Dependence of the anticancer activity of 1,3-oxazole derivatives on the donor/acceptor nature of his substitues

Article abstract of DOI:10.1002/jhet.3711

A series of new 1,3-oxazole derivatives, containing in position 5 both donor and acceptor substituents were synthesized. These substances were considered as potentially active anticancer pharmacophores in the human tumor cell line panel derived from nine cancer types, including lung, colon, melanoma, renal, ovarian, brain, leukemia, breast, and prostate. Primary in vitro one-dose anticancer screening was shown that compounds with acceptor substituents (such as –C(O)OMe, –CN) in the position 5 inhibit the growth of most cell lines, and compounds with donor substituents (such as –NHR, ?SR) in the position 5 do not practically inhibit the growth of cancer cell lines. It can be assumed that the pharmacological activity of 1,3-oxazole derivatives depends on donor/acceptor nature of the substituents in position 5. It was proposed to evaluate the donor/acceptor ability of 1,3-oxazole derivatives using the special parameter φ₀, which takes into account the relative position of the boundary levels (HOMO end LUMO). The quantum-chemical modeling was performed; the special parameter φ₀ for 1,3-oxazole derivatives correlates with the experimental results. Quantum-chemical calculations of the special parameter φ₀ allow modeling the pharmacological activity of 1,3-oxazole derivatives by introducing donor or acceptor substituents at position 2 or 5. This work may be useful for chemists to develop a target synthesis of potential biologically active compounds.

Full text of DOI:10.1002/jhet.3711

Received: 18 May 2019
DOI: 10.1002/jhet.3711
Revised: 1 August 2019
Accepted: 19 August 2019
A R T I C L E
Dependence of the anticancer activity of 1,3‐oxazole
derivatives on the donor/acceptor nature of his substitues
Maryna V. Kachaeva1
| Diana M. Hodyna1
| Nataliya V. Obernikhina2
| Volodymyr M. Prokopenko1
|
Stepan G. Pilyo1
| Yulia S. Kovalenko3
|
Oleksiy D. Kachkovsky1
| Volodymyr S. Brovarets1
1 Department of chemistry of bioactive
nitrogen containing heterocyclic bases, V.
P. Kukhar Institute of Bioorganic
Abstract
A series of new 1,3‐oxazole derivatives, containing in position 5 both donor and
acceptor substituents were synthesized. These substances were considered as
potentially active anticancer pharmacophores in the human tumor cell line panel
derived from nine cancer types, including lung, colon, melanoma, renal, ovarian,
brain, leukemia, breast, and prostate. Primary in vitro one‐dose anticancer
screening was shown that compounds with acceptor substituents (such as –
C(O)OMe, –CN) in the position 5 inhibit the growth of most cell lines, and com-
pounds with donor substituents (such as –NHR, −SR) in the position 5 do not
practically inhibit the growth of cancer cell lines. It can be assumed that the phar-
macological activity of 1,3‐oxazole derivatives depends on donor/acceptor nature
of the substituents in position 5. It was proposed to evaluate the donor/acceptor
ability of 1,3‐oxazole derivatives using the special parameter φ0, which takes into
account the relative position of the boundary levels (HOMO end LUMO). The
quantum‐chemical modeling was performed; the special parameter φ0 for 1,3‐
oxazole derivatives correlates with the experimental results. Quantum‐chemical
calculations of the special parameter φ0 allow modeling the pharmacological
activity of 1,3‐oxazole derivatives by introducing donor or acceptor substituents
at position 2 or 5. This work may be useful for chemists to develop a target synthe-
sis of potential biologically active compounds.
Chemistry and Petrochemistry of the
National Academy of Sciences of Ukraine,
1, Murmanskaya str, Kyiv 02094, Ukraine
2 Department of Bioorganic and Biological
Chemistry, O.O. Bogomolets National
Medical University, 13 T. Shevchenko
boul., 01601 Kyiv, Ukraine
3 Nizhyn Mykola Gogol State University, 2,
Grafska Str, Nizhyn 16600, Ukraine
Correspondence
Nataliya V. Obernikhina, O.O. Bogomolets
National Medical University, Department
of Bioorganic and Biological Chemistry, 13
T. Shevchenko boul., 01601. Kyiv,
Ukraine.
Email: nataliya.obernikhina@gmail.com
Funding information
US Public Health Service and National
Cancer Institute, USA
1 | INTRODUCTION
antidiabetic and antiobesity,[19–22] antiviral, and analgesic
effect.[5,6] Thus, 1,3‐oxazole could be considered as
The heterocyclic compounds with branched conjugated
systems including oxazole, thiazole, or pyrazole moieties
have shown themselfes as powerful scaffolds in
drug design.[1–10] 1,3‐Oxazoles play a vital role in the
manufacture of various biologically active drugs as
brain‐derived neurotrophic factor inducers,[11] analge-
sic,[12] trypanocidal activity,[13] antimitotic agents
with pro‐apoptotic activity,[14] antibacterial and anti-
tuberculosis properties,[15] antifungal activity,[16] anti‐
inflammatory,[17] antidepressant,[18] antimicrobial,[3]
perspective moiety in the design and further synthesis of
novel biologically active agents that exert anticancer
activity.[1–4,23–34]
So, the QSAR models were developed for wide site of
1,3‐oxazole derivatives showing inhibitory effect on the
NCI‐60 cancer cell lines,[2,35] and the well correlation
was established between many descriptors and biologi-
cal activity. So, it was investigated the interaction of
the azole derivatives with the tubulin inhibitors which
significantly improve the clinical effectivity of novel
J Heterocyclic Chem. 2019;1–13.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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KACHAEVA ET AL.
proposed biological active molecules as anticancer
agents.[10]
Among the molecular characteristics to be used
for structure‐pharmacological activity relationship, the
highest occupied molecular orbital (HOMO) and the low-
est unoccupied molecular orbital (LUMO) energies have
been shown to correlate particularly well with various
biological activities.[36–42]
It is to be taken into account that biological activity or
generation of the stable “rigid” structure with the recep-
tors depends on the chemical constitution of target,
including its possible electron structure.
In this case, the π‐electron system of the 1,3‐oxazole
should effectively take part in the generation of the stable
“rigid” complex with the receptors. Therefore, introduc-
ing of donor or/and acceptor substituents in the oxazole
cycle can considerably influence on the positions of its
frontier levels and hence on the donor or acceptor proper-
ties substitutiens of 1,3‐oxazole core. We could propose
that such intentional change of molecular level energies
may influence on the biological activity.
This paper presents the results of the synthesis of the
new promising biologically active agents and quantum‐
chemical modeling as well as the pharmacological testing
of synthesized compounds.
SCHEME 1 Synthesis of 5‐amino‐ (5, 6), 5‐sulfanyl‐ (7–11), and
5‐sulfonyl‐ (12–16) 1,3‐oxazole‐4‐carbonitriles. Reagents and
conditions: (a) 2‐(methylamino)ethanol, Et3N, THF, rt, 12 hours; (b)
2‐(4‐chlorophenyl)‐2‐piperidin‐1‐ylethanamine, Et3N, THF, rt,
12 hours; (c) arenethiol, Et3N, acetonitrile, rt, 8 hours; Ag2CO3,
acetonitrile, reflux, 8 to 10 hours; (d) H2O2, AcOH, reflux, 1 hour
sulfonyl chlorides 17 or 18[47] by refluxing with appropri-
ate amine and excess of triethylamine (Scheme 2).
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
Methyl
5‐((5‐amino‐3‐1H‐pyrazol‐1‐yl)sulfonyl)‐1,3‐
oxazole‐4‐carboxylates 24, 25 were prepared by refluxing
The 2‐acylamino‐3,3‐dichloroacrylonitriles 1‐4 are known
to be useful precursors for diverse 5‐amino‐, 5‐sulfanyl‐,
and 5‐sulfonyl derivatives of 1,3‐oxazole (Scheme 1).[43]
The convenient protocol of Drach et al[44] enabled
efficient access to compounds 5 and 6 preparing from
2‐acylamino‐3,3‐dichloroacrylonitriles 1 or 2[43] with
appropriate amine using excess of triethylamine.
The compounds 8 and 13 and its synthetic route were
described previously.[45] The synthesis of similar
1,3‐oxazoles 7, 9, 12, and 14‐16 was made by the same
approach as for 8 and 13.[45] The preparation of sulfanyl
derivatives 7‐11 involves treatment of 2‐acylamino‐3,3‐
dichloroacrylonitriles 1‐4 with arenethiols in the presence
of
triethylamine
to
obtain
2‐acylamino‐3,3‐bis
(arylsulphanyl)acrylonitriles, which can be cyclized in
the presence of silver carbonate to form 5‐arylsulphanyl‐
1,3‐oxazole‐4‐carbonitriles 7‐11. The latter were con-
verted into the corresponding sulfonyl derivatives 12‐16
by oxidation with hydrogen peroxide.[46]
SCHEME 2 Synthesis of 4‐cyano‐1,3‐oxazole‐5‐sulfonyl amides
19‐22. Reagents and conditions: (a) 3‐ or 4‐methylpiperidine, Et3N,
dioxane, reflux, 2 hours; (b) 2‐methylaminoethanol, Et3N, dioxane,
reflux, 2 hours; (c) 2‐(4‐chlorophenyl)‐2‐piperidin‐1‐ylethanamine,
Et3N, dioxane, reflux, 2 hours
4‐Cyano‐1,3‐oxazole‐5‐sulfonyl amides 19‐22 have
been synthesized according to the procedure[35] from

KACHAEVA ET AL.
3
of methyl 5‐chlorosulfonyl‐2‐phenyl‐1,3‐oxazole‐4‐carbo-
xylate (23) with 3‐methyl‐ or 3‐phenyl‐1H‐pyrazol‐5‐
amine and triethylamine in dioxane (Scheme 3).[48]
Data of synthesized novel 1,3‐oxazole derivatives are
presented in Section 4. NMR (1H and 13C NMR),
chromato‐mass, and elemental analysis confirm reliably
the structure of the obtained compounds. The structure
and composition of all obtained 1,3‐oxazoles have been
5‐Arylsulfonyl‐1,3‐oxazoles 12‐16 and sulfonamides
19‐22, 24, and 25 have been demonstrated potent
anticancer activity against different cell lines unlike
5‐amino‐ (5, 6) and 5‐sulfanyl‐ (7‐9) 1,3‐oxazole‐4‐
carbonitriles.
1,3‐Oxazole‐5‐sulfonyl amides 21, 22, 24, and 25 have
demonstrated good antitumor activity against all lines of
leukemia ranging from −18,14 (for compound 21,
HL‐60(TB)) to 58,90 (for compound 24, HL‐60(TB)),
non‐small cell lung cancer from −25,83 (for compound
25, NCI‐H522) to 123,50 (for compound 21, NCI‐H226),
almost all cell lines of colon cancer ranging from −63,88
(for compound 25, COLO 205) to 115,34 (for compound
25, HCC‐2998), SF‐539 of CNS cancer (43,01 for
compound 21), LOX IMVI of melanoma (from 21,91 for
compound 22 to 76,84 for compound 25) and MALME‐
3 M of melanoma (−37,06 for compound 25, 2,22 for
compound 24), IGROV1 (44,16 for compound 22),
OVCAR‐3 of ovarian cancer (42,30 for compound 21;
20,43 for compound 25), ACHN of renal cancer (−86,23
for compound 25; 19,19 for compound 24), T‐47D of
breast cancer (22,46 for compound 25, 49,51 for
compound 24).
1
in good accordance with data of elemental analysis, Н,
13С NMR, IR spectroscopy, and mass spectrometry. All
1
CH‐proton signals are visible in the H NMR spectrum.
The signal of the OH group (5, 21) is in the range from
4.79 to 4.93 ppm; NH2 group (24, 25) is from 6.32 to
6.55 ppm. The intensive absorption bands of SO2‐group
appeared at 1152 to 1192 сm−1 and 1353 to 1386 сm−1
in the IR spectra of compounds 12‐16, 19‐22, 24, and 25.
Also, the broad intensive bands at 1731 to 1732 cm−1
corresponded to esters C═O bond of compounds 24, 25,
and intensive bands at 2198 to 2251 cm−1 corresponded
to CN group of 5‐16, 19‐22 were observed.
5‐Arylsulphonyl‐1,3‐oxazoles 12‐16 exhibited high‐
cytotoxic and cytostatic influence against different cell
lines; sulfamides 19, 20 demonstrated high‐cytostatic
activity against most of the cell lines.
2.2 | In vitro evaluation of the anticancer
activity
The synthesized compounds 5‐16, 19‐22, 24, and 25 were
screened for anticancer activity in the 60‐cell panel in
accordance with the protocol of the NCI, USA,[49–52]
and the results of the single‐dose (10μM) testing (5‐16,
19‐22, 24, and 25) and five‐dose (0.01, 0.1, 1, 10, and
100μM) (12, 14‐16, 19, and 20) experiments are presented
in Supplementary material.
1,3‐Oxazole derivatives exhibited distinctive pattern of
anticancer activity. Compounds 5‐9 and with amino or
mercapto group in the position 5 of 1,3‐oxazole ring have
been shown to exhibit moderate anticancer activity rang-
ing from 67.29 (for compound 7, NCI‐H522 of non‐small
cell lung cancer) to 131.64 (for compound 9, OVCAR‐3
of ovarian cancer).
Compound 12 was active against leukemia: CCRF‐
CEM (−21,44), HL‐60(TB) (37,30), K‐562 (3,28), MOLT‐
4 (−24,16), SR (0,73); non‐small cell lung cancer:
NCI‐H522 (−81,24); colon cancer: HCT‐116 (−49,12),
SW‐620 (−55,05); melanoma: LOX IMVI (30,03),
MALME‐3M (−54,48), M14 (41,75); renal cancer: ACHN
(−0,84), TK‐10 (−32,35); breast cancer: T‐47D (−15,19).
Compound 13 was active against leukemia: CCRF‐
CEM (−10,68), K‐562 (54,67), MOLT‐4 (−6,82); colon
cancer: SW‐620 (54,03); melanoma: LOX IMVI (38,89).
Compound 14 was active against leukemia: CCRF‐
CEM (−13,84), HL‐60(TB) (36,09), K‐562 (1,85),
MOLT‐4 (−36,39), SR (−27,66); non‐small cell lung
cancer: NCI‐H522 (−82,02); colon cancer: HCT‐116
(0,21), SW‐620 (−37,71); melanoma: LOX IMVI (7,99),
MALME‐3M (−47,84), M14 (38,39); renal cancer: ACHN
(24,37), TK‐10 (−25,29); breast cancer: T‐47D (3,98).
Compound 15 was active against leukemia: CCRF‐
CEM (−14,67), HL‐60(TB) (8,92), K‐562 (2,06), MOLT‐4
(−18,46), SR (5,77); non‐small cell lung cancer:
NCI‐H23 (37,91), NCI‐H522 (−68,79); colon cancer:
HCT‐116 (−91,06), SW‐620 (−68,59); melanoma: LOX
IMVI (39,82), MALME‐3M (−56,67), M14 (27,28); ovarian
cancer: OVCAR‐4 (−16,60); renal cancer: ACHN
(−84,39), TK‐10 (−78,27); breast cancer: MCF7 (34,27),
T‐47D (−7,72), MDA‐MB‐468 (42,03).
SCHEME 3 Synthesis of methyl‐5‐((5‐amino‐3‐1H‐pyrazol‐1‐yl)
sulfonyl)‐1,3‐oxazole‐4‐carboxylates 24, 25. Reagents and
conditions: (a) 3‐phenyl‐ or 3‐methyl‐1H‐pyrazol‐5‐amine, Et3N,
dioxane, reflux, 2 hours

4
KACHAEVA ET AL.
Compound 16 was active against leukemia:
One‐Dose Screening were tested against the panels of
60 cancer cell lines of NCI of the five‐dose assay for
anticancer activity against each cancer cell line.[46]
Compound 12 showed GI50 values ranging from
0.41μM (non‐small cell lung cancer NCI‐H522 cell line)
to 37.3μM (CNS Cancer SNB‐19 cell line), TGI—from
1.67μM (non‐small cell lung cancer NCI‐H522 cell line)
to 75.9μM (CNS Cancer SF‐395 cell line), and LC50—from
6.0μM (renal cancer RXF‐393 cell line) to 83.9μM (non‐
small cell lung cancer A549/ATCC cell line). LC50 for
leukemia panel, EKVX, HOP‐62, and NCI‐H226 (lung
cancer), SF‐295 and SNB‐19 (CNS cancer), NCI/ADR‐
RES and SK‐OV‐3 (ovarian cancer), HS‐578T and T‐47D
(breast cancer) exceeded 100μM. TGI for SNB‐19 (CNS
cancer) was also more than 100μM.
CCRF‐CEM (−33,31), HL‐60(TB) (6,70), K‐562 (0,29),
MOLT‐4 (−26,32), RPMI‐8226 (49,16); non‐small cell
lung cancer: HOP‐92 (−16,17), NCI‐H226 (−7,94),
NCI‐H23 (53,46), NCI‐H522 (−83,93); colon cancer:
COLO 205 (−92,68), HCT‐116 (−96,54), HCT‐15
(−92,16), HT29 (−76,26), SW‐620 (−91,05); melanoma:
LOX IMVI (−88,95), MALME‐3M (−61,25), M14
(−57,85), MDA‐MB‐435 (39,08), UACC‐257 (−4,49); ovar-
ian cancer: OVCAR‐3 (−93,53), OVCAR‐4 (36,18),
OVCAR‐8 (33,48); renal cancer: 786‐0 (14,00), ACHN
(−99,41), CAKI‐1 (−94,50), RXF 393 (−89,62), SN12C
(−22,92), TK‐10 (−98,10), UO‐31 (−73,68); breast cancer:
MCF7 (11,21), BT‐549 (−84,34), T‐47D (−67,62),
MDA‐MB‐468 (−80,16).
Compound 19 was active against leukemia: CCRF‐
CEM (−15,49), HL‐60(TB) (−57,01), K‐562 (−14,65),
MOLT‐4 (−41,86), RPMI‐8226 (−42,02); non‐small cell
lung cancer: HOP‐92 (−37,91), NCI‐H226 (−36,24),
NCI‐H23 (−54,62), NCI‐H522 (−75,15); colon cancer:
COLO 205 (−92,62), HCT‐116 (−100,00), HCT‐15
(−53,74), HT29 (−38,65), SW‐620 (−78,76); melanoma:
LOX IMVI (−89,06), MALME‐3M (−49,95), M14
(−70,71), MDA‐MB‐435 (−58,10), SK‐MEL‐2 (−39,82),
SK‐MEL‐28 (−34,74), SK‐MEL‐5 (−30,05), UACC‐257
(−41,20), UACC‐62 (−60,96); ovarian cancer: IGROV1
(−22,11), OVCAR‐3 (−94,30), OVCAR‐5 (−2,97),
OVCAR‐8 (−59,58), NCI/ADR‐RES (12,71); renal cancer:
786‐0 (0,76), ACHN (−95,60), CAKI‐1 (−87,89), RXF 393
(−95,60), SN12C (−52,21), UO‐31 (−84,30); prostate
cancer: DU‐145 (−48,76); breast cancer: MCF7 (10,15),
MDA‐MB‐231/ATCC (−2,03), BT‐549 (−36,19), T‐47D
(−51,57), MDA‐MB‐468 (−67,54).
Compound 20 was active against leukemia:
CCRF‐CEM (−19,88), HL‐60(TB) (−0,66), K‐562
(−27,22), MOLT‐4 (−45,41), RPMI‐8226 (−34,62); non‐
small cell lung cancer: HOP‐92 (−34,77), NCI‐H226
(−63,05), NCI‐H23 (−62,69), NCI‐H522 (−78,38); colon
cancer: COLO 205 (−86,32), HCT‐116 (−100,00), HCT‐
15 (−47,42), HT29 (−20,13), SW‐620 (−68,38); melanoma:
LOX IMVI (−100,00), MALME‐3M (−6,41), M14
(−54,13), MDA‐MB‐435 (−64,23), SK‐MEL‐2 (−35,32),
SK‐MEL‐28 (−54,08), SK‐MEL‐5 (−74,73), UACC‐257
(−13,34), UACC‐62 (−4,37); ovarian cancer: IGROV1
(−18,64), OVCAR‐3 (−72,09), OVCAR‐5 (2,59), OVCAR‐
8 (−64,35), NCI/ADR‐RES (−6,77); renal cancer: 786‐0
(5,76), ACHN (−91,21), CAKI‐1 (−89,51), RXF 393
(−98,82), SN12C (−57,79), UO‐31 (−87,13); prostate
cancer: DU‐145 (−1,72); breast cancer: MCF7 (13,43),
MDA‐MB‐231/ATCC (7,11), BT‐549 (−30,17), T‐47D
(−32,93), MDA‐MB‐468 (−69,95).
Compound 14 showed GI50 values ranging from
0.63μM (leukemia CCRF‐CEM cell line) to 25.6μM (CNS
Cancer SNB‐19 cell line), TGI—from 2.2μM (non‐small
cell lung cancer NCI‐H522 cell line) to 85.3μM (CNS can-
cer SNB‐19 cell line), and LC50—from 6.1μM (non‐small
cell lung cancer NCI‐H522) to 84.2μM (non‐small cell
lung cancer HOP‐62 cell line). LC50 of compound NSC‐
762315 for leukemia panel, EKVX (lung cancer), SF‐295
and SNB‐19 (CNS cancer), NCI/ADR‐RES (ovarian can-
cer) and HS‐578T (breast cancer) cell lines exceeded
100μM.
Compound 15 showed GI50 values ranging from
0.27μM (non‐small cell lung cancer NCI‐H522 cell line)
to 21.3μM (CNS Cancer SNB‐19 cell line), TGI—from
1.7μM (non‐small cell lung cancer NCI‐H522 cell line)
to 55.5μM (Breast Cancer HS 578 T cell line), and
LC50—from 5.8μM (colon cancer SW‐620 cell line) to
98.0μM (ovarian cancer SK‐OV‐3 cell line). LC50 of
compound NSC‐762314 for leukemia panel with the
exception of HL‐60(TB), and cell lines NCI‐H23
(lung cancer), SNB‐19 (CNS cancer), NCI/ADR‐
RES (ovarian cancer), and HS 578T (breast cancer)
exceeds 100μM.
Compound 16 showed GI50 values ranging from
0.43μM (leukemia SR cell line) to 22.4μM (breast cancer
HS 578T cell line), TGI—from 2.5μM (colon cancer
HCT‐116 cell line) to 37.6μM (non‐small cell lung cancer
A549/ATCC cell line), and LC50—from 5.0μM (colon
cancer HCT‐116) to 98.6μM (non‐small cell lung cancer
NCI‐H460 cell line). LC50 for leukemia panel, NCI‐H226
(lung cancer), HT29 (colon cancer), OVCAR‐4 and
NCI/ADR‐RES (ovarian cancer), SF‐295 and SNB‐19
(CNS cancer), OVCAR‐4 and NCI/ADR‐RES (ovarian
cancer), MCF‐7, MDA‐MB‐231/ATCC, and T‐47D (breast
cancer) cell lines exceeded 100μM.
Both compounds 19 and 20 exhibited significant dose‐
dependent potent patterns of activity against most cancer
cell lines.
Compounds 12, 14‐16, 19, and 20 satisfied the
predetermined threshold inhibition criteria of the NCI‐60

KACHAEVA ET AL.
5
The compound 19 had a broad action spectrum. The
NCI‐60 GI50 values ranged from 0.15μM to 6.4μM; the
most sensitive cell lines were the leukemia SR,
CCRF‐CEM, MOLT‐4, and K‐562 (0.15μM, 0.19μM,
0.25μM, 0.30μM, respectively), colon cancer HCT‐116,
HCT‐15, SW‐620, and COLO 205 (0.21μM, 0.25μM,
0.35μM, 0.50 μM, respectively), melanoma MALME‐3M,
LOX IMVI, MDA‐MB‐435, and M14 (0.30μM, 0.57μM,
0.62μM, 0.79μM, respectively), ovarian cancer OVCAR‐8
and breast cancer MCF‐7 cell lines showing
submicromolar GI50 values of 0.60μM and 0.78μM,
respectively. The least growth inhibitory activity was for
the non‐small cell lung cancer NCI‐H322M cell line
(GI50 = 6.4μM).
For 20, the NCI‐60 GI50 values ranged from 0.21μM to
16.9μM. The leukemia cell lines showed a significant
sensitivity to this compound; for out of five of the tested
cell lines, namely, SR, CCRF‐CEM, MOLT‐4, and K‐562
showed submicromolar GI50 values as small as 0.21μM,
0.24μM, 0.26μM, and 0.35μM, respectively, followed colon
cancer HCT‐15, HCT‐116, and SW‐620 cell lines showing
submicromolar GI50 values of 0.38μM, 0.43μM, and
0.68μM, respectively. The least growth inhibitory activity
was for the CNS cancer SNB‐75 cell line (GI50 = 16.9μM).
Thus, compounds 12, 14‐16, 19, and 20 displayed
growth inhibitory (GI50), and cytostatic activities (TGI)
against the most sensitive cell lines at submicro-
molar (0.2μM‐0.6μM) and micromolar concentrations
(1μM‐3μM), respectively. Cytotoxic activity (LC50) of com-
pounds 12, 14‐16, 19, and 20 against the most sensitive
cell lines was also high (5μM‐6μM).
formation of the π‐σ interaction between the conjugated
systems of the 1,3‐oxazole ligand and peptide fragment
(σ is lone electron pair at nitrogen atom), which stabilizes
the protein‐ligand complex; the predicted binding affinity
≈ −7.7 kcal/mol. Consequently, the whole π‐electron sys-
tem of 1,3‐oxazole takes, supposedly, part in the forming
of stable complex with receptor and hence influences on
the first stage of bioactivity process.
On other hand, stability of the generated complex
agent‐biopolimer should undoubtedly depend on the
donor/acceptor properties of the 1,3‐oxazole derivatives,
ie, on their electron structure. Therefore, we carried,
additionally, out the quantum‐chemical calculations of
some molecules I in order to try to find out the possible
connections between electron characteristic molecules
studied and their biological activity or, more correctly,
stability of the complex.
In our work, we could propose that the electron levels
and charge distribution of the central conjugated part of
molecules I are undoubtedly connected with the stability
of the former complex and hence the relative position of
the frontier level (connecting experimentally with
electron affinity and first ionization potential) gives the
substantial contribution in total biological activity.
In the quantum‐chemical calculations, the nonconju-
gated fragments are modeled only by methyl groups.
The optimization of molecular geometry and calculation
of charge distribution as well as the change frontier level
position were calculated by DFT/6‐31 (d,p)/CAM‐B3LYP
method (package GAUSSIAN 09).[53]
As a reference molecule, the unsubstituted 1,3‐oxazole
26 was chosen; then the influence of the used donor and
Comparisons of active and inactive compounds
provided preliminary structure‐activity relationship infor-
mation. The significant role of acceptor SO2‐group on
antitumor activity of 1,3‐oxazole derivatives should be
highlighted. Further theoretical analyses are necessary
for understanding the relationship between molecular
properties and the biological effects.
acceptor
substituents
was
quantum‐chemically
investigated.
Firstly, the calculations show that the molecules I are
planar; all conjugated substituents, Ph, CN, Me2N,
MeNH, C(O)OMe, lie in the plane of 1,3‐oxazole cycle,
while the acceptor groups SO2Z (Z = Me (33), Ph (34),
4‐ClC6H4 (35), 4‐BrC6H4 (14)) are out from this plane.
As regards to donor substitients MeS (molecule 31) and
PhS (molecule 32), the residues Me and Ph at the sulphur
atom are out from the 1,3‐oxazole–S‐fragment plane.
Also, it is to be noticed that some substituents can rotate
around single bond and hence can additionally increase
the effective molecular space.
Introducing of the substituents influences not only on
charge distribution in the 1,3‐oxazole cycle but also
on the positions of the frontier levels. Here, we have sup-
posed that the positions of the highest occupied levels
and the lowest vacant levels affect directly on the donor
and acceptor ability of the compound studied and hence
to a biological activity. So, it was stated above that the
1,3‐oxazole derivatives exhibit the biological activity and
2.3 | Quantum‐chemical modeling of
donor/acceptor property of substituted
1,3‐oxazoles
To understand the connection between the chemical con-
stitution of the 1,3‐oxazole derivatives and their biological
activity, particularly, as potential anticancer agents, the
detailed study of the qualitative structure‐activity
relationship (QSAR) of the some substituted 2‐phenyl‐
1,3‐oxazoles were early performed.[2,35] It was a modeled
formation of complex in the binding site of tubulin, and
it showed the effective protein‐ligand interaction. So,
the results of molecular docking have indicated the

6
KACHAEVA ET AL.
could generate the complex with the biological polymers
by the non‐covalent interaction between ligand and
polimer molecule. Then, we could assume the non‐
covalent interaction should depend on donor‐acceptor
properties of the probe molecules.
where εLUMO and εHOMO are energies of the frontier levels
while α is an energy of the so‐called nonbonding MOs.
For neutral conjugated molecules, α corresponds such
dispositions of the frontier levels when the donor and
acceptor properties are mutually balanced, for example,
in long unsubstituted polyenes: then φ0 = 0.5, ie, the
energy gap is disposit symmetrically in respect to the
imaginary level α. The calculation of the comparatively
long polyene, C12H24, gives: εLUMO = −1.296 eV;
εHOMO = −5.747 eV and α = −3.524 eV; consequently,
φ0 = 0.5. Then, the shifting of the energy gap up and
hence increasing of the parameter φ0 > 0.5 indicates on
the predominately donor properties of the conjugated
molecules. Whereas, if the parameter φ0 < 0.5 and the
energy is shifted down, then the molecule is predomi-
nately acceptor.[55]
Table 1 gives the values φ0 calculated for the com-
pounds studied. One can see that introducing of the
conjugated acceptor substituent (CN (molecule 26) or
C(O)OMe (molecule 28)) in position 4 not only decreases
the lowest occupied level, but also decreases the
donor/acceptor parameter φ0, relatively to the model
molecule: compare data for compounds 26, 27 and 28.
On the contrast, introducing of the conjugated donor
substituent, Me2N, in position 5 (model molecule 29
causes shifting of the highest occupied and also the
lowest vacant levels up; therefore, the donor/acceptor
parameter naturally increases, so that φ0 > 0.5.
The calculated energies of the molecules I with differ-
ent donors and acceptors are collected in Table 1.
It is to be primarily noticed that both frontier MOs are
totally delocalized within the 1,3‐oxazole cycle and phe-
nyl substituent at position 5. Introducing of the donor
or/and acceptor substituents influences weakly on the
shape of both frontier MOs connected with
donor/acceptor properties of conjugated molecules I.
But the introduced substituents are seen from Table 1 to
affect essentially on the positions of the molecular levels.
So, going from the reference compound 26 with R1 = H,
R2 = H to compounds with the acceptor residues (CN
(27), C(O)OMe (28) or SO2Z (33‐35, 14)) of 1,3‐oxazole
cycle is accompanied by the appreciable shift down of
the highest occupied level, in the exact accordance with
their electronic nature, while the shift of the lowest
vacant levels is different, what is connected with the dif-
ferent change of the energy gap.
Earlier,[54] it was proposed to estimate the
donor/acceptor ability of the conjugated systems by
special parameter φ0, which calculated as the relative
position of the frontier levels by the following formulas:
Now, let us consider simultaneously introducing of
donor and acceptor substituents in the adjacent positions
4 and 5; just that these cases are modeled the synthesized
1,3‐oxazoles. So, the compound series contain the
constant conjugated acceptor cyano group (CN) in
the position 4, while the carbon in next position 8 of the
oxazole cycle is bonded with such unambiguous donor
substituent Me2N or S‐Y (Y = Me, Ph). It is followed from
Table 1 the electron effect is predominant and hence the
parameter is higher than the balanced value: φ0 > 0.5
(compare 30–32 with φ0 = 0.40 for the reference molecule
26. We could suppose that the donor substituted do not
stabilize the complex with the active biological center;
then similar compounds do not influence on the inhibi-
tion process.
In other hand, it is logical that simultaneously
introducing of two acceptor substituents in the positions
4 and 5 should induces the opposite substantial effect.
In Table 1, the compounds 33–35 and 14 are presented;
they contain the non‐conjugated acceptor group SO2Z,
as well as the conjugated acceptor CN. Indeed, one
can see that the calculated parameter φ0 decreases
appreciably: 0.46 for the molecule 33–35 or even to
0.45 for the compound 14. Though, the effect of Cl
or Br substituents in phenyl moiety is negligible
ε
LUMO − εF
φ0 ¼
;
ε
LUMO − εHOMO
TABLE 1 Frontier level energies and index φ0 calculated for
some 1,3‐oxazole molecules (in eV)
Compound I R1
R2
εHOMO εLUMO φ0
26
27
28
29
30
31
32
33
34
35
14
H
H
−7.45 0.22
−8.03 0.33
−7.69 0.17
−6.08 0.64
−6.72 0.12
−8.33 2.24
−8.56 2.13
−9.38 1.43
−9.23 1.34
0.49
CN
C(O)OMe
H
H
0.46
0.47
0.62
0.53
0.54
0.53
0.46
0.46
0.46
0.45
H
Me2N
Me2N
MeS
PhS
CN
CN
CN
CN
CN
CN
CN
MeSO2
PhSO2
4‐ClC6H4SO2 −9.04 1.26
4‐BrC6H4SO2 −9.26 1.19
Remark: donor substituents are marketed out by red color, acceptor substit-
uents—by blue color.

KACHAEVA ET AL.
7
TABLE 2 Anticancer activity of 5‐amino‐4‐cyano‐1,3‐oxazoles 5,
6, its sulphonamide analogs 21, 22, 5‐arylsulfanyl‐(7–9), its 5‐sulfo-
nyl analogs (12–16), and sulfamides 19, 20, 24 and 25
analogous 1,3‐oxazole derivatives which contain the
donor substituents (5–9) in position 5 do not practically
affecting on the inhibition process (Table 2). Changing
the substituent at position 2 of 1,3‐oxazole ring from aryl
to tert‐butyl in the series of 5‐arylsulphonyl‐1,3‐oxazole‐4‐
carbonitriles 15, 16 also increases the activity signifi-
cantly. 1,3‐oxazole derivatives containing an acceptor
group ‐SO2 in position 5, balanced by a donor substituent
‐N‐Me, ‐NH, ‐N‐N‐ (13, 21, 22, 24, 25), do not show an
unambiguous inhibition human cancer cell lines (such
as leukemia (CCRF‐CEM), melanoma (LOX IMVI), colon
Cancer (SW‐620)), unlike acceptor (‐SO2) substituents.
We have formed a mathematical relationship between
donor‐acceptor properties and anticancer activity of
1,3‐oxazoles. We can correlate the anticancer activity
with increasing of the relative position of the energy gap
and hence increasing of the stability of the possible
complex of 1,3‐oxazole derivatives with protein. Different
anticancer selectivity among sulfonyl derivatives can
indicate the importance of steric factor on anticancer
activity and/or possible complex forming with different
targets.
Anticancer activity, cell growth, %
Leukemia
Melanoma
Colon Cancer
Compound (CCRF‐CEM) (LOX IMVI) (SW‐620)
R3 – Donor substitute
7
9
5
6
8
+92.23
+94.62
+81.93
+84.77
+88.91
+98.21
+92.56
+100.62
+97.22
+80.25
+112.93
+107.13
+100.72
+97.42
+107.65
R3 – Balanced Donor‐Acceptor substitute
25
24
13
21
22
+27.18
+9.20
−10.68
+2.67
+1.94
+72.29
+76.84
+38.89
+41.92
+21.91
+10.92
+6.13
+54.03
+35.14
+26.52
R3 – Acceptor substitute
14
15
12
19
20
16
−13.84
−14.67
−21.44
−15.49
−19.88
−33.31
+7.99
+39.82
+30.03
−89.06
−100.00
−88.95
−37.71
−68.59
−55.05
−78.76
−68.38
−91.05
4 | EXPERIMENTAL
4.1 | Chemistry
Melting points were determined on a Fisher‐Johns appa-
ratus. IR spectra were recorded on a Vertex‐70 spectrom-
eter from KBr pellets. 1H and 13C NMR spectra were
recorded on Varian Mercury 400 (400 and 100 MHz,
respectively) and Bruker Avance DRX 500 (500 and
125 MHz, respectively) spectrometers in DMSO‐d6 or
CDCl3 taking its residual protons signal as a standard.
LC–MS analysis was performed on an Agilent 1200 Series
system equipped with a diode array and a G6130A
mass‐spectrometer (atmospheric pressure electrospray
ionization). Combustion elemental analysis was
performed in the V.P. Kukhar Institute of Bioorganic
Chemistry and Petrochemistry analytical laboratory. 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, chlorine – by the mercurometric
method.
Remarck: Each value indicated percent growth of the treated cells when
compared to the untreated control cells. The negative values represent per-
cent of the dead cells compared with control before experiment.
(Δφ0 ≈ 0.01). Parallelly, the calculations give the consid-
erable shifting of the frontier levels.
Of course, the changes in the donor‐acceptor parame-
ter φ0 upon introducing of the donor or acceptor
substituents are appreciable, but they cannot be enough
to intercommunicate between electronic influence of
any substitutes and biological effects. Nevertheless, this
simplest model enables to find the interrelation between
the chemical constitution of the substrat and stability of
its complex with biological polymer.
3 | CONCLUSIONS
Chemicals and reagents were purchased from
commercialy available sourses. 2‐Methylaminoethanol,
3‐phenyl‐ and 3‐methyl‐1H‐pyrazol‐5‐amine were
The analysis of relationship between pharmacological
activity and molecule structure shows unambiguously
that compounds with the high acceptor substituents (12,
14–16, 19, 20) at specific position 5 of 1,3‐oxazole ring
demonstrate the appreciable higher level of the effective
inhibition of the cell growth comparing with the
purchased
from
Aldrich.
2‐(4‐Chlorophenyl)‐2‐
piperidin‐1‐ylethanamine was synthesized by the
previously described method.[56] 2‐Acylamino‐3,3‐
dichloroacrylonitriles 1–4 and its synthetic procedure

8
KACHAEVA ET AL.
were described in.[43,44] 4‐Cyano‐2‐(4‐methylphenyl)‐1,3‐
oxazole‐5‐sulfonyl chloride (17) and 4‐cyano‐2‐phenyl‐
1,3‐oxazole‐5‐sulfonyl chloride (18) were synthesized
previously[47] from appropriate enamide 1 or 2. Methyl
5‐chlorosulfonyl‐2‐phenyl‐1,3‐oxazole‐4‐carboxylate (24)
have been synthesized by the method described in the
literature.[48]
C23H23ClN4O: C, 67.89; H, 5.70; Cl, 8.71; N, 13.77. Found:
C, 67.85; H, 5.69; Cl, 8.69; N, 13.69.
4.3 | General procedure for the synthesis
of compounds 7–11
To a solution of appropriate 2‐acylamino‐3,3‐dichlo-
roacrylonitriles 1–4 (0.01 mol) in 30 ml of acetonitrile,
triethylamine (0.02 mol) and an appropriate arenethiol
(0.02 mol) were added, and the mixture was stirred at
room temperature for 8 h. The residue was triturated with
water to give a crude product which was separated,
recrystallized, dried at 70–80°C, dissolved in 40 ml of
acetonitrile and stirred at reflux for 8–10 h with three‐fold
excess of dry silver carbonate. The mixture was kept at
room temperature for 8 h. The residue was triturated with
water to give a crude product which was separated,
recrystallized, and dried at 70–80°C.
4.2 | General procedure for the synthesis
of compounds 5 and 6
To a solution of 2‐acylamino‐3,3‐dichloroacrylonitrile 1
or
2 (0.01 mol) in 40 ml of tetrahydrofurane,
triethylamine (0.022 mol) and an appropriate amine
(2‐methylaminoethanol or 2‐(4‐chlorophenyl)‐2‐pipe-
ridin‐1‐ylethanamine (0.025 mol) were added. The
mixture was stirred at room temperature during 12 h.
The residue was triturated with water to give a crude
product which was separated, recrystallized, and dried
at 70–80°C.
4.3.1 | 2‐(4‐Fluorophenyl)‐5‐
phenylsulfany)‐1,3‐oxazole‐4‐carbonitrile
(7)
4.2.1 | 5‐(2‐Hydroxyethylmethylamino)‐2‐
(4‐methylphenyl)‐1,3‐oxazole‐4‐carbonitrile
(5)
White solid; 70% yield (2.07 g); mp 106–108°C, (ethanol).
1
IR: 2238 (CN). H NMR (DMSO‐d6, 400 MHz) δ, ppm
8.14–8.07 (4H, m, ArH), 7.93–7.77 (3H, m, ArH),
7.45–7.43 (2H, m, ArH). 13C NMR (DMSO‐d6, 100 MHz)
δ, ppm 163.6, 152.9, 131.1, 130.6, 130.0, 129.9, 129.5,
122.1, 119.7, 117.3, 117.1, 112.4. MS (ESI) m/z 297
[M + 1]+. Anal.calcd for C16H9FN2OS: C, 64.85; H,
3.06; N, 9.45; S, 10.82. Found: C, 64.82; H, 3.04; N,
9.37; S, 10.71.
White solid; 70% yield (1.8 g); mp 104–106°C, (ethanol).
IR: 3446 (OH), 2198 (CN). 1H NMR (DMSO‐d6,
400 MHz) δ, ppm 7.72 (2H, d, J = 8.0 Hz, ArH), 7.30
(2H, d, J = 8.0 Hz, ArH), 4.92 (1H, t, J = 5.2 Hz, OH),
3.65–3.62 (2H, m, CH2), 3.57–3.54 (2H, m, CH2), 3.21
(3H, s, NMe), 2.34 (3H, s, Me). 13C NMR (CDCl3,
125 MHz) δ, ppm 160.5, 150.9, 140.5, 129.5, 125.4, 123.1,
116.8, 84.8, 59.9, 54.0, 38.0, 21.5. MS (ESI) m/z 258
[M + 1]+. Anal.calcd for C14H15N3O2: C, 65.36; H, 5.88;
N, 16.33. Found: C, 65.28; H, 5.86; N, 16.35.
4.3.2 | 5‐(4‐Bromophenylsulfanyl)‐2‐phe-
nyl‐1,3‐oxazole‐4‐carbonitrile (9)
Yellow solid; 67% yield (2.4 g); mp 83–84°C, (ethanol).
IR: 2239 (CN). H NMR (DMSO‐d6, 400 MHz) δ, ppm
1
4.2.2 | 5‐(2‐(4‐Chlorophenyl)‐2‐piperidin‐1‐
ylethylamino)‐2‐phenyl‐1,3‐oxazole‐4‐
carbonitrile (6)
7.98 (2H, d, J = 6.4 Hz, ArH), 7.65–7.51 (7H, m, ArH).
13C NMR (DMSO‐d6, 100 MHz) δ, ppm 164.5, 152.1,
133.3, 132.9, 129.9, 127.2, 122.9, 120.0, 112.4. MS (ESI)
m/z 359 [M + 1]+. Anal.calcd for C16H9BrN2OS: C,
53.80; H, 2.54; N, 7.84; S, 8.98. Found: C, 53.77; H, 2.52;
N, 7.76; S, 8.87.
Yellow solid; 68% yield (2.76 g); mp 174–176°C, (ethanol).
IR: 3340 (NH); 2206 (CN). 1H NMR (DMSO‐d6, 500 MHz)
δ, ppm 8.23 (1H, s, NH), 7.78 (2H, d, J = 8.0 Hz, ArH),
7.47–7.29 (7H, m, ArH), 3.98–3.95 (1H, m, 1/2CH2),
3.72–3.69 (1H, m, CH), 3.54–3.51 (1H, m, 1/2CH2), 2.41
(2H, bs, CH2), 2.20 (2H, bs, CH2), 1.36 (bs, 4H, 2CH2),
1.21–1.20 (2H, m, CH2). 13C NMR (DMSO‐d6, 125 MHz)
δ, ppm 162.0, 149.8, 136.1, 132.5, 131.0, 130.5, 129.5,
128.3, 126.3, 125.5, 116.3, 84.1, 68.6, 50.9, 44.6, 26.4,
24.6. MS (ESI) m/z 407 [M + 1]+. Anal.calcd for
4.3.3 | 2‐Tert‐butyl‐5‐phenylsulfanyl‐1,3‐
oxazole‐4‐carbonitrile (10)
The product was obtained as brown oil used in the next
step without purification.

KACHAEVA ET AL.
9
4.3.4 | 5‐(4‐Bromophenylsulfanyl)‐2‐tert‐
butyl‐1,3‐oxazole‐4‐carbonitrile (11)
4.4.3 | 5‐Phenylsulfonyl‐2‐tert‐butyl‐1,3‐
oxazole‐4‐carbonitrile (15)
White solid; 68% yield (2.3 g); mp 47–49°C, (acetonitrile).
IR: 2242 (CN). 1H NMR (DMSO‐d6, 400 MHz) δ, ppm 7.63
(2H, d, J = 8.4 Hz, ArH), 7.40 (2H, d, J = 8.4 Hz, ArH),
1.31 (9H, s, tBu). 13C NMR (DMSO‐d6, 100 MHz) δ,
ppm 175.1, 151.4, 133.4, 132.6, 130.3, 122.8, 118.4, 112.5,
34.7, 28.1. MS (ESI) m/z 339 [M + 1]+. Anal.calcd for C,
49.86%; H, 3.89%; N, 8.31%; S, 9.51%. Found: C, 49.84%;
H, 3.87%; N, 8.39%; S, 9.45%.
White solid; 68% yield (1.97 g); mp 118–120°C, (ethanol).
IR: 2251 (CN); 1354, 1162 (SO2). H NMR (400 MHz,
1
DMSO‐d6) δ, ppm 8.07 (2H, d, J = 7.6 Hz, ArH), 7.75–
7.91 (3H, m, ArH), 1.29 (9H, s, tBu). 13C NMR
(125 MHz, DMSO‐d6) δ, ppm 175.5, 153.0, 137.5, 136.5,
130.9, 128.6, 117.1, 110.8, 34.8, 28.0. MS (ESI) m/z 291
[M + 1]+. Anal.calcd for C14H14N2O3S: C, 57.92; H,
4.86; N, 9.65; S, 11.04. Found: C, 57.90; H, 4.84; N, 9.55;
S, 10.92.
4.4 | General procedure for the synthesis
of compounds 12, 14–16[46]
4.4.4 | 5‐(4‐Bromophenylsulfonyl)‐2‐tert‐
butyl‐1,3‐oxazole‐4‐carbonitrile (16)
Solution of appropriate 5‐arylsulfanyl‐1,3‐oxazole‐4‐car-
bonitrile 7–11 (0.01 mol) in glacial acetic acid (20 ml)
was heated to reflux. Three portions of 30% H2O2 of
2 ml each were added during 2 h. The mixture was kept
at room temperature for 8 h. The residue was triturated
with water to give a crude product which was separated,
recrystallized, and dried at 70–80°C.
White solid; 73% yield (2.67 g); mp 93–95°C, (ethanol).
IR: 2251 (CN); 1357, 1164 (SO2). H NMR (400 MHz,
1
DMSO‐d6) δ, ppm 7.98 (4H, s, Ar), 1.30 (9H, s, tBu). 13C
NMR (125 MHz, DMSO‐d6) δ, ppm 175.6, 152.4, 136.7,
134.0, 130.9, 130.6, 117.4, 110.7, 34.8, 27.9. MS (ESI) m/z
367 [M + 1]+. Anal.calcd for C14H13BrN2O3S: C, 45.54;
H, 3.55; N, 7.59; S, 8.68. Found: C, 45.51; H, 3.54; N,
7.50; S, 8.60.
4.4.1 | 2‐(4‐Fluorophenyl)‐5‐
phenylsulfonyl‐1,3‐oxazole‐4‐carbonitrile
(12)
4.5 | General procedure for the synthesis
of compounds 19–22, 24 and 25
To a solution of 4‐cyano‐2‐phenyl‐1,3‐oxazole‐5‐sulfonyl
chloride (0.01 mol) in THF appropriate amine
(0.011 mol) and Et3N (0.011 mol) were added. The mix-
ture was heated for 2 h and kept at 20–25°C for 12 h.
The precipitate was filtered off, the solvent was removed
in a vacuum. The residue was treated whis water, filtered
off, dried and recrystallized.
White solid; 73% yield (2.39 g); mp 155–160°C, (glacial
acetic acid). IR: 2252 (CN); 1328, 1157 (SO2). H NMR
1
(400 MHz, DMSO‐d6) δ, ppm 8.03–8.05 (2H, m, ArH),
7.40–7.58 (7H, m, ArH). 13C NMR (125 MHz, DMSO‐d6)
δ, ppm 165.8, 163.8, 163.6, 152.9, 131.1, 130.6, 130.0,
129.9, 129.5, 122.1, 119.6, 117.3, 117.1, 112.4. MS (ESI)
m/z 329 [M + 1]+. Anal.calcd for C16H9FN2O3S: C,
58.53; H, 2.76; F, 5.79; N, 8.53; S, 9.77. Found: C, 58.50;
H, 2.74; F, 5.70; N, 8.45; S, 9.69.
4.5.1 | 5‐((3‐Methylpiperidin‐1‐yl)‐sulfo-
nyl)‐2‐phenyl‐1,3‐oxazole‐4‐carbonitrile (19)
White solid; 71% yield (2.35 g); mp 141–143°C, (ethanol).
IR: 2248 (CN); 1378, 1152 (SO2). H NMR (400 MHz,
4.4.2 | 5‐(4‐Bromophenylsulfonyl)‐2‐phe-
nyl‐1,3‐oxazole‐4‐carbonitrile (14)
1
DMSO‐d6) δ, ppm 8.06 (2H, d, J = 7.6 Hz, Ar), 7.62–7.73
(3H, m, CH2CH2), 3.58–3.68 (2H, m, CH2), 2.91–2.96
(1H, m, 1/2CH2), 2.63 (1H, t, J = 10.8 Hz, 1/2CH2),
1.67–1.79 (3H, m, CH2CH2), 1.47–1.56 (1H, m, 1/2CH2),
0.96–1.06 (1H, m, 1/2CH2), 0.89 (3H, d, J = 6.4 Hz, Me).
13C NMR (125 MHz, CDCl3) δ, ppm 163.4, 151.1, 133.1,
129.5, 127.4, 124.4, 117.2, 110.8, 51.7, 45.7, 30.8, 30.2,
24.1, 18.5. MS (ESI) m/z: 332 [M + 1]+. Anal.calcd for
C16H17N3O3S: C, 57.99; H, 5.17; N, 12.68; S, 9.68. Found:
C, 57.92; H, 5.14; N, 12.83; S, 9.89.
White solid; 66% yield (2.56 g); mp 163–165°C, (glacial
acetic acid). IR: 2246 (CN); 1332, 1154 (SO2). H NMR
1
(400 MHz, DMSO‐d6) δ, ppm 7.97–8.06 (6H, m, ArH),
7.58–7.71 (3H, m, ArH). 13C NMR (125 MHz, DMSO‐d6)
δ, ppm 164.7, 152.5, 136.7, 134.0, 133.9, 131.0, 130.8,
130.0, 128.0, 124.5, 119.0, 110.9. MS (ESI) m/z 389
[M + 1]+. Anal.calcd for C16H9BrN2O3S: C, 49.37;
H, 2.33; N, 7.20; S, 8.24. Found: C, 49.35; H, 2.31;
N, 7.12; S, 8.13.

10
KACHAEVA ET AL.
4.5.2 | 5‐((4‐Methylpiperidin‐1‐yl)‐sulfo-
nyl)‐2‐phenyl‐1,3‐oxazole‐4‐carbonitrile (20)
4.5.5 | Methyl‐5‐((5‐amino‐3‐phenyl‐1H‐
pyrazol‐1‐yl)sulfonyl)‐2‐phenyl‐1,3‐oxazole‐
4‐carboxylate (24)
White solid; 75% yield (2.48 g); mp 146–148°C, (etha-
nol). IR: 2247 (CN); 1376, 1161 (SO2). 1H NMR
(400 MHz, DMSO‐d6) δ, ppm 8.05 (2H, d, J = 7.2 Hz,
Ar), 7.62–7.72 (3H, m, Ar), 3.72 (2H, d, J = 11.6 Hz,
CH2), 2.95 (2H, t, J = 11.6 Hz, CH2), 1.75 (2H, d,
J = 12.0 Hz, CH2), 1.46 (1H, br s, 1/2CH2), 1.13–1.22
(2H, m, CH2), 0.89 (3H, d, J = 6.4 Hz, Me). 13C NMR
(125 MHz, CDCl3) δ, ppm 163.4, 151.1, 133.1, 129.5,
127.4, 124.4, 117.3, 110.8, 45.6, 32.8, 28.8, 21.2. MS
(ESI) m/z: 332 [M + 1]+. Anal.calcd for C16H17N3O3S:
C, 57.99; H, 5.17; N, 12.68; S, 9.68. Found: C, 57.94;
H, 5.15; N, 12.78; S, 9.79.
White solid; 88% yield (3.73 g); mp 183–185°C, (acetoni-
trile). IR: 3481 (NH2); 1731 (C=O); 1339, 1192 (SO2). H
1
NMR (500 MHz, DMSO‐d6) δ, ppm 7.72 (2H, d,
J = 8 Hz, ArH), 7.72 (2H, d, J = 6 Hz, ArH), 7.57–7.68
(3H, m, ArH), 7.39 (3H, s, ArH), 6.55 (2H, s, NH2), 5.90
(1H, s, CH), 3.93 (3H, s, OMe). 13C NMR (125 MHz,
DMSO‐d6) δ, ppm 162.5, 159.5, 157.4, 154.2, 146.5,
135.8, 133.5, 131.7, 130.0, 129.2, 127.6, 126.5, 124.7, 85.9,
53.8. MS (ESI) m/z 425 [M + 1]+. Anal.calcd for
C20H16N4O5S: C, 56.60; H, 3.80; N, 13.20; S, 7.55. Found:
56.58; H, 3.79; N, 13.18; S, 7.48.
4.5.6 | Methyl‐5‐((5‐amino‐3‐methyl‐1H‐
pyrazol‐1‐yl)sulfonyl)‐2‐phenyl‐1,3‐oxazole‐
4‐carboxylate (25)
4.5.3 | 4‐Cyano‐N‐(2‐hydroxyethyl)‐N‐
methyl‐2‐(4‐methylphenyl)‐1,3‐oxazole‐5‐
sulfonamide (21)
Yellow solid; 86% yield (3.11 g); mp 144–146°C, (acetoni-
1
trile). IR: 3481 (NH2); 1732 (C=O); 1338, 1157 (SO2). H
White solid; 75% yield (2.48 g); mp 137–140°C, (etha-
nol). IR: 3552 (OH); 2252 (CN); 1371, 1155 (SO2). H
NMR (400 MHz, DMSO‐d6) δ, ppm 7.96 (2H, d, J = 7.2 Hz,
ArH), 7.59–7.69 (3H, m, ArH), 6.32 (2H, s, NH2), 5.27
(1H, s, CH), 3.90 (3Н, s, ОMe), 1.98 (3H, s, CH3). 13C
NMR (125 MHz, CDCl3) δ, ppm 162.2, 158.9, 155.9,
150.5, 146.0, 134.7, 131.9, 128.1, 126.8, 126.7, 123.7, 89.1,
51.9, 12.7. MS (ESI) m/z 363 [M + 1]+. Anal.calcd for
C15H14N4O5S: C, 49.72; H, 3.89; N, 15.46; S, 8.85. Found:
C, 49.69; H, 3.87; N, 15.38; S, 8.66.
1
NMR (400 MHz, DMSO‐d6) δ, ppm 7.93 (2H, d,
J = 8.4 Hz, ArH), 7.43 (2H, d, J = 8.0 Hz, ArH), 4.79
(1H, s, OH), 3.56 (2H, s, CH2), 3.35 (2H, s, CH2), 3.02
(3H, s, NMe), 2.41 (3H, s, Me). 13C NMR (125 MHz,
CDCl3) δ, ppm 163.1, 151.1, 143.2, 129.1, 126.5, 120.6,
116.5, 109.4, 58.7, 51.1, 34.4, 20.2. MS (ESI) m/z 322
[M + 1]+. Anal.calcd for C14H15N3O4S: C, 52.33; H,
4.70; N, 13.08; S, 9.98. Found: C, 52.29; H, 4.69; N,
13.13; S, 9.85.
4.6 | Pharmacology
4.6.1 | One doses full NCI 60 cell panel
assay
4.5.4 | N‐(2‐(4‐Chlorophenyl)‐2‐piperidin‐
1‐ylethyl)‐4‐cyano‐2‐phenyl‐1,3‐oxazole‐5‐
sulfonamide (22)
The newly synthesized compounds were submitted to
National Cancer Institute NCI, Bethesda, Maryland,
U.S.A., under the Developmental Therapeutic Program
DTP. The cell line panel engaged a total of 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, in which the full
NCI 60 panel lines were inoculated onto a series of
Yellow solid; 68% yield (2.3 g); mp 175–178°C, (ethanol).
IR: 3251 (NH); 2250 (CN); 1364, 1164 (SO2). H NMR
1
(400 MHz, CDCl3) δ, ppm 8.04 (1H, d, J = 7.2 Hz, ArH),
7.51–7.62 (3H, m, ArH), 7.23 (2H, d, J = 8.0 Hz, Ar),
7.05 (2H, d, J = 8.0 Hz, ArH), 5.01 (1H, bs, NH),
3.58–3.64 (2H, m, CH2), 3.45–3.52 (1H, m, CH), 2.36
(2H, bs, CH2), 2.20 (2H, bs, CH2), 1.52 (bs, 4H, 2CH2),
1.32 (2H, bs, CH2). 13C NMR (125 MHz, CDCl3) δ, ppm
163.5, 153.0, 134.2, 133.5, 133.1, 129.7, 129.3, 128.6,
127.6, 124.3, 117.2, 110.3, 67.1, 43.3, 50.3, 26.1, 24.2. MS
(ESI) m/z 471 [M + 1]+. Anal.calcd for C23H23ClN4O3S:
C, 58.66; H, 4.92; N, 11.90; S, 6.81. Found: C, 58.65; H,
4.91; N, 11.87; S, 6.68.
standard 96‐well microtiter plates on day
0
at
5000–40000 cells/well in RPMI 1640 medium containing
5% fetal bovine serum and 2 mM L‐glutamine, and then
preincubated in absence of drug at 37°C, and 5% CO2
for 24 h. Test compounds were then added at one concen-
tration of 10−5 M in all 60 cell lines, and incubated for a
further 48 h at the same incubation conditions. Following

KACHAEVA ET AL.
11
this, the media were removed, the cells were fixed in situ,
washed, and dried. The sulforhodamine B assay is 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) trichloro-
acetic acid and stained for 30 min, then the excess dye
were 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.
The LC50, which signifies a cytotoxic effect, is calcu-
lated as:
½ðT − T0Þ=T0ꢀ × 100 ¼ −50; when T < T0:
ACKNOWLEDGMENTS
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.
4.6.2 | Five doses full NCI 60 cell panel
assay
All the 60 cell lines, representing nine cancer subpanels,
were incubated at five different concentrations (0.01,
0.1, 1, 10 and 100 μM) of the tested compounds. The
outcomes were used to create log10 concentration versus
percentage growth inhibition curves and three response
parameters (GI50, TGI and LC50) were calculated for each
cell line. The GI50 value (growth inhibitory activity)
corresponds to the concentration of the compound
causing 50% decrease in net cell growth. The TGI value
(cytostatic activity) is the concentration of the compound
resulting in total growth inhibition. The LC50 value
(cytotoxic activity) is the concentration of the compound
causing net 50% loss of initial cells at the end of the
incubation period of 48 h.
DISCLAIMER
This material should not be interpreted as representing
the viewpoint of the National Institute of Allergy and
Infectious Diseases (USA) and its Collaborative Antiviral
Testing Group.
CONFLICT OF INTERESTS
The authors declare that there is no conflict of interests
regarding the publication of this paper.
ORCID
Data calculations were made according to the me-
thod described by the NCI Development Therapeutics
Program (https://dtp.cancer.gov/discovery_development/
nci‐60/default.htm).
Maryna V. Kachaeva
4807
Diana M. Hodyna https://orcid.org/0000-0001-6161-9833
Nataliya V. Obernikhina
https://orcid.org/0000-0003-1517-
https://orcid.org/0000-0003-
The % growth curve is calculated as:
1143-8924
Stepan G. Pilyo https://orcid.org/0000-0003-1072-2990
Yulia S. Kovalenko https://orcid.org/0000-0003-4791-7011
½ðT − T0Þ=ðC − T0Þꢀ × 100;
Volodymyr M. Prokopenko
9764-3990
Oleksiy D. Kachkovsky
5154
Volodymyr S. Brovarets
3412
https://orcid.org/0000-0001-
https://orcid.org/0000-0003-3711-
https://orcid.org/0000-0001-6668-
where T0 is the cell count at day 0,
C is the vehicle control (without drug) cell count (the
absorbance of the SRB of the control growth).
T is the cell count at the test concentration at day 3.
The GI50 and TGI value are determined as the drug
concentration that results in a 50% and 0% growth at
48 h drug exposure. Growth inhibition of 50% (GI50) is
calculated from:
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