Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів
This research presents a highly efficient method for synthesizing diverse aminomethylcoumarin libraries through the interaction of Mannich bases of coumarins and primary amines. The developed amination process demonstrated versatility and compatibility with various substituents. Reactions were compl...
Gespeichert in:
| Datum: | 2023 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
|
| Schlagworte: | |
| Online Zugang: | https://bioorganica.com.ua/index.php/journal/article/view/74 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Ukrainica Bioorganica Acta |
| Завантажити файл: |  |
Institution
Ukrainica Bioorganica Acta| _version_ | 1871193600572784640 |
|---|---|
| author | Hlibov, Eugen K. Moskvina, Viktoriia S. Malets, Yehor S. Khilya, Volodymyr P. |
| author_facet | Hlibov, Eugen K. Moskvina, Viktoriia S. Malets, Yehor S. Khilya, Volodymyr P. |
| author_institution_txt_mv | [
{
"author": "Eugen K. Hlibov",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine "
},
{
"author": "Viktoriia S. Moskvina",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
},
{
"author": "Yehor S. Malets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine "
},
{
"author": "Volodymyr P. Khilya",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
}
] |
| author_sort | Hlibov, Eugen K. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | This research presents a highly efficient method for synthesizing diverse aminomethylcoumarin libraries through the interaction of Mannich bases of coumarins and primary amines. The developed amination process demonstrated versatility and compatibility with various substituents. Reactions were completed within short timeframes, yielding high-purity products with substantial yields, as well as facilitating the scale-up of the process. The synthesized derivatives exhibited structural diversity, incorporating carboxylic and amino groups, as well as amide, hydrazide, and hydroxamic acid moieties. In silico ADME predictions highlighted the potential of these aminomethylcoumarins as promising candidates for further optimization in the development of oral chemotherapeutic agents |
| doi_str_mv | 10.15407/bioorganica2023.02.022 |
| first_indexed | 2025-07-17T12:19:56Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
UDC 547.814/.816
DOI: https://doi.org/10.15407/bioorganica2023.02.022
22
º
Ukrainica Bioorganica Acta
www.bioorganica.org.ua
RESEARCH ARTICLE
Exploring aminomethylcoumarins: versatile synthesis, structural
diversity, and ADME prediction
Eugen K. Hlibov1, Viktoriia S. Moskvina1,2*, Yehor S. Malets2, Volodymyr P. Khilya1
1 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
2 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: This research presents a highly efficient method for synthesizing diverse aminomethylcoumarin libraries through the interaction
of Mannich bases of coumarins and primary amines. The developed amination process demonstrated versatility and compatibility with
various substituents. Reactions were completed within short timeframes, yielding high-purity products with substantial yields, as well as
facilitating the scale-up of the process. The synthesized derivatives exhibited structural diversity, incorporating carboxylic and amino
groups, as well as amide, hydrazide, and hydroxamic acid moieties. In silico ADME predictions highlighted the potential of these
aminomethylcoumarins as promising candidates for further optimization in the development of oral chemotherapeutic agents.
Keywords: coumarin; amine; aminomethylcoumarin; amination; ADME.
Introduction
Synthetic transformations of bioactive plant metabolites
represent a current focal point in modern organic chemistry.
These transformations involve the synthesis of new
biologically active compounds and compounds of novel
structural motifs, which hold promise for medicinal
chemistry. Coumarin derivatives are widely distributed in
the plant kingdom and, due to the presence of hydroxyl,
methoxyl, and acetyl groups, serve as versatile starting
materials for functionalization. On the other hand, it is well-
documented that the introduction of primary amino
functionality into the coumarin ring often leads to the
emergence of new types of biological activity or the
enhancement of biological effects. Comprehensive
exploration of their physicochemical properties, including
fluorescence, opens up new application avenues. The
Mannich reaction is recognized as one of the methods for
structurally modifying drug-like substrates, particularly
Received:
Revised:
Accepted:
Published online:
06.09.2023
25.10.2023
28.11.2023
30.12.2023
Corresponding author. Tel.: +380-66-791-0921;
e-mail: v.moskvina@gmail.com (V.S. Moskvina)
ORCID: 0000-0001-5556-9147
Figure 1. Examples of aminomethyl derivatives of coumarins that
have found practical applications in various area.
benzopyran-2-ones. This reaction results in the
incorporation of a pharmacophoric primary aminomethyl
function into the coumarin system [1]. It is worth noting
that aminomethyl derivatives of coumarins can readily be
transformed into the corresponding ammonium salts, which
exhibit enhanced solubility in aqueous environments. This
© Hlibov E.K. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
https://orcid.org/0000-0001-5556-9147
E.K. Hlibov et al.
23
attribute holds significant importance in medicinal
chemistry. Figure 1 illustrates only a limited selection of
aminomethyl derivatives of coumarins; for instance,
coumarins 1 and 2 are utilized as antimicrobial agents [2].
Another noteworthy example is coumarin 3, which impacts
the human nervous system and finds application in medical
practice for the treatment of psychoses and schizophrenia
[3]. Additionally, coumarin 4 is employed as a plant growth
regulator [4]. Furthermore, coumarin-based Zn2+ probes,
compounds 5 and 6, have been utilized for ratiometric
fluorescence imaging [5]. Hence, considering the diverse
biological activities of aminomethyl derivatives of
coumarins, the development of effective synthesis methods
and targeted functionalization, as well as the investigation
of the physicochemical properties of the obtained
compounds, represents a practically beneficial endeavor.
Simultaneously, a meticulous assessment of Absorption,
Distribution, Metabolism, and Excretion (ADME)
parameters, coupled with extensive investigations into the
biological activities of these derivatives, will facilitate the
discernment of a diverse array of compounds suitable for
applications in medicinal chemistry, agrochemistry, and
allied fields.
In our previous work, we developed an efficient
methodology for the synthesis of aminomethyl derivatives
of coumarins, their acetoxy derivatives [6], as well as
formyl/acetyl derivatives of coumarins and furocoumarins
[7]. In this study, we investigated the interaction of
aminomethyl derivatives of coumarins 7{1-10} with
structurally diverse primary amines, demonstrating the
synthetic attractiveness of the resulting derivatives and
conducting an assessment of ADME parameters.
Results and Discussion
As an initial model reaction to assess key reaction
parameters, we examined the amination reaction of
dimethylaminocoumarin 7{1a} (N(Alk)2 = N(Me)2) and
diethylaminocoumarin 7{1b} (N(Alk)2 = N(Et)2) with
commercially available benzylamine 8{1}. This allowed us
to primarily evaluate the impact of the leaving group in this
transformation. We conducted initial tests of the reaction of
starting materials (7{1a} or 7{1b}, and 8{1}) in the presence
of various solvents to optimize the reaction conditions (see
Table 1). It is important to note that the progress of this
reaction at room temperature was very slow, as indicated by
LCMS data. Therefore, further investigations aimed at
optimizing the methodology were carried out at the boiling
point of the respective solvent. Indeed, upon the interaction
of the starting reagents in a molar ratio of 1:1.5 in 10 ml of
MeOH under reflux conditions for 2.5 hours, the reaction
yielded the product 9{1-1} with a 23% yield for 7{1a} and
31% for 7{1b} (Entry 1, Table 1). The product 9{1-1} also
formed in relatively low yields when using EtOH (28% for
7{1a} and 38% for 7{1b}, respectively) and AcCN (21% for
7{1a} and 26% for 7{1b}, respectively) (Entry 2 and 4,
Table 1). Conducting the reaction in i-PrOH allowed us to
obtain the product 9{1-1} with yields of 43% for 7{1a} and
54% for 7{1b}, respectively (Entry 3). Therefore, the most
favorable approach, primarily based on the yield of the key
reaction product, was to perform the reaction in i-PrOH
under reflux conditions for 2.5 hours. We also observed that
when the reaction was carried out under these conditions
with an increased molar ratio of the starting reagents (1:2
and 1:3), the yield of 9{1-1} increased as well (Entry 5 and
6), and at a 1:4 ratio, the product 9{1-1} formed with
moderate yields (38% for 7{1a} and 43% for 7{1b},
respectively), along with unidentified mixtures of complex
products (Entry 7). Hence, the optimal methodology for
conducting the amination reaction involved using a molar
ratio of reagents of 1:3 in i-PrOH under reflux conditions. It
is noteworthy that in all cases, the yield of the target
product was higher when the corresponding 7{1b} was used
as the starting compound. Therefore, in subsequent
experiments, diethylaminocoumarin derivatives were
chosen as the starting substrates.
With the optimized reaction conditions established, we
embarked on the exploration of substituted
diethylaminocoumarins 7{1-10} (10 examples) and various
Table 1. Optimization of the reaction conditions on the example of compound 7{1a} and 7{1b} synthesis.
Entry
Aminomethyl coumarin
(1 eq.)
Amount of
benzylamine
(eq.)a
Solvent
Reaction
time
(h)
Yield of product
9{1-1} (%)b
1 7{1a} / 7{1b} 1.5 MeOH 2.5 23 / 31
2 7{1a} / 7{1b} 1.5 EtOH 2.5 28 / 38
3 7{1a} / 7{1b} 1.5 i-PrOH 2.5 43 / 54
4 7{1a} / 7{1b} 1.5 AcCN 2.5 21 / 26
5 7{1a} / 7{1b} 2 i-PrOH 2.5-3 51 / 63
6 7{1a} / 7{1b} 3 i-PrOH 2.5-3 68 / 84
7 7{1a} / 7{1b} 4 i-PrOH 2-2.5 38 / 43
a Reaction conditions: 7{1a} or 7{1b} (1.0 eq.) and benzylamine (1.5-4 eq.), appropriate solvent (10 ml), reflux;
b Yields of isolated compound 9{1-1};
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
24
structurally diverse primary amines 8{1-10} (10 examples),
which were selected randomly to obtain a variety of product
9 in this reaction (Scheme 2). As a result, 98 experiments
were conducted, allowing us to achieve the target product 9
with a high success rate of 86%, and with good purity
(>95% according to HPLC). In the majority of cases, the
yields fell within the range of 36-83%, and for more than
50% of the representative set, the yield exceeded 70%.
Scheme 1. Investigation of the amination reaction of
dimethylaminocoumarins 7{1a,b} and benzylamine 8{1} as a
model reaction.
Scheme 2. The aminomethylcoumarins 9 library generation.
The representative substrates, diethylaminocoumarins
7{1-10} and primary amines 8{1-10}, are listed in Figure 2.
First, we examined the compatibility of various primary
amines in these amination reactions. To our delight, a wide
range of alkyl groups in the case of primary amines 8{1-10}
including methyl, ethyl, propyl, cyclopropyl, cyclopentyl,
allyl, propargyl, benzyl, and ester, were found to be well-
suited for this transformation. Substituted
diethylaminocoumarins 7{1-10} with methyl, ethyl, and
propyl substituents were also tolerated in this procedure,
illustrating the generality of the method. However, higher
yields were observed for 4-Ph substituted
diethylaminocoumarins 7{6-10}. As an example, using
coumarin 7{6} and amine 8{6}, we successfully scaled up
the synthesis method and obtained aminomethylcoumarin
9{6-6} in a quantity of 15 grams; after crystallization from
EtOH, the product yield reached 74%. Additionally, the
synthetic potential of the obtained derivatives was
demonstrated using aminomethylcoumarin 9{6-9} as
example. Contrary to our expectations, the hydrolysis of
9{6-9} under acidic conditions failed to produce the desired
product, both at room temperature and under reflux
conditions. However, conducting the hydrolysis under basic
conditions, using 1M NaOH in i-PrOH at 50 °C for 4 hours,
resulted in the formation of the corresponding acid 10 with
a yield of 67% (Scheme 3). We also explored the direct
amidation of aminomethylcoumarin 9{6-9} with ester
group. The amidation of 9{6-9} with i-PrNH2, as well as
with 1,2-binucleophilic reagents, hydrazine hydrate, and
hydroxylamine, yielded amide 11, hydrazide 12, and
hydroxamic acid 13 with yields of 56%, 78%, and 67%,
respectively (Scheme 3). Considering that the treatment of
benzopyran-2-ones under basic conditions results in the
opening of the coumarin system, in this case, both
hydrolysis and interaction with N-,N- and N-,O-
binucleophiles proceeded while preserving the coumarin
ring. This is confirmed by the presence of a singlet signal at
6.13-6.19 ppm in the 1H NMR spectra.
Figure 2. Scope of diethylaminocoumarins 7{1-10} and primary
amines 8{1-10}.
Additionally, the synthetic potential of the obtained
derivatives was demonstrated using aminomethylcoumarin
9{6-9} as example. Contrary to our expectations, the
hydrolysis of 9{6-9} under acidic conditions failed to
E.K. Hlibov et al.
25
Scheme 3. Synthetic utility of aminomethylcoumarin 9{6-9}.
produce the desired product, both at room temperature and
under reflux conditions. However, conducting the
hydrolysis under basic conditions, using 1M NaOH in i-
PrOH at 50 °C for 4 hours, resulted in the formation of the
corresponding acid 10 with a yield of 67% (Scheme 3). We
also explored the direct amidation of aminomethylcoumarin
9{6-9} with ester group. The amidation of 9{6-9} with i-
PrNH2, as well as with 1,2-binucleophilic reagents,
hydrazine hydrate, and hydroxylamine, yielded amide 11,
hydrazide 12, and hydroxamic acid 13 with yields of 56%,
78%, and 67%, respectively (Scheme 3). Considering that
the treatment of benzopyran-2-ones under basic conditions
results in the opening of the coumarin system, in this case,
both hydrolysis and interaction with N-,N- and N-,O-
binucleophiles proceeded while preserving the coumarin
ring. This is confirmed by the presence of a singlet signal at
6.13-6.19 ppm in the 1H NMR spectra.
The hydrolysis of aminomethylcoumarin 9{9-10} with a
Boc-group under anhydrous acidic conditions led to the
formation of aminomethylcoumarin 14 with an 86% yield,
which contained an additional free amino group (Scheme
4).
O
Ph
OHO
Me
9{9-10}
NH
BocHN
O
Ph
OHO
Me
NH
H2N
TFA, CH2Cl2
r.t., 2h; 86%
14
Scheme 4. The hydrolysis of aminomethylcoumarin 9{9-
10}.
In contemporary drug discovery, the exploration of
absorption, distribution, metabolism, and excretion
(ADME) plays a pivotal role. The early assessment of these
properties is crucial in identifying compounds with
favorable pharmacokinetic characteristics for further drug
development. In this study, the in silico ADME screening
systems were employed to anticipate the performance of
synthesized aminomethylcoumarins 9 in an in vivo setting.
The estimation encompassed physicochemical attributes,
pharmacokinetic properties, and ADME parameters, and
was conducted using the SwissADME free web tool [8].
The results of the calculations are presented in Table S1-S2
(see Supplemental Materials) and Figure 3.
Figure 3. Dependence of logP from Molecular Weight (MW) and
C(sp3) for aminomethylcoumarins 9 library.
The analysis of the obtained data reveals that the
synthesized aminomethylcoumarins 9 exhibit favorable
physicochemical properties. Overall, there is a consistent
pattern of increasing theoretical logP with rising molecular
weight, aligning with expectations given the structural
similarity of the substructural fragments of coumarin
derivatives 7. However, the impact of sp3-hybridized
carbons on lipophilicity is relatively modest. Another
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
26
observed trend, with an unaltered amine, demonstrates an
increase in logP with a higher percentage of sp3-hybridized
carbons for coumarins 7{1, 4, 5, 2, 3}, attributed to alkyl
substituents in the phenyl ring. Subsequently, there is a
sharp decline in the share of sp3-hybridized carbons upon
transitioning from substructural fragment 7{3} to 7{6}
(introduction of a phenyl substituent in position 4),
followed by a linear dependence of logP on the number of
sp3-hybridized carbons for derivatives 7{6, 9, 10, 7, 8}.
Compounds featuring the N-Boc fragment of diamine 8{10}
demonstrate a substantial decrease in calculated
lipophilicity (1-2 orders of magnitude). Conversely, the
presence of a glycine fragment deviates from the general
trend and is predicted to significantly enhance the
hydrophilicity of the compound. Additionally, in
comparison to amine derivatives 8{7}, compounds with the
8{8} substructure exhibit approximately 0.8-0.9 times
higher calculated lipophilicity (attributed to the presence of
halogens in the phenyl nucleus). This deviation from the
anticipated linear trend, where the extrapolated difference
should be around two orders of magnitude, suggests a
unique influence of the specific structural features on the
lipophilic nature of these compounds.
Conclusions
In conclusion, we have successfully demonstrated an
efficient and practical method for synthesizing libraries of
structurally diverse aminomethylcoumarins through the
interaction of Mannich bases of coumarins and primary
amines. This amination process was effective for both
Mannich bases of coumarins and primary amines, as
evidenced by the successful outcomes in 86 out of 98
experiments. The reactions were completed in short reaction
times (2.5-3 hours) with high purity and good yields
(ranging from 36% to 83%, and for over 50% of the
representative set, the yield exceeded 70%). The versatility
of this protocol was demonstrated by its compatibility with
a wide range of substituents, allowing for the practical
synthesis of target compounds with diverse substituents.
The developed synthesis methodology also facilitated the
scale-up of the process, with 15 grams of product obtained
in a single step. We explored the synthetic potential of the
obtained derivatives, resulting in the generation of products
containing carboxylic and amino groups, as well as amide,
hydrazide, and hydroxamic acid moieties within their
structures. The in silico prediction of physicochemical and
pharmacokinetic characteristics of the new synthesized
aminomethylcoumarins indicated their potential as
promising candidates for further refinement in the quest for
oral chemotherapeutic agents.
Experimental section
The solvents were purified according to the standard
procedures. All materials were purchased from commercial
sources and used without further purification. Reaction flow
and identity of obtained compounds was controlled with
TLC on Merck F254 plates using CHCl3 : MeOH (9:1, v/v)
system as eluents. The success rate was calculated as the
number of successful experiments divided by the total
number of experiments. NMR spectra were recorded on a
Mercury-400 spectrometer (spectrometer frequency for 1H:
400 MHz, 13C: 100 MHz) from DMSO-d6 solutions. The
TMS signal was used as an internal standard. Mass spectra
were recorded on Agilent 1100 LC/MSD instrument with
chemical ionization (CI). Melting points were determined
using a Kofler-type Leica Galen III micro hot stage
microscope. Elemental analyses for C, H, and N were
conducted using Perkin-Elmer C, H, N Analyzer, their
results were found to be in good agreement (± 0.2%) with
the calculated values.
The Experimental Section describes 25 compounds
selected in random manner, which corresponds to generally
accepted approaches in combinatorial chemistry (according
to ACS standards).
The starting diethylaminocoumarins 7{1-10} were
synthesized previously [6].
The molecular structures for the compound library 9
were introduced in simplified molecular-input lineentry
specification (SMILES) nomenclature into the SwissADME
web tool. The results of the calculations are presented in
Table S1-S2 (see Supplemental Materials).
General procedure for the preparation of amino-
methylcoumarins 9
To a solution of 7{1-10} (1 mmol) in 10 mL of i-PrOH,
3 mmol of the corresponding primary amine 8{1-10} was
added. The reaction mixture was refluxed for 2.5-3 hours
(the reaction progress was monitored by TLC). After the
completion of the reaction, the mixture was allowed to cool,
and the resulting precipitate was filtered. In cases where no
precipitate formed, the reaction mixture was evaporated,
and the residue was crystallized from EtOH. All products 9
were obtained as yellow-orange needle-shaped crystals.
8-((Benzylamino)methyl)-7-hydroxy-4-methyl-2H-chro-
men-2-one (9{1-1})
Yield: 543 mg, 88%. Mp 211-213 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.16 (1Н, br.s., ОН), 7.81 (1Н, d, J 7.6
Hz), 7.35 (2H, d, J 7.7 Hz), 7.26-7.29 (3Н, m), 6.98 (1H, d,
J 7.6 Hz), 6.17 (s, 1Н), 5.58 (m, NH), 4.02 (2Н, d, J 4.6
Hz), 3.89 (2Н, d, J 4.6 Hz), 2.46 (s, 3Н). 13C NMR (125
MHz, DMSO-d6) δ 161.4, 153.8, 155.4, 151.4, 141.3,
129.3×2, 126.5, 127.4, 128.1×2, 118.6, 112.8, 113.4, 112.1,
58.6, 44.2, 21.6. HPLC (CI) m/z (M+H)+ 296.4.
8-((sec-Butylamino)methyl)-7-hydroxy-4-methyl-2H-
chromen-2-one (9{1-3})
Yield: 486 mg, 73%. Mp 183-184 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.18 (1Н, br.s., ОН), 0.89 (3Н, d, J 3.8
Hz), 7.84 (1Н, d, J 7.6 Hz), 7.03 (1Н, d, J 7.6 Hz), 6.13
(1Н, s), 5.56 (m, NH), 4.06 (2Н, d, J 4.2 Hz), 2.76 (1Н, m),
2.48 (3Н, s), 1.54 (2Н, m), 1.10 (3Н, d, J 3.6 Hz). 13C NMR
(125 MHz, DMSO-d6) δ 161.6, 155.6, 154.6, 151.3, 126.2,
118.4, 112.8, 113.6, 112.3, 56.0, 42.1, 33.1, 22.4, 18.6,
12.6. HPLC (CI) m/z (M+H)+ 262.4.
E.K. Hlibov et al.
27
8-(((1-Cyclopropylbut-3-en-1-yl)amino)methyl)-7-hyd-
roxy-4-methyl-2H-chromen-2-one (9{1-6})
Yield: 538 mg, 83%. Mp 181-182 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.21 (1Н, br.s., ОН), 7.61 (1Н, d, J 7.6
Hz), 6.94 (1Н, d, J 7.6 Hz), 6.18 (1Н, s), 5.52 (m, NH), 4.9-
5.4 (m, 3Н), 4.21 (2Н, d, J 4.2 Hz), 2.51-2.53 (1Н, m), 2.46
(3Н, s), 2.11 (2Н, m), 1.54 (2Н, m), 1.04 (4Н, m), 0.22-0.29
(4Н, m). 13C NMR (125 MHz, DMSO-d6) δ 160.9, 153.7,
155.1, 151.2, 137.6, 125.8, 116.7, 112.8, 117.0, 113.3,
112.1, 66.4, 41.6, 39.4, 20.8, 18.2, 4.6×2. HPLC (CI) m/z
(M+H)+ 300.5.
8-((Cyclopentylamino)methyl)-6-ethyl-7-hydroxy-4-me-
thyl-2H-chromen-2-one (9{2-4})
Yield: 551 mg, 89%. Mp 188-189 °C. 1H NMR (400
MHz, DMSO-d6) δ 1.18 (3Н, d, J 3.6 Hz), 1.63-1.74 (8Н,
m), 2.48 (3Н, s), 2.51 (2Н, d, J 3.6 Hz), 2.67 (1Н, m), 3.88
(2Н, d, J 4.2 Hz), 5.64 (m, NH), 6.16 (1Н, s), 7.43 (1Н, s),
10.52 (1Н, br.s., ОН). 13C NMR (125 MHz, DMSO-d6) δ
161.4, 153.9, 152.6, 149.3, 123.8, 124.5, 116.1, 114.2,
113.1, 58.4, 42.1, 36.4×2, 23.7, 24.2×2, 21.6, 16.1. HPLC
(CI) m/z (M+H)+ 302.5.
6-Ethyl-7-hydroxy-4-methyl-8-((prop-2-yn-1-ylamino)-
methyl)-2H-chromen-2-one (9{2-5})
Yield: 460 mg, 74%. Mp 188-189 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.54 (1Н, br.s., ОН), 7.48 (1Н, s), 6.19
(1Н, s), 5.72 (m, NH), 3.84 (2Н, d, J 4.6 Hz), 3.38 (2Н, d, J
4.2 Hz), 3.16 (1Н, d, J 4.2 Hz), 2.52 (2Н, d, J 3.6 Hz), 2.46
(3Н, s), 1.16 (3Н, d, J 3.6 Hz). 13C NMR (125 MHz,
DMSO-d6) δ 161.2, 153.4, 152.3, 149.1, 124.6, 124.3,
116.8, 113.7, 113.1, 82.9, 74.6, 43.7, 41.3, 23.4, 21.2, 16.3.
HPLC (CI) m/z (M+H)+ 272.4.
6-Ethyl-7-hydroxy-4-methyl-8-(((1-(1-phenylcyclo-pro-
pyl)ethyl)amino)-methyl)-2H-chromen-2-one (9{2-7})
Yield: 546 mg, 84%. Mp 197-198 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.51 (1Н, br.s., ОН), 7.42 (2Н, m),
7.38 (1Н, s), 7.36 (2Н, m), 7.22 (1Н, m), 6.16 (1Н, s), 5.61
(m, NH), 4.21 (2Н, d, J 4.2 Hz), 3.40 (1Н, m), 3.10 (3Н, d,
J 3.8 Hz), 2.54 (2Н, d, J 3.6 Hz), 2.48 (3Н, s), 1.14-1.18
(2Н, m), 0.84-0.96 (4Н, m). 13C NMR (125 MHz, DMSO-
d6) δ 161.4, 153.7, 152.8, 151.6, 149.5, 129.8×2, 127.3,
7.4×2, 126.1×2, 124.9, 124.6, 116.4, 113.8, 113.1, 71.4,
15.6, 42.3, 32.3, 23.2, 21.4, 17.4. HPLC (CI) m/z (M+H)+
378.6.
8-((((3-Bromo-2,5-difluorophenyl)(cyclopropyl)methyl)-
amino)methyl)-7-hydroxy-4-methyl-6-propyl-2H-chromen-
2-one (9{3-8})
Yield: 564 mg, 91%. Mp 215-216 °C. 1H NMR (400
MHz, DMSO-d6) δ 0.42-0.48 (4Н, m), 1.08 (3Н, t, J 3.6
Hz), 1.14 (1Н, m), 1.74 (2Н, m), 2.51 (3Н, s), 2.68 (2Н, d, J
3.8 Hz), 3.86 (1Н, m), 4.12 (2Н, d, J 4.6 Hz), 5.56 (m, NH),
6.18 (1Н, s), 6.93 (1Н, s), 7.38 (1Н, s), 7.46 (2Н, s), 10.61
(1Н, br.s., ОН). 13C NMR (125 MHz, DMSO-d6) δ 4.3×2,
16.1, 19.4, 22.1, 26.7, 36.1, 41.8, 62.4, 110.1, 111.9, 113.2,
114.6, 116.7, 117.3, 120.9, 122.6, 125.3, 153.4, 154.0,
160.8, 161.2, 162.3. HPLC (CI) m/z (M+H)+ 493.5.
6-((Cyclopentylamino)methyl)-7-hydroxy-4,8-dimethyl-
2H-chromen-2-one (9{4-4})
Yield: 544mg, 84%. Mp 179-180 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.54 (1Н, s), 6.17
(1Н, s), 5.68 (m, NH), 3.86 (2Н, d, J 4.2 Hz), 2.66 (1Н, m),
2.46 (3Н, s), 2.18 (3Н, s), 1.62-1.74 (8Н, m). 13C NMR
(125 MHz, DMSO-d6) δ 160.9, 154.3, 153.4, 151.9, 125.1,
121.4, 118.6, 114.3, 113.1, 59.3, 46.9, 24.6×2, 36.1×2, 28.4,
21.6. HPLC (CI) m/z (M+H)+ 288.2.
tert-Butyl (2-(((7-hydroxy-4,8-dimethyl-2-oxo-2H-chro-
men-6-yl)methyl)-amino)ethyl)carbamate (9{4-10})
Yield: 436 mg, 72%. Mp 176-177 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.72 (1Н, br.s., ОН), 7.49 (1Н, s), 6.89
(1Н, d, J 4.4 Hz), 6.14 (1Н, s), 5.56 (m, NH), 3.84 (2Н, d, J
4.2 Hz), 3.32 (2Н, m), 2.69 (2Н, m), 2.49 (3Н, s), 2.19 (3Н,
s), 1.46 (9Н, s). 13C NMR (125 MHz, DMSO-d6) δ 160.9,
156.3, 153.4, 152.8, 151.6, 125.3, 121.8, 118.1, 113.8,
113.2, 80.4, 50.1, 49.3, 41.6, 31.2, 29.5, 29.3×2, 20.6.
HPLC (CI) m/z (M+H)+ 363.2.
6-((Benzylamino)methyl)-5-hydroxy-4,7-dimethyl-2H-
chromen-2-one (9{5-1})
Yield: 465 mg, 91%. Mp 192-193 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.64 (1Н, br.s., ОН), 7.46 (2H, m),
7.32 (3Н, m), 6.77 (1H, s), 6.13 (1Н, s), 5.68 (m, NH), 3.83
(2Н, d, J 4.3 Hz), 3.78 (2Н, d, J 4.2 Hz), 2.48 (3Н, s), 2.34
(3H, s). 13C NMR (125 MHz, DMSO-d6) δ 160.8, 158.3,
156.4, 151.1, 143.2, 138.5, 129.4×2, 128.3×2, 127.8, 121.7,
113.3, 112.1, 111.2, 59.1, 47.3, 25.1, 20.9. HPLC (CI) m/z
(M+H)+ 310.4.
7-Hydroxy-4-phenyl-8-((propylamino)methyl)-2H-chro-
men-2-one (9{6-2})
Yield: 476 mg, 73%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.59 (1Н, br.s., ОН), 7.69 (1Н, d, J 7.2
Hz), 7.38-7.41 (5Н, m), 6.93 (1Н, d, J 7.2 Hz), 6.19 (1Н, s),
4.58 (1Н, m, NH), 3.83 (2Н, d, J 3.4 Hz), 2.59 (2Н, m),
1.52 (2Н, m), 1.12 (3Н, d, J 3.2 Hz). 13C NMR (125 MHz,
DMSO-d6) δ 161.3, 166.1, 154.9, 138.4, 129.3×2, 128.9×2,
128.1, 126.7, 118.1, 113.9, 113.1, 112.6, 52.8, 51.7, 44.6,
25.1, 14.6. HPLC (CI) m/z (M+H)+ 310.2.
Methyl ((7-hydroxy-2-oxo-4-phenyl-2H-chromen-8-yl)-
methyl)glycinate (9{6-9})
Yield: 480 mg, 76%. Mp 183-184 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.71 (1Н, d, J 7.2
Hz), 7.36-7.38 (5Н, m), 6.94 (1Н, d, J 7.2 Hz), 6.17 (1Н, s),
4.66 (1Н, m, NH), 4.01 (3Н, s), 3.86 (2Н, d, J 3.4 Hz), 3.48
(2Н, d, J 3.4 Hz). 13C NMR (125 MHz, DMSO-d6) δ 170.3,
160.9, 156.2, 155.4, 151.6, 136.8, 129.9×2, 129.1×2, 128.3,
127.7, 118.3, 113.9, 113.1, 112.8, 52.8, 49.6, 43.9. HPLC
(CI) m/z (M+H)+ 340.1.
8-((Benzylamino)methyl)-6-ethyl-7-hydroxy-4-phenyl-
2H-chromen-2-one (9{7-1})
Yield: 546 mg, 85%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.63 (1Н, br.s., ОН), 7.53 (1Н, s),
7.38-7.41 (5Н, m), 7.31-7.34 (5Н, m), 6.19 (1Н, s), 5.38
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
28
(1Н, m, NH), 3.84 (2Н, d, J 3.4 Hz), 3.78 (2Н, d, J 3.4 Hz),
2.51 (2Н, d, J 3.2 Hz), 1.19 (3Н, d, J 3.2 Hz). 13C NMR
(125 MHz, DMSO-d6) δ 160.8, 156.4, 152.3, 148.7, 136.7,
141.4, 131.9, 131.2, 130.5×2, 129.1×2, 128.2, 127.9×2,
127.1, 126.3, 124.6, 113.4, 112.9, 116.6, 58.6, 24.6, 16.8.
HPLC (CI) m/z (M+H)+ 386.2.
7-Hydroxy-4-phenyl-8-((prop-2-yn-1-ylamino)methyl)-6-
propyl-2H-chromen-2-one (9{8-5})
Yield: 482 mg, 71%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.63 (1Н, br.s., ОН), 7.54 (1Н, s),
7.32-7.35 (5Н, m), 6.19 (s, 1Н), 4.89 (1Н, m, NH), 3.86
(2Н, d, J 3.4 Hz), 3.32 (2Н, s), 3.11 (1Н, s), 2.68 (2Н, d, J
3.2 Hz), 1.72 (2Н, m), 1.12 (3Н, d, J 3.2 Hz). 13C NMR
(125 MHz, DMSO-d6) δ 160.8, 156.8, 154.1, 149.3, 136.7,
129.1×2, 128.4×2, 127.2, 125.4, 118.1, 113.4, 112.9, 84.3,
74.6, 42.7, 40.9, 34.6, 26.3, 15.1. HPLC (CI) m/z (M+H)+
348.4.
6-((Benzylamino)methyl)-7-hydroxy-8-methyl-4-phenyl-
2H-chromen-2-one (9{9-1})
Yield: 564 mg, 92%. Mp 197-198 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.64 (1Н, br.s., ОН), 7.58 (1Н, s),
7.38-7.41 (5Н, m), 7.31-7.34 (5Н, m), 6.17 (s, 1Н), 5.14
(1Н, m, NH), 3.79 (4Н, m), 2.24 (3Н, s). 13C NMR (125
MHz, DMSO-d6) δ 161.3, 156.8, 153.7, 151.7, 141.3, 136.4,
130.2×2, 129.4×2, 128.8×2, 128.1, 127.9×2, 127.3, 125.3,
121.4, 118.6, 113.4, 112.8, 58.3, 56.1, 29.4. HPLC (CI) m/z
(M+H)+ 372.5.
6-(((1-Cyclopropylbut-3-en-1-yl)amino)methyl)-7-hyd-
roxy-8-methyl-4-phenyl-2H-chromen-2-one (9{9-6})
Yield: 514 mg, 72%. Mp 184-185 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.61 (1Н, br.s., ОН), 7.61 (1Н, s),
7.32-7.36 (5Н, m), 6.19 (s, 1Н), 5.26 (1Н, m, NH), 4.93-
5.13 (3Н, m), 3.89 (2Н, d, J 3.4 Hz), 2.48 (1Н, m), 2.21
(3Н, s), 1.96-1.98 (2Н, m), 1.12 (1Н, m), 0.86-0.89 (4Н,
m). 13C NMR (125 MHz, DMSO-d6) δ 160.9, 156.8, 153.4,
151.7, 137.3, 136.4, 129.3×2, 128.6×2, 128.1, 125.3, 121.3,
118.4, 116.7, 113.8, 113.1, 66.1, 48.3, 39.6, 29.3, 18.7,
6.4×2. HPLC (CI) m/z (M+H)+ 376.6.
7-Hydroxy-8-methyl-4-phenyl-6-(((1-(1-phenylcyclo-
propyl)ethyl)amino)-methyl)-2H-chromen-2-one (9{9-7})
Yield: 536 mg, 81%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.63 (1Н, br.s., ОН), 7.54 (1Н, s),
7.41-7.45 (5Н, m), 7.32-7.35 (5Н, m), 6.19 (1Н, s), 5.74
(1Н, m, NH), 4.18 (2Н, d, J 4.2 Hz), 3.21 (1Н, m), 2.24
(3Н, s), 1.15 (3Н, d, J 3.6 Hz), 0.86-0.98 (4Н, m). 13C NMR
(125 MHz, DMSO-d6) δ 160.9, 156.8, 153.4, 151.6, 150.3,
136.7, 129.8×2, 129.1×2, 128.3×2, 127.6, 125.9, 125.4×2,
124.8, 121.8, 118.6, 113.3, 112.8, 71.2, 44.3, 32.7, 26.4,
17.6, 7.6×2. HPLC (CI) m/z (M+H)+ 426.4.
tert-Butyl (2-(((7-hydroxy-8-methyl-2-oxo-4-phenyl-2H-
chromen-6-yl)-methyl)amino)ethyl)carbamate (9{9-10})
Yield: 490 mg, 73%. Mp 183-184 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.69 (1Н, br.s., ОН), 7.51 (1Н, s),
7.34-7.37 (5Н, m), 6.94 (1Н, d, J 4.4 Hz), 6.16 (1Н, s), 1.48
(9Н, s), 5.58 (1H, m, NH), 3.84 (2Н, d, J 4.2 Hz), 3.34 (2Н,
m), 2.68 (2Н, m), 2.21 (3Н, s). 13C NMR (125 MHz,
DMSO-d6) δ 160.9, 156.4, 153.5, 152.8, 151.9, 136.7,
128.8×2, 128.4×2, 127.7, 125.4, 121.6, 118.3, 113.9, 113.2,
80.6, 50.4, 49.6, 41.8, 31.4, 29.4, 29.1. HPLC (CI) m/z
(M+H)+ 425.6.
5-Hydroxy-7-methyl-4-phenyl-6-((propylamino)methyl)-
2H-chromen-2-one (9{10-2})
Yield: 481 mg, 71%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.53 (1Н, br.s., ОН), 7.39-7.42 (5Н,
m), 6.72 (1Н, s), 6.21 (1Н, s), 4.58 (1Н, m, NH), 3.84 (2Н,
d, J 3.4 Hz), 2.61 (2Н, m), 2.36 (3Н, s), 1.54 (2Н, m), 1.14
(3Н, d, J 3.2 Hz). 13C NMR (125 MHz, DMSO-d6) δ 172.1,
170.3, 163.0, 156.5, 155.7, 145.0, 134.7, 131.3, 126.2,
125.9, 125.9, 125.4, 123.9, 123.6, 121.7, 119.2, 109.6, 69.7,
67.5, 58.4, 39.2, 28.0, 27.3. HPLC (CI) m/z (M+H)+ 324.4.
6-((Cyclopentylamino)methyl)-5-hydroxy-7-methyl-4-
phenyl-2H-chromen-2-one (9{10-4})
Yield: 474 mg, 79%. Mp 178-179 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.54 (1Н, s),
7.38-7.41 (5Н, m), 6.17 (1Н, s), 5.68 (1H, m, NH), 3.86
(2Н, d, J 4.2 Hz), 2.66 (1Н, m), 2.46 (3Н, s), 2.18 (3Н, s),
1.62-1.74 (8Н, m). 13C NMR (125 MHz, DMSO-d6) δ
172.1, 170.3, 163.0, 156.5, 155.7, 145.0, 134.7, 131.3,
126.2, 125.9, 125.9, 125.4, 123.9, 123.6, 121.7, 119.2,
109.6, 69.7, 67.5, 58.4, 39.2, 28.0, 27.3. HPLC (CI) m/z
(M+H)+ 350.5.
((7-Hydroxy-2-oxo-4-phenyl-2H-chromen-8-yl)methyl)-
glycine (10)
Compound 9{6-9} (1 equiv.) was dissolved in i-PrOH,
and a 1M solution of NaOH (1.2 equiv.) was added. The
mixture was then stirred at 50 °C for 4 hours. After cooling,
reaction mixture acidified to pH 3-4 with concentrated HCl.
The resulting precipitate was filtered and crystallized from
i-PrOH. Yield: 276 mg, 71%. Mp 173-174 °C. 1H NMR
(400 MHz, DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.71 (1Н, d,
J 7.2 Hz), 7.36-7.38 (5Н, m), 6.94 (1Н, d, J 7.2 Hz), 6.17
(1Н, s), 4.66 (1Н, m, NH), 4.01 (3Н, s), 3.86 (2Н, d, J 3.4
Hz), 3.48 (2Н, d, J 3.4 Hz). 13C NMR (125 MHz, DMSO-
d6) δ 172.1, 170.3, 163.0, 156.5, 155.7, 145.0, 134.7, 131.3,
126.2, 125.9, 125.9, 125.4, 123.9, 123.6, 121.7, 119.2,
109.6, 69.7, 67.5, 58.4, 39.2, 28.0, 27.3. HPLC (CI) m/z
(M+H)+ 326.3.
2-(((7-Hydroxy-2-oxo-4-phenyl-2H-chromen-8-yl)-me-
thyl)amino)-N-iso-propylacetamide (11)
A mixture of ester 9{6-9} (1.0 mmol), isopropylamine
(5.0 mmol), and DBU (0.2 mmol) was stirred at room
temperature for 48 hours. Ethyl acetate (15 mL) was added,
and the organic phase was washed with saturated aqueous
NH4Cl solution (4 × 15 mL), dried over Na2SO4,
evaporated, and the residue was crystallized from acetone.
Yield: 283 mg, 75%. Mp 181-182 °C. 1H NMR (400 MHz,
DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.71 (1Н, d, J 7.2 Hz),
7.36-7.38 (5Н, m), 6.94 (1Н, d, J 7.2 Hz), 4.66 (1Н, m,
NH), 4.01 (3Н, s), 6.17 (1Н, s), 3.86 (2Н, d, J 3.4 Hz), 3.48
(2Н, d, J 3.4 Hz). 13C NMR (125 MHz, DMSO-d6) δ 172.1,
E.K. Hlibov et al.
29
170.3, 163.0, 156.5, 155.7, 145.0, 134.7, 131.3, 126.2,
125.9, 125.9, 125.4, 123.9, 123.6, 121.7, 119.2, 109.6, 69.7,
67.5, 58.4, 39.2, 28.0, 27.3. HPLC (CI) m/z (M+H)+ 367.5.
2-(((7-Hydroxy-2-oxo-4-phenyl-2H-chromen-8-yl)-me-
thyl)amino)aceto-hydrazide (12)
Ester 9{6-9} (1 mmol) was dissolved in methanol (20
mL), and hydrazine hydrate (1.5 mmol) was added. The
mixture was allowed to stand overnight at 25 °C. The
resulting product was separated, collected by suction
filtration, washed with methanol, and recrystallized from
acetone. Yield: 296 mg, 83%. Mp 175-176 °C. 1H NMR
(400 MHz, DMSO-d6) δ 10.56 (1Н, br.s., ОН), 7.71 (1Н, d,
J 7.2 Hz), 7.36-7.38 (5Н, m), 6.94 (1Н, d, J 7.2 Hz), 6.17
(1Н, s), 4.66 (1Н, m, NH), 4.01 (3Н, s), 3.86 (2Н, d, J 3.4
Hz), 3.48 (2Н, d, J 3.4 Hz). 13C NMR (125 MHz, DMSO-
d6) δ 172.1, 170.3, 163.0, 156.5, 155.7, 145.0, 134.7, 131.3,
126.2, 125.9, 125.9, 125.4, 123.9, 123.6, 121.7, 119.2,
109.6, 69.7, 67.5, 58.4, 39.2, 28.0, 27.3. HPLC (CI) m/z
(M+H)+ 340.2.
N-hydroxy-2-(((7-hydroxy-2-oxo-4-phenyl-2H-chromen-
8-yl)methyl)-amino)acetamide (13)
To a mixture of ester 9{6-9} (1 mmol) and NH2OH·HCl
(0.204 g, 3 mmol) in H2O (3 mL) at 0-5 °C, a solution of
KOH (0.392 g, 7 mmol) in H2O (1 mL) was added dropwise
with stirring. The reaction mixture was stirred at room
temperature for 1-4 hours, then acidified to pH 5-6 with
concentrated HCl. The resulting precipitate was collected
by filtration, washed with water, and dried to yield product
13. Yield: 265 mg, 79%. Mp 178-179 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.68 (br. s, 2H), 10.03 (br. s, 1H), 7.58
(d, J 6.8 Hz, 1H), 7.36-7.39 (m, 2H), 7.32-7.34 (m, 3H),
6.93 (d, J 6.8 Hz, 1H), 6.19 (s, 1H), 4.75-4.76 (m, 1H),
3.81-3.83 (d, J 5.6 Hz, 2H), 3.17-3.19 (d, J 5.6 Hz, 2H). 13C
NMR (125 MHz, DMSO-d6) δ 168.2, 160.6, 156.7, 155.8,
155.3, 151.4, 136.3, 129.5×2, 128.7×2, 128.1, 127.3, 117.3,
113.6, 112.9, 49.7, 42.1. HPLC (CI) m/z (M+H)+ 341.4.
6-(((2-Aminoethyl)amino)methyl)-7-hydroxy-8-methyl-4-
phenyl-2H-chromen-2-one (14)
To a solution of ester 9{6-9} (1 mmol) in CH2Cl2 (10 mL)
was added TFA (2 mL). The reaction mixture was stirred
for 2h at room temperature, after which time the solvents
were removed in vacuo. The resulting material was
triturated with MTBE to provide the product as an white
solid. Yield: 216 mg, 87%. Mp 186-187 °C. 1H NMR (400
MHz, DMSO-d6) δ 10.25 (br. s, 1H), 7.56 (s, 1H), 7.40-7.42
(m, 2H), 7.36-7.37 (m, 3H), 6.24 (s, 1H), 5.63-5.66 (m,
2H), 4.54-4.56 (m, 1H), 3.86-3.88 (d, J 5.6 Hz, 2H), 2.66-
2.68 (m, 2H), 2.53-2.55 (m, 2H). 13C NMR (125 MHz,
DMSO-d6) δ 160.9, 155.7, 153.2, 150.6, 136.1, 128.6×2,
128.1×2, 127.1, 125.6, 121.7, 118.3, 113.1, 112.3, 52.7,
49.3, 42.4, 29.6. HPLC (CI) m/z (M+H)+ 325.6
Notes
Acknowledgments and finances. The work was funded
by Ministry of Education and Science of Ukraine (Grant
No. 0122U001962 (22BF037-02). The authors thank all
brave defenders of Ukraine who made this publication
possible.
The authors declare no conflict of interest.
References
1. Roman, G. Mannich bases in medicinal chemistry and drug design.
Eur. J. Med. Chem. 2015, 89, 743-816.
2. Rao, A.K.; Raju, M.S.; Raju, K.M. Synthesis and antimicrobial
activity of some new Mannich bases derived from 7-hydroxy-4-
phenylcoumarin J. Ind. Chem. Soc. 1981. 58, 1021-1023.
3. US Patent No 6020364. Compounds and method of treating
psychosis and schizophrenia / Connor, D.T.; Johnson, S.J.; Kesten,
S.R.; Miller, S.R.; Unangst, P.C.; Wise, L.D. Patent appl. No
09/255120 22.02.1999. Publ. 01.02.2000.
4. Babin, V.V.; Shibanov, G.N.; Isakova, L.I.; Palchkov, V.A.;
Morozovskij, V.V.; Burij, V.S.; Kuznetsova, M.A.; Khlistovskaya,
S.G.; Shepelev, V.I.; Guzenko, E.G. Plant growth regulator. Sev
Kavkazskij NII Fitopatolog. 23.03.1982, SU 914017.
5. Mizukami, Sh.; Okada, S.; Kimura, S.; Kikuchi, K. Design and
Synthesis of Coumarin-Based Zn2+ Probes for Ratiometric
Fluorescence Imaging. Inorg. Chem. 2009, 48, 7630-7638.
6. Glibov, E.K.; Moskvina, V.S.; Khilya, V.P. Coumarins mannich
bases in acylation reactions. Ukr. Chem. J. 2018, 84, 93-101
(in Ukrainian).
7. Shokol, T.V.; Moskvina, V.S.; Glebov, E.K.; Khilya, V.P.
Neoflavonoid Angelicin Derivatives. Chem. Nat. Comp. 2019, 55,
716-718.
8. Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to
evaluate pharmacokinetics, drug-likeness and medicinal chemistry
friendliness of small molecules. Sci. Rep. 2017, 7, 42717.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
30
Дослідження амінометилкумаринів: універсальний синтез, структурна
різноманітність, прогнозування ADME параметрів
Є.К. Глібов1, В.С. Москвіна1,2*, Є.С. Малець2, В.П. Хиля1
1 Київський національний університет імені Тараса Шевченка, Київ, Україна
2 Інститут біорганічної хімії та нафтохімії імені В.П. Кухаря НАН України, Київ, Україна
Резюме: В роботі розроблено ефективний метод синтезу бібліотеки структурно-різноманітних амінометилкумаринів при взаємодії основ Манніха
на основі кумаринів з первинними амінами. Розроблена процедура амінування продемонструвала універсальність підходу та його сумісність з
різними замісниками. Реакції завершувались утворенням продуктів з високими виходами та проходили за короткий час, що дозволило
масштабувати розроблену методику. На основі отриманих похідних продемонстрована можливість проведення структурної модифікації , що
дозволило отримати похідні з різноманітними функціональними групами, зокрема карбоксильною, аміно-, амідною, гідразидною та
гідроксамовою групами. Проведення in silico досліджень ADME параметрів підтвердило потенціал отриманих амінометилкумаринів як
перспективних кандидатів для подальшої оптимізації при розробці лікарських засобів.
Ключові слова: кумарин; амін; амінометилкумарин; амінування; ADME.
|
| id | oai:ojs2.bioorganica.com.ua:article-74 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:17Z |
| publishDate | 2023 |
| 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/a9/b6eb50846f94ea3cadb683e711bb3da9.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-742026-07-19T14:56:54Z Exploring aminomethylcoumarins: versatile synthesis, structural diversity, and ADME prediction Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів Hlibov, Eugen K. Moskvina, Viktoriia S. Malets, Yehor S. Khilya, Volodymyr P. coumarin amine aminomethylcoumarin amination ADME кумарин амін амінометилкумарин амінуванн ADME This research presents a highly efficient method for synthesizing diverse aminomethylcoumarin libraries through the interaction of Mannich bases of coumarins and primary amines. The developed amination process demonstrated versatility and compatibility with various substituents. Reactions were completed within short timeframes, yielding high-purity products with substantial yields, as well as facilitating the scale-up of the process. The synthesized derivatives exhibited structural diversity, incorporating carboxylic and amino groups, as well as amide, hydrazide, and hydroxamic acid moieties. In silico ADME predictions highlighted the potential of these aminomethylcoumarins as promising candidates for further optimization in the development of oral chemotherapeutic agents В роботі розроблено ефективний метод синтезу бібліотеки структурно-різноманітних амінометилкумаринів при взаємодії основ Манніха на основі кумаринів з первинними амінами. Розроблена процедура амінування продемонструвала універсальність підходу та його сумісність з різними замісниками. Реакції завершувались утворенням продуктів з високими виходами та проходили за короткий час, що дозволило масштабувати розроблену методику. На основі отриманих похідних продемонстрована можливість проведення структурної модифікації, що дозволило отримати похідні з різноманітними функціональними групами, зокрема карбоксильною, аміно-, амідною, гідразидною та гідроксамовою групами. Проведення in silico досліджень ADME параметрів підтвердило потенціал отриманих амінометилкумаринів як перспективних кандидатів для подальшої оптимізації при розробці лікарських засобів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-12-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/74 10.15407/bioorganica2023.02.022 Ukrainica Bioorganica Acta; Vol. 18 No. 2 (2023): Ukrainica Bioorganica Acta; 22-30 Ukrainica Bioorganica Acta; Том 18 № 2 (2023): Ukrainica Bioorganica Acta; 22-30 1814-9766 1814-9758 10.15407/bioorganica2023.02 en https://bioorganica.com.ua/index.php/journal/article/view/74/74 https://bioorganica.com.ua/index.php/journal/article/view/74/75 Copyright (c) 2023 Eugen K. Hlibov, Viktoriia S. Moskvina, Yehor S. Malets, Volodymyr P. Khilya https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | кумарин амін амінометилкумарин амінуванн ADME Hlibov, Eugen K. Moskvina, Viktoriia S. Malets, Yehor S. Khilya, Volodymyr P. Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title | Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title_alt | Exploring aminomethylcoumarins: versatile synthesis, structural diversity, and ADME prediction |
| title_full | Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title_fullStr | Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title_full_unstemmed | Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title_short | Дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування ADME параметрів |
| title_sort | дослідження амінометилкумаринів: універсальний синтез, структурна різноманітність, прогнозування adme параметрів |
| topic | кумарин амін амінометилкумарин амінуванн ADME |
| topic_facet | coumarin amine aminomethylcoumarin amination ADME кумарин амін амінометилкумарин амінуванн ADME |
| url | https://bioorganica.com.ua/index.php/journal/article/view/74 |
| work_keys_str_mv | AT hliboveugenk exploringaminomethylcoumarinsversatilesynthesisstructuraldiversityandadmeprediction AT moskvinaviktoriias exploringaminomethylcoumarinsversatilesynthesisstructuraldiversityandadmeprediction AT maletsyehors exploringaminomethylcoumarinsversatilesynthesisstructuraldiversityandadmeprediction AT khilyavolodymyrp exploringaminomethylcoumarinsversatilesynthesisstructuraldiversityandadmeprediction AT hliboveugenk doslídžennâamínometilkumarinívuníversalʹnijsintezstrukturnaríznomanítnístʹprognozuvannâadmeparametrív AT moskvinaviktoriias doslídžennâamínometilkumarinívuníversalʹnijsintezstrukturnaríznomanítnístʹprognozuvannâadmeparametrív AT maletsyehors doslídžennâamínometilkumarinívuníversalʹnijsintezstrukturnaríznomanítnístʹprognozuvannâadmeparametrív AT khilyavolodymyrp doslídžennâamínometilkumarinívuníversalʹnijsintezstrukturnaríznomanítnístʹprognozuvannâadmeparametrív |