Synthesis and Antimicrobial Activity of Amines Containing Carbamoylmethylsulfonyl Fragments

Article abstract of DOI:10.1134/S107036321811004X

A series of amines containing long hydrocarbon substituents and carbamoylmethylsulfonyl fragments have been synthesized. Antimicrobial activity of the prepared amines and their hydrochlorides against several test microorganisms has been investigated.

Full text of DOI:10.1134/S107036321811004X

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 11, pp. 2263–2268. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © M.M. Shulaeva, A.D. Voloshina, A.S. Sapunova, N.V. Kulik, V.E. Semenov, 2018, published in Zhurnal Obshchei Khimii, 2018,
Vol. 88, No. 11, pp. 1782–1788.
Dedicated to the 115th anniversary of B.A. Arbuzov’s birth
Synthesis and Antimicrobial Activity of Amines
Containing Carbamoylmethylsulfonyl Fragments
M. M. Shulaevaa*, A. D. Voloshinaa, A. S. Sapunovaa, N. V. Kulika, and V. E. Semenova
a A.E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences,
ul. Akademika Arbuzova 8, Kazan, Tatarstan, 420088 Russia
*e-mail: mshulaeva@iopc.ru
Received May 24, 2018
Abstract—A series of amines containing long hydrocarbon substituents and carbamoylmethylsulfonyl
fragments have been synthesized. Antimicrobial activity of the prepared amines and their hydrochlorides
against several test microorganisms has been investigated.
Keywords: antimicrobial activity, antimycobacterial activity, amines, carbamoylmethylsulfonyl group
DOI: 10.1134/S107036321811004X
Many of tertiary ammonium compounds are known
to exhibit bacteriostatic and bactericide properties and
have been widely used as antiseptics in medicine
[1–3]. The mechanism of their action is based on the
interaction with phospholipids of cytoplasmatic
membrane of a bacterial cell which causes its dis-
organization, flowing out of intracellular low-
molecular compounds, decomposition of the proteins
and nucleic acids, and lysis of cell wall [4, 5]. Low
doses of tertiary ammonium compounds cause less
deep changes and disorder the membrane functions:
change the osmotic pressure, permeability, and rate of
transfer of molecules and ion through the membrane,
inhibit the metabolic processes and biological
oxidation, and retard cell fission [5]. However,
majority of the drugs of this group is inactive against
intracellularly localized viruses, endospore form of
bacteria, and tuberculosis mycobacteria [5–7]. On the
other hand, it is known that different alkyl derivatives
containing terminal carbamoylmethylsulfonyl group
exhibit antimycobacterial properties but at the same
time do not exhibit antimicrobial action against other
microorganisms [8–10]. The investigation of n-octyl-
sulfonylacetamide has shown that such compounds can
affect the ATP-synthetase and components of respire-
tory chain of mycobacteria [11, 12]. The functionaliza-
tion of such structures with alkylamine or alkylammo-
nium groups may result in new properties, in parti-
cular, the combination of antimycobacterial and anti-
microbial activity against different microorganisms.
In this study, we synthesized a series of amines
containing long hydrocarbon substituents and carba-
moylmethylsulfonyl fragments in the N-alkyl chain. It
was supposed that such compounds might exhibit a
wide range of antimicrobial activity including that
against tuberculosis mycobacteria. The key starting
2-[(2-chloroethyl)sulfonyl]acetamide 1 was prepared
via the reaction of amide of thioglycolic acid with
1-bromo-2-chloroethane with further oxidation of the
formed 2-[(2-chloroethyl)sulfanyl]acetamide 2 with
hydrogen peroxide (Schemes 1 and 2). Significant
amount of bis-1,2-(carbamoylmethylsulfanyl)ethane 3
was formed during the alkylation of thioglyconate [9].
To avoid its formation, the reaction should be carried
out with large excess of 1-bromo-2-chloroethane. The
optimal temperature for oxidation of 2-chloroethyl-
sulfide 2 with hydrogen peroxide in acetic acid was
found to be of 50–60°С; otherwise the yield of sulfone
1 was critically decreased.
The target tertiary (4a–5c) and secondary (6a, 6b)
amines containing carbamoylmethylsulfonyl fragments
in the N-alkyl chain were prepared via the reaction of
2-[(2-chloroethyl)sulfonyl]acetamide 1 with different
primary and secondary amines in the presence of
carbonates (Schemes 3 and 4). The corresponding
2263

2264
SHULAEVA et al.
Scheme 1.
NH2
Br
Cl
+
+
HS
O
O
MeONa_MeOH
Cl
NH2
S
NH2
S
H2N
S
O
O
2
3
Scheme 2.
O
S
H2O2_AcOH
20 h, 60oC
Cl
NH2
Cl
NH2
S
O
O
O
1
2
hydrochlorides 7a, 7b were prepared via the reaction
of dodecyl(methyl)amine 4a and hexadecylamine 6b
with HCl.
The screening of antimicrobial activity against a
series of test microorganisms was performed for the
prepared amines 4–6 and their hydrochlorides 7a, 7b.
The results are given in Table 1. According to the
obtained data, dodecyl(methyl)amine 4a and its
hydrochloride 7a exhibited the highest bacteriostatic
activity against Staphylococcus aureus and Bacillus
cereus as compared with other studied compounds.
The MIC value was 31.3 and 15.6 µg/mL, respec-
tively, 2–4 times higher than that of reference drug
Dinonylamine 4b and didecylamine 4c were tar-
like substances, other amines 4–6 were isolated as
crystalline substances which did not exhibit a distinct
melting point. Amines 4–6 were soluble in methanol
and acetone, poorly soluble in ethyl acetate and
acetonitrile, and insoluble in water.
Scheme 3.
R1
O
O
S
Na2CO3_CH3CN
4_6 h
Cl
NH2
N
NH2
R1R2NH
S
O
1
+
R2
O
O
4а−4c
O
R1 = CH3, R2 = C12H25 (4a); R1 = R2 = C9H19 (4b), R1 = R2 = C10H21 (4c).
Scheme 4.
R
O
S
O
O
S
Cl
NH2
H2N
N
NH2
Na2CO3_CH3CN
15_20 h
RNH2
+
S
O
O
O
O
O
O
O
5а_5c
1
R
N
O
NH2
+
S
H
O
6а, 6b
R = C8H17 (5a, 6а), C9H19 (5b), C16H33 (5c, 6b).
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF AMINES
2265
Table 1. Bacteriostatic, fungistatic (MIC), bactericide (MBC), and fungicide (MFC) activity of 2-(carbamoylmethylsulfonyl)-
ethylamines 4–6a and their hydrochlorides 7
Staphylococcus aureus
Bacillus сereus
Candida albicans
Compound
MIC,
µg/mL
MBC/MFC,
µg/mL
MBC/MFC,
MBC/MFC,
MIC, µg/mL
MIC, µg/mL
µg/mL
µg/mL
4a
15.6±1.2
62.5±5.7
125.0±11.0
15.6±1.2
–
15.6±1.2
125.0±11.0
–
31.3±2.7
–
62.5±5.7
62.5±5.7
4b
–
–
31.3±2.6
31.3±2.6
6b
–
–
31.3±2.6
–
–
–
7a
7b
15.6±1.3
125.0±12.0
15.6±1.3
–
31.3±2.5
31.3±2.5
–
–
–
–
Chloramphenicol
62.5±5.8
62.5±5.6
а Compounds 4c and 5a–c did not exhibit activity.
chloramphenicol. At the same time, the studied
compounds limited the growth of yeast fungus
C. аlbicans at concentrations 62.5 and 31.3 µg/mL, in
contrast to chloramphenicol, and did not affect
negatively on E. coli. The hydrochloride 7a was found
to be more active than the amine 4a, probably because
of the higher solubility in water. Dinonylamine 4b
exhibited bacteriostatic activity comparable with
chloramphenicol against bacteria St. aureus (MIC
62.5 µg/mL) and fungistatic activity against fungi C.
albicans (MIC 31.3 µg/mL). The investigated com-
pounds were inactive against bacteria Escherichia coli,
Pseudomonas aeruginosa, Aspergillus niger, and
Trichophyton mentagrophytes.
In summary, novel derivatives of amines containing
long alkyl substitutes and carbamoylmethylsulfonyl
fragments were synthesized. Some of them, in
particular, [2-(carbamoylmethylsulfonyl)ethyl]dodecyl-
amine 4a and its hydrochloride 7a, exhibited anti-
microbial action against Staphylococcus aureus and
Bacillus cereus as well as yeast fungus Candida
albicans at concentrations 15.6–62.5 µg/mL and
against lab strain of tuberculosis mycobacteria at
concentration 12.5 µg/mL. Those compounds were not
cytotoxic for human blood erythrocytes at concentra-
tions suppressing the growth of bacteria and fungi.
Taking into account the mentioned facts, the search of
novel antiseptic drugs in the discussed class of the
compounds is promising.
The investigation of bactericide and fungicide
action of the prepared compounds showed that
compound 7a at concentrations 15.6–31.3 µg/mL
inhibited growth and caused death of microorganisms
(Table 1). For example, hydrochloride 7a exhibited
bactericide action against St. aureus and B. cereus
strains (MBC 15.6 and 31.3 µg/mL, respectively) and
fungicide action against C. albicans (MFC 31.3 µg/mL).
EXPERIMENTAL
1
The H and 13С NMR spectra (DMSO-d6) were
registered using AVANCE-600 and Bruker MSL-400
Table 2. Hemolytic activity of compounds 4a, 4b, and 7a
Compound
Concentration, µg/mL Hemolysis, %
Moreover, tuberculostatic activity of hydrochloride
7a against lab strain M. tuberculosis H37Rv was
investigated. Compound 7a inhibited the growth of
mycobacteria at concentration 12.5 µg/mL.
4a
15.6
31.3
62.5
0.9
0.4
0.9
4b
7a
31.3
62.5
0.4
5.2
The degree of hemolysis of erythrocytes of human
blood was measured for the most active compounds
(Table 2). Compounds 4a, 4b, and 7a at concentrations
15.6–62.5 µg/mL exhibited low hemolytic activity
(0.4–5.2%). Hemolytic activity of the reference drug
gramicidin S under the same conditions was 98–100%.
15.6
31.3
0.5
1.1
Gramicidin S
15.6
31.3
62.5
98
99
100
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2266
SHULAEVA et al.
spectrometers (internal reference—Me4Si). Thin-layer
chromatography was performed on Silufol-254 plates
(developer – iodine). Melting points were measured
using a Boёtius heating bench. Mass spectra (MALDI-
TOF) were registered using an Ultraflex III (Bruker)
device (matrix—p-nitroaniline). The С, Н, and N
contents in the prepared compounds were determined
using a CHN-3 device. The assessment of hemolytic
activity of the synthesized compounds was performed
using an AP-101 digital photoelectrocalorimeter (Apel).
and 0.79 g (0.004 mmol) of dodecyl(metyl)amine were
added to 0.74 g (0.004 mol) of 2-[2-(chloroethyl)-
sulfonyl]acetamide in 40 mL of anhydrous acetonitrile.
The mixture was refluxed for 4 h, then cooled down
and kept for 1 day. White crystals were filtered off,
triturated in water, filtered, and dried. Yield 1.05 g
(75.5%), mp 75‒80°C. IR spectrum (KBr), ν, cm–1:
3391 s, 3196 s (N‒H), 2976 m, 2920 s, 2850 s (C‒H),
1670 s (amide I), 1629 m (amide II), 1467 m, 1421 m,
1378 m, 1313 s (S=O), 1172 s, 1123 s (S=O), 863 m,
831 сm, 697 m, 655 m, 572 m, 536 m, 500 m. 1Н NMR
spectrum, δ, ppm (J, Hz): 0.86 t (3Н, CH3, 3JHH = 7.1),
1.25 br. s (18Н, СН2), 1.39 m (2Н, СН2), 2.17 s (3Н,
2-[(2-Chloroethyl)sulfonyl]acetamide (1). 15.5
mL of 35% solution of H2O2 was added dropwise to a
solution of 9.27 g (0.06 mol) of 2-[(2-chloroethyl)-
sulfanyl]acetamide 2 in 100 mL of glacial acetic acid
so that temperature of the reaction mixture did not
exceed 60°C. The mixture was heated at 55‒60°C for
20 h, then cooled down, and filtered. The filtrate was
evaporated off under reduced pressure (not to dryness).
100 mL of Et2O‒MeOH mixture (10 : 1) was added to
the residue, the precipitate was triturated, filtered, and
dried. Yield 8.17 g (73%), white crystalline substance,
3
CH3N), 2.30 t (2Н, CH2N, JHH = 7.0), 2.75 t (2Н,
3
3
CH2N, JHH = 6.8), 3.41 t (2Н, CH2SO2, JHH = 6.8),
13
4.07 s (2Н, CH2CO), 7.40 s and 7.70 s (2Н, NH2). С
NMR spectrum, δC, ppm: 14.40 (CH3), 22.58, 27.15,
27.33, 29.20, 29.53, 31.79 (CH2, С12H25), 41.83
(NCH3), 50.30 (NCH2, C12H25), 50.53 (NCH2), 57.17
(CH2SO2), 59.28 (SO2CH2CO), 164.38 (C=O). Mass
spectrum (MALDI-TOF), m/z: 349.3 [M + H]+, 371.3
[M + Na]+ (calculated for С17H36N2O3S: 348.5).
1
mp 126‒127°C. Н NMR spectrum, δ, ppm (J, Hz):
3
3.81 t (2Н, CH2SO2, JHH = 7.1), 3.97 t (2Н, CH2Cl,
2-{[2-(Dinonylamino)ethyl]sulfonyl}acetamide (4b)
was prepared similarly from 0.68 g (3.8 mmol) 2-[(2-
chloroethyl)sulfonyl]acetamide, 0.39 g (3.8 mmol) of
sodium carbonate, and 1.12 g (3.8 mmol) dinonyl-
amine hydrochloride; reaction duration 5 h. Yield 1.22 g
(80%), light yellow tranparent thick oil. 1Н NMR spec-
trum, δ, ppm (J, Hz): 0.90 t (6Н, CH3, 3JHH = 6.8), 1.28
br. s (24Н, СН2), 1.48 br. s (4Н, СН2), 2.51 t (4Н,
CH2N, 3JHH = 7.6), 3.07 t (2Н, CH2N, 3JHH = 6.5), 3.38
3JHH = 7.1), 4.12 s (2Н, CH2CO), 7.50 s and 7.77 s
(2Н, NH2). 13С NMR spectrum, δС, ppm: 36.61
(ClCH2), 55.15 (CH2SO2), 59.07 (SO2CH2CO), 164.11
(C=O). Found, %: С 25.83; Н 4.31; Cl 19.06; N 7.52;
S 17.28. С4H8ClNO3S. Calculated, %: С 25.88; Н
4.34; Cl 19.10; N 7.55; S 17.27.
2-[(Chloroethyl)sulfanyl]acetaminde (2). A solution
of 9 g (0.1 mmol) of amide of sulfanylacetic acid in
100 mL of МеОН was added dropwise to sodium
methylate prepared from 2.3 g (0.1 mol) of sodium in
100 mL of МеОН. The obtained solution of thiolate
was slowly added to 12.3 mL (21.45 g, 0.15 mol) of
1-bromo-2-cloroethane at 15‒20°C. The reaction
mixture was kept overnight and filtered. The filtrate
was evaporated off under reduced pressure. 100 mL of
EtOAc was added. The mixture was filtered and
evaporated off after a day. Yield 9.3 g (62%), thick oil
3
t (2Н, CH2SO2, JHH = 6.4), 4.14 s (2Н, CH2CO), 7.46
s and 7.77 s (2Н, NH2). 13С NMR spectrum, δC, ppm:
14.38 (CH3), 22.59, 26.66, 27.20, 29.26, 29.40, 29.50,
31.80 (CH2, С9H19), 46.67 (NCH2, C9H19), 49.70
(NCH2), 53.33 (CH2SO2), 59.10 (SO2CH2CO), 164.32
(C=O). Mass spectrum (MALDI-TOF), m/z: 419.4
[M + H]+, 441.3 [M + Na]+, 457.2 [M + K]+ (calculated
for С22H46N2O3S: 418.7).
2-{[2-(Didecylamino)ethyl]sulfonyl}acetamide (4c)
was prepared similarly from 0.86 g (4.6 mmol) 2-[(2-
chloroethyl)sulfonyl]acetamide, 0.49 g (4.6 mmol) of
sodium carbonate, and 1.54 g (4.6 mmol) didecylamine
hydrochloride; reaction duration 6 h. Yield 1.20 g
1
crystallizing during storage, mp 60‒61°C. Н NMR
3
spectrum, δ, ppm (J, Hz): 2.94 t (2Н, CH2S, JHH
=
=
3
7.6), 3.13 s (2Н, CH2CO), 3.78 t (2Н, CH2Cl, JHH
7.6), 7.03 s and 7.46 s (2Н, NH2). 13С NMR spectrum,
δC, ppm: 36.61 (CH2Cl), 55.15 (CH2SO2), 59.07
(SO2CH2CO), 164.11 (C=O). Found, %: С 31.22; Н
5.18; Cl 23.06; N 9.08; S 20.83. С4H8ClNOS. Cal-
culated, %: С 31.27; Н 5.25; Cl 23.08; N 9.12; S 20.87.
1
(58%), light yellow transparent thick oil. Н NMR
spectrum, δ, ppm (J, Hz): 0.86 t (6Н, CH3, 3JHH = 6.7),
1.25 br. s (28Н, СН2), 1.37 br. s (4Н, СН2), 2.36 t (4Н,
CH2N, 3JHH = 7.1), 2.85 t (2Н, CH2N, 3JHH = 7.1), 3.38
3
2-({[2-Dodecyl(methyl)amino]ethyl}sulfonyl)acet-
amide (4a). 0.51 g (0.004 mol) of sodium carbonate
t (2Н, CH2SO2, JHH = 6.7), 4.06 s (2Н, CH2CO), 7.40
s and 7.69 s (2Н, NH2). 13С NMR spectrum, δC, ppm:
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF AMINES
2267
14.36 (CH3), 22.57, 26.80, 27.21, 29.18, 29.38, 29.45,
29.52, 31.78 (CH2, С10H21), 46.73 (NCH2, C10H21),
49.79 (NCH2), 53.34 (CH2SO2), 59.12 (SO2CH2CO),
164.34 (C=O). Mass spectrum (MALDI-TOF), m/z:
446.4 [M]+, 469.4 [M + Na]+, 485.4 [M + K]+
(calculated for С24H50N2O3S: 446.7).
7.71 s (4Н, NH2). 13С NMR spectrum, δC, ppm: 14.43
(CH3), 22.57, 26.85, 27.28, 29.15, 29.47, 29.51, 31.77
(CH2, С9H19), 46.53 (NCH2, C10H21), 50.13 (NCH2),
52.99 (CH2SO2), 59.08 (SO2CH2CO), 164.30 (C=O).
Mass spectrum (MALDI-TOF), m/z: 442.2 [M + H]+,
464.2 [M + Na]+ (calculated for С17H35N3O6S2: 441.6).
Bis-[2-(carbamoylmethylsulfonyl)ethyl]octylamine
(5a). 0.53 g (3.8 mmol) of sodium carbonate and 0.25 g
(1.9 mmol) of octylamine were added to 0.79 g (4.2 mmol)
of 2-[(2-chloroethyl)sulfonyl]acetamide in 40 mL of
anhydrous acetonitrile. The obtained mixture was
refluxed for 15 h, then cooled down and kept for 1 day.
The precipitate was filtered off, the filtrate was
evaporated off. The residue was washed with ethyl
acetate, dried, and ground in water. Yield 0.48 g (57%),
Bis-[2-(carbamoylmethylsulfonyl)ethyl]hexadecyl-
amine (5c) was prepared similalry from 1.5 g (8.1 mmol)
2-[(2-chloroethyl)sulfonyl]acetamide, 0.78 g (7.2 mmol)
sodium carbonate, and 0.88 g (3.6 mmol) of hexa-
decylamine; reaction duration 15 h. Yield 0.40 g
(20%), white crystals, mp 103‒108°C. 1Н NMR
spectrum, δ, ppm (J, Hz): 0.86 t (3Н, CH3, 3JHH = 6.9),
1.24 br. s (26Н, СН2), 1.40 br. s (2Н, СН2), 2.43 br. s
(2Н, CH2N), 2.90 t (4Н, CH2N, 3JHH = 7.0), 3.43 t (4Н,
1
3
white crystals, mp 85‒90°C. Н NMR spectrum, δ,
CH2SO2, JHH = 7.0), 4.05 s (4Н, CH2CO), 7.43 s and
3
7.72 s (4Н, NH2). 13С NMR spectrum, δC, ppm: 14.38
(CH3), 22.53, 27.24, 29.15, 29.50, 31.74 (CH2,
С16H33), 46.47 (NCH2, C16H33), 50.03 (NCH2), 52.97
(CH2SO2), 59.00 (SO2CH2CO), 164.26 (C=O). Mass
spectrum (MALDI-TOF), m/z: 540.4 [M + H]+, 562.3
[M + Na]+ (calculated for С24H49N3O6S2: 539.8).
ppm (J, Hz): 0.86 t (3Н, CH3, JHH = 6.8), 1.26 br. s
(10Н, СН2), 1.41 br. s (2Н, СН2), 2.45 t (2Н, CH2N,
3
3JHH = 7.1), 2.92 t (4Н, CH2N, JHH = 6.8), 3.45 t (4Н,
3
CH2SO2, JHH = 6.8), 4.06 s (4Н, CH2CO), 7.44 s and
7.73 s (4Н, NH2). 13С NMR spectrum, δC, ppm: 14.44
(CH3), 22.51, 26.65, 27.15, 29.00, 29.03, 31.63 (CH2,
С8H17), 46.48 (NCH2, C8H17), 50.23 (NCH2), 52.92
(CH2SO2), 58.94 (SO2CH2CO), 164.27 (C=O). Mass
spectrum (MALDI-TOF), m/z: 428.2 [M + H]+, 450.1
[M + Na]+ (calculated for С16H33N3O6S2: 427.6).
2-{[(2-Hexadecylamino)ethyl]sulfonyl]}acetamide
(6b). Yield 0.88 g (45%), white crystals, mp 97‒101°C.
1Н NMR spectrum, δ, ppm (J, Hz): 0.86 t (3Н, CH3,
3JHH = 6.8), 1.25 br. s (26Н, СН2), 1.53 br. s (2Н,
3
2-{[(2-Octylamino)ethyl]sulfonyl]}acetamide (6a).
The precipitate obtained after filtration of the reaction
mixture was washed with acetonitrile and dried. Yield
СН2), 2.60 t (2Н, CH2N, JHH = 7.1), 3.03 t (2Н,
3
3
CH2N, JHH = 7.1), 3.47 t (2Н, CH2SO2, JHH = 7.1),
13
4.11 s (2Н, CH2CO), 7.44 s and 7.76 s (2Н, NH2). С
1
0.30 g (36%), white crystals, mp 70‒75°C. Н NMR
NMR spectrum, δC, ppm: 14.42 (CH3), 22.57, 27.18,
29.18, 29.51, 31.77 (CH2, С16H33), 42.47 (NCH2,
C16H33), 49.00 (NCH2), 52.68 (CH2SO2), 59.29
(SO2CH2CO), 164.27 (C=O). Mass spectrum (MALDI-
TOF), m/z: 391.4 [M + H]+, 413.3 [M + Na]+ (calculated
for С20H42N2O3S: 390.6).
spectrum, δ, ppm (J, Hz): 0.86 t (3Н, CH3, 3JHH = 8.1),
1.25 br. s (10Н, СН2), 1.39 br. s (2Н, СН2), 2.60 t (2Н,
CH2N, 3JHH = 7.1), 2.90 t (2Н, CH2N, 3JHH = 7.2), 3.71
3
t (2Н, CH2SO2, JHH = 6.8), 4.18 s (2Н, CH2CO), 7.42
s and 7.72 s (2Н, NH2). 13С NMR spectrum, δC, ppm:
14.39 (CH3), 22.51, 26.65, 29.18, 28.97, 31.63 (CH2,
С16H33), 46.48 (NCH2, C16H33), 50.71 (NCH2), 52.93
(CH2SO2), 58.94 (SO2CH2CO), 164.09 (C=O). Mass
spectrum (MALDI-TOF), m/z: 279.2 [M + H]+, 301.11
[M + Na]+ (calculated for С12H26N2O3S: 278.4).
Hydrochlorides 7a, 7b (general procedure). 0.1 M
solution of HCl (1.1 mol of HCl per 1 mol of amine)
was added to a solution of compound 4a or 6b in 20 mL
of methanol. The obtained mixture was kept at room
temperature for 5‒15 days. The solution was filtered
and evaporated off. The residue was ground in acetone‒
diethyl ether mixture (1 : 2).
Bis-[2-(carbamoylmethylsulfonyl)ethyl]nonyl-
amine (5b) was prepared similalry from 0.90 g (4.8 mmol)
2-[(2-chloroethyl)sulfonyl]acetamide, 0.46 g (4.4 mmol)
sodium carbonate, and 0.32 g (2.2 mmol) of nonyl-
amine; reaction duration 20 h. Yield 0.65 g (66%),
[2-(Carbamoylmethylsulfonyl)ethyl](dodecyl)-
(methyl)amine hydrochloride (7a). Yield 85%, white
crystals. There was no clear melting point, the
substance became transparent at temperature above
110°C and melted at further heating. 1Н NMR
spectrum, δ, ppm (J, Hz): 0.86 t (3Н, CH3, 3JHH = 6.9),
1.26 s and 1.28 br. s (18Н, СН2), 1.67 br. s (2Н, СН2),
1
white crystals, mp 92‒95°C. Н NMR spectrum, δ,
3
ppm (J, Hz): 0.86 t (3Н, CH3, JHH = 6.6), 1.25 br. s
(12Н, СН2), 1.40 br. s (2Н, СН2), 2.43 t (2Н, CH2N,
3
3JHH = 7.1), 2.90 t (4Н, CH2N, JHH = 6.6), 3.43 t (4Н,
3
CH2SO2, JHH = 6.8), 4.04 s (4Н, CH2CO), 7.43 s and
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2268
SHULAEVA et al.
2.76 s (3Н, CH3N), 3.03 br. s and 3.12 br. s (2Н,
CH2N), 3.49 br. s and 3.56 br. s (2Н, CH2N), 3.90 t
(2Н, CH2SO2, 3JHH = 7.6), 4.22 s (2Н, CH2CO), 7.54 s
and 7.93 s (2Н, NH2). Found, %: С 53.34; Н 9.12; Cl
9.18; N 7.11; S 8.04. С17H36N2O3S.HCl. Calculated, %:
С 53.03; Н 9.67; Cl 9.21; N 7.28; S 8.33.
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[2-(Carbamoylmethylsulfonyl)ethyl]hexadecyl-
amine hydrochloride (7b). Yield 69%, white crystals.
There was no clear melting point, the substance became
transparent at temperature above 130°C and melted at
1
further heating. Н NMR spectrum, δ, ppm (J, Hz):
3
0.86 t (3Н, CH3, JHH = 6.7), 1.25 br. s (26Н, СН2),
1.60 br. s (2Н, СН2), 2.94 br. s (2Н, CH2N), 3.34 br. s
3
(2Н, CH2N), 3.78 t (2Н, CH2SO2, JHH = 7.7), 4.23 s
(2Н, CH2CO), 7.56 s and 7.91 s (2Н, NH2), 9.13 br. s
(2Н, NH2). Found, %: С 56.85; Н 9.43; Cl 8.12; N
6.41; S 7.48. С20H42N2O3S.HCl. Calculated, %: С
56.24; Н 10.15; Cl 8.30; N 6.56; S 7.51.
The bacteriostatic and fungistatic activities of the
prepared compounds against strains of bacteria
Pseudomonas aeruginosa АТСС 9027, Escherichia
coli CDC F-50, Staphylococcus aureus АТСС 209-P,
Bacillus cereus АТСС 8035 and fungi Trichophyton
mentagrophytes var. gypseum 1773, Aspergillus niger
BKMF-1119, and Candida albicans NCTC 885-653
were determined using twofold serial dilutions method
in liquid nutrient media [13]. The bactericide and
fungicide activities were determined as described in
[14].
The hemolytic action of the compounds was
estimated using a method based on the comparation of
absorbance of blood in the presence of the tested
compound with that of the blood after complete
hemolysis [15]. The investigation of tuberculostatic
activity was performed by vertical diffusion method
using lab strain H37Rv on solid medium “Novaya”.
The growth of tuberculosis mycobacteria was
estimated using a standard procedure [16].
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 11 2018