Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

Article abstract of DOI:10.3762/bjoc.15.126

Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner-Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combination of

Full text of DOI:10.3762/bjoc.15.126

Doebner-type pyrazolopyridine carboxylic acids in an
Ugi four-component reaction
Maryna V. Murlykina1,2,3, Oleksandr V. Kolomiets1,2, Maryna M. Kornet4,
Yana I. Sakhno1, Sergey M. Desenko1,2, Victoriya V. Dyakonenko1,
Svetlana V. Shishkina1,2, Oleksandr A. Brazhko4, Vladimir I. Musatov1,
Alexander V. Tsygankov5, Erik V. Van der Eycken3,6 and Valentyn A. Chebanov*1,2,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1281–1288.
1Division of Chemistry of Functional Materials, State Scientific
doi:10.3762/bjoc.15.126
Institution “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Nauky Ave., 60, 61072, Kharkiv, Ukraine,
Received: 03 March 2019
Accepted: 17 May 2019
Published: 12 June 2019
2Faculty of Chemistry, V. N. Karazin Kharkiv National University,
Svobody sq., 4, 61077, Kharkiv, Ukraine, 3Laboratory for Organic &
Microwave-Assisted Chemistry (LOMAC), KU Leuven,
Celestijnenlaan 200F, B-3001, Leuven, Belgium, 4Laboratory of
Biotechnology of Physiologically Active Substances, Zaporizhzhia
National University, Zhukovsky str., 66, Zaporizhzhya, Ukraine,
This article is part of the thematic issue "Multicomponent reactions III".
Guest Editor: T. J. J. Müller
69600, 5National Technical University “Kharkiv Polytechnic Institute”,
Kyrpychova str., 2, 61002, Kharkiv, Ukraine and 6Peoples' Friendship
University of Russia, Miklukho-Maklya str., 6, 117198, Moscow,
Russia
© 2019 Murlykina et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Valentyn A. Chebanov* - chebanov@isc.kh.ua
*
Corresponding author
Keywords:
antibacterial activity; Doebner reaction; pyrazolo[3,4-b]pyridine
carboxylic acids; Ugi reaction
Abstract
Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a
Doebner–Ugi multicomponent reaction sequence in a convergent and versatile manner using diversity generation strategies: combi-
nation of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores
pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily available starting materials in-
cluding scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity.
Introduction
Modern medicinal chemistry is faced with the task of quick and Therefore, in turn, organic chemistry has to solve an equally im-
effective screening a variety of organic molecules in order to portant task of the rapid generating focused libraries of drug-
identify new active pharmaceutical ingredients among them. like compounds characterized by several important features,
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e.g., molecular complexity and diversity at different levels, high broad spectrum of biological activity: β-secretase (BACE1)
variability and easy accessibility from relatively simple inhibitory activity [15]; inducing apoptosis in colorectal cancer
reagents. These challenges can be overcome by using multi- cells [16]; antimalarial activity against a chloroquine (CQ) non-
component reactions (MCRs) but also other strategies can be resistant Plasmodium falciparum 3D7 strain [17]; antagonists of
applied in addition to MCRs for generating diversity, e.g., p53-Mdm2 interaction [18]; antiproliferative activity in the
build/couple/pair- (BCP), single reactant replacement- (SRR), human solid tumor cell lines A549 (lung), HBL-100 (breast),
modular reaction sequences- (MRS), conditions-based diver- HeLa (cervix), SW1573 (lung), T-47D (breast), and
gence- (CBD) and combination of multicomponent reactions WiDr(colon) [19]; cyclophilin A inhibitory activity for the treat-
(
MCR2) strategies (for more details and examples see [1-3] and ment of hepatitis C virus infections [20], etc.
Scheme 1). A synergetic application of several diversity-
oriented synthesis (DOS) instruments allows an effective deco- Among the variety of heterocyclic acids used in Ugi-4CR [15-
ration of the privileged scaffolds for creating collections of 19,21-42] only a few of them in addition to bearing a simple
unique, highly potent bioactive compounds [4,5].
pharmacophore core (group I, Scheme 1) are also characterized
by the complexity and diversity of the skeleton itself gained
The pyrazolopyridine scaffold can be regarded as a privileged through multi-step transformations (group II) [18,19,34-36] or
motif as it exhibits various biological actions: antiproliferative allow for generating additional diversity through post-cycliza-
[
6-9], antimicrobial [10,11], anxiolytic [12], analgesic [13], tion reactions (group III) [18,35-42]. Meanwhile the complexi-
hypnotic [13], antiviral [13], anti-HIV [13] activities, etc. ty of the acid skeleton can be achieved by MCR. Several publi-
Soural et al. [14] explored different data and showed the rele- cations illustrated this principle: synthesis of heterocyclic acids
vance of compounds composed of two or more heterocyclic [26,43] or enols [44] in a first multicomponent step, followed
rings for drug discovery. The target products containing a by subjecting them to a subsequent Ugi process, thus, applying
heterocyclic core bound to a peptide-like chain also showed a the MCR2 approach (group IV, Scheme 1).
Scheme 1: An overview of heterocyclic acids used in the Ugi reaction.
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Actually, there was no example for the combined application of types of structurally complex products from a limited number of
Doebner and Ugi-type MCRs although the former condensation relatively simple starting materials just by varying the reaction
easily affords the azoloazine pharmacophore that is able to conditions (temperature, solvent–catalyst system, activation
participate as an acid component in the latter reaction. It should method, forced realization of one of the cascades of multicom-
be noted, that Cowen et al. [6] reported N-substituted-1H-pyra- ponent treatment). We decided to use this strategy and to
zolo[3,4-b]pyridine-4-carboxamides being SMYD2 inhibitors synthetize heteroaromatic carboxylic acids 4 and 7 starting from
(
an oncogenic methyltransferase that represses the functional the same reactants but using a multicomponent and a sequential
activity of the tumor suppressor proteins p53 and RB); the simi- protocol. We chose these heterocyclic acids to be subjected to
lar structures can be obtained using the methodology of sequen- the further Ugi transformation based on their higher stability
tial Doebner- and Ugi-type MCRs.
compared to other azoloazine carboxylic acids (e.g., tetrahydro-
49,50] and dihydroazoloazines that may undergo oxidation
[
In the present work we combined several diversity-oriented syn- during the Ugi 4CR) and as they do not contain additional func-
thetic (DOS) approaches. First, by using CBD and MCR strate- tional groups that may influence the subsequent Ugi reaction
gies in a Doebner-type reaction we synthesized pyrazolopyri- (e.g., hydroxy group in tetrahydro- [46,51], dihydro- [51] or ar-
dine carboxylic acids which were subsequently applied in the omatic derivatives [51]).
Ugi reaction, thus, combining two multicomponent procedures.
Two different reaction pathways were applied based on known
Results and Discussion
synthetic procedures (Scheme 2): the three-component reaction
As mentioned above, the diversification of the privileged scaf- between pyruvic acid (1), aromatic aldehydes 2a,b and
fold using different DOS strategies allowed to significantly 5-amino-3-methylpyrazole (3) (HOAc, Δ, 30 min) [45] and a
increase the diversity of the final products. In our study pyra- two-component condensation of the preliminary synthetized
zolo[3,4-b]pyridine scaffold was chosen as a privileged one and 4-(4-methoxyphenyl)-2-oxobut-3-enoic acid (5b) [52,53] with
based on this, we combined two MCRs: the previously well- 5-amino-3-methyl-N-phenylpyrazole (6) (HOAc, Δ, 5 h). As a
studied three-component Doebner-type condensation of result, two different types of pyrazolo[3,4-b]pyridines contain-
aminopyrazoles, aldehydes and pyruvic acid [45,46] with the ing the carboxylic group either at C4 position (compounds 4a,b)
isocyanide-based four-component Ugi reaction.
or at the C6 position (compound 7b) were synthetized
Scheme 2). We modified the earlier described methodology for
(
As we have shown before [47,48] the application of the CBD the synthesis of pyrazolo[3,4-b]pyridine-6-carboxylic acid (7b)
strategy to multicomponent Doebner-type condensations in- [45]: the solvent was changed from DMF to HOAc and the
volving aminoazoles allowed the synthesis of several chemo- reaction time was increased from 30 min to 5 hours. Despite of
Scheme 2: Synthesis of pyrazolopyridine carboxylic acids 4 [45] and 7 [45] in Doebner-type reaction.
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Beilstein J. Org. Chem. 2019, 15, 1281–1288.
the longer reaction time the whole procedure became more effi- structures 11 and 12 was made by X-ray analysis for the struc-
cient due to the easier work-up stage as well as due to avoiding ture 11n (Figure 1).
the formation of impurities of the dihydropyrazolo[3,4-
b]pyridines.
Thus, starting from the same set of reactants two different types
of heterocyclic acids 4 and 7 containing two diversity points
were obtained. Afterwards compounds 4a,b were introduced
into the Ugi four-component reaction to create 3 additional
points of diversity. However, due to the low solubility of the
pyrazolopyridine acids 4a,b under the literature standard reac-
tion conditions for the Ugi transformation (stirring in methanol
at rt and similar procedures) the reaction did not take place.
Under these conditions, the pyrazolopyridine carboxylic acids
4
a,b did not dissolve and remained unreacted even after
prolonged stirring and heating. Consequently, the solvent was
changed to DMF that allowed us to isolate the Ugi products 11
after long stirring (48–72 h) at rt. It must be noted, that in many
cases the pyrazolopyridine acids 4a,b did not fully dissolve in
DMF at rt that resulted in considerably decreased yields.
In an attempt to increase the yield of the products the reaction
was repeated at different temperatures ranging from rt to 80 °C
and it was found that heating at 70 °C afforded the best results.
At this temperature not only the yields increased but also the
reaction time could be reduced to 48 hours. When applying a
solvent mixture of DMF and MeOH the yields further in-
Figure 1: Molecular structure of N-(2-(tert-butylamino)-1-(4-chloro-
phenyl)-2-oxoethyl)-6-(4-methoxyphenyl)-3-methyl-N-p-tolyl-1H-pyra-
zolo[3,4-b]pyridine-4-carboxamide (11n) according to X-ray diffraction
data. Non-hydrogen atoms are presented as thermal ellipsoids with
50% probability.
creased, with the best results obtained using a ratio of 1:2. We Antibacterial activity
presume that methanol provides the optimal acidity to the reac- It is worth mentioning that the modification of the pyrazolo[3,4-
tion medium needed for successful protonation of the intermedi- b]pyridine scaffold through Ugi reaction allowed not only to
ate azomethine, formed between the aromatic aldehyde 8 and introduce three additional diversity points but also to increase
aniline 9, to the corresponding iminium cation and its further significantly the solubility of the products 11 and 12 compared
transformation involving carboxylic acid 4 and isocyanide 10. to the starting acids 4 and 7. Compounds 11 are soluble in
MeOH, EtOH, iPrOH, acetone, EtOAc, CH3CN, DCM, CHCl3
As a result, we developed an efficient procedure for the synthe- and compounds 12 are soluble in acetone, CH3CN, DCM,
sis of compounds 11a–q through reaction of aromatic alde- CHCl3 and partially soluble when heated in EtOAc, MeOH,
hydes 8a–d, amines 9a–f, tert-butylisocyanide (10) and EtOH, showing the advantages of this protocol for investigat-
heteroaromatic carboxylic acids 4a,b in a 2:1 mixture of metha- ing the activity of pyrazolo[3,4-b]pyridine moiety in biological
nol and DMF at 70 °C. Following this procedure, a small library experiments. Particularly, the evaluation of the antibacterial ac-
of seventeen Ugi products was obtained (Table 1).
tivity of the small library of new compounds 11 and 12 was
carried out.
Next, we applied pyrazolo[3,4-b]pyridine-6-carboxylic acid 7b
with another positional location of the substituents in compari- We next screened some selected compounds for their antibacte-
son with compounds 4 in the Ugi reaction with the same rial activity (Table 2, Supporting Information File 1) against the
reagents 8, 9 and 10 using the optimized procedure (Table 1). reference bacterial strains Bacillus subtilis (strain 1211),
This expanded the library of Ugi products by adding com- Staphylococcus aureus (strain 2231) (gram-positive) and
pounds 12a–f.
Escherichia coli (strain 1257), Pseudomonas aeruginosa (strain
111) (gram-negative).
1
The purity and structures of the obtained heterocyclic products
were established by means of NMR spectroscopy, mass spec- Generally, the compounds were found to be less active than
trometry, and elemental analysis. The final assignment of the nitroxoline being the reference substance. The results obtained
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Beilstein J. Org. Chem. 2019, 15, 1281–1288.
Table 1: Synthesis of compounds 11 and 12 by combination of Doebner and Ugi-type MCRs.
Starting materials
Products
Entry
Acid
R1
8
R2
9
R3
11,12
yield, %
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
7b
7b
7b
7b
7b
7b
H
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
8c
8a
8a
8b
8b
8d
8d
H
H
9a
9b
9c
9d
9e
9f
H
11a
11b
11c
11d
11e
11f
39
40
30
28
30
42
43
53
37
37
35
42
44
49
34
37
20
50
51
34
36
46
25
H
4-CH3
4-Br
H
H
H
H
2-CH3O
3-CH3O
4-CH3O
H
H
H
H
H
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
H
9a
9b
9c
9d
9e
9f
11g
11h
11i
H
4-CH3
4-Br
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
2-CH3O
3-CH3O
4-CH3O
H
11j
H
11k
11l
H
Cl
9a
9b
9c
9f
11m
11n
11o
11p
11q
12a
12b
12c
12d
12e
12f
Cl
4-CH3
4-Br
Cl
Cl
4-CH3O
H
NO2
H
9a
9a
9b
9a
9b
9a
9b
H
H
4-CH3
H
Cl
Cl
4-CH3
H
CH3O
CH3O
4-CH3
indicate that some substances inhibited the growth of the test coli strain. The gram-negative bacterium P. aeruginosa showed
microorganisms demonstrating weak antimicrobial effect resistance to all compounds tested in the given concentration
(
Table 2). The growth of gram-positive bacteria (strains of range. The observed low level of antibacterial activity of
S. aureus and B. subtilis) was inhibited in a more effective way. the synthesized heterocycles is a good prerequisite for
Particularly, compound 11b inhibited the growth of B. subtilis screening them for other types of activity, e.g., anticancer,
at a concentration of 125 mg/L. A bacteriostatic activity against antidiabetic, etc., because in these cases a negative
S. aureus was observed only at the higher concentrations of 250 influence on the microflora of the organism would be de-
and 500 mg/L. The same situation was found for the tested E. creased [54].
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Beilstein J. Org. Chem. 2019, 15, 1281–1288.
Table 2: Antibacterial activity results.
Entry
Compound
MICa/MBCb,
mg/L
Strains of test cultures
Escherichia coli
Pseudomonas
aeruginosa
Staphylococcus Bacillus subtilis
aureus
1
2
3
4
5
6
7
11a
11b
MIC
MBC
MIC
250
–
–c
–
250
250
–
–
500
–
–
500
125
–
MBC
MIC
–
–
11f
–
–
–
–
MBC
MIC
–
–
–
–
11g
250
–
–
–
–
250
–
MBC
MIC
–
11l
–
–
–
–
MBC
MIC
–
–
–
–
11m
500
–
–
250
–
250
–
MBC
MIC
–
nitroxoline
15.6
15.6
62.5
62.5
31.25
31.25
1.9
1.9
MBC
aMIC – minimum inhibitory concentration; bMBC – minimum bactericidal concentration; cthe substance at concentration ≤ 500 mg/L does not inhibit
culture growth.
Conclusion
Acknowledgements
In summary, two multicomponent reactions of Doebner and V. Chebanov was supported by a scholarship of KU Leuven
Ugi-type were combined in a convergent and versatile manner (SF/14/006). M. Murlykina was supported by an Erasmus
giving substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyra- Mundus scholarship and by the Grant of National Academy of
zolo[3,4-b]pyridine-6-carboxamides. The use of a conditions- Sciences of Ukraine for young scientists’ research laboratories
based divergence strategy allowed introducing the scaffold and groups. The authors also thank the National Academy of
diversity and obtaining two types of structures with different Sciences of Ukraine for financial support in the frame of the
orientation of substituents (containing a carboxylic group either projects "Creation of modern bases for obtaining and analyzing
at C4 or C6 position of the pyrazolopyridine core). The optimal substances and components of materials for pharmaceutical
methodology for the synthesis of target products was elabo- purposes" (0119U100727) and "Investigation of structural fea-
rated (mixture of methanol and DMF (2:1) and heating to tures of nitrogen containing heterocycles with potential biologi-
7
0 °C) and a small focused library of 23 Ugi products was cal activity" (0119U100716). We thank Dr. E. Muravyouva for
created. The target compounds containing two pharmacophore measuring the part of LC–MS spectra.
pyrazolopyridine and peptidomimetic moieties were screened
for their antibacterial activity and demonstrated weak antibacte- ORCID® iDs
rial effect.
Maryna V. Murlykina - https://orcid.org/0000-0002-0019-5237
Maryna M. Kornet - https://orcid.org/0000-0002-9251-5700
Sergey M. Desenko - https://orcid.org/0000-0001-8914-3232
Alexander V. Tsygankov - https://orcid.org/0000-0001-5298-8450
Valentyn A. Chebanov - https://orcid.org/0000-0001-7564-778X
Supporting Information
Supporting Information File 1
Experimental and analytical data.
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