Synthesis and antimycobacterial activity of pyridinium compounds with sulfonylacetamide substituent in N-alkyl chain

Article abstract of DOI:10.1007/s10593-018-2362-3

[Figure not available: see fulltext.] Pyridines containing amine, amide, or hydrazide substituent were quaternized with (ω-haloalkyl)sulfonylacetamides, resulting in new pyridinium compounds that exhibited tuberculostatic activity against the strain H37Rv

Full text of DOI:10.1007/s10593-018-2362-3

DOI 10.1007/s10593-018-2362-3
Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
Synthesis and antimycobacterial activity of
pyridinium compounds with sulfonylacetamide
substituent in N-alkyl chain
Marina M. Shulaeva1*, Marionella A. Kravchenko2, Vyacheslav E. Semenov1
1 A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
8 Akademika Arbuzova St., Kazan 420088, Russia; е-mail: mshulaeva@iopc.ru
2 Ural Research Institute of Phthysiopulmonology – branch of the National Medical Research Center of Phthysiopulmonology
and Infectious Diseases, Ministry of Health of the Russian Federation,
50 22-go Parts'yezda St., Yekaterinburg 620039, Russia; e-mail: urniif@urniif.ru
Submitted May 21, 2018
Accepted June 29, 2018
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(9), 868–874
Pyridines containing amine, amide, or hydrazide substituent were quaternized with (ω-haloalkyl)sulfonylacetamides, resulting in new
pyridinium compounds that exhibited tuberculostatic activity against the strain H37Rv of Mycobacterium tuberculosis.
Keywords: carbamoylmethylsulfonyl group, pyridinium compounds, sulfonylacetamides, quaternization, antituberculosis activity.
Pyridinium salts are known for a great variety of useful
properties that provide reasons for widespread use of such
compounds. In the role of cationic surfactants they find
applications as corrosion inhibitors, emulgators, detergents,
antistatic additives, and phase-transfer catalysts. Pyridinium
salts are also used as electrolytes, additives during
extraction, polymerization, water treatment, and flotation
processes.1 N-Alkylpyridinium salts are used as organic
synthesis reagents for the preparation of compounds
belonging to various classes, for example, phenacylides,
which can be further used in 1,3-dipolar cycloaddition and
some types of condensation reactions.2,3 The ability of
N-alkylpyridinium salts to affect the permeability of
biological membranes show promise in the development of
new drugs, biosensors, and gene transfection agents4 in the
field of genetic engineering.
N-Alkylpyridinium salts show a broad spectrum of
biological activity, primarily strong antibacterial activity
against a range of microorganisms, including tuberculosis
mycobacteria.5–10 Pyridinium compounds containing
steroid structures have been characterized with strong
antimycobacterial activity, reaching the minimum
inhibitory concentration (MIC) of 0.4 µl/ml.5 It is essential
to continue the efforts directed toward the discovery of new
antituberculosis compounds, especially because of the
emergence of highly resistant strains of mycobacteria.11
Thus, it is worthwhile to synthesize new pyridine
derivatives, including pyridinium salts, and to study their
antimycobacterial activity.
It is known that compounds containing a carbamoyl-
methylsulfonyl moiety, in particular n-octylsulfonyl-
acetamide, exhibit antimycobacterial properties that are not
accompanied by antimicrobial action on other micro-
organisms.12–14 Such compounds have been synthesized as
potential inhibitors of β-ketoacyl synthase – an enzyme
involved in the biosynthesis of fatty acids in mycobacteria.
We have previously reported the synthesis of isocyanurate
derivatives with tuberculostatic activity, containing
terminal carbamoylmethylsulfonyl groups in their N-alkyl
chains.15,16 We assumed that the replacement of iso-
cyanurate moiety with a pyridine ring can lead to new
compounds with a broad spectrum of antimicrobial activity,
including activity against Mycobacterium tuberculosis.
During the current study we synthesized a series of
pyridinium salts 1 containing carbamoylmethylsulfonyl
group in the N-alkyl chain, while the length of methylene
chain in the N-substituent and the type of other pyridine
ring substituents were varied.
0009-3122/18/54(9)-0868©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
Scheme 1
The key starting materials for the synthesis of
Table 1. The structures, yields, and tuberculostatic activity of
pyridinium salts 1a–o
compounds 1 were (ω-haloalkyl)sulfonylacetamides 2,
which were obtained during this work by the reaction of
thioglycolamide (3) with α,ω-dihaloalkanes 4a–c, followed
by oxidation of the obtained ω-haloalkyl sulfides 5a–c
(Scheme 1). The alkylation reactions of thioglycolamide (3)
produced significant amounts of α,ω-bis(carbamoyl-
methylsulfanyl)alkanes 6,17 but their formation could be
minimized by employing a large excess of α,ω-di-
haloalkanes 4a–c. It should be also noted that exceeding
the optimal reaction temperature during the oxidation of
ω-halo sulfides 5a–c substantially decreased the yields of
sulfones 2a–c.
Reaction
Yield,
%
MIC,
µg/ml
Compound
R
n
Hal duration,
h
H
H
2
3
5
2
3
5
2
5
5
2
5
2
5
2
5
–
Cl
Cl
Br
Cl
Cl
Br
Cl
Br
Br
Cl
Br
Cl
Br
Cl
Br
–
4
45
8
6.2
1a
1b
1c
1d
1e
1f
39
11
4
12.5
H
59
96
16
81
89
67
39
37
42
50
52
32
43
12.5
4-NH2
12.5
4-NH2
10
10
5
12.5
4-NH2
12.5
2-NH2
12.5
1g
1h
1i
Sulfonylacetamides 2a–c were used in reactions with
various pyridine derivatives 7a–g, giving a series of
pyridinium salts 1a–o (Table 1). As it was expected, the
alkylating activity of ω-chloroalkyl sulfones 2a–c in
reactions with pyridines dropped sharply with an increase
in the number of methylene groups from 2 to 3 and
improved when the chlorine atom was replaced with
bromine. For example, refluxing pyridine (7a) and 3-chloro-
propyl sulfone 2b in acetonitrile for 39 h gave only 8%
yield of pyridinium salt 1b, while the analogous reaction
with 2-chloroethyl sulfone 2a produced pyridinium salt 1a
in 45% yield already after 4 h, and the reaction with
5-bromopentyl sulfone 2c resulted in the formation of
compound 1с in 59% yield after 11 h.
2-NH2
12
18
17
18
22
22
22
21
Not determined
3-COOMe
3-C(O)NH2
3-C(O)NH2
3-C(O)NHNH2
3-C(O)NHNH2
4-C(O)NHNH2
4-C(O)NHNH2
Not determined
3.1
12.5
12.5
1.5
1j
1k
1l
1m
1n
1o
1.5
12.5
0.1
Isoniazid 4-CONHNH2
(7g)
Scheme 2
Aminopyridines 7b,c were alkylated at the ring nitrogen
atom, forming crystalline salts in good yields (Table 1). The
reaction of 4-aminomethylpyridine (7h) with 2-chloroethyl
sulfone 2a did not yield the respective pyridinium salt.
Instead, HCl was eliminated already at room temperature
and 2-(vinylsulfonyl)acetamide (8) was obtained (Scheme 2).
The presence of electron-withdrawing carbonyl
substituents in the pyridine ring hindered the quaternization
of ring nitrogen atom, for example, the refluxing of
isoniazid (7g) with 2-chloroethyl sulfone 2a for 22 h gave
salt 1n in merely 32% yield (Table 1).
Compound 1n was also obtained by an alternative
method, through the reaction of vinyl sulfone 8 with
isoniazid (7g) in the presence of hydrochloric acid18
(Scheme 3). These conditions allowed to significantly
shorten the reaction duration (to 5 h) and to obtain
pyridinium salt 1n in 56% yield.
All of the obtained pyridinium salts 1, except for the salt
1i, were isolated as crystalline products that were readily
soluble in water.
The synthesized compounds 1a–g,j–o were screened in
vitro for antituberculosis activity against the laboratory
strain H37Rv of M. tuberculosis (Table 1). All of the
investigated pyridinium salts showed tuberculostatic
activity with MIC values ranging from 1.5 to 12.5 µl/ml.
First of all, we should note the lower tuberculostatic
869

Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
Scheme 3
Preparation of 2-[(ω-haloalkyl)sulfanyl]acetamides
5a–c (General method). Sodium methoxide solution was
prepared by dissolving metallic sodium (2.3 g, 0.1 mol) in
MeOH (100 ml), and a solution of mercaptoacetamide (3)
(9 g, 0.1 mol) in MeOH (100 ml) was added dropwise. The
obtained thiolate solution was slowly dropwise added into
a flask with α,ω-dihaloalkane 4a–c (0.2 mol), while
maintaining 15–20°C temperature. The reaction mixture
was stirred for 8 h, the precipitate was removed by
filtration and the filtrate was evaporated at reduced
pressure. The residue was taken up in EtOAc (100 ml),
filtered after 1 day and the filtrate was evaporated.
activity of pyridinium salts 1n,o compared to isoniazid
(7g). With β-carbamoylmethylsulfonyl group present in the
N-alkyl chain, pyridinium salts 1a,j,n showed
tuberculostatic activity with MIC values of 6.2, 3.1, and
1.5 µl/ml, respectively. The presence of longer methylene
chains resulted in a decrease of the MIC value to 12.5 µl/ml
(compounds 1b,c,k,o, Table 1). However, when a
hydrazide substituent was introduced at the meta position
of pyridinium ring, the opposite trend was observed,
namely, the activity increased for compounds containing
longer methylene spacer chains in their molecules: the MIC
value for salt 1l with two methylene groups was 12.5 µl/ml,
whereas salt 1m containing a chain of five methylene
groups had the MIC value of 1.5 µl/ml. The presence of an
amino group in the pyridinium ring was accompanied by an
increase in the MIC value to 12.5 µl/ml for compounds
1d,g, compared to compound 1a containing an un-
substituted pyridinium ring (MIC 6.2 µl/ml). The presence
of an amide or hydrazide substituent in the pyridinium ring
generally helped to improve the tuberculostatic activity of
the respective compounds (Table 1). The highest activity
with MIC 1.5 µl/ml was shown by compounds 1m,n
containing hydrazide substituents in the pyridinium ring.
Thus, we have prepared new pyridinium compounds
containing carbamoylmethylsulfonyl group in the N-alkyl
chain as pharmacophoric structural motif. Such compounds
exhibited tuberculostatic activity against M. tuberculosis
strain H37Rv with MIC values in the range of 1.5–12.5 µl/ml.
The activity of the obtained compounds depended both on
the number of methylene groups in the spacer chain and on
the pyridinium ring substituents.
2-[(Chloroethyl)sulfanyl]acetamide (5a)20 was obtained
from 1-bromo-2-chloroethane (4a). Yield 9.5 g (62%),
thick transparent oil that crystallized upon storage, mp 60–
61°C (Et2O). 1H NMR spectrum (400 MHz), δ, ppm (J, Hz):
2.94 (2Н, t, J = 7.6, CH2S); 3.13 (2Н, s, CH2CO); 3.78 (2Н,
t, J = 7.6, CH2Cl); 7.03 (1Н, s) and 7.46 (1Н, s, NH2).
Found, %: С 31.22; Н 5.18; Cl 23.06; N 9.08; S 20.83.
С4H8ClNOS. Calculated, %: С 31.27; Н 5.25; Cl 23.08;
N 9.12; S 20.87.
2-[(3-Chloropropyl)sulfanyl]acetamide
(5b) was
obtained from 1-bromo-3-chloropropane (4b). Yield 11.7 g
(70%), thick transparent oil that crystallized upon storage,
mp 68–69°C (Et2O). 1H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 1.97–2.01 (2Н, m, СН2); 2.68 (2Н, t, J = 7.1,
CH2S); 3.07 (2Н, s, CH2CO); 3.71 (2Н, t, J = 6.4, CH2Cl);
6.98 (1Н, s) and 7.42 (1Н, s, NH2). Found, %: С 35.78;
Н 5.97; Cl 21.08; N 8.32; S 19.10. С5H10ClNOS.
Calculated, %: С 35.82; Н 6.01; Cl 21.15; N 8.35; S 19.13.
2-[(5-Bromopentyl)sulfanyl]acetamide
(5c)
was
obtained from 1,5-dibromopentane (4c). Yield 20.9 g
(87%), thick transparent oil that crystallized upon storage,
mp 83–84°C (Et2O). 1H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 1.43–1.49 (2Н, m, СН2); 1.53–1.60 (2Н, m, СН2);
1.77–1.84 (2Н, m, СН2); 2.56 (2Н, t, J = 7.2, CH2S); 3.05
(2Н, s, CH2CO); 3.53 (2Н, t, J = 6.7, CH2Br); 6.97 (1Н, s)
and 7.39 (1Н, s, NH2). Found, %: С 34.98; Н 5.82;
Br 33.21; N 5.79; S 13.30. С7H14BrNOS. Calculated, %:
С 35.01; Н 5.88; Br 33.27; N 5.83; S 13.35.
Preparation of 2-[(ω-haloalkyl)sulfonyl]acetamides
2a–c (General method). A solution of 2-[(ω-haloalkyl)-
sulfanyl]acetamide 5a–c (0.05 mol) in glacial acetic acid
(100 ml) was treated by dropwise addition of 35% H2O2
(12.3 ml, 0.12 mol) in a way that the temperature did not
exceed 60°C. The reaction mixture was further stirred at
55–60°C for 20 h. The mixture was cooled, filtered, and
concentrated at reduced pressure, while avoiding
evaporation to dryness. The residue was diluted with 10:1
Et2O–MeOH mixture (100 ml), the precipitate was
triturated and filtered off.
Experimental
1H and 13С NMR spectra were acquired on Bruker
Avance 600 (600 and 150 MHz, respectively) or Bruker
MSL-400 spectrometers (400 and 100 MHz, respectively)
in DMSO-d6, internal standard TMS. The signals in
13С NMR spectrum were assigned by relying on the
reference spectra of related compounds.19 MALDI-TOF
mass spectra were recorded on a Bruker Ultraflex III
instrument, using metallic target and p-nitroaniline matrix;
conditions for recording of the mass spectrum: Nd:YAG,
λ 355 nm, linear mode without adding of mass spectra. The
elemental composition (С, Н, and N) was determined on a
CHN-3 analyzer, halogens were determined by Shöniger
method, sulfur – by pyrolysis in oxygen stream. Melting
points were determined on a Boetius hot stage.
2-[(2-Chloroethyl)sulfonyl]acetamide
(2a)21
was
obtained from 2-[(2-chloroethyl)sulfanyl]acetamide (5a)
(9.27 g, 0.06 mol). Yield 8.17 g (73%), white crystals,
1
mp 126–127°C. H NMR spectrum (600 MHz), δ, ppm
(J, Hz): 3.81 (2Н, t, J = 7.1, CH2SO2); 3.97 (2Н, t, J = 7.1,
CH2Cl); 4.12 (2Н, s, CH2CO); 7.50 (1Н, s) and 7.77 (1Н, s,
NH2). 13C NMR spectrum (150 MHz), δ, ppm: 36.6
(ClCH2); 55.2 (CH2SO2); 59.1 (SO2CH2CO); 164.1 (C=O).
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Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
Found, %: С 25.83; Н 4.31; Cl 19.06; N 7.52; S 17.28.
spectrum (150 MHz), δ, ppm: 23.5 (CH2); 50.4 (CH2SO2);
53.4 (SO2CH2CO); 59.7 (CH2N+); 128.4 (C-3,5 Py); 145.5
(C-4 Py); 146.3 (C-2,6 Py); 164.1 (C=O). Mass spectrum,
m/z: 243 [M–Cl]+. Found, %: С 42.93; Н 5.38; Cl 12.65;
N 10.02; S 11.41. С10H15ClN2O3S. Calculated, %: С 43.09;
Н 5.42; Cl 12.72; N 10.05; S 11.50.
С4H8ClNO3S. Calculated, %: С 25.88; Н 4.34; Cl 19.10;
N 7.55; S 17.27.
2-[(3-Chloropropyl)sulfonyl]acetamide (2b) was
obtained from 2-[(3-chloropropyl)sulfanyl]acetamide (5b)
(8.38 g, 0.05 mol). Yield 5.14 g (52%), white crystals,
1
mp 114–115°C. H NMR spectrum (400 MHz), δ, ppm
1-[5-(Carbamoylmethylsulfonyl)pentyl]pyridinium
bromide (1c) was obtained from pyridine (7а) (0.4 g,
5.0 mmol) and 2-[(5-bromopentyl)sulfonyl]acetamide (2c)
(1.36 g, 5.0 mmol), the refluxing duration was 11 h. Yield
(J, Hz): 2.15–2.22 (2Н, m, СН2); 3.42 (2Н, t, J = 7.7,
CH2SO2); 3.77 (2Н, t, J = 6.5, CH2Cl); 4.07 (2Н, s, CH2CO);
7.45 (1Н, s) and 7.74 (1Н, s, NH2). 13C NMR spectrum
(100 MHz), δ, ppm: 21.2 (CH2); 35.7 (ClCH2); 52.5
(CH2SO2); 58.2 (SO2CH2CO); 163.8 (C=O). Found, %:
С 30.02; Н 4.98; Cl 17.67; N 6.92; S 16.02. С5H10ClNO3S.
Calculated, %: С 30.08; Н 5.05; Cl 17.76; N 7.02; S 16.06.
1
1.04 g (59%), white crystals, mp 129–130°C. H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 1.39–1.46 (2Н, m,
СН2); 1.74–1.81 (2Н, m, СН2); 1.94–2.01 (2Н, m, СН2);
3.27 (2Н, t, J = 7.9, CH2SO2); 4.02 (2Н, s, CH2CO); 4.65
(2Н, t, J = 7.4, CH2N+); 7.44 (1Н) and 7.78 (1Н, s, NH2);
8.18 (2Н, t, J = 7.1, H-3,5 Py); 8.62 (1Н, t, J = 7.8, H-4
Py); 9.13 (2Н, d, J = 5.7, H-2,6 Py). 13C NMR spectrum
(150 MHz), δ, ppm: 21.1 (CH2); 24.6 (CH2); 30.6 (CH2);
52.8 (CH2SO2); 58.3 (SO2CH2CO); 60.8 (CH2N+); 128.6
(C-3,5 Py); 145.3 (C-4 Py); 146.0 (C-2,6 Py); 164.3 (C=O).
Mass spectrum, m/z: 271 [M–Br]+. Found, %: С 40.97;
Н 5.42; Br 22.68; N 7.94; S 9.11. С12H19BrN2O3S.
Calculated, %: С 41.03; Н 5.45; Br 22.75; N 7.98; S 9.13.
4-Amino-1-[2-(carbamoylmethylsulfonyl)ethyl]pyridinium
chloride (1d) was obtained from 4-aminopyridine (7b)
(0.47 g, 5.0 mmol) and 2-[(2-chloroethyl)sulfonyl]acet-
amide (2a) (0.93 g, 5.0 mmol), the refluxing duration was
4 h. Yield 1.32 g (95%), white crystals, mp 208–209°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 3.94 (2Н, t,
J = 6.2, CH2SO2); 4.22 (2Н, s, CH2CO); 4.66 (2Н, t,
J = 6.2, CH2N+); 6.85 (2Н, d, J = 7.1, H-3,5 Py); 7.53 (1Н, s)
and 7.92 (1Н, s, NH2); 8.22 (2Н, d, J = 7.1, H-2,6 Py); 8.29
2-[(5-Bromopentyl)sulfonyl]acetamide
(2c) was
obtained from 2-[(5-bromopentyl)sulfanyl]acetamide (5c)
(8.14 g, 0.033 mol). Yield 7.11 g (77%), white crystals,
1
mp 112–113°C. H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 1.48–1.55 (2Н, m, СН2); 1.70–1.78 (2Н, m, СН2);
1.81–1.88 (2Н, m, СН2); 3.28 (2Н, t, J = 7.9, CH2SO2);
3.54 (2Н, t, J = 6.7, CH2Br); 4.00 (2Н, s, CH2CO); 7.43
(1Н, s) and 7.72 (1Н, s, NH2). 13C NMR spectrum (100 MHz),
δ, ppm: 20.8 (CH2); 26.8 (CH2); 32.1 (CH2); 35.1 (CH2);
52.8 (CH2SO2); 58.2 (SO2CH2CO); 164.2 (C=O). Found,
%: С 30.82; Н 5.14; Br 29.28; N 5.09; S 11.73.
С7H14BrNO3S. Calculated, %: С 30.89; Н 5.18; Br 29.36;
N 5.15; S 11.78.
Preparation of 1-[ω-(carbamoylmethylsulfonyl)alkyl]-
pyridinium halides 1a–o (General method). Equimolar
amounts of 2-[(ω-haloethyl)sulfonyl]acetamide 2a–c and
pyridine (7а) or substituted pyridine derivative 7b–g were
refluxed in anhydrous MeCN (40–50 ml) for
4–36 h. The precipitate that formed was filtered off and
washed with anhydrous MeCN.
1-[2-(Carbamoylmethylsulfonyl)ethyl]pyridinium
chloride (1a) was obtained by starting from pyridine (7а)
(0.43 g, 5.5 mmol) and 2-[(2-chloroethyl)sulfonyl]acet-
amide (2а) (1.02 g, 5.5 mmol), the refluxing duration was
4 h. Yield 0.65 g (45%), white crystals, mp 197–199°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 4.19 (2Н, t,
J = 6.4, CH2SO2); 4.32 (2Н, s, CH2CO); 5.21 (2Н, t,
J = 6.4, CH2N+); 7.56 (1Н, s) and 7.98 (1Н, s, NH2); 8.20
(2Н, t, J = 7.2, H-3,5 Py); 8.65 (1Н, t, J = 7.7, H-4 Py); 9.21
(2Н, d, J = 5.6, H-2,6 Py). 13C NMR spectrum (100 MHz),
δ, ppm: 53.0 (CH2SO2); 54.2 (SO2CH2CO); 58.9 (CH2N+);
128.3 (C-3,5 Py); 146.0 (C-4 Py); 146.8 (C-2,6 Py); 163.9
(C=O). Mass spectrum, m/z: 229 [M–Cl]+. Found, %:
С 40.72; Н 4.89; Cl 13.32; N 10.54; S 12.01. С9H13ClN2O3S.
Calculated, %: С 40.83; Н 4.95; Cl 13.39; N 10.58; S 12.11.
1-[3-(Carbamoylmethylsulfonyl)propyl]pyridinium
chloride (1b) was obtained by starting from pyridine (7а)
(0.4 g, 5.0 mmol) and 2-[(3-chloropropyl)sulfonyl]acet-
amide (2b) (1.0 g, 5.0 mmol), the refluxing duration was
40 h. Yield 0.11 g (8%), light-brown crystals, mp 200–201°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 2.43–2.47
(2Н, m, СН2); 3.40 (2Н, t, J = 7.3, CH2SO2); 4.12 (2Н, s,
CH2CO); 4.78 (2Н, t, J = 7.3, CH2N+); 7.46 (1Н, s) and 7.95
(1Н, s, NH2); 8.18 (2Н, t, J = 7.1, H-3,5 Py); 8.63 (1Н, t,
J = 7.9, H-4 Py); 9.15 (2Н, d, J = 5.9, H-2,6 Py). 13C NMR
13
(2Н, s, 4-NH2 Py). C NMR spectrum (100 MHz), δ, ppm:
50.4 (CH2SO2); 53.0 (SO2CH2CO); 58.9 (CH2N+); 109.7
(C-3,5 Py); 143.7 (C-2,6 Py); 159.4 (C-1 Py); 164.0 (C=O).
Mass spectrum, m/z: 244 [M–Cl]+. Found, %: С 38.61;
Н 4.98; Cl 12.63; N 14.97; S 11.41. С9H14ClN3O3S.
Calculated, %: С 38.64; Н 5.04; Cl 12.67; N 15.02;
S 11.46.
4-Amino-1-[3-(carbamoylmethylsulfonyl)propyl]pyri-
dinium chloride (1e) was obtained from 4-aminopyridine
(7b) (0.47 g, 5.0 mmol) and 2-[(3-chloropropyl)sulfonyl]-
acetamide (2b) (1.0 g, 5.0 mmol), the refluxing duration
was 10 h. Yield 0.24 g (16%), white crystals, mp 213–214°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 2.22–2.26
(2Н, m, СН2); 3.33 (2Н, t, J = 7.9, CH2SO2); 4.11 (2Н, s,
CH2CO); 4.26 (2Н, t, J = 7.1, CH2N+); 6.89 (2Н, d, J = 6.5,
H-3,5 Py); 7.46 (1Н, s) and 7.92 (1Н, s, NH2); 8.20 (2Н, d,
J = 6.5, H-2,6 Py); 8.34 (2Н, br. s, 4-NH2 Py). 13C NMR
spectrum (150 MHz), δ, ppm: 23.4 (CH2); 49.9 (CH2SO2);
55.6 (SO2CH2CO); 58.3 (CH2N+); 110.0 (C-3,5 Py); 143.3
(C-2,6 Py); 159.3 (C-1 Py); 164.2 (C=O). Mass spectrum,
m/z: 258 [M–Cl]+. Found, %: С 40.85; Н 5.47; Cl 12.04;
N
14.24; S 10.88. С10H16ClN3O3S. Calculated, %:
С 40.88; Н 5.49; Cl 12.07; N 14.30; S 10.92.
4-Amino-1-[5-(carbamoylmethylsulfonyl)pentyl]pyri-
dinium bromide (1f) was obtained from 4-aminopyridine
(7b) (0.47 g, 5.0 mmol) and 2-[(5-bromopentyl)sulfonyl]-
acetamide (2c) (1.36 g, 5.0 mmol), the refluxing duration was
871

Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
10 h. Yield 1.48 g (81%), beige crystals, mp 180–182°C.
4.02 (2Н, s, CH2CO); 4.74 (2Н, t, J = 7.6, CH2N+); 7.42
(1Н, s) and 7.76 (1Н, s, NH2); 8.30 (1Н, t, J = 6.9, H-5 Py);
8.99 (1Н, d, J = 8.1, H-4 Py); 9.33 (1Н, d, J = 5.7, H-6 Py);
9.66 (1Н, s, H-2 Py). 13C NMR spectrum (150 MHz),
δ, ppm: 21.1 (CH2); 24.6 (CH2); 30.7 (CH2); 52.8 (OCH3);
54.0 (CH2SO2); 58.3 (SO2CH2CO); 61.3 (CH2N+); 128.9
(C-5 Py); 130.4 (C-3 Py); 145.6 (C-4 Py); 146.5 (C-2 Py);
148.5 (C-6 Py); 162.7 (COОМе); 164.3 (C(O)NH2). Mass
spectrum, m/z: 329 [M–Br]+. Found, %: С 40.96; Н 5.14;
Br 19.48; N 6.80; S 7.77. С14H21BrN2O5S. Calculated, %:
С 41.08; Н 5.17; Br 19.52; N 6.84; S 7.83.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.33–1.40
(2Н, m, СН2); 1.71–1.82 (4Н, m, СН2); 3.28 (2Н, t, J = 7.8,
CH2SO2); 4.01 (2Н, s, CH2CO); 4.14 (2Н, t, J = 7.2,
CH2N+); 6.85 (2Н, d, J = 7.4, H-3,5 Py); 7.43 (1Н, s) and
7.77 (1Н, s, NH2); 8.10 (2Н, s, 4-NH2 Py); 8.21 (2Н, d,
J = 7.4, H-2,6 Py). 13C NMR spectrum (150 MHz), δ, ppm:
21.1 (CH2); 24.6 (CH2); 30.0 (CH2); 52.8 (CH2SO2); 57.2
(SO2CH2CO); 58.3 (CH2N+); 109.9 (C-3,5 Py); 143.3
(C-2,6 Py); 159.1 (C-1 Py); 164.3 (C=O). Mass spectrum, m/z:
286 [M–Br]+. Found, %: С 39.30; Н 5.48; Br 21.77;
N 11.42; S 8.73. С12H20BrN3O3S. Calculated, %: С 39.35;
Н 5.50; Br 21.81; N 11.47; S 8.75.
3-Carbamoyl-1-[2-(carbamoylmethylsulfonyl)ethyl]-
pyridinium chloride (1j) was obtained from nicotinamide
(7е) (0.64 g, 5.2 mmol) and 2-[(2-chloroethyl)sulfonyl]-
acetamide (2а) (0.97 g, 5.2 mmol), the refluxing duration was
17 h. Yield 0.60 g (37%), white crystals, mp 188–189°C.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 4.24 (2Н, t,
J = 6.4, CH2SO2); 4.32 (2Н, s, CH2CO); 5.24 (2Н, t, J = 6.4,
CH2N+); 7.57 (1Н, s) and 7.95 (1Н, s, CH2С(О)NH2); 8.16
(1Н, s) and 8.69 (1Н, s, С(О)NH2); 8.30 (1Н, dd, J = 8.1,
J = 7.8, H-5 Py); 9.03 (1Н, d, J = 8.2, H-4 Py); 9.31 (1Н, d,
J = 6.0, H-6 Py); 9.68 (1Н, s, H-2 Py). 13C NMR spectrum
(100 MHz), δ, ppm: 52.9 (CH2SO2); 54.6 (SO2CH2CO);
58.8 (CH2N+); 128.0 (C-5 Py); 134.0 (C-3 Py); 144.7 (C-4 Py);
146.1 (C-2 Py); 147.7 (C-6 Py); 163.2 (C(O)NH2); 163.9
(CH2C(O)NH2). Mass spectrum, m/z: 272 [M–Cl]+. Found, %:
С 38.97; Н 4.52; Cl 11.46; N 13.63; S 10.39. С10H14ClN3O4S.
Calculated, %: С 39.03; Н 4.59; Cl 11.52; N 13.65; S 10.42.
3-Carbamoyl-1-[5-(carbamoylmethylsulfonyl)pentyl]-
pyridinium bromide (1k) was obtained from nicotinamide
(7е) (0.61 g, 5.0 mmol) and 2-[(5-bromopentyl)sulfonyl]-
acetamide (2с) (1.36 g, 5.0 mmol), the refluxing duration
was 18 h. Yield 0.83 g (42%), white crystals, mp 140–141°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.43–1.47
(2Н, m, СН2); 1.76–1.80 (2Н, m, СН2); 1.99–2.03 (2Н, m,
СН2); 3.30 (2Н, t, J = 7.8, CH2SO2); 4.02 (2Н, s, CH2CO);
4.69 (2Н, t, J = 7.4, CH2N+); 7.42 (1Н, s) and 7.77 (1Н, s,
CH2С(О)NH2); 8.14 (1Н, s) and 8.57 (1Н, s, С(О)NH2);
8.28 (1Н, t, J = 7.1, H-5 Py); 8.97 (1Н, d, J = 8.0, H-4 Py);
9.25 (1Н, d, J = 6.2, H-6 Py); 9.55 (1Н, s, H-2 Py).
13C NMR spectrum (100 MHz), δ, ppm: 21.1 (CH2); 24.6
(CH2); 30.5 (CH2); 52.7 (CH2SO2); 58.3 (SO2CH2CO); 61.2
(CH2N+); 128.3 (C-5 Py); 134.3 (C-3 Py); 143.9 (C-4 Py);
145.2 (C-2 Py); 146.8 (C-6 Py); 163.3 (C(O)NH2); 164.3
(CH2C(O)NH2). Mass spectrum, m/z: 314 [M–Br]+. Found,
%: С 39.57; Н 5.08; Br 20.21; N 10.62; S 8.11.
С13H20BrN3O4S. Calculated, %: С 39.60; Н 5.11; Br 20.27;
N 10.66; S 8.13.
2-Amino-1-[2-(carbamoylmethylsulfonyl)ethyl]pyri-
dinium chloride (1g) was obtained from 2-aminopyridine
(7c) (0.44 g, 4.6 mmol) and 2-[(2-chloroethyl)sulfonyl]-
acetamide (2a) (0.86 g, 4.6 mmol), the refluxing duration
was 5 h. Yield 1.12 g (89%), white crystals, mp 212–213°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 3.90 (2Н, t,
J = 6.2, CH2SO2); 4.28 (2Н, s, CH2CO); 4.71 (2Н, t,
J = 6.2, CH2N+); 6.90 (1Н, t, J = 6.7, H-5 Py); 7.12 (1Н, d,
J = 9.0, H-3 Py); 7.61 (1Н, s, NH2); 7.96 (1Н, s) and 7.88
(1Н, t, J = 7.8, H-4 Py); 8.06 (1Н, d, J = 5.7, H-2 Py); 8.73
(2Н, br. s, 2-NH2 Py). 13C NMR spectrum (150 MHz), δ, ppm:
47.1 (CH2SO2); 50.1 (SO2CH2CO); 59.0 (CH2N+); 113.0
(C-3 Py); 115.4 (C-5 Py); 141.2 (C-4 Py); 143.1 (C-6 Py);
154.5 (C-2 Py); 164.4 (C=O). Mass spectrum, m/z: 244
[M–Cl]+. Found, %: С 38.60; Н 5.02; Cl 12.64; N 14.98;
S 11.41. С9H14ClN3O3S. Calculated, %: С 38.64; Н 5.04;
Cl 12.67; N 15.02; S 11.46.
2-Amino-1-[5-(carbamoylmethylsulfonyl)pentyl]pyri-
dinium bromide (1h) was obtained from 2-aminopyridine
(7c) (0.37 g, 4.0 mmol) and 2-[(5-bromopentyl)sulfonyl]-
acetamide (2c) (1.09 g, 5.0 mmol), the refluxing duration
was 12 h. Yield 1.46 g (67%), beige crystals, mp 169–170°C.
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.44–1.49
(2Н, m, СН2); 1.71–1.79 (4Н, m, СН2); 3.29 (2Н, t, J = 7.8,
CH2SO2); 4.01 (2Н, s, CH2CO); 4.16 (2Н, t, J = 7.4, CH2N+);
6.92 (1Н, t, J = 6.2, H-5 Py); 7.07 (1Н, d, J = 8.2, H-3 Py);
7.43 (1Н, s) and 7.75 (1Н, s, NH2); 7.87 (1Н, t, J = 7.4,
H-4 Py); 8.08 (1Н, d, J = 6.7, H-2 Py); 8.45 (2Н, br. s,
2-NH2 Py). 13C NMR spectrum (150 MHz), δ, ppm: 21.3
(CH2); 24.8 (CH2); 27.3 (CH2); 52.8 (CH2SO2); 53.2
(SO2CH2CO); 58.3 (CH2N+); 113.5 (C-3 Py); 115.4 (C-5 Py);
140.5 (C-4 Py); 142.7 (C-6 Py); 154.1 (C-2 Py); 164.3
(C=O). Mass spectrum, m/z: 286 [M–Br]+. Found, %:
С 39.32; Н 5.44; Br 21.78; N 11.45; S 8.72. С12H20BrN3O3S.
Calculated, %: С 39.35; Н 5.50; Br 21.81; N 11.47; S 8.75.
1-[5-(Carbamoylmethylsulfonyl)pentyl]-3-(methoxy-
carbonyl)pyridinium bromide (1i) was obtained from
methyl nicotinate (7d) (0.55 g, 4.0 mmol) and 2-[(5-bromo-
pentyl)sulfonyl]acetamide (2c) (1.09 g, 4.0 mmol), the
refluxing duration was 18 h. The reaction mixture was
filtered, the filtrate was evaporated, the residue was washed
with acetone (20 ml) and MeOH (20 ml), then dried at
reduced pressure. Yield 0.64 g (39%), yellow transparent thick
oil. 1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.43–1.46
(2Н, m, СН2); 1.76–1.79 (2Н, m, СН2); 1.97–2.01 (2Н, m,
СН2); 3.29 (2Н, t, J = 7.8, CH2SO2); 4.00 (3Н, s, OCH3);
1-[2-(Carbamoylmethylsulfonyl)ethyl]-3-hydrazino-
carbonylpyridinium chloride (1l) was obtained from
nicotinyl hydrazide (7f) (0.60 g, 4.4 mmol) and 2-[(2-chloro-
ethyl)sulfonyl]acetamide (2a) (0.81 g, 4.4 mmol), the
refluxing duration was 22 h. Yield 0.70 g (50%), yellowish
1
powder, mp 227–228°C. H NMR spectrum (600 MHz),
δ, ppm (J, Hz): 3.78 (2Н, t, J = 5.9, CH2SO2); 3.97 (2Н, t,
J = 6.0, CH2N+); 4.50 (2Н, s, CH2CO); 7.52 (1Н, s, C(O)NH2);
7.56–7.58 (1H, m, H-5 Py); 7.89 (1Н, s, C(O)NH2); 8.23
(1Н, d, J = 8.1, H-4 Py); 8.79 (1Н, d, J = 6.2, H-6 Py); 9.05
(1Н, s, H-2 Py); 11.16 (1Н, s, NHNH2). 13C NMR spectrum
872

Chemistry of Heterocyclic Compounds 2018, 54(9), 868–874
(150 MHz), δ, ppm (J, Hz): 47.2 (CH2SO2); 49.3
(J, Hz): 1.45–1.47 (2Н, m, СН2); 1.74–1.78 (2Н, m, СН2);
1.98–2.00 (2Н, m, СН2); 3.29 (2Н, t, J = 6.9, CH2SO2);
4.02 (2Н, s, CH2CO); 4.68 (2Н, t, J = 6.9, CH2N+); 7.42 (1Н, s)
and 7.78 (1Н, s, C(O)NH2); 7.82–7.84 (2Н, m, H Py); 8.81–8.83
(SO2CH2CO); 56.9 (CH2N+); 124.2 (C-5 Py); 128.1 (C-3 Py);
135.9 (C-4 Py); 149.1 (C-2 Py); 153.3 (C-6 Py); 161.2
(C(O)NHNH2); 164.2 (C(O)NH2). Mass spectrum, m/z: 287
[M–Cl]+. Found, %: С 37.18; Н 4.67; Cl 10.93; N 17.31;
S 9.90. С10H15ClN4O4S. Calculated, %: С 37.21; Н 4.68;
Cl 10.98; N 17.36; S 9.93.
13
(2Н, m, J = 6.2, H-6 Py); 10.90 (1Н, s, NHNH2). C NMR
spectrum (100 MHz), δ, ppm (J, Hz): 21.0 (CH2); 24.38
(CH2); 30.4 (CH2); 52.7 (CH2SO2); 58.4 (SO2CH2CO);
58.6 (CH2N+); 124.2 (C-3,5 Py); 128.8 (C-4 Py); 146.1
(C-2,6 Py); 161.5 (C(O)NHNH2); 162.4 (C(O)NH2). Mass
spectrum, m/z: 329 [M–Br]+. Found, %: С 38.11; Н 5.15;
Br 19.48; N 13.67; S 7.81. С13H21BrN4O4S. Calculated, %:
С 38.15; Н 5.17; Br 19.52; N 13.69; S 7.83.
2-(Vinylsulfonyl)acetamide (8). 4-Aminomethylpyridine
(7h) (0.4 g, 3.8 mmol) was added to a solution of 2-[(2-chloro-
ethyl)sulfonyl]acetamide (2а) (0.7 g, 3.8 mmol) in MeCN
(40 ml), the reaction mixture was stirred for 15 min,
filtered, evaporated, and the residue was washed with
diethyl ether. Yield 0.52 g (93%), light-green thick oil that
crystallized during storage, mp 78°C (CHCl3) (mp 81°C22).
1H NMR spectrum (600 MHz), δ, ppm (J, Hz): 4.06 (2Н, s,
CH2CO); 6.22–6.26 (2Н, m, CH2= CH); 7.00–7.04 (1Н, m,
CH2=CH); 7.40 (1Н, s) and 7.66 (1Н, s, NH2). Found, %:
С 32.18; Н 4.69; N 9.37; S 21.43. С4H7NO3S. Calculated,
%: С 32.21; Н 4.73; N 9.39; S 21.50.
Tuberculostatic activity studies of compounds 1a–o, 7g
were performed according to the vertical diffusion method
using laboratory strain H37Rv of M. tuberculosis on ''New''
brand dense nutrient medium. The nutrient medium (5 ml
portions) was poured into test tubes rolling so that part of
the bottom of each test tube remained free. The rolled
nutrient medium was inoculated with 0.1 ml of suspension
containing the strain H37Rv of M. tuberculosis, diluted to
10 units according to L. A. Tarasevich State Control
Institute turbidity standards, and placed in thermostat in
inclined position for 24 h to enable the growth of
M. tuberculosis. The next day, the test tubes were turned to
vertical position and solutions of the study compounds
(0.3 ml) with concentrations of 12.5, 6.2, 3.1, 1.2, 0.6, and
0.3 µl/ml were added along the free side of each test tube.
The test tubes were then placed in thermostat at 37°С
temperature and incubated for 10 days. The growth of
M. tuberculosis was evaluated according to standard
method, where the presence of growth inhibition zones
(larger than 10 mm) served as evidence of tuberculostatic
properties of the compounds at the applied concentrations.
The size of growth inhibition zone for M. tuberculosis (in
mm) was proportional to the degree of tuberculostatic acti-
vity of the compounds. Growth inhibition zones of 100 mm
or larger were interpreted as complete inhibition of
M. tuberculosis growth.22
1-[5-(Carbamoylmethylsulfonyl)pentyl]-3-hydrazino-
carbonylpyridinium bromide (1m) was obtained from
nicotinyl hydrazide (7f) (0.32 g, 2.4 mmol) and 2-[(5-bromo-
pentyl)sulfonyl]acetamide (2c) (0.64 g, 2.4 mmol), the
refluxing duration was 22 h. Yield 0.50 g (52%), light-
yellow hygroscopic powder. 1H NMR spectrum (600 MHz),
δ, ppm (J, Hz): 1.47–1.49 (2Н, m, СН2); 1.76–1.78 (2Н, m,
СН2); 1.99–2.02 (2Н, m, СН2); 3.29 (2Н, t, J = 6.7,
CH2SO2); 4.02 (2Н, s, CH2CO); 4.71 (2Н, t, J = 6.7,
CH2N+); 7.42 (1Н, s) and 7.78 (1Н, s, C(O)NH2); 7.60–7.62
(1Н, m, H-5 Py); 8.27 (1Н, d, J = 8.0, H-4 Py); 8.81 (1Н, d,
J = 6.2, H-6 Py); 9.04 (1Н, s, H-2 Py); 11.10 (1Н, s,
NHNH2). 13C NMR spectrum (100 MHz), δ, ppm: 21.1
(CH2); 24.7 (CH2); 30.5 (CH2); 52.8 (CH2SO2); 58.4
(SO2CH2CO); 61.4 (CH2N+); 118.5 (C-5 Py); 124.4
(C-3 Py); 136.3 (C-4 Py); 148.8 (C-2 Py); 153.4 (C-6 Py);
164.3 (C(O)NHNH2); 165.0 (C(O)NH2). Mass spectrum, m/z:
329 [M–Br]+. Found, %: С 38.13; Н 5.15; Br 19.47;
N 13.66; S 7.80. С13H21BrN4O4S. Calculated, %: С 38.15;
Н 5.17; Br 19.52; N 13.69; S 7.83.
1-[2-(Carbamoylmethylsulfonyl)ethyl]-4-hydrazino-
carbonylpyridinium chloride (1n). Method I. Compound
1n was prepared according to the general method from iso-
nicotinyl hydrazide (7g) (0.55 g, 4.0 mmol) and 2-[(2-chloro-
ethyl)sulfonyl]acetamide (2a) (0.74 g, 4.0 mmol), the
refluxing duration was 22 h. Yield 0.41 g (32%), yellow
hygroscopic powder.
Method II. A solution of 2-vinylsulfonylacetamide (8)
(1.1 g, 7.3 mmol) in EtOH (15 ml) was added to a solution
of isonicotinyl hydrazide (7g) (1.0 g, 7.3 mmol) in a mixture
of EtOH (20 ml), water (6 ml), and concd HCl (0.7 ml).
The mixture was refluxed for 5 h, filtered, and evaporated.
The residue was dissolved in MeOH, filtered, evaporated,
and dried at reduced pressure. Yield 1.32 g (56%), light-
1
brown powder. H NMR spectrum (400 MHz), δ, ppm
(J, Hz): 3.80 (2Н, t, J = 5.7, CH2SO2); 3.98 (2Н, t, J = 5.7,
CH2N+); 4.53 (2Н, s, CH2CO); 7.56–7.58 (1H, m, H-5 Py);
8.15 (1Н, s, C(O)NH2); 8.22–8.24 (2Н, m, H Py); 8.94 (1H,
s, C(O)NH2); 8.99–9.04 (1Н, m, H-6 Py); 11.81 (1Н, s,
NHNH2). 13C NMR spectrum (100 MHz); δ, ppm (J, Hz):
47.0 (CH2SO2); 49.2 (SO2CH2CO); 56.9 (CH2N+); 124.5
(C-3,5 Py); 129.8 (C-4 Py); 146.1 (C-2,6 Py); 161.0
(C(O)NHNH2); 163.4 (C(O)NH2). Mass spectrum, m/z: 287
[M–Cl]+. Found, %: С 37.16; Н 4.65; Cl 10.94; N 17.32;
S 9.89. С10H15ClN4O4S. Calculated, %: С 37.21; Н 4.68;
Cl 10.98; N 17.36; S 9.93.
This study received financial support from the Russian
Science Foundation (project 14-50-00014).
1-[5-(Carbamoylmethylsulfonyl)pentyl]-4-hydrazino-
carbonylpyridinium bromide (1o) was obtained from iso-
nicotinyl hydrazide (7g) (0.37 g, 2.7 mmol) and 2-[(5-bromo-
pentyl)sulfonyl]acetamide (2c) (0.74 g, 2.7 mmol), the
refluxing duration was 21 h. Yield 0.48 g (43%), light-
yellow resin. 1H NMR spectrum (400 MHz), δ, ppm
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