Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду
A thirteen 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide analogs have been synthesized and characterized by spectroscopy methods, elemental analysis. Their growth inhibiting activity was determined in vitro in the one dose assay against the total NCI-60 human cancer cell line panel. The five-dose analy...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2024
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Ukrainica Bioorganica Acta| _version_ | 1871193609184739328 |
|---|---|
| author | Pilyo, Stepan G. Kachaeva, Maryna V. Severin, Oleksandr O. Kozachenko, Oleksandr P. Zhirnov, Victor V. Brovarets, Volodymyr S. |
| author_facet | Pilyo, Stepan G. Kachaeva, Maryna V. Severin, Oleksandr O. Kozachenko, Oleksandr P. Zhirnov, Victor V. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr O. Severin",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr P. Kozachenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Victor V. Zhirnov",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Pilyo, Stepan G. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | A thirteen 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide analogs have been synthesized and characterized by spectroscopy methods, elemental analysis. Their growth inhibiting activity was determined in vitro in the one dose assay against the total NCI-60 human cancer cell line panel. The five-dose analysis was performed on the six compounds with greater cytotoxicity. Two compounds 8 and 9 exhibited the greatest potency against total NCI-60 cancer cell lines in the five dose assay. Furthermore, compound 9 with 3-methylpiperidine fragment turned out to be two times more active than compound 8 with 4-methylpiperidine (GI50 = 1.4±0.1 against 2.5±0.4, GI = 3.9±0.6 against 7.1±1.3 and LC50 = 7.1±1.0 against 16.4±2.3 µM). The lack of commonly used drugs that show a high correlation with the majority of analyzed compounds, based on two out of three calculated parameters of anticancer potency, suggests that they may interact with a unique target. The ADMET analysis results predict that this compound meets the drug similarity criteria and does not belong to interfering molecules that react non-specifically with numerous targets. The prediction of lead likeness for all compounds is also included, meaning that any of them can be optimized to enhance selectivity and other pharmacological properties that characterize their chemotherapeutic potential |
| doi_str_mv | 10.15407/bioorganica2024.01.030 |
| first_indexed | 2025-07-17T12:20:00Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
UDC 547.78 + 547.551.525.211.1
DOI: https://doi.org/10.15407/bioorganica2024.01.030
30
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Design, synthesis, in silico and in vitro investigation of 4-cyano-2-phenyl-
1,3-oxazole-5-sulfonamide derivatives
Stepan G. Pilyo, Maryna V. Kachaeva*, Oleksandr O. Severin, Oleksandr P. Kozachenko,
Victor V. Zhirnov, Volodymyr S. Brovarets
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A thirteen 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide analogs have been synthesized and characterized by spectroscopy
methods and elemental analysis. Their growth inhibiting activity was determined in vitro in the one dose assay against the total NCI-60
human cancer cell line panel. The five-dose analysis was performed on the six compounds with greater cytotoxicity. Two compounds 8
and 9 exhibited the greatest potency against total NCI-60 cancer cell lines in the five-dose assay. Furthermore, compound 9 with
3-methylpiperidine fragment turned out to be two times more active than compound 8 with 4-methylpiperidine (GI50 = 1.4±0.1 against
2.5±0.4, GI = 3.9±0.6 against 7.1±1.3 and LC50 = 7.1±1.0 against 16.4±2.3 µM). The lack of commonly used drugs that show a high
correlation with the majority of analyzed compounds, based on two out of three calculated parameters of anticancer potency, suggests that
they may interact with a unique target. The ADMET analysis results predict that this compound meets the drug similarity criteria and does
not belong to interfering molecules that react non-specifically with numerous targets. The prediction of lead likeness for all compounds is
also included, meaning that any of them can be optimized to enhance selectivity and other pharmacological properties that characterize
their chemotherapeutic potential.
Keywords: 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamides; anticancer activity; SAR analysis; COMPARE correlation; ADMET analysis.
Introduction
Small synthetic molecules and rapid growth of biologics
are critical in drug development and dominate the
pharmaceutical market [1]. In medicinal chemistry, five-
membered heteroaromatic rings containing nitrogen and
oxygen are widely used for the synthesis of anticancer
compounds due to the metabolic stability, solubility, and
bioavailability of the resulting derivatives. The specific
physicochemical properties and wide range of interactions
with various molecular targets have made them a key
structural motif in many clinically effective drugs, including
anticancer drugs [2].
Received:
Revised:
Accepted:
Published online:
20.02.2024
18.03.2024
09.04.2024
30.06.2024
Corresponding author. Tel.: +380-44-573-2596;
e-mail: kachaeva@bpci.kiev.ua (M.V. Kachaeva)
ORCID: 0000-0003-1517-4807
This work presents 4-cyano-2-phenyl-1,3-oxazole-5-
sulfonamides functionalized at the fifth position with
various cyclic and acyclic nitrogen-containing moieties as
active functional substituents in compounds with anticancer
activity, such as dimethylamine (participation in binding the
side chain of tamoxifen with the steroid-binding site of the
estrogen receptor) [3], piperazine and piperidine (tubulin
polymerization blockers) [4, 5], morpholine and pyrazole
(tyrosine kinase - EGFR inhibitors) [6, 7]. The work also
involves five N-(4-cyano-1,3-oxazol-5-yl)sulfonamides that
were synthesized previously but not tested for antitumor
activity. Additionally, three derivatives have previously
been published as anticancer active compounds but have not
been tested by COMPARE and ADMET analyses.
Results and Discussion
Chemistry
2-Phenyl-4-cyano-1,3-oxazole-5-sulfonylamides (1-13)
were synthesized from 2-phenyl-4-cyano-1,3-oxazole-5-
sulfonyl chloride [9] (II) with ammonia and corresponding
© Pilyo S.G. 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.
S.G. Pilyo, M.V. Kachaeva et al.
31
Table 1. Chemical structures of 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamides (1-13).
Compound/
NCI numbers
Structure IUPAC Name Ref.
1
832049
4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide [9]
2
832051
4-cyano-N,N-dimethyl-2-phenyl-1,3-oxazole-5-sulfonamide -
3
811817
2-phenyl-5-((4-phenylpiperazin-1-yl)sulfonyl) -1,3-oxazole-4-
carbonitrile
-
4
802786
5-((4-(4-fluorophenyl)piperazin-1-yl)sulfonyl)-2-phenyl-1,3-
oxazole-4-carbonitrile
-
5
811818
5-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-2-phenyl-1,3-
oxazole-4-carbonitrile
[10]
6
832050
2-phenyl-5-((4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)sulfonyl) -
1,3-oxazole-4-carbonitrile
-
7
832048
2-phenyl-5-(piperidin-1-ylsulfonyl) -1,3-oxazole-4-carbonitrile [10]
8
76529
5-((4-methylpiperidin-1-yl)sulfonyl)-2-phenyl-1,3-oxazole-4-
carbonitrile
[11, 12]
9
765530
5-((3-methylpiperidin-1-yl)sulfonyl)-2-phenyl-1,3-oxazole-4-
carbonitrile
[11, 12]
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
32
Table 1. (Contd.)
10
821734
5-(morpholinosulfonyl)-2-phenyl-1,3-oxazole-4-carbonitrile [9]
11
802791
5-((5-amino-3-methyl-1H-pyrazol-1-yl)sulfonyl)-2-phenyl-1,3-
oxazole-4-carbonitrile
[11]
12
802792
5-((5-amino-3-phenyl-1H-pyrazol-1-yl)sulfonyl)-2-phenyl-1,3-
oxazole-4-carbonitrile
[11]
13
795290
N-(2-(4-chlorophenyl)-2-(piperidin-1-yl)ethyl)-4-cyano-2-
phenyl-1,3-oxazole-5-sulfonamide
[11]
O
HN
Cl
Cl
CN
O
N
S Cl
CN
O
O
O
N
S
CN
1) NaSH, HCl
2) BnCl, Et3N
3) Cl2/AcOH, H2O,
0-5 oC
1-13I II
NR1R2
O
O
NR1R2 = NH2, NAlk2
NHR1R2
Et3N,
Scheme 1. Synthesis of 2-phenyl-4-cyano-1,3-oxazole-5-sulfonamides (1-13).
amines – dimethylamine, N-substituted piperazines [16],
piperidines, morpholine, 2-(4-chlorophenyl)-2-(1-piperidi-
nyl)ethanamine [17] (Scheme 1).
In the IR spectra of obtained compounds 1-13, there are
absorption bands of the CN group (ν CN 2246-2253 cm-1),
as well as characteristic absorption bands at ν 1151-
1188 cm-1 and ν 1333-1391 cm-1, which correspond to
symmetric and asymmetric vibrations of the SO2 group. In
the spectra of sulfonamides 2-13, there are signals of all
CH2 and/or CH3 groups in the aliphatic region.
The one dose assay
Only compounds 6-9 demonstrated growth inhibition
(GI) of the total subpanel cell lines exceeding 50%.
Derivatives 8 and 9 demonstrated cytotoxicity against
leukemia, colon cancer, melanoma, ovarian cancer, renal
cancer, and breast cancer subpanels, as well as very high
(GI 90%) antiproliferative activity against non-small cell
lung cancer (Table 2).
These derivatives were cytotoxic against two prostate
cancer cell lines DU-145 (GI = 149 and 172%, respectively)
and moderately inhibited PC-3 proliferation (GI = 51 and
55%, respectively). Only three CNS cancer cell lines (SF-
268, SF-539, and U251) showed moderate activity or
tended to have a moderate cytostatic response to them. All
other derivatives weakly or very weakly inhibited or even
stimulated the growth of some cell lines of this subpanel
(Table S1). Compounds 6 and 7 exhibited significant
antiproliferative activity against Leukemia and renal cancer
(GI > 90%), high activity against colon cancer (GI > 70%),
and moderate activity against melanoma and breast
cancer subpanels (GI > 50%). Compound 7 demonstrated
high activity against leukemia, moderate activity against
colon cancer and melanoma, and cytotoxic activity
against renal cancer. The breast cancer subpanel de-
monstrated poor sensitivity to this derivative. Compound 2
S.G. Pilyo, M.V. Kachaeva et al.
33
Table 2. Average growth inhibitory activity of 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamides (1-13) against
NCI-60 subpanels*.
Compound
Subpanel 1 2 3 4 5 6 7 8 9 10 11 12 13
Leukemia 74.3
±6.6
89.3
±14.0
66.1
±12.2
99.9
±11.1
79.7
±8.4
94.8
±7.3
80.0
±15.0
125.6
±7.5
134.2
±8.3
91.4
±14.3
77.1
±17.7
57.9
±18.2
94.0
±1.8
Non-Small Cell
Lung Cancer
20.0
±16.0
25.1
±20.4
5.5
±6.2
14.5
±11.4
15.2
±9.8
29.1
±21.1
25.6
±18.2
95.1
±25.0
90.4
±23.6
16.4
±17.5
13.8
±8.0
8.0
±2.2
21.0
±13.0
Colon Cancer 38.6
±13.3
48.2
±17.2
18.8
±11.6
47.6
±9.9
47.6
±16.2
73.9
±20.5
67.7
±20.6
128.5
±25.3
133.5
±26.6
48.3
±19.1
34.6
±18.6
1.6
±3.7
45.5
±12.7
CNS Cancer 12.0
±10.6
3.2
±4.5
3.7
±6.1
6.5
±3.6
8.6
±5.3
8.4
±5.7
3.3
±4.8
44.8
±7.3
46.4
±10.9
2.0
±2.5
1.7
±3.7
2.6
±4.1
12.6
±4.2
Melanoma 40.7
±7.9
45.1
±22.2
16.1
±6.0
30.4
±8.7
31.9
±9.3
66.5
±22.8
59.0
±25.0
145.2
±11.0
152.7
±6.3
18.9
±6.8
24.1
±16.0
4.0
±2.7
25.6
±7.5
Ovarian Cancer 16.9
±9.7
8.8
±11.9
2.0
±5.1
17.9
±10.4
18.0
±7.8
23.0
±16.2
30.1
±24.4
117.8
±18.8
119.1
±21.2
21.2
±12.1
2.3
±2.9
0.6
±2.2
16.7
±9.4
Renal Cancer 37.4
±5.4
76.9
±24.0
0.5
±3.6
27.0
±7.4
13.4
±7.5
91.6
±28.8
107.5
±28.1
145.7
±27.7
145.7
±26.8
38.8
±22.9
33.8
±20.6
0.6
±3.6
11.9
±6.
Prostate Cancer 18.1
±0.5
38.3
±27.0
-0.7
±5.9
16.9
±15.6
2.1
±5.9
19.3
±5.3
35.1
±23.3
73.1
±28.6
99.9
28.8±
-1.5
±1.0
-1.4
±1.4
-6.8
±4.1
18.3
±2.7
Breast Cancer 42.3
±9.3
40.4
±10.5
10.2
±8.0
35.7
±10.0
26.3
±9.6
53.1
±20.8
47.8
±14.7
100.8
±25.0
108.5
±24.1
23.2
±10.9
13.5
±8.3
5.2
±5.2
31.6
±10.8
Total
34.0
±4.2
(59)
41.7
±6.8
(58)
13.7
±3.4
(60)
32.7
±4.5
(60)
28.0
±4.2
(60)
53.9
±7.6
(58)
50.8
±8.1
(57)
113.2
±7.9
(56)
118.5
±7.9
(55)
30.2
±5.9
(60)
22.2
±5.3
(57)
6.9
±2.5
(57)
30.6
±4.4
(59)
* The number of tested lines in subpanels is indicated in parentheses. Compounds were added at a concentration 1 x 10-5 M and the cell cultures were
incubated for 48 h. The number reported for the one-dose assay is growth inhibition (%) relative to the no-drug control, and relative to the time zero number
of cells. Data are represented as mean ±SE, %.
Table 3. Cell lines with a cytotoxic response to test compounds 1-13 in the one dose assay.
Compound Cell lines with cytotoxic response
Cytotoxicity index (CI)*, %
Subpanel Total
1 NSCLC: NCI-H522 (144.5) 11 1,7
2
Leukemia: MOLT-4 (113.1), SR (119.7) 34
12.1
NSCLC: NCI-H522 (164.7) 11
Colon Cancer: HCT-15 (111.6) 14
Melanoma: LOX IMVI (180.7) 11
Renal Cancer: ACHN (183.9), UO-31 (151.0) 25
3 0 0 0
4 Leukemia: CCRF-CEM (131.0), MOLT-4 (115.7), SR (120.3) 50 5.0
5 0 0 0
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
34
Table 3. (Contd.)
6
Leukemia: SR (119.2) 16.7
19.0
NSCLC: NCI-H522 (166.0) 12.5
Colon Cancer: HCT-15 (127.2}, HT29 (105.8), SW-620 (124.2) 42.8
Melanoma: LOX IMVI (179.2), MALME-3M (166.9) 22.2
Renal Cancer: ACHN (195.5), RXF 393 (154.7), UO-31 (142.3) 42.9
Breast Cancer: T-47D (124.2) 16.7
7
NSCLC: NCI-H522 (162.0) 33.3
17.5
Colon Cancer: HCT-15 (135.3), SW-620 (112.8) 14.3
Melanoma: LOX IMVI (182.5), MALME-3M (168.8), M141(115.3) 33.3
Ovarian Cancer: OVCAR-3 (154.3) 14.3
Renal Cancer: ACHN (193.4), RXF 393 (171.8), UO-31 (182.2) 42.9
8
Leukemia: CCRF-CEM (119.9), HL-60(TB) (100.7}, K-562 (127.2), MOLT-4
(145.4), RPMI-8226 (134.6)
100
64.3
NSCLC: HOP-92 (134.8), NCI-H226 (163.1), NCI-H23 (162.7), NCI-H522 (178.4) 50.0
Colon Cancer: COLO 205 (186.3), HCT-116 (200), HCT-15 (147.4), HT29 (120.1),
SW-620 (168.4)
71.4
Melanoma: LOX IMVI (200), MALME-3M (106.4), M14 (154.1), MDA-MB-435
(164.2), SK-MEL-2 (135.3), SK-MEL-28 (154.1), SK-MEL-5 (174.7), UACC-257
(113.3), UACC-62 (104.4)
100
Ovarian Cancer: IGROV1 (118.6), OVCAR-3 (172.1), OVCAR-8 (164.3),
NCI/ADR-RES (106.8)
66.7
Renal Cancer: ACHN (191.2), CAKI-1 (189.5), RXF 393 (198.8), SN12C (157.8),
UO-31 (187.1)
71.4
Prostate Cancer: DU-145 (117.2) 50.0
Breast Cancer: BT-549 (130.2), T-47D (132.9), MDA-MB-468 (169.9) 50.0
9
Leukemia: CCRF-CEM (115.5), HL-60(TB) (157.0}, K-562 (114.7), MOLT-4
(141.9),
RPMI-8226 (142.6)
100
67.3
NSCLC: HOP-92 (137.9), NCI-H226 (136.2), NCI-H23 (154.6), NCI-H522 (175.1) 50.0
Colon Cancer: COLO 205 (192.6), HCT-116 (200), HCT-15 (153.7), HT29 (138.7),
SW-620 (278.8)
71.4
Melanoma: LOX IMVI (189.1), MALME-3M (149.9), M14 (170.7), MDA-MB-435
(158.1), SK-MEL-2 (139.8), SK-MEL-28 (134.7), SK-MEL-5 (130.1), UACC-257
(141.2), UACC-62 (161.0)
100
Ovarian Cancer: IGROV1 (122.1), OVCAR-3 (194.3), OVCAR-5 (103.0),
OVCAR-8 (159.6)
66.7
Renal Cancer: ACHN (195.1), CAKI-1 (187.9), RXF 393 (195.6), SN12C (152.2),
TK-10 (184.3)
71.4
Prostate Cancer: DU-145 (148.8) 50.0
Breast Cancer: MDA-MB-231/ATCC (102.0), BT-549 (136.2), T47D (151.6),
MDA-MB-468 (167.5)
66.7
10
Leukemia: CCRF-CEM (120.0), MOLT-4 (116.0) 33.3
8.3
NSCLC: NCI-H522 (155.5) 11.1
S.G. Pilyo, M.V. Kachaeva et al.
35
Table 3. (Contd.)
Colon Cancer: HCT-15 (115.4) `6.7
Renal Cancer: ACHN (197.7) 12.5
11
Colon Cancer: COLO 205 (134.0) 14.3
5.3 Melanoma: MALME-3M (149.0) 11.1
Renal Cancer: CAKI-1 (149.4) 12.5
12 0 0 0
13 NSCLC: NCI-H522 (118.3) 11.1 1.7
* Cytotoxicity Index (CI) is expressed as the ratio of the number of cell lines showing a cytotoxic response to the test compound to the total/subpanel
number of cell lines tested.
was highly active only against leukemia and renal cancer.
The remaining compounds showed weak activity against all
subpanels. According to the average degree of inhibition of
total cell growth (given in brackets as %), the compounds
form the following series: 9 (119) > 8 (113) > 6 (54) > 7
(51) > 2 (42) > 1 (34) > 4 (33) > 13 (31) > 10 (30) > 5 (28)
> 11 (22) > 3 (14) > 12 (7). Based on this parameter, the
compounds can be divided into three groups. The first
group includes compounds 8 and 9, which showed excellent
growth inhibition of NCI-60 cell lines (GI 100%). The
second group includes compounds 6 and 7, which showed
moderate activity (100% ≥ GI 50%). The remaining
compounds form the third group of compounds with low
activity (GI < 50%). The differences in activity between
these groups were statistically significant, except for
compound 2 of the third group, whose inhibitory activity
was not significantly different from that of the compounds
belonging to the second group.
Since all subpanels included cell lines with a cytotoxic
response, their total cytotoxicity index was used as an
additional criterion for selecting compounds for further tests
(Table 3).
According to the value of total CI, the compounds are
ranked as follows: 9 (67.4) > 8 (64.3) > 6 (19.0) > 7 (17.5)
> 2 (12.1) > 10 (8.3) > 11 (5.3) > 4 (5.0) > 1 and 13 (1.7) >
3, 5 and 12 (0), which in the first five terms does not differ
from the previous series, but among the compounds of the
3rd group derivative 10 has the highest rank.
Compounds 8 and 9 showed the average cytotoxicity
against all subpanels except NSCLC, CNS, and prostate
cancer. They also showed absolute cytotoxicity against the
leukemia and melanoma subpanels and high cytotoxicity
against the ovarian, renal, and breast cancer subpanels. This
series's first six most active members were subjected to a
five-dose study.
Structure-activity relationship
Isomers 8 and 9 showed the most significant antitumor
activity in terms of overall growth inhibition (GI). They
differ only in the methylation position of the piperidine
heterocycle, which does not affect their antitumor activity.
However, GI decreased by more than 2-fold with
demethylation of piperidine 7. Replacing piperidine with
pyridinethylpiperazine 6 does not significantly affect this
parameter. However, the introduction of dimethylamine 2
noticeably reduces it. Further functionalization of 4-cyano-
2-phenyl-1,3-oxazole-5-sulfonylamides with such substitu-
ents as amino- (1), (4-fluorophenyl)piperazine (4), 2-(4-
chlorophenyl)-2-(1-piperidinyl)ethanamine (13), morpho-
line (10), and (4-methoxyphenyl)piperazine (5), can also
impact GI. The activity of these derivatives gradually
reduces in the indicated order with the worst performance
found in compound 12, which contains 5-amino-3-phenyl-
1H-pyrazole at the sulfonyl group. The addition of
phenylpiperazine 3, (4-methoxyphenyl)piperazine 5, and
5-amino-3-phenyl-1H-pyrazole (12) eliminates the activity
of the resulting derivatives. Based on the cytotoxicity
parameter (CI), the first five derivatives exhibit a similar
arrangement. The functionalization of 4-cyano-2-phenyl-
1,3-oxazole-5-sulfonylamide with morpholine 10 and
(4-fluorophenyl)piperazine (4) reduces CI by approximately
two times. Similarly, the functionalization with 5-amino-3-
methyl-1H-pyrazole and 2-(4-chlorophenyl)-2-(1-piperidi-
nyl)ethanamine reduces CI by approximately 6 and 7 times,
respectively, when compared to the derivative containing
dimethylamine 2. The cytotoxicity of resulting derivatives
is eliminated by the addition of phenylpiperazine 3,
(4-methoxyphenyl)piperazine (5), and 5-amino-3-phenyl-
1H-pyrazole (12).
Not a single physicochemical parameter of the
compounds predicted by ADMET analysis showed a
significant correlation with their inhibitory activity. For
example, the coefficients of determination calculated for
total polar area, water solubility, and lipophilicity presented
in the table did not exceed 28% (Table 4). Moreover, these
low R2 values were insignificant (p < 0.05). Similar results
were obtained for the remaining calculated indices (data not
shown).
The five-dose assay
Table S1 displays the complete analysis data, while
Table S2 presents the statistical results.
The antitumor potency of the compounds in the five-dose
assay was not determined for all cell lines of the NCI-60
panel, so the total number of analyzed lines for each
compound differed from each other. Table 5 shows the cell
lines not included in the analysis and the total number of
lines analyzed for each compound.
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36
Table 4. Results of regression analysis of the degree of relationship between some physicochemical properties of
compounds 1-13 and their growth inhibitory activity.
Properties of
сompounds
1 2 3 4 5 6 7 8 9 10 11 12 13 R2*
TPSA, Ų 110.0 87.2 90.4 90.4 99.7 103.3 87.2 87.2 87.2 96.4 128.5 128.5 99.2 0.28
logS -3.77 -4.03 -5.30 -5.47 -5.45 -4.14 -4.94 -5.27 -5.21 -4.18 -2.80 -3.69 -4.89 0.14
LogP 1.47 1.99 3.530 3.62 3.559 2.32 3.02 3.39 3.33 1.91 1.86 3.08 4.39 0.02
Total GI 34.0 41.7 13.7 32.7 28.0 53.9 50.8 113.2 118.5 30.2 22.2 6.9 30.6 -
* R2 is the coefficient of determination, which is a measure of the degree of linear relationship between variables, which shows the proportion of changes
due to the influence of factor characteristics in the total variability of the resulting characteristic.
Table 5. Cell lines for which the corresponding parameter has not been determined.
Compound
Cell lines not included in the analysis Number of cell
lines tested GI50 TGI LC50
2 NSCLC: NCI-H23 59
6 Leukemia: CCRF-CEM; NSCLC: NCI-H23 58
7 Leukemia: HL-60(TB), K-562, MOLT-4, SR; NSCLC: NCI-H23 55
8
NSCLC:NCI-H23, NCI-H522
CNS Cancer: SF-295
Leukemia: K-562, SR
NSCLC: NCI-H23, NCI-H522
CNS Cancer: SF-295
Leukemia: HL-60(TB) NSCLC:NCI-
H23, NCI-H522
CNS Cancer: SF-295
GI50: 57
TGI: 55
LC50: 56
9
NSCLC: EKVX, NCI-H23
CNS Cancer: SF-295
Leukemia: SR;
NSCLC:EKVX, NCI-H23;
CNS Cancer: SF-295;
Ovarian Cancer: NCI/ADR-RES
NSCLC: A549/ATCC, EKVX, NCI-
H23, NCI-H522;
CNS Cancer: SF-295;
Ovarian Cancer: OVCAR-8
GI50: 57
TGI: 55
LC50: 54
10 ‒ 60
Table 6. COMPARE analysis results for the tested compounds.
No
Vector
GI50 TGI LC50
2 Rifamycin SV, r = 0.73 - -
6 Rifamycin SV, r = 0.67 Rifamycin SV, r = 0.65 Macbecin II, r = 0.65
7 Rifamycin SV, r = 0.76 - -
8 Rifamycin SV, r = 0.65 - Rifamycin SV, r = 0.74
9 - - Rifamycin SV, r = 0.74
10 Rifamycin SV, r = 0.65 - -
As follows from Table 5, all compounds tested in the
five-dose assay were potent anticancer agents according to
all calculated parameters. The potency rank of compounds
for all calculated parameters (GI50, TGI, LC50) against the
total panel form a statistically significant series (p ≤ 0.05): 9
> 8 > 6 = 10 > 2 = 7, coinciding with those obtained in a
single-dose analysis for inhibition parameters cell growth
and cytotoxicity index. In general, this order of average
parameter values is observed for all subpanels. However, in
many cases, due to small sample sizes and significant
variation in the sensitivity of individual cell lines to the
tested compounds, the rank difference, in this case, was
unreliable. Compounds 8 and 9 showed equal and the
highest antiproliferative potency against leukemia, while
the lowest was observed against the CNS subpanel.
However, all the tested compounds showed no cytotoxicity
against all cell lines in this subpanel (LС50 > 100 µM) with
the only exception of compound 9, whose LС50 against HL-
60(TB) was 8.63 µM. Furthermore, compound 9 exhibited a
100% SI for all subpanels in terms of both antiproliferative
activity parameters (GI50 and TGI), while compounds 8 and
10 only showed a 100% SI for GI50.
COMPARE correlations
The COMPARE analysis suggests molecular
mechanisms of action of compounds based on calculated
S.G. Pilyo, M.V. Kachaeva et al.
37
parameters of their antitumor activity in vitro compared to
standard agents. The correlation analysis data obtained for
the tested compounds are presented in Table 6. Only
standard compounds with a threshold of r 0,65 were
selected as significant.
It should be noted that the two standard agents that
showed correlation with the tested compounds are
ansamycin antibiotics, despite having quite different
antiblastic activity mechanisms [18]. All compounds except
9 showed a moderate tendency to high or high positive
correlation in the GI50 vector with rifamycin SV, which
disrupts the mechanisms of DNA replication, transcription,
and translation of RNA into proteins in tumor cells [19]. In
addition, except 6, none of the compounds had a significant
correlation with the probe compounds along the TGI vector.
A high correlation with rifamycin SV along the cytotoxicity
vector was only observed for compounds 8 and 9.
It has also been shown that rifamycin and its derivative
rifampicin primarily affect RNA synthesis in the
mitochondria, which may lead to inhibition of the synthesis
of mitochondrial proteins closely linked to the regulation of
oxidative phosphorylation [20, 21]. Thus, mitochondria
may be the main potential target for rifampicin SV in its
cellular cytotoxicity. At least some rifamycin derivatives
induce disruption of the ultrastructure of mitochondria,
which results in excessive production of reactive oxygen
species and release of cytochrome c into the cell cytoplasm.
The latter activates caspases, triggering the process of
intrinsic apoptosis [22, 23]. Thus, mitochondria may be the
main potential target for rifampicin in its cellular
cytotoxicity. However, if rifamycin's molecular
mechanisms of action were the primary mechanism for
compounds 8 and 9, similar values for the parameters of
antitumor activity would be expected. Nevertheless,
compound 9's parameters were two or more times different
from those of compound 8, indirectly indicating the
involvement of targets other than those inherent in
rifamycin.
Macbecin II (geldanamycin) binds to Hsp90 and inhibits
its chaperoning function, resulting in the degradation of
Hsp90 client proteins that control the cell cycle, cell
proliferation, differentiation, and apoptosis. [24, 25]. TNF
receptor associated protein 1 (TRAP1), acting as an Hsp90-
like chaperone in mitochondria, is also inhibited by
geldanamycin. TRAP1 maintains mitochondrial integrity,
reducing the production of reactive oxygen species and
reprogramming cellular metabolism to enable cancer cells
to better adapt to harsh tumor environments. Inactivation of
TRAP1 induces massive apoptosis in cancer cells in vitro
and in vivo [26, 27].
In general, that the absence of a robust correlation (r
0.90) according to the calculated parameters with standard
agents suggests the presence of specific molecular targets
for these compounds that underlie their antiproliferative
activity and cytotoxicity. However, this does not exclude
the possible role of molecular mechanisms inherent to
rifamycins in their antitumor activity since the average
graphs of all the derivatives analyzed showed at least one
parameter moderately correlated with this agent.
ADMET properties
Drug similarity is based on a probabilistic assessment of
the influence of the physicochemical properties of
compounds predicted in silico on their molecular behavior
in vivo. Drug likeness is a crucial consideration when
selecting compounds during the early stages of drug
discovery. ADMET analysis is a valuable tool for
predicting the fundamental properties of synthesized and
tested compounds in vitro. This helps select drug candidates
to further study their biological effectiveness, assuming
they have the necessary characteristics for in vivo use.
Oral bioavailability
The correlation between molecules physicochemical
properties and its bio-pharmaceutical properties, specifi-
cally its impact on oral bioavailability, is achieved through
this method. The Lipinski, Ghose, Egan, Muegge, Veber,
GSK, Pfizer Rule, and Golden Triangle binary filters were
applied to the compounds with high anticancer potency to
determine their oral bioavailability properties. Table 7
shows that these compounds meet the criteria based on their
physicochemical and pharmacokinetic properties, indicating
drug likeness.
Medicinal chemistry
The main purpose of this section is to eliminate so-called
interfering molecules. Two complementary pattern
recognition methods, PAINS (pan assay interference
compounds) and Brenk at al. (2008) [36], can identify
potentially problematic molecules containing substructures
that exhibit a strong response independent of the target
protein. Such fragments, which give a false-positive
biological result, could potentially lead to the emergence of
promiscuous compounds. In addition, structural alert,
introduced by Brenk, identifies those suspected to be toxic,
chemically reactive, metabolically unstable, or have
properties responsible for poor pharmacokinetics.
These and other physicochemical filters are also used to
identify compounds that meet “lead likeness” criteria. This
concept is similar to drug similarity but focuses on the
physicochemical boundaries that define the molecular
structure suitable for optimization. The synthetic
accessibility (SA) of test compounds is evaluated using the
SA score, which is normalized between 1 (indicating easy
synthesis) and 10 (indicating complicated synthesis) [37].
The studied molecules have synthetic availability values
within a narrow range of knowledge (3 > SA score < 4),
indicating that they can be easily synthesized. All
compounds do not exceed the boundaries of the descriptors
included in the specified filters, except compound 6, whose
molecular weight exceeded the threshold value (Table 8).
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38
Table 7. Drug similarity of compounds 2 and 6-10 predicted analytical filters used by ADMET and SwissADME to
differentiate drug-like and non-drug-like compounds*.
Filter Descriptors (Ref.)
Drug likeness of
compounds 2, 6-10
Binary filters
Lipinski MW, LogP, nHD and nHA [28] Accepted
Ghose MW, logP, AMR and nA [29] Accepted
Egan logP and PSA [30] Accepted
Muegge MW, nRing, nC, nHet, nRot, nHD, nHA, LogP and PSA [31] Accepted
Veber nRot and PSA [32] Accepted
GSK Sw, PA, BA, VD, PPB, BBB, BTB, P-gp, hERG and cytP450 [33] Accepted
Pfizer Rule MW, logP, and PSA [34] Accepted
Golden Triangle MW and logD [35] Accepted
* MW - molecular weight, LogP - calculated n-octanol/water distribution coefficient, LogD - LogP at pH = 7.4, nHD - number of H-bond donors, nHA -
number of H-bond acceptors, AMR - atom molar refractivity, nA - the total number of atoms, PSA - polar surface area, nRot - number of rotatable bonds,
nC - number of carbons, nHet - number of heteroatoms, SW - solubility in water, PA - permeability, BA - oral bioavailability, VD - volume of distribution,
PPB - plasma protein binding, BBB - CNS penetration, BTB - brain tissue binding, Pg - P-gp efflux, hERG - hERG inhibition, cytP450 - cytochrome P450
1A2/2C9/2C19/2D6/3A4 inhibition.
Table 8. Investigated descriptors
Filter Compound
2 6 7 8 9 10
PAINS 0 alert 0 alert 0 alert 0 alert 0 alert 0 alert
Brenk 0 alert 0 alert 0 alert 0 alert 0 alert 0 alert
Lead likeness Yes No; 1 violation: MW>350 Yes Yes Yes Yes
Synthetic accessibility 3.18 3.66 3.18 3.28 3.74 3.24
Lipophilicity and water solubility
According to all five methods used by the Swiss platform
for assessment, the analyzed compounds predicted
lipophilicity was within the acceptable range of logP o/w
values (from -0.7 to + 6). The test compounds are predicted
to have aqueous solubility, with logS (ESOL) ranging from
-2.72 (10) to -3.92 (6). The solubility class is estimated
qualitatively using the logS scale as follows: insoluble
< -10 < poorly soluble < -6 < moderately soluble < -4 <
good soluble < -2 < very soluble < 0 < highly soluble.
These results suggest that all tested compounds meet the
requirements for drug formation.
Pharmacokinetics
ADMET analysis enables the generation of
pharmacokinetic profiles, which are crucial for evaluating
the pharmacodynamic activity of molecules.
Multidrug resistance (MDR) considerably limits the
effectiveness of chemotherapy. One of the mechanisms
responsible for MDR is the overexpression of
chemotherapy drug efflux transporters, such as P-glyco-
protein (P-gp) and the ATP-binding cassette (ABC)
transporter [38]. These transporters reduce the intracellular
concentration of drugs by transporting them into the
extracellular environment. The tested compounds are
unlikely to develop resistance through the P-glycoprotein
pathway, as they are predicted to have a low probability of
interaction with this enzyme, except for 2, which is
predicted to have a high probability of inhibition (Table 9).
Enzymatic drug metabolism and transport are essential
for absorption, metabolism, and elimination of a drug
within the body. Compounds 7-10 were predicted to have
very weak substrate specificity for all cytochromes studied
(except CYP2C9). Therefore, they are probably not subject
to oxidative metabolism by these cytochromes. Moreover,
the estimated inhibitory activity of all compounds regarding
cytochrome CYP2C9 either exceeds 7, 9, and 10 or has an
equal probability of substrate specificity 2, 6, and 8 of the
analyzed derivatives.
This indirectly indicates inhibition by the substrate.
Therefore, it is impossible to make any assumptions about
their metabolism by this enzyme based on ADMET
analysis, and the final result can only be determined
experimentally. Cytochromes CYP3A4, the most dominant
drug-metabolizing enzyme in the body [39], and CYP2D6,
unlike other enzymes, are not inhibited by these
compounds. The high and very high likelihood of inhibition
of CYP1A2, CYP2C19, and CYP2C9 suggests the
possibility of potentiation of the biological activity of drugs
metabolized by these compounds when used together. The
S.G. Pilyo, M.V. Kachaeva et al.
39
Table 9. Predicted pharmacokinetic profiles of compounds 2, 6-10*.
Compd
P-glycoprotein Cytochrome P450 substate
GI
absorption
BBB permeant
Inh Sub
CYP1A2 CYP2C19 CYP2C9 CYP2D6 CYP3A4
Inh Sub Inh Sub Inh Sub Inh Sub Inh Sub
2 ++ --- +++ ++ + --- ++ ++ --- - --- - High No
6 -- --- + -- ++ --- ++ ++ - ++ - + High No
7 -- --- +++ -- ++ --- +++ ++ --- -- -- -- High No
8 -- --- ++ -- ++ --- +++ +++ --- -- --- - High No
9 -- --- +++ -- +++ --- +++ ++ --- -- - - High No
10 --- --- ++ --- + --- ++ + --- -- --- - High No
* The prediction probability values are transformed into six symbols: 0-0.1(---), 0.1-0.3 (--), 0.3-0.5 (-), 0.5-0.7 (+), 0.7-0.9 (++), and 0.9-1.0 (+++).
high absorption capacity of these molecules in the human
intestine and their low CNS permeability and sensitivity to
cancer cell lines shown in vitro suggest the possibility of
using them to treat sensitive tumors without causing severe
side effects in the central nervous system.
Interaction with specific targets
Tox21 predictive modeling is a computational analysis
that involves probabilistically assessing the interactions of
compounds with specific targets to analyze and interpret the
data generated [40]. These data can be used in the early
stages of discovering antitumor compounds to predict their
molecular mechanisms of action. Table 10 summarises the
cell receptors that the test compounds may interact with,
according to the ADMETlab 2.0 data.
Table 10. The probability of compounds 2 and 6-10
interacting with specific receptors and ferments predicted
by ADMETlab2*.
Targets
Compound
2 6 7 8 9 10
Androgen receptor --- --- --- --- --- ---
Aryl hydrocarbon receptor -- -- + -- - -
Aromatase ++ - ++ +++ ++ ++
Estrogen receptor + + ++ + ++ ++
Peroxisome proliferator-activated
receptor gamma
+ ++ ++ + ++ ++
Antioxidant response element ++ ++ ++ ++ ++ ++
Heat shock factor response element --- --- --- --- --- ---
Mitochondrial membrane potential -- -- - -- -- --
Tumor suppressor protein p53 --- --- -- --- -- --
LC50, µM 63.5 38.1 60.2 16.4 7.1 40.7
* The prediction probability values are transformed into six symbols: 0-
0.1(---), 0.1-0.3(--), 0.3-0.5(-), 0.5-0.7(+), 0.7-0.9(++), and 0.9-1.0(+++)
All compounds, except for 6, demonstrated a high or
very high likelihood of interacting with either aromatase
(estrogen synthase) or the estrogen receptor. Compounds 7,
9, and 10 showed such interaction with both targets.
Aromatase and ER inhibitors are the two main classes of
endocrine tumor therapy [41]. Based on this premise, one
would anticipate comparable antitumor efficacy of
compounds that interact with these targets, particularly in
the case of breast cancer. However, the lack of such
evidence precludes us from assuming that these targets are
integral to the primary molecular mechanism of the
anticancer activity of 4-cyano-2-phenyl-1,3-oxazole-5-
sulfonamide derivatives.
The same applies to the other two targets. It is assumed
that all potent compounds may interact with the antioxidant
response element. However, their effectiveness against the
entire NCI-60 panel of cell lines varies significantly.
Therefore, this target cannot be considered the predominant
mechanism of action for these derivatives. Furthermore, it is
anticipated that these compounds are unlikely to interact
with androgen and aryl hydrocarbon receptors, the
antioxidant response element, the heat shock factor
response element, the mitochondrial membrane potential,
and the p53 tumor suppressor protein. This implies that
their involvement in the mechanisms of action of these
compounds can be disregarded.
Conclusions
The results show that all compounds are effective
anticancer agents, although with varying degrees of
potency. Unfortunately, in vitro, evaluation of anticancer
activity within the framework of the Developmental
Therapeutic Program does not provide for the determination
of the cytotoxic selectivity of the tested compounds
between cancer and normal cells, which significantly affects
the effectiveness of the discovery of new anticancer drugs.
However, the values of quantitative indicators of the in vitro
anticancer potency of compounds cannot reflect their in
vivo effectiveness without a preliminary assessment of their
selectivity [42]. Therefore, it is significant that the ADMET
analysis predicted lead likeness for all compounds analyzed.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
40
Each compound can be optimized to improve selectivity
and other pharmacological properties, which characterize
their chemotherapeutic potential. This significantly
increases the probability of successfully developing new
effective drug candidates with antitumor activity based on
these compounds. Also, these derivatives are accepted by
all the most widely used filters as drug likeness. In addition,
their resistance to the development of tumor resistance
through the P-gp pathway, a low probability of oxidative
metabolism by cytochromes P-450, and high absorption in
the human intestine, which is significant when administered
orally, is predicted. Compare correlation showed the
absence of a robust correlation of antiproliferative activity
and cytotoxicity with standard agents, suggesting the
presence of specific molecular targets that realize their
antitumor activity. Therefore, there is some possibility that
previously unidentified targets will be experimentally
identified, opening new opportunities for developing
effective anticancer drugs. Moreover, among the studied
drugs, none had an average graph similar with a high
probability to compounds 2, 7, 9, and 10 for two calculated
parameters of anticancer potency out of three.
Notes
Acknowledgments and finances. This work was
supported by the National Academy of Sciences of Ukraine
under Grants of the NAS of Ukraine to research
laboratories/groups of young scientists of the NAS of
Ukraine to conduct research in the priority directions of the
development of science and technology in 2024-2025
"Novel synthetic nitrogen-containing heterocyclic
compounds with antimicrobial and anticancer activity"
(Contract №29/02-2024(5) from 19.02.2024).
The authors declare no conflict of interest. The
authors declare that there is no conflict of interest regarding
the publication of this paper.
Author contributions. S.G.P.: synthesis of compounds,
investigation of synthetic results, writing experimental
chemical section, editing. M.V.K.: investigation, formal
analysis, writing chemical experimental section. O.O.S.:
synthesis of compounds, formal analysis, editing. O.P.K.:
synthesis and spectral analysis of compounds. V.V.Z.:
investigation of biological results, writing biological
experimental section, abstract, introduction and
conclusions. V.S.B.: conceptualization, supervision,
writing, review, editing
Supporting information
SI presents Tables S1 (Сomplete NCI analysis data) and
S2 (the tested compounds average values of calculated
parameters for antitumor activity against the NCI-60
panel/subpanel).
Experimental section
Synthesis
1H and 13C NMR spectra (400 and 101 MHz,
respectively) of obtained products were recorded on a
Varian Unity Plus 400 spectrometer in DMSO-d6, with
chemical shifts reported in ppm using the solvent residual
signal as internal standard (2.50 ppm for the 1H nuclei and
39.5 ppm for the 13C nuclei). IR spectra were recorded on a
Vertex-70 spectrometer in KBr pellets. Combustion
elemental analysis was performed in the V.P. Kukhar
Institute of Bioorganic Chemistry and Petrochemistry
analytical laboratory, their results were found to be in good
agreement (±0.4%) with the calculated values. The carbon
and hydrogen contents were determined using the Pregl
gravimetric method, nitrogen – using the Duma's
gasometrical micromethod, sulfur – by the Scheininger
titrimetric method.
N-(2,2-Dichloro-1-cyanovinyl)benzamide (I) and its
synthetic procedure were described in [8].
4‐Cyano‐2‐phenyl‐1,3‐oxazole‐5‐sulfonyl chloride (II)
was synthesized previously [9] from compound (I).
4-Cyano-2-phenyl-1,3-oxazole-5-sulfonamide (1) was
synthesized following a procedure described in the
literature [9].
4-Cyano-N,N-dimethyl-2-phenyl-1,3-oxazole-5-sulfona-
mide (2).
Solution of 2.68 g of 4-cyano‐2‐phenyl‐1,3‐oxazole‐5‐
sulfonyl chloride (II) (10.0 mmol) in 40 ml of anhydrous
dioxane was added dropwise to solution of 2.0 ml of
aqueous dimethylamine (25.0 mmol) and 1.54 ml of Et3N
(11.0 mmol). The mixture was heated for 2 h and kept at
20-25 °C for 12 h. The residue was treated with water,
filtered off, dried, and recrystallized from ethanol, yielding
a yellow precipitate. Yield: 2.22 g, 80 %; Mp 140-142 ºС;
1H NMR (400 MHz, DMSO-d6) δ 7.84-7.83 (m, 2H, Ar),
7.50-7.48 (m, 3H, Ar), 3.17 (s, 6H, NMe2); 13C NMR
(125 MHz, DMSO-d6) δ 156.6, 132.0, 129.3, 129.1, 129.0,
127.9, 127.8, 117.3, 86.3, 35.7, 35.0; IR (KBr) ν 2220 (CN),
1339 (SO2), 1150 (SO2); Anal. calcd for C12H11N3O3S, %:
C, 61.18; H, 4.28; N, 11.89; S, 9.07. Found, %: C, 61.09; H,
4.20; N, 11.98; S, 9.39.
2-Phenyl-5-((4-phenylpiperazin-1-yl)sulfonyl)-1,3-oxazo-
le-4-carbonitrile (3).
To a solution of 2.68 g of 4-cyano‐2‐phenyl‐1,3‐oxazole‐
5‐sulfonyl chloride (II) (10.0 mmol) in 40 ml of anhy-
drous dioxane solution of 1.78 g of 1-phenylpiperazine
(11.0 mmol) and 1.54 ml of Et3N (11.0 mmol) was added.
The mixture was heated for 2 h and kept at 20-25 ºС for
12 h. The residue was treated with water, filtered off, dried,
and recrystallized from ethanol, yielding a white precipitate.
Yield: 2.96 g, 75 %; Mp 192-195 ºС. 1H NMR (400 MHz,
DMSO-d6) δ 8.06 (d, J 8.0 Hz, 2H, Ar), 7.71-7.62 (m, 3H,
Ar), 7.24-7.20 (m, 2H, Ar), 6.95 (d, J 8.4 Hz, 2H, Ar), 6.81
(t, J 7.6 Hz, 2H, Ar), 3.51-3.50 (m, 4H, 2CH2), 3.30 (s, 4H,
2CH2); 13C NMR (101 MHz, DMSO-d6) δ 156.6, 150.9,
132.0, 129.9, 129.8, 129.7, 129.6, 129.1, 127.9, 127.8,
S.G. Pilyo, M.V. Kachaeva et al.
41
120.3, 117.3, 116.8, 116.7, 84.6, 50.9, 50.8, 45.8, 45.7; IR
(KBr) ν 2226 (CN), 1332 (SO2), 1153 (SO2); Anal. calcd for
C20H18N4O3S, %: C, 60.90; H, 4.60; N, 14.20; S, 8.13.
Found, %: C, 60.80; H, 4.49; N, 14.45; S, 8.34.
5-((4-(4-Fluorophenyl)piperazin-1-yl)sulfonyl)-2-phenyl-
1,3-oxazole-4-carbonitrile (4) was synthesized from 2.68 g
of 4‐cyano‐2‐phenyl‐1,3‐oxazole‐5‐sulfonyl chloride (II)
(10.0 mmol) and 1.98 g of 1-(4-fluorophenyl)piperazine
(11.0 mmol) following a procedure for compound 3. Yield:
3.18 g, 77 %; Mp 152-155 ºС; 1H NMR (400 MHz, DMSO-
d6) δ 7.91 (s, 2H, Ar), 7.52 (s, 3H, Ar), 7.12-7.06 (m, 4H,
Ar), 3.75 (s, 4H, 2CH2), 3.30 (s, 4H, 2CH2); 13C NMR
(101 MHz, DMSO-d6) δ 158.2, 156.6, 149.9, 132.0, 129.6,
129.8, 129.1, 127.9, 127.8, 118.9, 118.5, 117.8, 117.6,
117.3, 84.6, 50.9, 50.8, 45.7, 45.1; IR (KBr) ν 2225 (CN),
1328 (SO2), 1143 (SO2); Anal. calcd for C20H18N4O3S, %:
C, 58.24; H, 4.15; N, 13.58; S, 7.77. Found, %: C, 58.16; H,
4.05; N, 13.89; S, 7.95.
5-((4-(4-Methoxyphenyl)piperazin-1-yl)sulfonyl)-2-phe-
nyl-1,3-oxazole-4-carbonitrile (5) was synthesized from
2.68 g of 4‐cyano‐2‐phenyl‐1,3‐oxazole‐5‐sulfonyl chloride
(II) (10.0 mmol) and 2.11 g of 1-(4-methoxyphenyl)-
piperazine (11.0 mmol) following a procedure for compo-
und 3. Yield: 3.10 g, 73 %; Mp 189-190 ºС; TLC
(hexane/EtOAc 2:3) Rf 0.7; 1H NMR (400 MHz, DMSO-d6)
δ 7.91 (s, 2H. Ar), 7.52 (s, 3H, Ar), 7.12-7.06 (m, 4H, Ar),
3.75 (s, 4H, 2CH2), 3.69 (s, 3H, OCH3), 3.30 (s, 4H, 2CH2);
13C NMR (101 MHz, DMSO-d6) δ 158.2, 156.6, 149.9,
132.0, 129.6, 129.8, 129.1, 127.9, 127.8, 118.9, 118.5,
117.8, 117.6, 117.3, 84.6, 50.9, 50.8, 45.7, 45.1; IR (KBr) ν
2225 (CN), 1328 (SO2), 1143 (SO2); Anal. calcd for
C21H20N4O4S, %: C, 59.42; H, 4.75; N, 13.20; S, 7.55.
Found, %: C, 59.31; H, 4.66; N, 13.40; S, 7.76.
2-Phenyl-5-((4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)sul-
fonyl)-1,3-oxazole-4-carbonitrile (6) was synthesized from
2.68 g of 4‐cyano‐2‐phenyl‐1,3‐oxazole‐5‐sulfonyl chloride
(II) (10.0 mmol) and 2.10 g of 1-(2-(pyridin-2-
yl)ethyl)piperazine (11.0 mmol) following a procedure for
compound 3. Yield: 3.10 g, 78 %; Mp 165-167 ºС; 1H NMR
(400 MHz, DMSO-d6) δ 8.56 (s, 2H, Ar), 7.88-7.82 (m, 4H.
Ar), 7.65 (t, J 8.0 Hz, 1H, Ar), 7.20-7.12 (m, 2H, Ar), 3.66-
3.60 (m, 4H, 2CH2), 3.10 (t, J 8.0 Hz, 2H, 2CH2), 2.82 (t, J
8.0 Hz, 2H, CH2), 2.68 (s, 4H, 2CH2); 13C NMR (101 MHz,
DMSO-d6) δ 156.9, 156.6, 148.1, 139.7, 132.3, 129.3,
129.2, 129.1, 127.9, 127.8, 123.2, 121.4, 117.3, 84.6, 53.9,
53.6, 53.2, 46.9, 46.7, 32.6; IR (KBr) ν 2218 (CN), 1318
(SO2), 1138 (SO2); Anal. calcd for C21H21N5O3S, %: C,
59.56; H, 5.00; N, 16.54; S, 7.57. Found, %: C, 59.45; H,
5.12; N, 16.78; S, 7.69.
2-Phenyl-5-(piperidin-1-ylsulfonyl)-1,3-oxazole-4-carbo-
nitrile (7) was synthesized following a procedure described
in the literature [10].
5-((4-Methylpiperidin-1-yl)sulfonyl)-2-phenyl-1,3-oxazo-
le-4-carbonitrile (8) was synthesized following a procedure
described in the literature [11, 12].
5-((3-Methylpiperidin-1-yl)sulfonyl)-2-phenyl-1,3-oxazo-
le-4-carbonitrile (9) was synthesized following a procedure
described in the literature [11, 12].
5-(Morpholinosulfonyl)-2-phenyl-1,3-oxazole-4-carboni-
trile (10) was synthesized following a procedure described
in the literature [9].
5-((5-Amino-3-methyl-1H-pyrazol-1-yl)sulfonyl)-2-phe-
nyl-1,3-oxazole-4-carbonitrile (11) was synthesized
following a procedure described in the literature [11].
5-((5-Amino-3-phenyl-1H-pyrazol-1-yl)sulfonyl)-2-phe-
nyl-1,3-oxazole-4-carbonitrile (12) was synthesized
following a procedure described in the literature [11].
N-(2-(4-Chlorophenyl)-2-(piperidin-1-yl)ethyl)-4-cyano-
2-phenyl-1,3-oxazole-5-sulfonamide (13) was synthesized
following a procedure described in the literature [11].
In vitro anticancer screening of the tested compounds
One dose full NCI 60 cell panel assay
Synthesized compounds (Table 1) were submitted to the
National Cancer Institute (NCI), Bethesda, Maryland,
U.S.A., under the Developmental Therapeutic Program
(DTP). The cell line panel engaged 60 different human
tumor cell lines derived from nine cancer types, including
lung, colon, melanoma, renal, ovarian, brain, leukemia,
breast, and prostate.
Primary in vitro one-dose anticancer screening was
initiated by cell inoculating of each 60-panel line into a
series of standard 96-well microtiter plates at 5000-40000
cells/well in RPMI 1640 medium containing 5% fetal
bovine serum and 2 mM L-glutamine (day 0), and then
preincubated in the absence of drug at 37 ºС and 5% CO2
for 24 h. Test compounds were added to the plates at one
concentration of 1 x 10 -5 M (day 1), followed by incubation
for 48 h under the same conditions. Then, the media was
removed, and the cells were fixed in situ, washed, and
dried. The sulforhodamine B assay was used for cell density
determination based on the measurement of cellular protein
content. After an incubation period, cell monolayers were
fixed with 10% (wt/vol) trichloroacetic acid and stained for
30 min, after which the excess dye was removed by
washing repeatedly with 1% (vol/vol) acetic acid. The
bound stain was resolubilized in 10 mM Tris base solution
and measured spectrophotometrically on automated
microplate readers for OD determination at 510 nm.
Statistical data analysis
The program Statistica v6.0 for Windows performed
statistical and correlation analyses of the results. The
unpaired Student t-test (p < 0.05) evaluated a statistically
significant difference between the two groups. The data are
presented as means ± SEM (standard error of the mean).
COMPARE correlation
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
42
Compounds with similar activity profiles often have
similar mechanisms of action. To measure the degree of
similarity between novel compounds and known drugs from
the NCI databases, a method using the Pearson
correlation coefficient as the comparison criterion
(COMPARE correlation) has been used
[https://dtp.cancer.gov/databases_tools/docs/compare/comp
are_methodology.htm#specon]. The graph of mean values
for compounds was subsequently used to run the
COMPARE algorithm from the NCI Developmental
Therapeutics Program and calculate the correlation
coefficient concerning compounds from the standard agent
database with a known mechanism of action. Briefly,
vectors of GI50, TGI, and LC50 concentrations for tested
compound, approximated from one dose assay, were
correlated with the set of average GI50, TGI, and LC50
vectors for all public NCI-60 vectors for the entire public
standard agent's database [13]. The quantitative evaluation
of the results obtained was carried out using the Chaddock
scale [14]. According to this scale, the interpretation of the
paired correlation coefficients is as follows: insignificant
(0.00-0.30), weak (0.30-0.50), moderate (0.50-0.70), high
(0.70-0.90) and very high (0.9-1.0). Pairwise correlation
coefficients greater than 0.65 were used as a threshold to
assess whether seeded and standard compounds have a
similar mechanism of action.
ADMET analysis
Available online websites ADMETlab 2.0, an inte-
grated online platform for Windows
(https://admetmesh.scbdd.com/service/screening/index),
and SwissADME (http://www.swissadme.ch/index.php) are
applied to explore the drug likeness and ADMET properties
of the studied molecules. These websites can reduce the
need for empirical experiments and increase the chances of
success in developing new drugs [15]. Binary filters were
employed as the primary screening method for drug
similarity properties. These filters utilize a range of
molecular properties selected based on their published
significance in determining drug similarity. Additionally,
the test compounds' pharmacokinetic, pharmacodynamic,
and toxic properties were predicted using ADMET. The
conversion of molecular structures into SMILES strings,
which is required for the operation of ADMET platforms,
was done using the Marvin JS widget, which also allowed
us to visualize the acceptor sites of the compounds
(https://docs.chemaxon.com/display/ltseuropium/introductio
n-to-marvinview.md)
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Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-
оксазол-5-сульфонаміду
С.Г. Пільо, М.В. Качаєва*, О.О. Северін, О.П. Козаченко, В.В. Жирнов, В.C. Броварець
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Тринадцять аналогів 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду були синтезовані та охарактеризовані методами спектроскопії та
елементного аналізу. Їх інгібувальну активність росту визначали in vitro в аналізі однієї дози проти загальної панелі людських ракових клітин
NCI-60. Аналіз п'яти доз проводили на шести сполуках з більшою цитотоксичністю. Cполуки 8 і 9 показали найбільшу ефективність проти
загальних ліній ракових клітин NCI-60 в аналізі з п'ятьма дозами. Крім того, сполука 9 з 3-метилпіперидиновим фрагментом виявилася вдвічі
активнішою за сполуку 8 з 4-метилпіперидином (GI50 = 1,4±0,1 проти 2,5±0,4, GI = 3,9±0,6 проти 7,1±1,3 і LC50 = 7,1±1,0 проти 16,4±2,3 мкМ).
Відсутність загальноприйнятих препаратів, які демонструють високу кореляцію з більшістю проаналізованих сполук на основі двох із трьох
розрахованих параметрів протипухлинної активності, свідчить про те, що вони можуть взаємодіяти з унікальною мішенню. Результати аналізу
ADMET передбачають, що ця сполука відповідає критеріям подібності ліків і не належить до нестандартних молекул, які неспецифічно реагують
з численними мішенями. Також включено передбачення подібності до лідера для всіх сполук, що означає, що будь-яку з них можна оптимізувати
з метою підвищення селективності та інших фармакологічних властивостей, які характеризують їх хіміотерапевтичний потенціал.
Ключові слова: 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміди; протиракова активність; SAR аналіз; COMPARE кореляція; ADMET аналіз.
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| id | oai:ojs2.bioorganica.com.ua:article-82 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:26Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
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| resource_txt_mv | bioorganicacomua/48/94eff5682afd2255f865015b553b5f48.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-822026-07-19T14:56:55Z Design, synthesis, in silico and in vitro investigation of 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide derivatives Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду Pilyo, Stepan G. Kachaeva, Maryna V. Severin, Oleksandr O. Kozachenko, Oleksandr P. Zhirnov, Victor V. Brovarets, Volodymyr S. 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamides anticancer activity SAR analysis COMPARE correlation ADMET analysis 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміди протиракова активність SAR аналіз COMPARE кореляція ADMET аналіз A thirteen 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide analogs have been synthesized and characterized by spectroscopy methods, elemental analysis. Their growth inhibiting activity was determined in vitro in the one dose assay against the total NCI-60 human cancer cell line panel. The five-dose analysis was performed on the six compounds with greater cytotoxicity. Two compounds 8 and 9 exhibited the greatest potency against total NCI-60 cancer cell lines in the five dose assay. Furthermore, compound 9 with 3-methylpiperidine fragment turned out to be two times more active than compound 8 with 4-methylpiperidine (GI50 = 1.4±0.1 against 2.5±0.4, GI = 3.9±0.6 against 7.1±1.3 and LC50 = 7.1±1.0 against 16.4±2.3 µM). The lack of commonly used drugs that show a high correlation with the majority of analyzed compounds, based on two out of three calculated parameters of anticancer potency, suggests that they may interact with a unique target. The ADMET analysis results predict that this compound meets the drug similarity criteria and does not belong to interfering molecules that react non-specifically with numerous targets. The prediction of lead likeness for all compounds is also included, meaning that any of them can be optimized to enhance selectivity and other pharmacological properties that characterize their chemotherapeutic potential Тринадцять аналогів 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду були синтезовані та охарактеризовані методами спектроскопії, елементного аналізу та хромато-мас-спектрометрії. Їхню інгібуючу активність росту визначали in vitro в аналізі однієї дози проти загальної панелі людських ракових клітин NCI-60. Аналіз п'яти доз проводили на шести сполуках з більшою цитотоксичністю. Дві сполуки (8) і (9) показали найбільшу ефективність проти загальних ліній ракових клітин NCI-60 в аналізі з п'ятьма дозами. Крім того, сполука (9) з 3‑метилпіперидиновим фрагментом виявилася вдвічі активнішою за сполуку (8) з 4-метилпіперидином (GI50 = 1,4±0,1 проти 2,5±0,4, GI = 3,9±0,6 проти 7,1±1,3 і LC50 = 7,1±1,0 проти 16,4±2,3 мкМ). Відсутність загальноприйнятих препаратів, які демонструють високу кореляцію з більшістю проаналізованих сполук на основі двох із трьох розрахованих параметрів протипухлинної активності, свідчить про те, що вони можуть взаємодіяти з унікальною мішенню. Результати аналізу ADMET передбачають, що ця сполука відповідає критеріям подібності ліків і не належить до заважаючих молекул, які реагують неспецифічно з численними мішенями. Також включено передбачення подібності до лідера для всіх сполук, що означає, що будь-яку з них можна оптимізувати з метою підвищення селективності та інших фармакологічних властивостей, які характеризують їхній хіміотерапевтичний потенціал V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-06-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/82 10.15407/bioorganica2024.01.030 Ukrainica Bioorganica Acta; Vol. 19 No. 1 (2024): Ukrainica Bioorganica Acta; 30-43 Ukrainica Bioorganica Acta; Том 19 № 1 (2024): Ukrainica Bioorganica Acta; 30-43 1814-9766 1814-9758 10.15407/bioorganica2024.01 en https://bioorganica.com.ua/index.php/journal/article/view/82/80 https://bioorganica.com.ua/index.php/journal/article/view/82/81 Copyright (c) 2024 Stepan G. Pilyo, Maryna V. Kachaeva, Oleksandr O. Severin, Oleksandr P. Kozachenko, Victor V. Zhirnov, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміди протиракова активність SAR аналіз COMPARE кореляція ADMET аналіз Pilyo, Stepan G. Kachaeva, Maryna V. Severin, Oleksandr O. Kozachenko, Oleksandr P. Zhirnov, Victor V. Brovarets, Volodymyr S. Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title | Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title_alt | Design, synthesis, in silico and in vitro investigation of 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamide derivatives |
| title_full | Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title_fullStr | Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title_full_unstemmed | Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title_short | Дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| title_sort | дизайн, синтез, in silico та in vitro дослідження похідних 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміду |
| topic | 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміди протиракова активність SAR аналіз COMPARE кореляція ADMET аналіз |
| topic_facet | 4-cyano-2-phenyl-1,3-oxazole-5-sulfonamides anticancer activity SAR analysis COMPARE correlation ADMET analysis 4-ціано-2-феніл-1,3-оксазол-5-сульфонаміди протиракова активність SAR аналіз COMPARE кореляція ADMET аналіз |
| url | https://bioorganica.com.ua/index.php/journal/article/view/82 |
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