинової та азетидин-3-карбонової кислот, діяли селективно лише на певні види та штами цитомегаловірусів і не були активними щодо інших: зокрема, були неефективними проти цитомегаловірусу морської свинки (22122), цитомегаловірусу миші (Сміт), але активні щодо цитомегаловірусу людини. Показники противірусної активності також залежали від методу виявлення. Значення EC50 сульфамідів естерів ніпекотинової та азетидин-3-карбонової кислот, а також сульфамідів пара-анізидину та N-Boc-піперазину були близькі до показників препаратів порівняння Ганцикловіру та Цидофовіру, хоча досліджувані сполуки мали невисокі хіміотерапевтичні індекси, особливо SI90. При аналізі протиракової активності синтезованих сульфамідів за результатами однодозових випробувань була встановлена висока активність похідних на основі заміщених бензиламінів, бензилметил- та алілметиламіну, N-Boc-піперазину та раніше синтезованого сульфаміду з фрагментом триптаміну. Найбільш перспективними у якості протиракових агентів виявились похідні бензилметил- та алілметиламіну, оскільки окрім активності в цілому вони виявляють високу селективність по відношенню до окремих ліній ракових клітин. У порівнянні із цими двома речовинами сульфамід на основі пара-метоксибензиламіну здатен до ефективного інгібування меншої кількості ліній ракових клітин; хоча середні показники EC50, отримані внаслідок п'ятидозових випробувань, для усіх трьох похідних були близькі. 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/43 10.15407/bioorganica2021.01.010 Ukrainica Bioorganica Acta; Vol. 16 No. 1 (2021): Ukrainica Bioorganica Acta; 10-17 Ukrainica Bioorganica Acta; Том 16 № 1 (2021): Ukrainica Bioorganica Acta; 10-17 1814-9766 1814-9758 10.15407/bioorganica2021.01 en https://bioorganica.com.ua/index.php/journal/article/view/43/43 Copyright (c) 2021 Yurii Eu. Kornii, Oleh V. Shablykin, Olga V. Shablykina, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | гідантоїни сульфаміди противірусна активність протипухлинна активність Kornii, Yurii Eu. Shablykin, Oleh V. Shablykina, Olga V. Brovarets, Volodymyr S. Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title | Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title_alt | New 4-iminohydantoin sulfamide derivatives with antiviral and anticancer activity |
| title_full | Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title_fullStr | Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title_full_unstemmed | Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title_short | Нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| title_sort | нові сульфамідні похідні 4-іміногідантоїну з противірусною та протираковою активністю |
| topic | гідантоїни сульфаміди противірусна активність протипухлинна активність |
| topic_facet | hydantoins sulfamides antiviral activity anticancer activity гідантоїни сульфаміди противірусна активність протипухлинна активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/43 |
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