Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET
The discovery of nucleoside antibiotics gave impetus to the development of the chemistry of pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines as biologically active compounds. This work describes a universal and efficient approach to the synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-...
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| Date: | 2024 |
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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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|---|---|
| author | Shevchenko, Nadiya М. Severin, Oleksandr O. Kachaeva, Maryna V. Kozachenko, Oleksandr Р. Velihina, Yevheniia S. Brovarets, Volodymyr S. |
| author_facet | Shevchenko, Nadiya М. Severin, Oleksandr O. Kachaeva, Maryna V. Kozachenko, Oleksandr Р. Velihina, Yevheniia S. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"author": "Nadiya М. Shevchenko",
"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": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleksandr Р. Kozachenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Yevheniia S. Velihina",
"institution": "ICOA, Université d’Orléans, Orléans, France"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Shevchenko, Nadiya М. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | The discovery of nucleoside antibiotics gave impetus to the development of the chemistry of pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines as biologically active compounds. This work describes a universal and efficient approach to the synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles. Their potential as biologically active compounds is considered and ADMET-score is predicted to assess their further application as pharmaceutical substances |
| doi_str_mv | 10.15407/bioorganica2024.02.021 |
| first_indexed | 2025-07-17T12:20:05Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
UDC 547.787
DOI: https://doi.org/10.15407/bioorganica2024.02.021
21
RESEARCH ARTICLE
Synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine
derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles, prediction and
evaluation of their ADMET properties
Nadiya М. Shevchenko1, Oleksandr O. Severin1, Maryna V. Kachaeva1, Oleksandr Р. Kozachenko1,
Stepan G. Pilyo1, Yevheniia S. Velihina2, Volodymyr S. Brovarets1
1V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
2 ICOA, Université d’Orléans, Orléans, France
Abstract: The discovery of nucleoside antibiotics gave impetus to the development of the chemistry of pyrrolo[2,3-d]pyrimidines and
thieno[2,3-d]pyrimidines as biologically active compounds. This work describes a universal and efficient approach to the synthesis of new
pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles. Their potential as
biologically active compounds is considered and ADMET-score is predicted to assess their further application as pharmaceutical
substances.
Keywords: pyrrolo[2,3-d]pyrimidine; thieno[2,3-d]pyrimidine; 1,3-oxazole; prediction ADMET.
Introduction
The discovery of nucleoside antibiotics has sparked
sustained interest in pyrrolo[2,3-d]pyrimidines and
thieno[2,3-d]pyrimidines as valuable scaffolds for the
development of biologically active compounds. The
presence of nitrogen atoms in heterocycle not only confer
altered electronic properties but also add a hydrogen bond
acceptors, lead to changing the physicochemical and
biological properties of a substance.
A particularly interesting group of these molecules are
amino-substituted pyrrolo[2,3-d]pyrimidines and thieno-
[2,3-d]pyrimidines, which appear in a variety of
biologically active molecules (Figure 1), can be particularly
challenging or lengthy to prepare via reported methods.
Received:
Revised:
Accepted:
Published online:
10.09.2024
14.10.2024
06.11.2024
30.12.2024
Corresponding author. Tel.: +380-44-296-0409;
e-mail: oleksandrseverin.chem@gmail.com (O.O. Severin)
ORCID: 0000-0003-3943-5063
A series of piperazine-substituted pyrrolo[2,3-
d]pyrimidine and thieno[2,3-d]pyrimidine derivatives were
found as antiviral [1] and anticancer [2] agents. Pyrrolo[2,3-
d]pyrimidine and thieno[2,3-d]pyrimidine fragments are the
parts of molecules – inhibitors of adenosine kinase [3, 4],
tyrosine kinases [5, 6], calcium channel blockers [7] and
modulators of aldehyde dehydrogenase (ALDH) enzymatic
activity [8].
N
N N
H
N
N
O
Ar
I
N
N N
H
N
N
III
Et
Cl
Me
H
N
N
Me
Me
N
N N
H
N
N
O
II
Ar
NH2
Me
Figure 1. Biologically active piperasine-substituted pyrrolo-[2,3-
d]pyrimidines and thieno[2,3-d]pyrimidines.
© Shevchenko N.M. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
22
NH
Cl O
Cl R
NC
O
N
NC
N R
N
N N
O
N
NC
N R
N
N N
S
NHN
N
N
S
NAr
NHN
N
N
N
Ar
R = CH3, C(CH3)3, C6H5, 4-CH3C6H4, 4-CH3OC6H4, 4-FC6H4, 4-ClC6H4;
Ar = 2-FC6H4, 3-CH3C6H4, 4-CH3OC6H4, 4-C2H5OC6H4, 3-ClC6H4
1-10
I
II
III
11-15
2Et3N, THF
2Et3N, THF
O
N
NC
N
NN
N
N
O
O
N
NC
N
NN
N
N
F
O
N
NC
N
NN
N
N
O
N
NC
N
NN
N
N
O
N
NC
N
NN
N
N
O
O
N
NC
N
NN
N
N
O
O
N
NC
N
NN
N
N
Cl
O
N
NC
N
NN
N
N
F
O
N
NC
N
NN
N
S
O
N
NC
N
NN
N
S
O
N
NC
N
NN
N
S
Cl
O
N
NC
N
NN
N
S
F
O
N
NC
N
NN
N
S
O
O
N
NC
N
NN
N
N
O
N
NC
N
NN
N
N
O
Cl
1 (76%)
3 (70%)
5 (72%) 7 (67%)
9 (70%)
2 (73%) 4 (75%)
6 (71%) 8 (74%)
10 (76%)
11 (70%) 12 (71%)
13 (76%) 14 (75%) 15 (68%)
Scheme 1. Synthesis of target 5-amino-4-cyano-1,3-oxazoles (1-15).
N.M. Shevchenko et al.
23
Table 1. Calculated druglikness parameters of compounds 1-15.
№
Physico-chemical indicators Lipophilicity Solubility in water
MW nA n-RB n-HBA n-HBD TPSA Log Po/w (cons) Log S (ESOL)
1 479.51 36 4 6 0 87.01 4.13 -6.39
2 521.59 39 5 6 0 87.01 4.98 -7.37
3 475.54 36 4 5 0 87.01 4.16 -6.53
4 551.64 42 5 5 0 87.01 5.46 -7.99
5 491.54 37 5 6 0 96.24 3.83 -6.30
6 533.62 40 6 6 0 96.24 4.68 -7.28
7 505.57 38 6 6 0 96.24 4.17 -6.54
8 547.65 41 7 6 0 96.24 4.99 -7.52
9 495.96 36 4 5 0 87.01 4.35 -6.83
10 538.04 39 5 5 0 87.01 5.21 -7.80
11 442.54 32 3 5 0 110.3 3.95 -6.19
12 456.56 33 3 5 0 110.3 4.35 -6.49
13 472.56 34 4 6 0 119.6 4.04 -6.26
14 460.53 33 3 6 0 110.3 4.34 -6.35
15 476.98 33 3 5 0 110.3 4.58 -6.78
MW – molecular weight;
nA – number of atoms in a molecule;
n-RB – number of rotational bonds;
n-HBA – number of O and N atoms as H-bond acceptors;
n-HBD – number of OH and NH groups as H-bond donors;
TPSA – topological polar surface area;
Log Po/w (cons) – coefficient between n-octanol and water. The consensus log Po/w is the arithmetic mean of the values predicted by the five
methods (XLOGP3, WLOGP, MLOGP, SILICOS-IT, iLOGP);
Log S (ESOL) – index water solubility [28].
Table 2. Druglikeness parameter filters.
Filter Lipinski Ghose Veber Egan Muegge
D
es
cr
ip
to
rs
MW < 500 Da 180-480 200-600
nHBD < 5 <=5
nHBA < 10 <=10
LogP < 5 -0.4 to +5.6 <=5.88 -2 to 5
nA 20 to 70
TPSA <=140 <=131.6 <150
nRB <=10 <=15
A series of 4-(piperazin-1-yl)-7H-pyrrolo[2,3-
d]pyrimidine derivatives I were found to be potential
anticancer agents and Akt inhibitors with IC50 values of
18.0 and 21.3 nM [9, 10]. Pyrrolopyrimidines described in
[11] have been regarded as a novel class of LIM-kinase 2
inhibitors. Compounds II demonstrated potent enzyme
inhibition of targets Akt1/2/3, p-PRAS40 in tumor
xenografts, combined with high solubility and good ADME
properties for development therapeutic agents [12].
Substance III is selective highly potent p70S6K inhibitor,
has a reasonable ADME profile, and is efficacious in the
PC3 xenograft model [13].
The development of the chemistry of functional
derivatives of 1,3-oxazole is due to the successful search for
bioactive drugs through these derivatives. In particular, in
recent years, a number of works have been published on the
biological activity of derivatives of 5-amino-1,3-oxazole-4-
carbonitriles, which have proven to be effective inhibitors
of pyruvate kinase [14], protein kinase SK2 [15],
aminoglycoside-modifying enzymes [16], monoamine
oxidase [17], lipoxygenase [18, 19], PHIP(2) [20], and have
also shown antitumor [21, 22] and antimicrobial [23]
activity. This allows us to consider such derivatives as
5-piperasine-substituted 1,3-oxazole-4-carbonitriles with
рyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine
fragments as promising compounds for further
functionalization to increase their biological activity and to
search for new potent drugs.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
24
Results and Discussion
Based on the previous developments in the field of
bioactive 5-amino-4-cyano-1,3-oxazoles [14-23] and also
pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines, we
chose the following synthesis path for the obtaining of
target structures 1-15.
Compounds II and III were obtained by the synthetic
route described in [24, 25]. Reaction of N-(2,2-dichloro-1-
cyanovinyl)amides I with piperazine-substituted
pyrrolo[2,3-d]pyrimidine II and thieno[2,3-d]pyrimidine III
derivatives was carried out according to the known
procedure [26, 27]. This reaction occurs at a temperature of
20-25 °C in anhydrous tetrahydrofuran in the presence of
triethylamine. The reaction proceeds regioselectively with
the formation of 5-amino-1,3-oxazoles 1-15 in yields of
67-76% (Scheme 1).
The composition and structure of substituted 2-amino-
1,3-oxazole-4-carbonitriles 1-15 are confirmed by the
results of elemental analysis, IR spectra, 1H NMR and
chromatographic-mass spectra (Experimental section).
Their IR spectra are characterized by absorption bands of
CN groups (2202-2216 cm-1). In the 1H NMR spectra, along
with the signals of the aryl substituents, characteristic
signals of pyrrolo[2,3-d]pyrimidine and thieno[2,3-
d]pyrimidine rings are presented as singlets in the ranges of
8.57-8.40 and 7.94-7.58 ppm, piperazine group appear in
the spectrum at δ 3.39-3.26 ppm. The molecular ion peaks
in the chromatographic-mass spectra correspond to the
calculated ones.
Molecular properties and Drugglikes evaluation
Predictions of the physicochemical properties of a
molecule are essential for ADMET (Absorption,
Distribution, Metabolism, Excretion, and Toxicity) and
drug similarity analysis. These predictions are based on
several factors, including the area of the polar Van der
Waals surface, which plays a crucial role in molecular
recognition. Additionally, the number of atoms that act as
donors or acceptors of bonds influences the molecule's
ability to form stable complexes with its target. Other
important properties include the molecule's solubility in
water, which is a key characteristic of bioavailability, and
lipophilicity, which refers to the ability of molecules to
permeate membranes. The prediction of these
physicochemical parameters was conducted using the
SwissADME online platform, and the results are presented
in Table 1.
To assess druglikeness, several filters can be applied to
evaluate compounds based on specific indicators, helping to
identify the most promising candidates. Table 2 provides
five distinct perspectives on the evaluation of druglikeness
parameters, along with the ranges for each individual
indicator.
Analyzing the obtained results, the following
observations can be noted:
• Molecular Weight: All compounds fall within the
acceptable ranges of the Lipinski and Muegge filters, with
only seven compounds passing the Ghose rule.
• Number of Hydrogen Bond Donors: All compounds
meet the criteria of the presented filters.
• Number of Hydrogen Bond Acceptors: All
compounds also pass the criteria of the presented filters.
• Number of Atoms: All compounds comply with the
Ghose rule filter.
• Number of Rotatable Bonds (nRot or nRB): All
compounds adhere to the Veber and Muegge rules.
• Topological Surface Polarization Area (TPSA): All
compounds satisfy the requirements of the Veber, Egan, and
Muegge rule filters.
• Lipophilicity Index: Compounds 4 and 10 do not meet
the Lipinski and Muegge rule filters but are included in the
analysis per the Ghose and Egan rules.
To estimate the water solubility index (Log S), we will
use the following ranking: insoluble <−10 <poorly <−6
<moderately <−4 <soluble <−2 <very <0 <highly [29].
Accordingly, the predicted values indicate poor solubility
for all products.
Pharmacocinetics
Pharmacokinetic parameters can help characterize a
molecule as a potential drug candidate. Predicting these
parameters is crucial for making informed decisions about
selecting compounds for in vitro evaluation, as well as
during the synthesis and optimization phases of molecular
design. This process can influence the structure of a
molecule to achieve high permeability, an optimal balance
of efficacy and safety, and improved metabolic stability.
Studying pharmacokinetic parameters in silico at the early
stages of drug candidate development can significantly
enhance the likelihood of overall success throughout the
process [30]. For predicting pharmacokinetic parameters,
we selected several tools, including the SwissADME and
pkCSM online resources, which are backed by substantial
theoretical evidence and are widely used in the scientific
community [31-35].
Absorption parameters predicted in pkCSM are
presented in Table 3, including Intestinal absorption, Caco2
permeability, Skin Permeability, P-glycoprotein substrate,
P-glycoprotein inhibitor I and II.
The pkCSM platform provides various metrics to
evaluate the absorptive properties of compounds, including:
• Caco-2 Permeability: This model predicts the
permeability coefficient of compounds through a monolayer
of human colorectal adenocarcinoma epithelial cells, based
on data from 574 molecules.
• Intestinal Absorption: Compounds with an absorption
rate of less than 30% are classified as poorly absorbed.
N.M. Shevchenko et al.
25
Table 3. Predicted absorption indices.
№
Absorption indices
Intestinal
absorption
(GI absorption)
Caco2
permeability
Skin Permeability
(Log Kp), cm/s
P-glycoprotein
substrate
(P-gp)
P-glycoprotein
inhibitor I
P-glycoprotein
inhibitor II
1 100% 1.25 -2.74 No Yes Yes
2 99.16% 1.29 -2.74 No Yes Yes
3 100% 1.10 -2.74 No Yes Yes
4 99.30 1.05 -2.735 No Yes Yes
5 100 0.44 -2.73 No Yes Yes
6 100 0.59 -2.73 No Yes Yes
7 100 0.43 -2.73 No Yes Yes
8 100 0.58 -2.73 No Yes Yes
9 98.63 1.09 -2.74 No Yes Yes
10 97.24 1.14 -2.74 No Yes Yes
11 94.58 1.37 -2.73 No Yes Yes
12 95.00 1.36 -2.72 No Yes Yes
13 95.48 1.06 -2.74 No Yes Yes
14 94.45 1.37 -2.73 No Yes Yes
15 93.55 1.35 -2.73 No Yes Yes
Table 4. Predicted distribution indices.
№ VDss (human) Fraction unbound (human) BBB permeability CNS permeability
1 0.057 0.341 -1.184 -2.103
2 0.032 0.339 -1.165 -1.823
3 0.28 0.322 -0.984 -1.94
4 0.122 0.327 -1.044 -1.537
5 0.705 0.27 -1.205 -2.132
6 0.507 0.27 -1.165 -1.817
7 0.791 0.267 -1.229 -2.14
8 0.583 0.268 -1.189 -1.825
9 0.29 0.318 -1.159 -1.899
10 0.306 0.307 -1.14 -1.619
11 0.003 0.209 -0.858 -1.787
12 0.293 0.099 -0.847 -1.721
13 0.068 0.12 -1.082 -2.037
14 0.14 0.101 -1.055 -1.834
15 0.281 0.093 -1.022 -1.681
VDss (human) – steady-state volume of distribution, the theoretical volume into which the total dose of a drug must be evenly
distributed to obtain the same concentration as in blood plasma.
Fraction unbound (human) – the fraction of the free form of the drug in the blood serum.
BBB permeability – an indicator characterizing the ability of the drug to penetrate the blood-brain barrier.
CNS permeability – permeability of the CNS.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
26
Table 5. Predicted metabolism indices.
№
CYP-450
CYP2D6
(S)
CYP3A4
(S)
CYP1A2 (I)
CYP2C19
(I)
CYP2C9 (I) CYP2D6 (I) CYP3A4 (I)
1 - + - + + - -
2 - + - + + - -
3 - + - + + - -
4 - + - + - - -
5 - + - + + - +
6 - + - + + - -
7 - + - + + - +
8 - + - + + - +
9 - + - + + - -
10 - + - + + - -
11 - + + + + - +
12 - + + + + - +
13 - + - + + - +
14 - + + + + - +
15 - + + + + - +
.
• Skin Permeability: A compound is considered to have
relatively low skin permeability if its log Kp is greater than
-2.5.
• P-glycoprotein Substrate: P-glycoprotein is an ATP-
binding cassette transporter (ABC) that serves as a
biological barrier, removing toxins and xenobiotics from
cells. Screening for P-glycoprotein transport is conducted
using MDR-knockout transgenic mice and cell systems. The
predictive model for this property is built using 332
compounds to determine whether a given compound is a P-
glycoprotein substrate.
• P-glycoprotein I Inhibitor and P-glycoprotein II
Inhibitor: Modulating P-glycoprotein-mediated transport
can have significant pharmacokinetic implications for P-
glycoprotein substrates. This can be leveraged for
therapeutic benefits or may lead to contraindications.
Predictive models were developed using compounds
characterized as inhibitors of P-glycoprotein I and II,
specifically compounds 1273 and 1275, respectively.
Compounds 1-15 exhibit a high degree of absorption
(over 95%) when administered orally. Most of these
compounds demonstrate significant permeability (greater
than 0.09) through a monolayer of human colorectal
adenocarcinoma epithelial cells, which serves as a model
for predicting absorption through the human intestinal
mucosa. However, compounds 5, 6, 7, and 8 show
moderately absorbent permeability values (below 0.6),
likely due to the presence of p-methoxy and p-ethoxy
functional groups.
Analyzing the LogKp index reveals that all compounds
are not expected to be absorbed through the skin (with a
value greater than -2.5), suggesting they should be safe for
skin contact, except in cases of specific allergic reactions
that this index does not account for.
To evaluate the stability of intracellular drug
concentrations, which is essential for maintaining a
consistent therapeutic effect, we assessed the compounds'
potential to act as substrates or inhibitors of P-glycoprotein
I and II. The prediction indicates that all compounds are
possible inhibitors of P-glycoprotein I and II while not
showing a tendency to be substrates for it.
Compounds 1-15 can achieve high concentrations in the
body, which may enhance treatment efficacy. However, this
also poses a risk of potentially toxic accumulation within
the body.
The distribution of compounds in the body is
characterized by several indicators: the steady-state volume
of distribution (VDss), the free form fraction, permeability
through the blood-brain barrier (BBB permeability), and
permeability into the central nervous system (CNS
permeability). The calculation of these distribution
indicators was performed using the online platform pkCSM
(Table 4).
A higher VDss indicates that the drug is more widely
distributed throughout the body rather than remaining in
blood plasma. An indicator is considered low if it is below –
0.15 and high if it is above 0.45.
When developing a new biologically active compound,
it's important to consider the potential for the molecule to
bind to serum proteins, as only the unbound (free) form is
biologically active. The bound form of the drug cannot
perform its pharmacological function.
The ability of a molecule to cross the blood-brain barrier
is crucial for drug biotargets in the brain, as this can help
N.M. Shevchenko et al.
27
reduce side effects and overall toxicity. A compound is
regarded as having good permeability across the blood-
brain barrier if its parameter value is greater than 0.3, while
a value above -1 indicates that the compound is poorly
distributed in the brain.
The CNS permeability index assesses the ability of a
compound to penetrate the central nervous system from the
bloodstream. Compounds with a value greater than -2 are
considered capable of penetrating the CNS, while those
with a value less than -3 are unable to do so.
The prediction results indicate that most compounds,
with the exception of compounds 5, 6, 7, and 8, are poorly
distributed throughout the body and tend to remain in the
blood plasma. Compounds 12, 13, 14, and 15 showed the
highest levels of binding to blood proteins, with only about
10% of the drug remaining in a free state. For the other
compounds, this figure ranges from 20-30%, which is
typical for most drugs. This allows them to circulate in the
blood and reduces the rate of excretion. A high fraction of
free drug can increase the risk of toxic effects; however,
compounds 1-15 did not exceed this threshold and exhibited
a moderate level of binding to blood proteins.
Cytochrome P450 inhibitors play a crucial role in drug
metabolism. Cytochrome P450 is an important
detoxification enzyme primarily found in the liver, where it
oxidizes xenobiotics to facilitate their excretion. This
enzyme can deactivate many medications, while some drugs
may be activated by it. Inhibitors, such as grapefruit juice,
can significantly impact drug metabolism and are therefore
contraindicated. The calculation of these metabolism
indicators was performed using the online platform pkCSM
(Table 5).
It is essential to assess the ability of compounds to
inhibit cytochrome P450, including models for different
isoforms. A compound is classified as an inhibitor if the
concentration required for 50% inhibition is less than
10 μM.
Compounds 1-15 are not substrates of CYP2D6 and act
as inhibitors of CYP1A2, with the exception of
compounds 11, 12, 14 and 15. This indicates a low
likelihood of these compounds interacting with other drugs
or being affected by genetic variations in metabolic activity.
All compounds are substrates of CYP3A4, allowing us to
predict their metabolism in the body. However, this also
increases the risk of interactions with other drugs.
Specifically, compounds 5, 7, 8 and 11-15 are also
inhibitors of CYP3A4, which can elevate the concentration
of drugs metabolized by this enzyme, raising the risk of
toxicity.
Additionally, all compounds except for compound 4
inhibit CYP2C9, potentially enhancing the effectiveness of
other drugs metabolized by this enzyme. This can be
particularly beneficial for medications with a narrow
therapeutic index. However, it may also increase the
concentration of drugs such as ibuprofen, diclofenac, and
warfarin, heightening the risk of toxicity and adverse
interactions. Lastly, all compounds have the potential to
inhibit CYP2C19, which can pose additional risks when
taken concurrently with certain medications, including
sertraline, citalopram, phenobarbital, carbamazepine,
omeprazole, and clopidogrel.
To evaluate excretion, the pkCSM platform analyzed
total clearance and the potential of compounds to act as
substrates for the renal organic cation transporter OCT2
(Table 6).
Table 6. Predicted excretion indices.
№
Total
Clearance
Renal OCT2
substrate
1 0.709 -
2 0.521 -
3 0.905 -
4 0.797 -
5 0.822 -
6 0.635 -
7 0.858 -
8 0.671 -
9 0.286 -
10 0.259 -
11 0.04 -
12 0.02 -
13 0.067 -
14 0.113 -
15 0.094 -
The total clearance for most compounds ranges from
0.259 to 0.905, which can be classified as normal,
moderate, or high clearance. In contrast, for compounds 11-
15, the total clearance was between 0.02 and 0.113,
indicating a low level of clearance and slow elimination
from the body. Based on the results obtained, compounds 1-
15 are not substrates of renal OCT2. To evaluate toxicity,
the pkCSM platform analyzed AMES toxicity, T.
pyriformis toxicity, maximum tolerated dose, minnow
toxicity, oral rat acute toxicity (LD50), oral rat chronic
toxicity (LOAEL), and specific toxicity: hERG I and II
inhibitors, hepatotoxicity, and skin sensitization (Table 7).
The results indicate that the compounds are not
mutagenic based on the AMES test. The calculated LD50
values suggest a very low toxicity for these compounds,
which corresponds to the 4th toxicity class as per the
toxicity classification set by the Organization for Economic
Cooperation and Development (OECD Test No. 425).
Substances in this category are generally not dangerous,
even at high doses. Oral rat chronic toxicity ranges from
0.010 to 0.574 mg/kg_bw/day. For compounds 1-15, the
chronic toxicity for rats can be estimated as low, since the
value is less than 1 mg/kg_bw/day.
The maximum tolerated dose for compounds 1, 4, 6 and
8 to 11 is over 0.477 mg/kg/day, while for the other
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
28
Table 7. Predicted toxicity indices.
№ Toxicity indices
AMES MTD hERG I
inhibitor
hERG II
inhibitor
LD50 LOAE
L
Hepatotoxicity Skin
Semsitisation
TP MT
1 - 0.698 - + 2.76 0.09 + - 0.285 -2.422
2 - 0.686 - + 2.826 0.161 + - 0.285 -3.033
3 - 0.659 - + 2.805 0.146 - - 0.285 -3.043
4 - 0.573 - + 2.636 -0.222 - - 0.285 -4.000
5 - 0.422 - + 2.977 0.517 - - 0.285 -2.279
6 - 0.625 - + 2.898 0.229 - - 0.285 -4.473
7 - 0.454 - + 2.979 0.524 - - 0.285 -2.444
8 - 0.644 - + 2.893 0.236 - - 0.285 -4.638
9 - 0.663 - + 2.784 -0.081 - - 0.285 -3.261
10 - 0.645 - + 2.871 -0.010 - - 0.285 -3.872
11 - 0.577 - + 2.564 0.233 + - 0.288 -2.462
12 - 0.145 - + 2.800 0.574 + - 0.295 -2.115
13 - 0.382 - + 2.903 0.433 + - 0.289 -2.110
14 - 0.141 - + 2.815 0.402 + - 0.293 -1.999
15 - 0.167 - + 2.836 0.347 + - 0.294 -2.333
AMES – is an evaluation method used to determine the mutagenic potential of substances on bacteria (еhe Ames test).
MTD – max. tolerated dose
LD50 – oral rat acute toxicity, mol/kg
LOAEL – Oral Rat Chronic Toxicity
TP – T.Pyriformis toxicity
MT – Minnow toxicity
compounds, it is lower than 0.477 mg/kg/day. In terms of
minnow toxicity, the lethal concentration (LC50) results
show that for compounds 1, 5, 7, and 11 to 15, this
concentration is low; however, for compounds 2 to 4 and 6
to 10, the LC50 values are high.
Specific toxicity assessments reveal concerns regarding
cardiotoxicity, hepatotoxicity, and skin sensitization.
Predictions regarding the compounds' potential to act as
hERG I and II inhibitors show that compounds 1 to 15 may
inhibit hERG II, which implies they could impact potassium
efflux in cardiac cells and potentially cause cardiac
arrhythmias. However, they do not inhibit hERG I,
suggesting that while these compounds may have
undesirable effects, they are not definitively cardiotoxic, as
the functions of hERG II have yet to be thoroughly studied.
Additionally, compounds 1, 2, and 11 to 15 are predicted
to be hepatotoxic, but none of the compounds show
sensitizing properties.
Conclusions
Fifteen new derivatives of pyrrolo[2,3-d]pyrimidine and
thieno[2,3-d]pyrimidine, specifically piperazin-1-yl-1,3-
oxazole-4-carbonitriles, were synthesized, and their
ADMET indices were predicted. The predictions included
an analysis of molecular properties, drug-likeness, and
pharmacokinetic parameters such as absorption,
distribution, metabolic stability, and excretion, as well as
toxicity profiles. Among the fifteen compounds,
compounds 1-4 and 9, 10 stood out as they passed most
drug-likeness filters and exhibited acceptable predicted
pharmacokinetic parameters along with a moderate toxicity
profile.
Notes
Acknowledgments and finances. We would like to
thank Enamine Ltd for the material and technical support
for the synthetic part of this work.
The authors declare no conflict of interest.
Author contributions. N.M.S.: synthesis of compounds.
O.O.S.: prediction ADMET, writing most of the
manuscript. M.V.K.: writing experimental section, writing
of the manuscript. O.P.K.: investigation, synthesis of
compound. S.G.P.: synthesis of the compound,
conceptualization, supervision. Ye.S.V.: writing of the
manuscript, synthesis of the compounds. V.S.B.:
supervision, review & editing.
Experimental section
The solvents were purified according to the standard
procedures. All materials were purchased from commercial
sources and used without further purification. 1H NMR
spectra were recorded on a Bruker Avance DRX-500 (500
MHz) or Varian VXR-400 spectrometer (400 MHz) and 13C
N.M. Shevchenko et al.
29
NMR spectra were recorded at Bruker 170 spectrometer
(101, 126 MHz) spectra in DMSO-d6 solution. Chemical
shifts are reported in ppm downfield from TMS as internal
standards. Mass spectra were recorded on an LC-MS
instrument with chemical ionization (CI). LC-MS data were
acquired on an Agilent 1100 HPLC system equipped with
DAD/ELSD/LCMS-6120 diode matrix and mass-selective
detector. Melting points were measured on a MPA100
OptiMelt automated melting point system. Combustion
elemental analysis was performed by hand 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, chlore – by the Scheininger titrimetric
method.
General methodology of synthesis of 5-amino-4-cyano-
1,3-oxazoles (1-15).
A mixture of 0.0020 mol of dichloroacrylonitrile I and
0.0040 mol of triethylamine in 20 ml of anhydrous
tetrahydrofuran, 0.0025 mol of the corresponding amine (II,
III) was added. The mixture was stirred on a magnetic
stirrer at 20-25 °C for 48 h. The precipitate was filtered of,
the solvent was removed in vacuo, the residue was treated
with water, filtered of, dried and purifed by
recrystallization.
5-(4-(7-(2-Fluorophenyl)-5-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)-2-methyloxazole-4-carbonitrile
(1).
Yield: 0,73 g (76%); white crystals, solid, mp 203-
205 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.45 (s, 1H),
7.93-7.88 (m, 3H), 7.60 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.7
Hz, 2H), 7.41-7.34 (m, 3H) or 7.37 (dt, J = 15.5, 8.1 Hz,
3H), 3.35-3.34 (m, 4H), 3.27-3.26 (m, 4H), 2.23 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 164.5, 161.3, 153.2,
151.7, 151.1, 139.1, 137.6, 134.3, 129.2, 129.1, 128.5,
127.6, 126.4, 125.2, 124.8, 121.5, 117.3, 116.4, 106.3, 82.2,
48.3, 45.7, 21.3; IR (KBr) ν 2360, 2335, 2211 (CN), 1637,
1596, 1558, 1511, 1441, 1420, 1386, 1369, 1233, 829, 757,
692, 510; Found, %: C, 67.74; H, 4.66; N, 20.47.
C27H22FN7O. Calculated, %: C, 67.63; H, 4.62; N, 20.45.
LC-MS (CI) m/z (M+H)+ 480.
2-(tert-Butyl)-5-(4-(7-(2-fluorophenyl)-5-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-carbo-
nitrile (2).
Yield: 0,76 g (73%); white crystals, solid, mp 204-
206 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.95
(s, 1H), 7.92-7.89 (m, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.51 (t,
J = 7.6 Hz, 2H), 7,42-7,35 (m, 3H) or 7.35-7.21 (m, 3H),
3.39-3.36 (m, 4H), 3.31-3.29 (m, 4H), 1.22 (s, 9H);
13C NMR (126 MHz, DMSO-d6) δ 163.6, 162.5, 161.2,
159.8, 158.2, 154.0, 151.3, 150.7, 134.4, 133.3, 130.4,
128.9, 128.2, 126.4, 125.6, 125.3, 125.1, 116.9, 116.2,
114.2, 103.6, 96.4, 47.6, 45.2, 33.3, 27.2, 18.4; IR (KBr) ν
2986, 2908, 2204 (CN), 1643, 1595, 1553, 1511, 1441,
1383, 1366, 1266, 1231, 1157, 1113, 1078, 1016, 965, 833,
764, 701, 654; Found, %: C, 69.15; H, 5.48; N, 18.83.
C30H28FN7O. Calculated, %: C, 69.08; H, 5.41; N, 18.80.
LC-MS (CI) m/z (M+H)+ 522.
2-Methyl-5-(4-(5-phenyl-7-(m-tolyl)-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)piperazin-1-yl)oxazole-4-carbonitrile (3).
Yield: 0,67 g (70%); white crystals, solid, mp 186-
188 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.92
(s, 1H), 7.69-7.65 (m, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.50 (t,
J = 7.6 Hz, 2H), 7.44-7.35 (m, 2H), 7.21 (d, J = 7.0 Hz,
1H), 3.35-3.34 (m, 4H), 3.28-3.26 (m, 4H+H2O), 2.39 (s,
3H), 2.23 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ
160.64, 160.43, 152.07, 151.61, 151.21, 139.19, 137.46,
134.83, 129.45, 129.15, 128.83, 127.76, 127.29, 125.49,
124.93, 121.60, 117.52, 116.64, 104.39, 85.12, 48.31,
45.82, 21.47, 13.52; IR (KBr) ν 2845, 2216 (CN), 2199,
1595, 1555, 1442, 1424, 1387, 1263, 778, 693; Found, %:
C, 70.76; H, 5.32; N, 20.64. C28H25N7O. Calculated, %: C,
70.72; H, 5.30; N, 20.62. LC-MS (CI) m/z (M+H)+ 476.
5-(4-(5-Phenyl-7-(m-tolyl)-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)piperazin-1-yl)-2-(p-tolyl)oxazole-4-carbonitrile (4).
Yield: 0,83 g (75%); white crystals, solid, mp 146-
148 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.90
(s, 1H), 7.61-7.65 (m, 6H), 7.48-7.53 (m, 2H), 7.34-7.39
(m, 2H), 7.21-7.25 (m, 3H), 3.31 (s, 8H), 2.39 (s, 3H), 2.31
(s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 160.3, 160.2,
152.2, 151.2, 151.1, 140.8, 139.2, 137.6, 134.8, 130.0,
129.4, 129.2, 128.8, 127.8, 127.3, 125.8, 125.4, 124.9,
123.3, 121.5, 117.4, 116.4, 104.3, 86.4, 48.3, 45.7, 39.3,
21.5; IR (KBr) ν 2972, 2214 (CN), 1610, 1553, 1443, 1423,
1382, 1248, 1263, 970. Found, %: C, 74.13; H, 5.34; N,
17.82. C34H29N7O. Calculated, %: C, 74.03; H, 5.30; N,
17.77. LC-MS (CI) m/z (M+H)+ 552.
5-(4-(7-(4-Methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-yl)piperazin-1-yl)-2-methyloxazole-4-carboni-
trile (5).
Yield: 0,71 g (72%); beige crystals, solid, mp 170-
172 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.85
(s, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H),
7.49 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.09 (d, J
= 9.0 Hz, 2H), 3.82 (s, 3H), 3.38-3.23 (m, 8H), 2.23 (s, 3H);
13C NMR (126 MHz, DMSO-d6) δ 162.5, 160.4, 160.1,
159.7, 159.0, 154.3, 152.5, 150.6, 134.4, 133.8, 130.2,
128.6, 128.3, 126.7, 125.5, 125.5, 125.3, 117.0, 116.0,
114.3, 103.6, 96.7, 55.5, 47.8, 45.3, 26.5; IR (KBr) ν 2861,
2210 (CN), 1635, 1591, 1553, 1513, 1439, 1186, 1158, 934,
835, 761, 697; Found, %: C, 68.46; H, 5.15; N, 19.98.
C28H25N7O2. Calculated, %: C, 68.42; H, 5.13; N, 19.95.
LC-MS (CI) m/z (M+H)+ 492.
2-(tert-Butyl)-5-(4-(7-(4-methoxyphenyl)-5-phenyl-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-car-
bonitrile (6).
Yield: 0,76 g (71%); white crystals, solid, mp 212-
214 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.76
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
30
(s, 1H), 7.70 (d, J = 9.2 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H),
7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.06 (d, J
= 9.2 Hz, 2H), 3.80 (d, J = 2.0 Hz, 3H), 3.36 (d, J = 5.2 Hz,
4H), 1.21 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 162.5,
160.4, 160.0, 159.6, 158.0, 154.1, 151.5, 150.5, 134.4,
133.7, 130.2, 128.6, 128.3, 126.7, 125.5, 125.5, 125.2,
116.9, 116.0, 114.3, 103.5, 96.7, 55.4, 47.8, 45.3, 33.1,
27.6, 18.4; IR (KBr) ν 2972, 2908, 2862, 2206 (CN), 1644,
1594, 1554, 1514, 1493, 1441, 1379, 1342, 1302, 1250,
1271, 1177, 1147, 1112, 1080, 1032, 968, 935, 909, 833.
Found, %: C, 69.79; H, 5.88; N, 18.39. C31H31N7O2.
Calculated, %: C, 69.77; H, 5.86; N, 18.37. LC-MS (CI)
m/z (M+H)+ 534.
5-(4-(7-(4-Ethoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)-2-methyloxazole-4-carbonitrile
(7).
Yield: 0,68 g (67%); white crystals, solid, mp 201-
203 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.58
(d, J = 3.0 Hz, 1H), 7.69-7.62 (m, 2H), 7.53 (d, J = 7.7 Hz,
2H), 7.47 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.10-
7.04 (m, 2H), 4.15-4.02 (m, 2H), 3.36-3.28 (m, 4H), 3.25-
3.22 (m, 4H), 1.35 (s, 3H), 1.22 (s, 3H); 13C NMR (126
MHz, DMSO-d6) δ 162.5, 160.5, 160.1, 159.7, 159.2, 154.3,
152.6, 150.9, 134.3, 133.3, 130.2, 128.6, 128.1, 126.7,
125.3, 125.2, 125.1, 116.9, 116.0, 114.3, 103.7, 96.8, 59.2,
56., 47.9, 45., 26.8; IR (KBr) ν 2861, 2210 (CN), 1641,
1595, 1553, 1512, 1436, 1380, 1280, 1246, 1189, 1174,
1156, 1118, 1045, 927, 963, 826, 761, 692. Found, %: C,
68.91; H, 5.39; N, 19.42. C29H27N7O2. Calculated, %: C,
68.89; H, 5.38; N, 19.39. LC-MS (CI) m/z (M+H)+ 506.
2-(tert-Butyl)-5-(4-(7-(4-ethoxyphenyl)-5-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-carbo-
nitrile (8).
Yield: 0,81 g (74%); white crystals, solid, mp 164-
166 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.78
(d, J = 3.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.57 (d, J = 7.7 Hz,
2H), 7.46 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.08-
7.00 (m, 2H), 4.13-4.00 (m, 2H), 3.38-3.31 (m, 4H), 3.31-
3.24 (m, 4H), 1.33 (s, 3H), 1.20 (s, 9H); 13C NMR (126
MHz, DMSO-d6) δ 164.9, 161.3, 160.3, 160.0, 158.6, 154.2,
151.7, 150.6, 134.4, 133.7, 130.4, 128.5, 128.2, 126.2,
125.2, 125.8, 125.3, 116.7, 116.7, 114.4, 103.7, 94.1, 82.3,
55.5, 47.4, 45.3, 33.0, 27.4, 21.3; IR (KBr) ν 2972, 2909,
2864, 2206 (CN), 1644, 1593, 1551, 1514, 1442, 1247,
1177, 1192, 1115. Found, %: C, 70.23; H, 6.11; N, 17.92.
C32H33N7O2. Calculated, %: C, 70.18; H, 6.07; N, 17.90.
LC-MS (CI) m/z (M+H)+ 548.
5-(4-(7-(3-Chlorophenyl)-5-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)-2-methyloxazole-4-carbonitrile
(9).
Yield: 0,69 g (70%); white crystals, solid, mp 190-
192 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.10
(d, J = 2.5 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.93 (dd, J =
8.0, 2.5 Hz, 1H), 7.64-7.54 (m, 3H), 7.54-7.47 (m, 2H),
7.44 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 3.38-3.33
(m, 8H), 2.24 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ
197.3, 183.6, 176.5, 173.6, 160.6, 160.3, 152.2, 151.8,
151.4, 140.1, 138.9, 134.5, 133.9, 131.3, 129.2, 128.8,
127.4, 126.9, 125.1, 123.8, 122.6, 118.0, 116.3, 104.5, 85.1,
48.3, 45.8, 13.5; IR (KBr) ν 2920, 2860, 2203 (CN), 1637,
1594, 1558, 1483, 1443, 1382, 1243, 694, 690; Found, % C,
65.41; H, 4.49; Cl, 7.14; N, 19.79. C27H22ClN7O.
Calculated, %: C, 65.39; H, 4.47; Cl, 7.15; N, 19.77. LC-
MS (CI) m/z (M+H)+ 496.
2-(tert-Butyl)-5-(4-(7-(3-chlorophenyl)-5-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-carbo-
nitrile (10).
Yield: 0,82 g (76%); white crystals, solid, mp 213-
215 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H),
8.11-7.91 (m, 3H), 7.65-7.36 (m, 7H), 3.39-3.28 (m, 8H),
1.25-1.22 (m, 9H); 13C NMR (101 MHz, DMSO-d6) δ
160.5, 160.2, 154.5, 152.3, 151.4, 141.8, 138.9, 134.6,
133.9, 131.3, 129.2, 128.8, 127.4, 126.9, 125.1, 123.8,
122.6, 118.1, 116.4, 104.5, 97.7, 85.0, 48.3, 45.7, 33.6,
28.1; IR (KBr) ν 2855, 2202 (CN), 1626, 1582, 1554, 1484,
1438, 1246, 1016, 772, 697. Found, %: C, 67.02; H, 5.28;
Cl, 6.55; N, 18.26. C30H28ClN7O. Calculated, %: C, 66.97;
H, 5.25; Cl, 6.59; N, 18.22. LC-MS (CI) m/z (M+H)+ 538.
2-Phenyl-5-(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-carbonitrile (11).
Yield: 0,62 g (70%); yellowish crystals, solid, mp 210-
212 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.88
(d, J = 5.3 Hz, 2H), 7.52-7.48 (m, 3H), 3.82-3.77 (m, 4H),
3.53-3.51 (m, 4H), 2.97-2.86 (m, 4H), 1.90-1.74 (m, 4H);
13C NMR (126 MHz, DMSO-d6) δ 193.2, 188.9, 181.4,
174.0, 167.4, 161.3, 160.2, 158.5, 151.4, 142.2, 131.9,
130.5, 129.1, 125.3, 116.1, 86.3, 49.1, 45.7, 26.0, 25.3,
22.2, 15.6; IR (KBr) ν 2945, 2866, 2834, 2211 (CN), 1607,
1583, 1533, 1504, 1437, 1372, 1245, 974, 694. Found, %:
C, 65.19; H, 5.08; N, 19.03; S, 7.24. C24H22N6OS.
Calculated, %: C, 65.14; H, 5.01; N, 18.99; S, 7.24. LC-MS
(CI) m/z (M+H)+ 443.
5-(4-(5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]py-
rimidin-4-yl)piperazin-1-yl)-2-(p-tolyl)oxazole-4-carbo-
nitrile (12).
Yield: 0,65 g (71%); yellowish crystals, solid, mp 228-
230 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H),
7.78-7.76 (m, 2H), 7.32 (d, J = 7.9 Hz, 2H), 3.80-3.77 (m,
4H), 3.53-3.51 (m, 4H), 2.96-2.87 (m, 4H), 2.35 (s, 3H),
1.95-1.70 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ
185.2, 171.1, 162.2, 158.5, 153.2, 150.3, 142.9, 138.1,
133.9, 130.5, 104.1, 97.1, 58.0, 47.4, 26.0, 15.1, 8.5; IR
(KBr) ν 2923, 2864, 2208 (CN), 1609, 1583, 1532, 1503,
1437, 1373, 975. Found, %: C, 65.81; H, 5.33; N, 18.45; S,
7.01. C25H24N6OS. Calculated, %: C, 65.77; H, 5.30; N,
18.41; S, 7.02. LC-MS (CI) m/z (M+H)+ 457.
2-(4-Methoxyphenyl)-5-(4-(5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-
carbonitrile (13).
N.M. Shevchenko et al.
31
Yield: 0,72 g (76%); white crystals, solid, mp 205-
207 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.81
(d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 3.84-3.74 (m,
8H), 3.35 (s, 3H), 2.97-2.86 (m, 4H), 1.90-1.75 (m, 4H);
13C NMR (126 MHz, DMSO-d6) δ 187.4, 171.1, 162.2,
158.5, 153.2, 150.3, 142.9, 138.1, 133.9, 130.5, 104.1, 97.1,
58.0, 47.4, 26.0, 15.1, 8.5; IR (KBr) ν 2940, 2860, 2837,
2215 (CN), 1610, 1533, 1502, 1363, 1252, 982. Found, %:
C, 63.59; H, 5.15; N, 17.79; S, 6.76. C25H24N6O2S.
Calculated, %: C, 63.54; H, 5.12; N, 17.78; S, 6.78. LC-MS
(CI) m/z (M+H)+ 473.
2-(4-Fluorophenyl)-5-(4-(5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-car-
bonitrile (14).
Yield: 0,69 g (75%); beige crystals, solid, mp 238-
240 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H),
7.94-7.92 (m, 2H), 7.37-7.34 (m, J = 8.7 Hz, 2H), 3.79 (t, J
= 4.9 Hz, 4H), 3.52 (t, J = 5.1 Hz, 4H), 2.97-2.86 (m, 4H),
1.91-1.74 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ
188.9, 181.4, 174.0, 167.4, 161.3, 160.2, 158.5, 151.4,
142.2, 131.9, 130.5, 129.1, 125.3, 116.1, 86.3, 49.1, 45.7,
26.0, 25.3, 22.2, 15.6; IR (KBr) ν 2942, 2868, 2209 (CN),
1620, 1599, 1534, 1503, 1436, 1224, 1151, 974. Found, %:
C, 62.64; H, 4.62; N, 18.29; S, 6.95. C24H21FN6OS.
Calculated, %: C, 62.59; H, 4.60; N, 18.25; S, 6.96. LC-MS
(CI) m/z (M+H)+ 461.
2-(4-Chlorophenyl)-5-(4-(5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)oxazole-4-car-
bonitrile (15).
Yield: 0,65 g (68%); yellowish crystals, solid, mp 218-
220 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.87
(d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 3.81-3.74 (m,
4H), 3.52-3.50 (m, 4H), 2.96-2.85 (m, 4H), 1.91-1.73 (m,
4H); 13C NMR (126 MHz, DMSO-d6) δ 195.4, 188.9, 181.4,
167.4, 161.3, 160.2, 158.5, 151.4, 142.2, 131.9, 130.5,
129.1, 125.3, 116.1, 86.3, 49.1, 45.7, 26.0, 25.3, 22.2, 15.6;
IR (KBr) ν 2939, 2866, 2210 (CN), 1617, 1598, 1534, 1435,
1371, 1246, 1088, 973. Found, %: C, 60.46; H, 4.48; Cl,
7.45; N, 17.66; S, 6.71. C24H21ClN6OS. Calculated, %: C,
60.43; H, 4.44; Cl, 7.43; N, 17.62; S, 6.72. LC-MS (CI) m/z
(M+H)+ 477.
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Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних
піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей
ADMET
Н.М Шевченко1, О.О. Северін1*, М.В. Качаєва1, О.П. Козаченко1, С.Г. Пільо1, Є.С. Велігіна2, В.С. Броварець1
1Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
2 Інститут органічної та аналітичної хімії (ICOA), Орлеан, Франція
Резюме: Відкриття нуклеозидних антибіотиків дало поштовх для розвитку хімії піроло[2,3-d]піримідинів і тієно[2,3-d]піримідинів як біологічно
активних сполук. У цій роботі описано універсальний та ефективний підхід до синтезу нових піроло[2,3-d]піримідинових та тієно[2,3-
d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів. Розглянуто їх потенціал як біологічно активних сполук і прогнозовано
ADMET-показники для оцінки їх подальшого застосування як фармацевтичних субстанцій.
Ключові слова: піроло[2,3-d]піримідин; тієно[2,3-d]піримідин; 1,3-оксазол; прогнозування ADMET.
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| id | oai:ojs2.bioorganica.com.ua:article-91 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:34Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/18/eb818fda4a10a289dcacb61eb513e318.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-912026-07-19T14:56:55Z Synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles, prediction and evaluation of their ADMET properties Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET Shevchenko, Nadiya М. Severin, Oleksandr O. Kachaeva, Maryna V. Kozachenko, Oleksandr Р. Velihina, Yevheniia S. Brovarets, Volodymyr S. pyrrolo[2,3-d]pyrimidine thieno[2,3-d]pyrimidine 1,3-oxazole prediction ADMET піроло[2,3-d]піримідин тієно[2,3-d]піримідин 1,3-оксазол прогнозування ADMET The discovery of nucleoside antibiotics gave impetus to the development of the chemistry of pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines as biologically active compounds. This work describes a universal and efficient approach to the synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles. Their potential as biologically active compounds is considered and ADMET-score is predicted to assess their further application as pharmaceutical substances Відкриття нуклеозидних антибіотиків дало поштовх для розвитку хімії піроло[2,3-d]піримідинів і тієно[2,3-d]піримідинів як біологічно активних сполук. У цій роботі описано універсальний та ефективний підхід до синтезу нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів. Розглянуто їх потенціал як біологічно активних сполук і прогнозовано ADMET-показники для оцінки їх подальшого застосування як фармацевтичних субстанцій. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/91 10.15407/bioorganica2024.02.021 Ukrainica Bioorganica Acta; Vol. 19 No. 2 (2024): Ukrainica Bioorganica Acta; 21-32 Ukrainica Bioorganica Acta; Том 19 № 2 (2024): Ukrainica Bioorganica Acta; 21-32 1814-9766 1814-9758 10.15407/bioorganica2024.02 en https://bioorganica.com.ua/index.php/journal/article/view/91/87 Copyright (c) 2024 Nadiya М. Shevchenko, Oleksandr O. Severin, Maryna V. Kachaeva, Oleksandr Р. Kozachenko, Yevheniia S. Velihina, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | піроло[2,3-d]піримідин тієно[2,3-d]піримідин 1,3-оксазол прогнозування ADMET Shevchenko, Nadiya М. Severin, Oleksandr O. Kachaeva, Maryna V. Kozachenko, Oleksandr Р. Velihina, Yevheniia S. Brovarets, Volodymyr S. Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title | Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title_alt | Synthesis of new pyrrolo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives of piperazin-1-yl-1,3-oxazole-4-carbonitriles, prediction and evaluation of their ADMET properties |
| title_full | Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title_fullStr | Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title_full_unstemmed | Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title_short | Синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей ADMET |
| title_sort | синтез нових піроло[2,3-d]піримідинових та тієно[2,3-d]піримідинових похідних піперазин-1-іл-1,3-оксазол-4-карбонітрилів, прогноз та оцінка їх властивостей admet |
| topic | піроло[2,3-d]піримідин тієно[2,3-d]піримідин 1,3-оксазол прогнозування ADMET |
| topic_facet | pyrrolo[2,3-d]pyrimidine thieno[2,3-d]pyrimidine 1,3-oxazole prediction ADMET піроло[2,3-d]піримідин тієно[2,3-d]піримідин 1,3-оксазол прогнозування ADMET |
| url | https://bioorganica.com.ua/index.php/journal/article/view/91 |
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