New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

Article abstract of DOI:10.3762/bjoc.13.104

The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an amine component in Ugi and Groebke-Blackburn-Bienaymé multicomponent reactions. The first example of an application of aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke-Blackburn-Bienaymé cyclocondensation are established and discussed. The heterocycles obtained were evaluated for their antibacterial activity and several of them demonstrated a weak antimicrobial effect, but for most of the compounds a 30-50% increase in biomass of Gram-positive strains (mainly B. subtilis) compared to control was observed.

Full text of DOI:10.3762/bjoc.13.104

New tricks of well-known aminoazoles in isocyanide-based
multicomponent reactions and antibacterial activity of the
compounds synthesized
Maryna V. Murlykina1,2, Maryna N. Kornet3, Sergey M. Desenko1,4,
Svetlana V. Shishkina1,4, Oleg V. Shishkin1, Aleksander A. Brazhko3,
Vladimir I. Musatov1, Erik V. Van der Eycken2 and Valentin A. Chebanov*1,2,4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1050–1063.
1Division of Chemistry of Functional Materials, State Scientific
Institution “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Nauky Ave., 60, 61001, Kharkiv, Ukraine,
2Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
KU Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium,
3Laboratory of Biotechnology of Physiologically Active Substances,
Zaporizhzhya National University, Zhukovsky str., 66, 69600,
Zaporizhzhya, Ukraine and 4Faculty of Chemistry, V. N. Karazin
Kharkiv National University, Svobody sq., 4, 61077, Kharkiv, Ukraine
doi:10.3762/bjoc.13.104
Received: 29 January 2017
Accepted: 02 May 2017
Published: 31 May 2017
Associate Editor: T. J. J. Müller
© 2017 Murlykina et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Valentin A. Chebanov* - chebanov@isc.kharkov.com
* Corresponding author
Keywords:
3-amino-5-methylisoxazole;
5-amino-N-aryl-1H-pyrazole-4-carboxamides; antibacterial activity;
Groebke–Blackburn–Bienaymé reaction; isocyanide Ugi reaction
Abstract
The well-known aminoazoles, 3-amino-5-methylisoxazole and 5-amino-N-aryl-1H-pyrazole-4-carboxamides, were studied as an
amine component in Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions. The first example of an application of
aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke–Blackburn–Bienaymé cyclocon-
densation are established and discussed. The heterocycles obtained were evaluated for their antibacterial activity and several of
them demonstrated a weak antimicrobial effect, but for most of the compounds a 30–50% increase in biomass of Gram-positive
strains (mainly B. subtilis) compared to control was observed.
Introduction
An intensive progress in pharmaceutical and medicinal chem- However, we are still facing the problem of untreated ones,
istry, as well as in the generation and improvement of medici- together with the appearance of unknown disorders and the
nal technologies has led to defeating a wide scope of diseases. dramatical growth of antimicrobial resistance caused by the
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continuous evolution of microorganisms [1-5]. Therefore, there incorporate a variety of functionalities and modifications extend
is urgency in careful screening the chemical space with the aim its application for the generation of organic compound libraries,
of finding new biologically active structures. Modern chem- following hit-to-lead optimization, choosing the hit structure
istry offers several approaches, for instance, diversity oriented and final marketed drug production [54-58]. Moreover, it has
synthesis (DOS) for the generation of diverse compound been acknowledged that the combination of two privileged scaf-
libraries [6-8]. From this point of view, multicomponent reac- folds in a single molecule (e.g., the combination of a
tions (MCRs), including isocyanide-based MCRs as the Ugi peptidomimetic structure with an azole fragment [59]) poten-
four-component reaction (Ugi-4CR) and the Groebke–Black- tially creates more active, new entities with unusual bioproper-
burn–Bienaymé reaction (GBB-3CR) in combination with post- ties [20,60,61]. In addition, the application of polyfunctional
cyclizations are powerful tools to access diversity as well as reagents in Ugi-4CR opens ways to different post-cyclization
complexity in a one-pot procedure; in this way they largely reactions, thereby broadening the scope. Thus the Ugi-4CR in-
cover the available chemical space [9-26]. The imidazohetero- volving substituted propiolic acids, can be followed by electro-
cyclic scaffold represents a promising area for the discovery of philic ipso-iodocyclization [62] or transition-metal-initiated
novel synthetic drug molecules [27-52]. Particularly, there are [63-68] and metal-free cyclizations [69,70].
several drugs containing the imidazo[1,2-a]pyridine moiety
such as zolpidem (treatment of insomnia) and olprinone There are examples of using aminoazoles as an amine compo-
(cardiotonic drug) and a lot of compounds in biological testing nent in GBB-3CR (Scheme 1). They mostly involve different
and preclinical evaluation such as soraprazan (clinical antiulcer substituted 3-amino-1,2,4-triazoles [71-75] and
compound), necopidem (sedative effect), and saripidem (anxi- 2-amino(benzo)thiazoles [71,72,76-88]. Several publications
olytic) [27]. The activity of different imidazoheterocycles was deal with 2-amino-1,3,4-thiadiazoles [71,83,84,89,90],
also studied against migraine [30], gastric [31,32], heart [34- 2-aminoimidazoles [71,72,91,92], 2-aminoxazoles [71] and
36], viral diseases [37-41] and an array of neurological 1,2,5-oxadiazole-3,4-diamine [93] with the formation of imida-
syndromes [52]. The imidazo[1,2-b]pyrazole core shows also a zoazoles. Among the pyrazoles only 5-amino-3-methylpyrazole,
pharmacological potential. Among others, anti-inflammatory 5-aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-
[28,43], antiviral [39,44], antidiabetic [45] effects and cancer carboxylate are described in GBB-3CR [29,71,83,84,94-96]. To
cell growth-inhibitory features should be mentioned [29,46-48]. the best of our knowledge, there is no information about the re-
activity of aminoazoles as an amine component in Ugi-4CR.
Ugi-4CR has been applied in the synthesis of natural products,
as bicyclomycin, furanomycin, penicillin etc. [53]. The high Taking into account the above-mentioned facts, several amino-
combinatorial potential of Ugi-4CR together with the ability to azoles, whose reactivity in isocyanide-based reactions had not
Scheme 1: Aminoazoles in GBB-3CR and Ugi-4CR.
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
been studied yet, were examined as an amine component in out in EtOH/H2O mixture with TFA (10 mol %) at room tem-
Ugi-4CR and GBB-3CR. The generated compounds were perature for 24 h (method A) resulting in the formation of
screened for their biological activity towards Bacillus subtilis, imidazopyrazoles 4a–m (Table 1, entries 1–13).
Staphylococcus aureus, Escherichia coli and Pseudomonas
aeruginosa.
This condensation was also carried out in TFE or MeOH with
addition of HClO4 (10 mol %), but a significant amount of
Schiff base 5 (Table 1) was observed in this case. The reaction
Results and Discussion
Since aminoazoles contain an exocyclic NH2 group and an involving aldehydes 1f–h bearing strong electron-withdrawing
endocyclic nucleophilic center, they can act both as primary groups under all the abovementioned conditions allowed
amines and as 1,3-binucleophiles, therefore, their treatments isolating a mixture of imidazopyrazoles 4n–v with a large quan-
with isocyanides, aldehydes and carboxylic acids may proceed tity of Schiff bases 5.
either as Ugi-4CR (aminoazole – primary amine, acid – reagent)
or as GBB-3CR (aminoazole – 1,3-binucleophile, acid – cata- Therefore, the conditions for the synthesis of compounds 4n–v
lyst). Literature data indicate [14,25,59,97-101] that 5-aminopy- were optimized employing 5-amino-N-(3-fluorophenyl)-1H-
razoles bearing in the fourth position electron-withdrawing sub- pyrazole-4-carboxamide (2b), methyl benzaldehyde-4-carboxyl-
stituents like carboxamide, carboxylate or a carbonitrile group, ate (1f) and tert-butylisocyanide (3a, Table 2).
posses chemical properties being different from other
5-aminopyrazoles but sometimes similar to 3-amino-1,2,4-tri- Obviously, this reaction requires a longer reaction time (min.
azole that was described as a component of GBB-3CR earlier 48 h) and a moderate temperature (not more than 85 °C) to
[71-75]. Therefore, the first type of aminoazoles studied in our avoid tarring. Thus, after 48 h of heating (oil bath) at 85 °C the
work was 5-amino-N-aryl-1H-pyrazole-4-carboxamide that starting materials 1f, 2b and 3a in EtOH/H2O with TFA
showed 1,3-binucleophile properties in the condensation with (10 mol %), imidazopyrazole 4q was isolated in 56% yield.
aromatic aldehydes and alkylisocyanides giving the product re- However, the mother liquor still contained unreacted Shiff base
sulting from GBB-3CR. On the other hand, 3-amino-5- 5q (entry 7, Table 2 ). On the other hand, using DMF/HClO4
methylisoxazole in MCRs often acted as primary amine [102- (10 mol %, method B) allowed obtaining the target compound
106], that was confirmed in our case by treatment with aromat- 4q in 88 % yield with no impurities (entry 9, Table 2).
ic aldehydes, alkylisocyanides and phenylpropiolic acid result-
ing in the corresponding products of the Ugi-4CR (Scheme 2). Similarly the reaction of 5-amino-N-(4-fluorophenyl)-1H-pyra-
zole-4-carboxamide (2a) with 4-nitrobenzaldehyde (1g) and
The scope and limitations of isocyanide-based reactions involv- tert-butylisocyanide (3a) in EtOH/H2O with TFA (10 mol %)
ing 5-amino-N-aryl-1H-pyrazole-4-carboxamides and 3-amino- also led to Shiff base 5o while stirring the starting materials in
5-methylisoxazole were studied in detail. It was established that DMF-HClO4 (10 mol %) for 48 h gave compound 4o (Table 3).
the optimal reaction conditions of a GBB-3CR involving
5-amino-N-aryl-1H-pyrazole-4-carboxamides 2a–d were differ- It should be noted that the conditions of method B are also suit-
ent depending on the other substrates. Particularly, the conden- able for obtaining imidazopyrazoles 4a–m in comparatively
sation involving tert-butylisocyanide (3a) and aldehydes 1a–e high yields; however, the synthesis in EtOH/H2O medium is
bearing electron-donating substituents was effectively carried preferred from the point of view of green chemistry. Thereby,
Scheme 2: Reactivity of 5-amino-N-aryl-1H-pyrazole-4-carboxamide and 3-amino-5-methylisoxazole in GBB-3CR and Ugi-4CR.
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
Table 1: CBB-3CR involving tert-butylisocyanide.
Entry
Starting materials
Aminopyrazoles
Method
Product
Yield, %
Aldehydes
R1
R2
1
2
1a
1b
1c
1d
1e
1b
1d
1e
1b
1d
1e
1b
1e
1f
H
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2a
2a
2a
2b
2b
2b
2c
2c
2c
4-F
4-F
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
4a
4b
4c
4d
4e
4f
54
75
77
75
72
83
64
89
82
64
66
85
53
85
87
90
88
87
82
61
79
83
2-CH3O
3-CH3O
4-CH3O
4-Cl
3
4-F
4
4-F
5
4-F
6
2-CH3O
4-CH3O
4-Cl
3-F
7
3-F
4g
4h
4i
8
3-F
9
2-CH3O
4-CH3O
4-Cl
2-CH2CH3
2-CH2CH3
2-CH2CH3
4-CH2CH3
4-CH2CH3
4-F
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
4k
4l
2-CH3O
4-Cl
4m
4n
4o
4p
4q
4r
4-CO2CH3
4-NO2
4-CN
1g
1h
1f
4-F
4-F
4-CO2CH3
4-NO2
4-CN
3-F
1g
1h
1f
3-F
3-F
4s
4t
4-CO2CH3
4-NO2
4-CN
2-CH2CH3
2-CH2CH3
2-CH2CH3
1g
1h
4u
4v
the optimal methodology for obtaining compounds 4a–m is the presence of electron-withdrawing substituents in the aldehyde
synthesis according to the method A (H2O/EtOH (1:1), TFA the corresponding Schiff bases 5 are less soluble and less basic.
(10 mol %), rt, 24 h) while for compounds 4n–v method B DMF increases solubility of imines 5, while the application of
(DMF, HClO4 (10 mol %), rt, 48 h) proved to be superior (Ta- strong acid (HClO4) promotes Shiff bases protonation.
ble 1, entries 14–22).
Phenylpyruvic acid (1') was also applied as carbonyl compo-
We presume that such difference in the outcome of GBB-3CR nent in GBB-3CR to obtain imidazopyrazoles having a
depending on the substitution pattern in the carbonyl compo- carboxylic group. However, the process of decarboxylation took
nent is related with the ability of the intermediate Schiff bases place in the reaction and 1-H-imidazopyrazole carboxamides
to be protonated as well as with their solubility. In case of the 4w,x were isolated as the sole reaction products (Table 4).
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
Table 2: Optimization of the reaction conditions for the synthesis of compound 4q.
Entry
Solvent, acid
Time, hours
T, °C
Products (ratio)
Yield, %a
1
2
3
4
5
6
7
8
9
TFE, HClO4, (10 mol %)
72
24
24
12
0.3b
2c
25
25
4 + 5 (2:1)
4 + 5 (1:1)
4 + 5 (1:1)
4 + 5 (2:1)
4 + 5 (4:5)
4 + 5d
–
–
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (20 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
DMF, HClO4, (10 mol %)
25
–
80
–
140
25
–
–
48
5b
85
4
56
–
140
25
4 + 5 (2:3)
4
48
88
aThe yields are indicated for compound 4 and are not calculated for the mixtures; bupon MW irradiation; cupon US irradiation; din a mixture with
starting materials and undetected impurities.
Table 3: Optimization of the reaction conditions for the synthesis of compound 4o.
Entry
Solvent
Time, hours
T, °C
Main product
Yield, (%)a
1
2
3
4
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
EtOH/H2O (1:1), TFA, (10 mol %)
DMF, HClO4, (10 mol %)
72
2
25
140c
90
5b
5b
5b
4
–
–
72
48
–
25
87
aThe yields are indicated for compound 4o; bin a mixture with starting materials and undetected impurities; cupon MW irradiation.
When replacing tert-butylisocyanide (3a) with ethyl Schiff bases 5. Moreover, only imines 5 with impurities of the
2-isocyanoacetate (3b), imidazo[1,2-b]pyrazole-7-carbox- starting compounds were isolated when applying DMF with
amides 6a–h were isolated. The condensation proceeded well in HClO4.
TFE with the addition of HClO4 (10 mol %) upon stirring for
24 h (Table 5). On the other hand, condensation of the starting Interestingly, in case of ethyl 2-isocyanoacetate (3b) the reac-
reagents 1d–g with 2a,b and 3b in EtOH/H2O (1:1) with tion proceeded equally well regardless of the substituent in the
TFA (10 mol %) resulted in the formation of the target aldehyde. This can be connected with an increased reactivity of
products 6 in a mixture with a substantial amount of ethyl 2-isocyanoacetate (3b) compared to tert-butylisocyanide
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
Table 4: Phenylpyruvic acid in GBB-3CR.
Entry
Starting materials
Aminopyrazoles
Product
Yield, %
R2
1
2
2a
2b
4-F
3-F
4w
4x
48
42
Table 5: GBB-3CR involving ethyl 2-isocyanoacetate.
Entry
Starting materials
Product
Yield, %
Aldehydes
R1
Aminopyrazoles
R2
1
2
3
4
5
6
7
8
1d
1e
1f
4-CH3O
4-Cl
2a
2a
2a
2a
2b
2b
2b
2b
4-F
4-F
4-F
4-F
3-F
3-F
3-F
3-F
6a
6b
6c
6d
6e
6f
77
95
67
85
78
84
82
80
4-CO2CH3
4-NO2
1g
1d
1e
1f
4-CH3O
4-Cl
4-CO2CH3
4-NO2
6g
6h
1g
(3a) due to sterical reasons thus leveling the influence of the acid (8) and tert-butylisocyanide (3a) gave peptidomimetics 9
solubility factor of imines 5.
under stirring the starting reagents in MeOH at room tempera-
ture for 24 h. In the presence of strong electron-withdrawing
As it has been already mentioned above, in contrast to 5-amino- substituents as nitro or cyano groups in para-position of the
N-aryl-1H-pyrazole-4-carboxamides 2, 3-amino-5-methylisoxa- aldehyde, despite the variation of the reaction conditions, only
zole (7) exhibited only properties of primary amines that imines 10 were isolated as the major products. In case of
allowed using it as an amine component in Ugi-4CR. Particular- 4-cyanobenzaldehyde (1h) we managed to isolate Ugi product
ly, its reaction with aromatic aldehydes 1a–h, phenylpropiolic 9g in a low yield of 18% (Table 6).
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
Table 6: Ugi-4CR involving 3-amino-5-methylisoxazole.
Entry
Starting materials
Product
Yieldb, %
Aldehydes
R1
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
9a
9b
49
67
51
73
43
43
–b
18
2-CH3O
3-CH3O
4-CH3O
4-Cl
9c
9d
9e
4-CO2CH3
4-NO2
9f
1g
1h
10ga
9h
4-CN
a9g was not isolated; bthe yields are indicated for compounds 9.
It should be noted that 5-amino-N-aryl-1H-pyrazole-4-carbox- as signals for other substituents. In case of imidazo[1,2-b]pyra-
amides 2 were also introduced into Ugi-4CR with aromatic zole-7-carboxamides 4w,x a broad signal for the tert-butyl
aldehydes 1, alkylisocyanides 3 and phenylpropiolic acid 8; NH group is shifted upfield to 4.2 ppm and an additional singlet
however, the acid 8 acted as a catalyst favouring the formation for the benzyl CH2 group is present at 3.9 ppm.
of GBB-3CR-products 4. The attempts to carry out GBB-3CR
involving 3-amino-5-methylisoxazole (7) according to the elab- The 1H NMR spectra of imidazo[1,2-b]pyrazole-7-carbox-
orated procedures (Table 1, methods A or B) as well as under amides 6 exhibit a broad signal for the NH group in the posi-
other conditions were not successful.
tion 1 at ≈11.8 ppm, a broad signal for the carboxamide
NH group at ≈9.6 ppm, a singlet for the pyrazole CH in the po-
sition 6 at ≈8.2 ppm, a broad signal for the NH group near the
Structure elucidation
The purity and structures of the heterocycles obtained were position 3 at ≈5.7 ppm, a singlet for the CH2 group in the
established by means of mass spectrometry (including HRMS), acetate moiety at ≈4.2 ppm, peaks for the ethoxy group: a
NMR spectroscopy and X-ray diffraction study.
quartet for CH2 group at ≈4.0 ppm and a triplet for the CH3
group at ≈1.0 ppm, peaks for the aromatic protons around
The 1H NMR spectra of imidazo[1,2-b]pyrazole-7-carbox- 6.7–7.7 ppm as well as signals for other substituents.
amides 4 exhibit a broad signal for the NH group in the posi-
tion 1 at ca. 11.8 ppm, a broad signal for the carboxamide NH The 1H NMR spectra of N-(1-arylethyl-2-(tert-butylamino)-2-
at ≈9.5 ppm, a singlet for pyrazole CH in the position 6 oxo)-N-(5-methylisoxazol-3-yl)-3-phenylpropiolamides 9 ex-
at ≈8.2 ppm, a broad signal for the NH group near the position 3 hibit a broad signal for the amide NH group at ≈7.9 ppm, singlet
at ≈5.1 ppm, a singlet for tert-butyl CH3 groups at ≈1.0 ppm, for the isoxazole CH at ≈6.3 ppm, a singlet for the CH group in
resonances for the aromatic protons around 6.9–8.2 ppm as well the position 1 at ≈6.0 ppm, a singlet for the isoxazole CH3
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
group at ≈2.3 ppm, a singlet for the tert-butyl CH3 groups at However, the final assignment of the structure A for hetero-
≈1.2 ppm, peaks for the aromatic protons around 6.8–7.5 ppm cycles 4 was made with the help of X-ray analysis (Figure 3).
as well as signals for other substituents.
As it was found earlier for 2-aminopyrimidines [107-109] GBB-
3CR may lead to the formation of two positional isomers A and
B (Figure 1).
Figure 3: Molecular structure of 3-(tert-butylamino)-2-(4-chlorophenyl)-
N-(4-fluorophenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide (4e)
(X-ray diffraction data). Non-hydrogen atoms are presented as ther-
Figure 1: Alternative structures A and B for compounds 4 and 6.
mal ellipsoids with 50% probability.
Experiment with D2O allowed to identify the signals of
NH protons while the HSQC spectrum showed the correlations In the case of compounds 9 the presence of NOE between the
between the signals of protons and corresponding carbon atoms signals of the methyl group and the CH group in the isoxazole
(in the position 6 and in tert-butyl group). The correlations be- moiety allowed to distinguish closely located signals of two
tween the signals of NH protons and corresponding carbon CH groups (Figure 4).
atoms (through two and three bonds, Figure 2) allowed final
distinguishing the shifts of three NH groups signals in 1H NMR
spectra.
Figure 4: Selected data of NOE and HSQC experiments for com-
pound 9d.
Ultimately, the structure of compounds 9 was proven by an
X-ray analysis of compound 9e (Figure 5).
Antibacterial activity
The antibacterial activity of compounds 4, 6 and 9 (Table 7)
was studied (see Experimental part in Supporting Information
File 1 for details) against reference bacterial cultures: Bacillus
subtilis (strain 1211), Staphylococcus aureus (strain 2231)
Figure 2: Selected data of HSQC and HMBC experiments for com-
pound 4a.
(Gram-positive) and Escherichia coli (strain 1257), Pseudomo-
nas aeruginosa (strain 1111) (Gram-negative).
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Beilstein J. Org. Chem. 2017, 13, 1050–1063.
As it follows from the results obtained several of the substances
studied inhibit the growth of test-microorganisms demon-
strating a weak antimicrobial effect (Table 7). Generally, the
compounds were found to be less active than nitroxoline (being
the reference substance).
The antimicrobial effect of the heterocycles studied is different
depending on each bacterical strain; however, some rules can be
seen. Only a few substances inhibited the growth of Gram-nega-
tive bacteria (strains of E. coli and P. aeruginosa) in an effec-
tive way. Particularly, compounds 4a and 6g inhibited the
growth of E. coli in concentration 125 mg/L. The bacteriostatic
activity against P. aeruginosa of compounds 4v and 6e was
fixed only in the highest concentration 500 mg/L. The Gram-
positive bacterium S. aureus showed the resistance to almost all
the compounds tested in the given concentration range. The
strain of B. subtilis was found to be sensitive to compounds 4i
Figure 5: Molecular structure of N-(2-(tert-butylamino)-1-(4-chloro-
phenyl)-2-oxoethyl)-N-(5-methylisoxazol-3-yl)-3-phenylpropiolamide
(9e) (X-ray diffraction data). Non-hydrogen atoms are presented as
thermal ellipsoids with 50% probability.
Table 7: Antibacterial activity results.
Entry
Substance
MICa/MBCb,
mg/L
Strains of test cultures
Escherichia
coli
Pseudomonas
aeruginosa
Staphylococcus
aureus
Bacillus
subtilis
MIC
MBC
MIC
125
–
–c
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–*
–
–
–
–
–
–
–
–
–
–
–
1
2
4a
4b
4c
4d
4e
4f
500
–
–
MBC
MIC
–
–
–
3
MBC
MIC
–
–
–
–
4
MBC
MIC
–
–
500
–
–
5
MBC
MIC
–
–
–*d
–
6
MBC
MIC
–
–
–
7
4g
4i
MBC
MIC
–
–
500
–
500
–
8
MBC
MIC
250
–
–*
–
9
4j
MBC
MIC
–
–
10
11
12
13
14
4k
4n
4o
4p
4q
MBC
MIC
–
–
–
–*
–
MBC
MIC
–
–
–
MBC
MIC
–
–
500
–
–
MBC
MIC
–
–
–*
–
MBC
–
1058

Beilstein J. Org. Chem. 2017, 13, 1050–1063.
Table 7: Antibacterial activity results. (continued)
MIC
MBC
MIC
250
–
–
–
–
–
–
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
4r
–
500
–
–
–
–*
–
4s
MBC
MIC
–
–
–
–
–
–*
–
4t
MBC
MIC
–
–
–
–
–
–
–
4u
MBC
MIC
–
–
–
–
500
–
500
–
–
–
4v
MBC
MIC
–
–
–
–
–
–
4w
MBC
MIC
–
–
–
–
–
–
–
–
4x
MBC
MIC
–
–
–
–
500
–
–
–
–*
–
6a
MBC
MIC
–
–
–
–
–
–
6b
MBC
MIC
–
–
–
–
500
–
–
–
–
6c
MBC
MIC
–
–
–
–
–
–
500
–
6d
MBC
MIC
–
–
–
–
500
–
–
–
6e
MBC
MIC
–
–
–
500
–
–
–
–
6f
MBC
MIC
–
–
–
125
–
–
–
–
6g
MBC
MIC
–
–
–
500
–
–
500
–
6h
MBC
MIC
–
–
–
–
–
–
–
9a
MBC
MIC
–
–
–
–
–
–
–
–*
–
9b
MBC
MIC
–
–
–
–
–
–
–*
–
9c
MBC
MIC
–
–
–
–
–
–
–*
–
9d
MBC
MIC
–
–
–
–
–
–
–
–
9e
9f
MBC
MIC
–
–
–
–
–
–
–*
–
MBC
MIC
–
–
–
15.6
15.6
62.5
62.5
31.25
31.25
1.9
1.9
Nitroxoline
MBC
aMIC – minimum inhibitory concentration; bMBC – minimum bactericidal concentration; cthe substance in concentration ≤500 mg/L does not inhibit the
culture growth; dincrease in biomass compared to control.
and 6d, but the bacteriostatic activity was fixed only in the tions of their biological action. An absence or a low level of
highest concentration 500 mg/L. The information about the in- antibacterial activity of the heterocycles synthesized is a good
fluence of the compounds on bacteria is important from the prerequisite for carrying out the research on the other promis-
point of view of choosing the further strategy for the investiga- ing types of activity, e.g., anticancer, antidiabetic, etc., because
1059

Beilstein J. Org. Chem. 2017, 13, 1050–1063.
in this case a negative influence on a microflora of the organ-
ism is decreased [110].
Supporting Information
Supporting Information File 1
Experimental and analytical data.
The other interesting feature of most of the compounds was the
30–50% increase in biomass of Gram-positive strains (mainly
B. subtilis) compared to control. As it follows from a brief liter-
ature overview there are a lot of applications of metabolites
(recombinant insulin [111], polyhydroxyalkanoates [112,113]
etc. [114-119]) produced by the strains studied. Therefore, the
found probiotic effect of the heterocycles has a very promising
area for the further application while scaling up the production
of biomass with the aim of shortening the time and saving
resources [120,121]. Although this is a subject for a future
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-104-S1.pdf]
Supporting Information File 2
NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-104-S2.pdf]
detailed study the results of antibacterial activity allowed Acknowledgements
outlining the positive tendency.
V. Chebanov was supported by a scholarship of KU Leuven
(SF/14/006). M. Murlykina was supported by an Erasmus
Mundus scholarship. We thank K. Duerinckx and D. Sysoiev
Conclusion
In summary, the behavior of 5-amino-N-aryl-1H-pyrazole-4- for recording some 1H NMR and 13C NMR spectra, B.
carboxamide and 3-amino-5-methylisoxazole as an amine com- Demarsin and D. Sysoiev for measuring HRMS and LC–MC
ponent in isocyanide-based multicomponent reactions was spectra, N. Gorobets and D. Sysoiev for the help with
studied. Particularly, 5-amino-N-aryl-1H-pyrazole-4-carbox- discussing the results.
amide reacted as 1,3-binucleophile with aromatic aldehydes and
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