Synthesis and Biological Activity of 3,4,-Tri-О-Acetyl-N-Acetylglucosamine and Tetraacetylglucopyranose Conjugated with Alkyl Phosphates

Article abstract of DOI:10.1134/S1068162019020110

Abstract: Conjugates of 3,4,6-tri-О-acetyl-N-acetylglucosamine and tetraacetyl glucopyranose with alkyl phosphates were synthesized. The dependence of their antibacterial and antituberculosis activities on the length of the alkyl substituent at the phosphate group was found. The conjugates with a decyl substituent exhibited in vitro the highest antituberculosis activity against Mycobacterium tuberculosis H37Rv (MIC 3?μg/mL) but the weakest effect towards Streptococcus aureus and Bacillus cereus (≤MIC 125 μg/mL). Vice versa, the conjugates with a cetyl substituent demonstrated the highest antibacterial activity in vitro towards S. aureus and B. cereus (MIC 16 μg/mL) but showed the lowest antituberculosis activity (MIC 12 μg/mL) among the compounds under study.

Full text of DOI:10.1134/S1068162019020110

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, No. 2, pp. 155–164. © Pleiades Publishing, Ltd., 2019.
Russian Text © R.R. Sharipova, B.F. Garifullin, A.S. Sapunova, A.D. Voloshina, M.A. Kravchenko, V.E. Kataev, 2019, published in Bioorganicheskaya Khimiya, 2019, Vol. 45,
No. 3, pp. 315–325.
Synthesis and Biological Activity of 3,4,-Tri-О-Acetyl-N-
Acetylglucosamine and Tetraacetylglucopyranose Conjugated
with Alkyl Phosphates
R. R. Sharipovaa, B. F. Garifullina , A. S. Sapunovaa, A. D. Voloshinaa,
M. A. Kravchenkob, and V. E. Kataeva, 1
aArbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
Kazan, 420088 Russia
bUral Research Institute for Phthisiopulmonology, Yekaterinburg, 620039 Russia
Received September 19, 2018; revised October 1, 2018; accepted October 11, 2018
Abstract⎯Conjugates of 3,4,6-tri-О-acetyl-N-acetylglucosamine and tetraacetyl glucopyranose with alkyl
phosphates were synthesized. The dependence of their antibacterial and antituberculosis activities on the
length of the alkyl substituent at the phosphate group was found. The conjugates with a decyl substituent
exhibited in vitro the highest antituberculosis activity against Mycobacterium tuberculosis H37Rv (MIC
3 μg/mL) but the weakest effect towards Streptococcus aureus and Bacillus cereus (≤MIC 125 μg/mL). Vice
versa, the conjugates with a cetyl substituent demonstrated the highest antibacterial activity in vitro towards
S. aureus and B. cereus (MIC 16 μg/mL) but showed the lowest antituberculosis activity (MIC 12 μg/mL)
among the compounds under study.
Keywords: antibacterial activity, antituberculosis activity, glucosamine, glucopyranose, glycoconjugates,
Mycobacterium tuberculosis
DOI: 10.1134/S1068162019020110
INTRODUCTION
[5–8]). Also, the known inhibitors are divided into
diphosphates (compounds (II) [5–8]) and mono-
phosphates (compounds (I) and (III) [4, 7]). It was
shown that inhibitors (II) and (III) are alternative sub-
strates for bacterial glucosyl and galactosyl transferases
and could inhibit to some extent the activity of various
bacterial enzymes [4–8]. It is interesting that the most
structurally simple compound (IV) (Fig. 1) can inhibit
M. tuberculosis GlmU-T at millimolar concentra-
tions [9]. It should seem that if a compound could
inhibit any enzyme on the way to bacterial PG, it
would inhibit bacterial growth as well. Surprisingly, we
have not found any publications describing how the
synthesized inhibitors of bacterial glucosyl or galacto-
syl transferases inhibited the growth of these bacteria.
We only found one comparative report of antienzy-
matic and antibacterial activities of glycosyl transfer-
ase inhibitors [4], the results of which were amazing.
In particular, compounds (III), the best inhibitors of
E. coli PBP1b PG-T, did not demonstrate antibacte-
rial activity [4].
Peptidoglycan is an important macromolecule,
which surrounds bacteria and mycobacteria, shapes
them and protects from the damaging effect of their
own high osmotic pressure. Inhibition of the PG syn-
thesis results in the lysis of bacterial cells. Therefore,
all the enzymes involved in its synthesis are attractive
targets for designing new antibacterial and antimyco-
bacterial (antituberculosis) agents. Of the wide
enzyme spectrum, the attention of researchers is
focused on GlmU-T and PG-Ts, which catalyze the
latest stages of PG biosynthesis [1–3].
In the recent decade, a series of Glm-U and PG-Ts
modified at carbohydrate residues, phosphate groups
or alkyl substituents has been synthesized (Fig. 1) [3–
9]. The most known inhibitors bear a disaccharide res-
idue composed of GlcNAc and N-acetylmuramic acid
fragments (MurNAc) (compounds (I) [4]) or contain
a single GlcNAc fragment (compounds (II) and (III)
Abbreviations: GlcNAc, N-acetylglucosamine; GlmU-T,
GlcNAc-1P-uridyl transferase; PG-T, PG glycosyl transferase;
GlcNAc-1-P-alkyl, N-acetylglucosamine 1-alkylphosphate;
MIC, minimal inhibitory concentration; PG, peptidoglycan;
TMS-OTF, trimethylsilyl trifluoromethanesulfonate.
Taking into consideration these data, we decided to
check whether the acetylation of carbohydrate hydroxyl
groups results in the appearance of antibacterial activity
of the compounds of type (III).
1 Corresponding author: phone: +7 (843) 273-9365; fax: +7 (843)
273-2253; e-mail: kataev@iopc.ru.
155

156
SHARIPOVA et al.
OH
OH
OH
O
O
O
O
HO
HO
HO
HO
O
O
O
P
O
AcHN
AcHN
AcHN
O
P
O
R
O
O
R
O
P
O
HO
OH
OH
OH
GlcNAc-1-4-MurNAc-1-P-R (I)
GlcNAc-1-PP-R (II)
OH
OH
O
O
HO
HO
HO
F
O
P
O
P
H2N
AcHN
O
O
R
OH
O
OH
OH
GlcNAc-1-P-R (III)
(IV)
R = prenyl (–C5H9); farnesyl (–C15H25); phenoxyhexyl (–C6H12OPh); decyl (–C10H21);
phenoxyundecyl (C11H22OPh); cetyl (–C16H33); phenoxycetyl (C16H32OPh)
Fig. 1. Some examples of enzyme inhibitors involved in the biosynthesis of bacterial and mycobacterial peptidoglycans.
RESULTS AND DISCUSSION
of the P–H group were seen along with characteristic
resonances of 3,4,6-tri-О-acetyl-N-acetylglucos-
amine (VII). The anomeric proton was observed as a
multiplet at 5.61–5.69 ppm, which implied the forma-
tion of the anomeric mixture. The 31P NMR of com-
pound (X) contained a singlet at 1.93 ppm inherent for
a phosphorus atom of H-phosphonates.
In this work, we described the synthesis, antibacte-
rial and antituberculosis activities of conjugates of
3,4,6-tri-О-acetyl-N-acetyl-D-glucosamine
and
tetraacetylated D-glucopyranose with alkyl phos-
phates.
As a starting compound for the synthesis of the tar-
get conjugates (hereafter glycophosphates) on the
basis of 3,4,6-tri-О-acetyl-N-acetyl-D-glucosamines
(XII) and (XIV) we used commercial glucosamine
hydrochloride (V) (Scheme 1). It was acetylated as
described in [10] and the resulting 1,3,4,6-tetra-О-
acetyl-N-acetyl-D-glucosamine (VI) was transformed
to 3,4,6-tri-О-acetyl-N-acetyl-D-glucosamine (VII)
by the regioselective removal of the protective group
from the anomeric hydroxyl group using methylamine
in methanol similarly to [11]. Compound (VII) was
At the next step, H-phosphonate (X) was activated
with pivaloyl chloride and treated with decanol. The
resulting glycophosphonate (XI) was oxidized with
aqueous iodine solution and the target glycophosphate
(XII) was obtained after chromatography in 23% yield.
Its structure was confirmed in the first place by the dis-
appearance in the 1H NMR spectrum of a proton reso-
nance of the P–H group at 6.9 ppm and the appearance
in the 31P NMR spectrum of a singlet at –2.27 ppm cor-
phosphonylated at its anomeric hydroxyl group with responding to the phosphate group in a monoanionic
2-chloro-2H,4H-1,3,2-benzodioxaphosphorin-4-one
form ( −). Mass spectral data also indicated the for-
PO4
(IX) [12], which was prepared from salicylic acid
(VIII) as described in [13]. H-Phosphonate (X) was
isolated after chromatography in 34% yield. In the
1H NMR spectrum of phosphonate (X), a triplet at
1.36 ppm (JH-H 7.3 Hz) and a quartet at 3.08 ppm (JH-H
7.3 Hz), which corresponded to the resonances of tri-
ethylammonium protons, and a doublet at 6.9 ppm
(JP-H 668 Hz) corresponding to the proton resonance
mation of glycophosphate (XII). The MALDI spec-
trum of glycophosphate (XII) contained a peak at
m/z 566.4 [M]– (C24H41NO12P). The resonance of the
anomeric proton of glycophosphate (XII) was
observed as a doublet of doublets at 5.51 ppm (3JH1,P
7.34 Hz, 3JH1,H2 3.22 Hz), which implied the formation
of the individual α-anomer.
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SYNTHESIS AND BIOLOGICAL ACTIVITY
OAc OAc
157
OH
O
O
O
AcO
AcO
AcO
AcO
AcHN
HO
HO
i
ii
OH
OAc
NHAc
.
NH2 HCl
OH
(V)
(VI)
(VII)
O
O
O
iii
OH
O
iv
P
OH
Cl
(IX)
(VIII)
H3C
O
Et3NH
O
OAc
OAc
O
P
O
O
vii
AcO
AcO
AcO
AcO
P
O
O
O
NHAc
NHAc
H
H
(X)
(XIII)
vi
v
H3C
9'
7'
3'
OAc
OAc
5'
O
H3C
O
O
AcO
AcO
O
AcO
AcO
P
O
O
O
P
1'
NHAc
H
AcHN
O
(XI)
O
(XIV)
vi
Et3NH
H3C
OAc
O
AcO
AcO
O
P
AcHN
O
O
(XII)
O
Et3NH
Scheme 1. The synthesis of glycophosphates (XII) and (XIV). Conditions and reagents: (i) Ac2O, Py, 0 → 20°С, 24 h;
(ii) CH3NH2, CH3OH, THF, rt, 0.5 h; (iii) PCl3, toluene, 110°С, 12 h; (iv) Et3N, H2O, THF, rt, 12 h; (v) CH3(CH2)9OH,
PivCl, Py, –15°С, 2 h; (vi) 1. I2, H2O, 20°С, 1 h; 2. Na2S2O3; (vii) CH3(CH2)15OH, PivCl, Py, –15°С, 2 h, rt.
For the evaluation of the impact of the length of anomeric proton of glycophosphate (XIV) was
observed as a doublet of doublets at 5.51 ppm (3JH1,P
7.18 Hz, 3JH1,H2 3.53 Hz), which implied the α-config-
uration of the glycoside bond.
For the evaluation of the influence of a glucos-
amine residue on the biological activity of glycophos-
phates (XII) and (XIV) we synthesized glycophos-
phates (XX) and (XXII), which contained tetracetyl-
ated D-glucopyranose instead of 3,4,6-tri-O-
acetylglucosamine (Scheme 2). The starting D-gluco-
pyranose (XV) was acetylated as described in [14], and
the anomeric protective group was removed with
alkyl substituents on the biological activity we synthe-
sized, in addition to glycophosphate (XII), glycophos-
phate (XIV) by the interaction of H-phosphonate (X)
with cetyl alcohol. After chromatography, it was iso-
lated in 10% yield. Its formation was confirmed by the
lack of the P-H resonance in the 1H NMR spectrum,
and the presence of a singlet at –2.43 ppm in the
31P NMR spectrum corresponding to the phosphate
group in a monoanionic form ( −). The MALDI
PO4
spectrum of glycophosphate (XIV) contained a peak at
m/z 650.6 [M]– (C30H53NO12P). The resonance of the
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 2 2019

158
SHARIPOVA et al.
hydrazine acetate as described in [15]. The reaction of nances of tetracetylated glucopyranose (XVII). The
31P NMR spectrum of compound (XVIII) contained a
singlet at 0.77 ppm corresponding to the phosphorus
resonance in H-phosphonates. In the MALDI spec-
trum of glycophosphate (XVIII) a peak at m/z 513.2
[M]– (C20H36NO12P) was present. The anomeric pro-
ton observed as a doublet of doublets at 5.75 ppm
(JH1,P 8.9 Hz, JH1,H2 3.4 Hz) evidenced the formation
the resulting 2,3,4,6-tetra-O-acetyl-α/β-D-glucopy-
ranose (XVII) with salicyl chlorophosphite (IX) led to
H-phosphonate (XVIII) isolated by column chroma-
1
tography in 44% yield. In its H NMR spectrum, a
triplet at 1.28 ppm (JH-H 7.3 Hz) and a quartet at 3.0
ppm (JH-H 7.3 Hz) corresponding to a triethylammo-
nium group as well as a doublet at 6.91 ppm (JP-H
638.9 Hz) corresponding to the proton of the P–H
group were observed along with characteristic reso- of the α-anomer.
OAc
OAc
OH
O
O
O
AcO
AcO
AcO
AcO
HO
HO
i
ii
OH
OAc
OH
OAc
(XVI)
OAc
(XVII)
OH
(XV)
(IX)
iii
H3C
OAc
OAc
AcO
O
P
O
O
vi
Et3NH
AcO
AcO
AcO
AcO
O
O
O
OAc
(XXI)
P O
H
O
H
(XVIII)
v
iv
H3C
OAc
O
OAc
AcO
H3C
O
P
O
AcO
AcO
AcO
AcO
O
O
P
O
OAc
H
O
O
(XIX)
O
(XXII)
v
Et3NH
H3C
OAc
O
AcO
AcO
O
P
AcO
(XX)
O
O
O
Et3NH
Scheme 2. The synthesis of glycophosphates (XX) and (XXII). Conditions and reagents: (i) Ac2O, Py; 0 → 20°С, 24 h;
(ii) H3N+
+2AcO–, DMF, 0 → 20°С, 3 h; (iii) THF, Et N, 20°С, 12 h; (iv) CH (CH ) OH, PivCl, Py, –15°С, 2 h;
NH3
3 2 9
(v) 1. H2O, I2, 20°С, 1 h, 2. Na2S2O3; (vi) CH3(CH2)15OH,3PivCl, Py, –15°С, 2 h.
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SYNTHESIS AND BIOLOGICAL ACTIVITY
159
Glycophosphates (XX) and (XXII) were obtained monosaccharide (VII) was phosphorylated by the
from H-phosphonate (XVIII) similarly to the synthesis of
glycophosphates (XII) and (XIV) (Scheme 1) described
above. Glycophosphate (XX) was isolated after chroma-
tography in 53% yield. Its MALDI spectrum contained a
peak at m/z 567.1 [M]– (C24H40NO13P). The resonance
reaction with dibenzyl N,N-diisopropylphosphorami-
date and 1H-tetrazole followed by oxidation with
hydrogen peroxide, debenzylation, and treatment with
tert-butylammonium hydroxide. The resulting salt was
subjected to the reaction with aliphatic bromides in
the presence of molecular sieves. We did not alkylate
glucosamine phosphate but H-phosphonate (X) which
of the phosphorus atom in the 31P NMR spectrum was
seen as a singlet at –2.69 ppm, which indicated the
presence of the phosphate group in a monoanionic was easily prepared by the interaction of 3,4,6-tri-О-
form ( −). The resonance of the anomeric proton
acetyl-N-acetylglucosamine (VII) with salicyl chloro-
PO4
phosphite (IX) [13]. The target glycophosphates (XII)
was observed as a doublet of doublets at 5.72 ppm
and (XIV) were obtained from H-phosphonate (X)
3
(3JH1,P 7.8 Hz, JH1,H2 3.3 Hz), which implied the for-
using oxidation of H-phosphonates (XI) and (XIII)
mation of the individual α-anomer. Glycophosphate
with iodine at the final stage. Glycophosphates (XX)
(XXII) was obtained in 35% yield after chromatogra-
and (XXII) were prepared from 2,3,4,6-tetraacetyl-α-
phy. Its MALDI spectrum contained a peak at
D-glucopyranose in a similar manner. The yields of
m/z 675.2 [M + Na]+ (C30H53NaO13P). In the
glycophosphates (XII) and (XIV) were small, but the
reaction conditions will be updated.
31P NMR spectrum of glycophosphate (XXII) only
one singlet at –2.31 ppm was present. The resonance
of the anomeric proton in the 1H NMR spectrum was
For the evaluation of the effect of alkyl substituents
in glycophosphates (XII) and (XIV) on the biological
activity we synthesized glycophosphate (XXV)
(Scheme 3). Oxazoline (XXIII) was obtained by the
reaction of 1,3,4,6-tetra-О-acetyl-N-acetyl-D-glu-
cosamine (VI) with TMS-OTF as described in [17].
Glycophosphate (XXV) was synthesized from oxazo-
line (XXIII) as described in [18] but without isolating
and purifying dibenzyl phosphate (XXIV). Glyco-
phosphate (XXV) as a trimethylammonium salt was
obtained in 27% yield. In its 31P NMR spectrum a sin-
glet at 1.94 ppm was present, which corresponded to
the monophosphate group in a monoanionic form
observed as a doublet of doublets at 5.57 ppm (3JH1,P
7.9 Hz, 3JH1,H2 3.5 Hz), which implied the formation of
glycophosphate (XXII) in the form of the individual
α-anomer.
We would like to emphasize the difference between
our method of synthesis of glycophosphates (XII) and
(XIV) and the known syntheses of glucosamine conju-
gates with phosphate or diphosphate fragments [4–8,
16]. First, it was the preparation of the key glucos-
amine derivative (VII) with protected hydroxyl groups
at positions C3, C4, and C6 and the free anomeric
hydroxyl group, which was phosphonylated at the next
stage. 3,4,6-Tri-О-acetyl-N-acetylglucosamine (VII)
was easily obtained by the regioselective removal of the
acetyl protective group from the monosaccharide (VI)
anomeric hydroxyl group using methylamine in meth-
anol. Second, we used another approach [12] for the
synthesis of conjugates of glucosamine derivative (VII)
(
−). In its MALDI spectrum a peak at m/z 426.3
PO4
[M]– (C14H21NO12P) was observed. Unlike glycophos-
phates (XII), (XIV), (XX), and (XXII), the anomeric
proton resonance of glycophosphate (XXV) was seen
as a triplet at 5.18 ppm (3JH1,H2 = 3JH1,P = 10 Hz), which
and a phosphate group. Normally (for example, [4]), indicated the formation of the β-anomer.
OAc
OAc
OAc
O
P
O
O
O
AcO
AcO
AcO
AcO
AcO
AcO
i
ii
OBn
OBn
OAc
NHAc
O
N
NHAc
(XXIV)
O
(VI)
(XXIII)
CH3
OAc
O
P
iii
O
OH
AcO
AcO
O
O
Et3NH
NHAc
(XXV)
Scheme 3. The synthesis of phosphate (XXV). Conditions and reagents: (i) TMS-OTF, C2H4Cl2, 50°C, 30 h;
(ii) (PhCH2O)2P(O)OH, Ag2CO3, CH2Cl2/CH3CN/Et2O, 0–20°C, 18 h; (iii) H2, Pd/C, MeOH, Et3N, 20°C, 4–8 h.
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SHARIPOVA et al.
Compounds (VI), (X), (XII), (XIV), (XX), (XXII), 12 μg/mL respectively). Fifth, the length of the alkyl
(XXV), and (XXVI) were examined for antituberculosis substituent in the glycophosphates under study affected
the antituberculosis and antibacterial activities in differ-
ent ways. In particular, glycophosphates (XII) and (XX)
with a decyl chain exibited in vitro the highest antitu-
berculosis activity against MBT (MIC 3 μg/mL) and
at the same time the weakest antibacterial activity
against S. aureus (MIC 62 and ≤500 μg/mL respec-
tively) and B. cereus (MIC 125 and ≤500 μg/mL respec-
tively). Conversely, glycophosphates (XIV) and (XXII)
with a cetyl substituent demonstrated the highest anti-
bacterial activity against S. aureus (MIC 16 μg/mL)
and B. cereus (MIC 62.5 μg/mL) and the lowest anti-
tuberculosis activity against MBT (MIC 12 μg/mL).
activity against Mycobacterium tuberculosis H37Rv
(MBT), as well as for antimicrobial activity, against
Gram-positive bacteria (Staphylococcus aureus
ATCC 209p and Bacillus cereus ATCC 8035), Gram-
negative bacteria (Escherichia coli CDCF-50 and Pseu-
domonas aeruginosa ATCC 9027), and fungi (Aspergillus
niger BKMF-1119, Trichophyton mentagrophytes var.
gypseum 1773, and Candida albicans 855-653). All the
compounds under study inhibited in vitro the MBT
growth (Table 1). Although their antituberculosis
activity was 30–125 times lower than the activity of
isoniazid, the antituberculosis drug, the activities of
compounds (X), (XIV), (XXII), and (XXV) were equal
to that of pyrazinamide, another antituberculosis
drug. Moreover, the antituberculosis activities of com-
pounds (VI) and (XXVI) were twice as high as the pyr-
azinamide activity, whereas the activities of com-
pounds (XII) and (XX) fourfold exceeded that of pyr-
azinamide (Table 1). Compounds (VI), (XX), (XXV),
and (XXVI) were inactive against all the bacteria and
fungi used in the antimicrobial testing. Only glyco-
phosphates (XII), (XIV), and (XXII) demonstrated
antibacterial activity against S. aureus and B. cereus
(Table 1). In regard to the other bacteria and fungi
used in the screening these compounds were inactive.
The analysis of MIC values (Table 1) allowed the fol-
lowing conclusions. First, it is the alkyl substituent
that leads to the appearance of antibacterial activity of
tetraacetylated glucopyranose and 3,4,6-tri-О-acetyl-
N-acetylglucosamine. Glucosamine derivatives (VI)
and (XXVI) and glycophosphates (XII) and (XX)
demonstrated approximately the same antituberculo-
sis activity. Second, glycophosphates (XIV) and
(XXII) bearing a hexadecyl substituent showed higher
antibacterial activity (MIC 16 μg/mL) than glyco-
phosphates (XII) and (XX) with a decyl substituent. In
particular, glycophosphates (XIV) and (XXII) with a
hexadecyl substituent inhibited in vitro the growth of
S. aureus four times more effectively than antibiotic
chloramphenicol, whereas the activity of glycolipid (XII)
bearing a decyl spacer was nearly equal to that of
chloramphenicol, and glycophosphate (XX) was inac-
tive against the bacteria and fungi tested. Third,
among the compounds under study, the nature of the
glycophosphate carbohydrate residue did not affect its
antibacterial activity, the length of the alkyl substituent
being more important. For example, one can see that
the in vitro antibacterial activities towards S. aureus
and B. cereus of glycophosphate (XIV) with a glucos-
amine residue and glycophosphate (XXII) containing
a glucopyranosyl fragment were the same. Fourth, the
length of the alkyl substituent significantly impacted
antituberculosis activity of the compounds under
study. Glycophosphates (XII) and (XX) with a decyl
substituent inhibited in vitro the MBT growth four
times more effectively than glycophosphates (XIV)
To summarize, we found that acetylation of car-
bohydrate hydroxyl groups in glycophosphates of
type (III) [4] supported the appearance of antibacte-
rial and antituberculosis activities.
EXPERIMENTAL
1H, 13C, and 31P NMR spectra (δ, ppm; J, Hz) were
registered on an Avance-400 spectrometer (Bruker,
Germany) with a frequency of 400 MHz (1H) and
100.6 MHz (13C and 31P) in CDCl3. Mass spectra
MALDI TOF were registered on an UltraFlex III
TOF/TOF mass spectrometer (Bruker Daltonik
GmbH, Bremen, Germany) in a linear mode. The
laser was Nd:YAG, λ 355 nm. The data were inter-
preted using the FlexAnalysis 3.0 program (Bruker
Daltonik GmbH, Bremen, Germany). The measure-
ments were conducted in the m/z range of 200 to 6000
with the registration of negatively charged ions. A metal
target was used with p-nitroaniline as a matrix. The sam-
ples were dissolved in methanol (10–3 mg/mL). Optical
rotation was measured on
a PerkinElmer-341
polarimeter (PerkinElmer, United States) at λ 589 nm
at 20°C. The reaction completeness and product
purity were monitored by TLC on Sorbfil plates (Imid
LLC, Krasnodar, Russia). The compounds were
developed with 5% sulfuric acid followed by heating to
120°C.
The reactions sensitive to air and/or moisture were
performed in an argon atmosphere in anhydrous sol-
vents, which were preliminarily purified and dried (if
necessary) according to the standard procedures.
Compounds (VI) [10], (VII) [11], (IX) [13], (XVI)
[14], (XVII) [15], (XXIII) [17], and (XXVI) [19, 20]
were synthesized using published procedures. Spectral
characteristics of compounds (VI), (VII), and (IX)
agreed with the published data [10, 11, 13]. Spectral
parameters of compounds (XVI), (XVII), and (XXIII)
correlated with the data in [21–23]. Characteristics of
compound (XXVI) corresponded to [19, 20]. Com-
mercial D-glucosamine hydrochloride (V) and D-glu-
copyranose (XV) were from Acros (Belgium).
3,4,6-Tri-О-acetyl-2-deoxy-2-acetamido-α/β-D-
and (XXII) with a hexadecyl group (MIC 3 μg/mL vs glucopyranosyl Н-phosphonate, triethylammonium salt (X).
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SYNTHESIS AND BIOLOGICAL ACTIVITY
161
Table 1. Antituberculosis and antimicrobial activities of the compounds synthesized
MIC, μg/mL
M. tuberculosis
S. aureus
ATCC 209p
B. cereus
ATCC 8035
H37Rv
OAc
O
AcO
AcO
6
6
>500
>500
>500
>500
AcO
OAc
NH2 . HCl
(XXVI)
OAc
O
AcO
OAc
NHAc
(VI)
OAc
O
P O
H
O
AcO
AcO
O
12
12
3
–
–
NHAc
(X)
Et3NH
OAc
O
O P
O
OH
O
AcO
AcO
>500
62
>500
125
62
NHAc
(XXV)
Et3NH
OAc
O
AcO
AcO
Et3NH
O
AcHN
P O C10H21
O
O
(XII)
OAc
O
AcO
AcO
Et3NH
O
12
3
16
AcHN
P O C16H33
O
O
(XIV)
OAc
O
AcO
Et3NH
O
P O C10H21
O
AcO
>500
16
>500
62
AcO
O
(XX)
OAc
O
AcO
Et3NH
O P O C16H33
(XXII)
O
AcO
AcO
12
O
Isoniazid
0.1
12
−
−
−
−
−
Pyrazinamide
Chloramphenicol
62
62
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 2 2019

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SHARIPOVA et al.
(C2'–C9'), 45.7 (CH2N+), 52.2 (C2), 61.9 (C6), 66.2
(C1'), 68.4 (C4), 68.7 (C3), 71.5 (C5), 94.1 (d, C1, JC,P
5.4), 169.5, 170.8, 171.0, 182.2 (4 C=O). 31P NMR: –2.27.
Salicyl chlorophosphite (IX) (0.42 g, 2 mmol) [13] was
added under stirring to a solution of 3,4,6-tri-О-ace-
tyl-N-acetylglucosamine (VII) (0.67 g, 2 mmol) [11]
and triethylamine (1.87 mL, 18.5 mmol) in dry THF
(10 mL) and the mixture was stirred for 3 h. Water
(1 mL) was added and the mixture was stirred for 1 h
and evaporated to dryness. The residue was chromato-
graphed on silica gel eluting with CH2Cl2–CH3OH
(40 : 1 → 5 : 1 and 1 vol % Et3N) to give 0.33 g (34%) of
20
2-Acetamido-2-deoxy-3,4,6-tri-О-acetyl-α-D-glu-
copyranosyl cetyl phosphate, triethylammonium salt (XIV).
α 2D0
+ 10.5 (c 0.846, CH2Cl2). Found, %: C 57.35;
[ ]
H 9.20; N 3.63; P 4.08. C36H69N2O12P. Calc., %:
C 57.43; H 9.24; N 3.72; P 4.11. MALDI-TOF MS:
m/z 650.6 [M]–. Calc. М– 650.3 (C30H53NO12P–).
compound (X) as colorless oil,
+ 56.7 (c 0.8,
[α]D
1H NMR: 0.86 (t, 3H, J 6.8, H16'), 1.19 (br s, 4H,
H15', H14'), 1.22–1.27 (m, 22H, H3'–H13'), 1.36
[t, 9H, J 7.33, N+(CH2CH3)3], 1.55–1.65 (m, 2H,
H2'), 1.94, 1.98, 1.99, 2.06 (all s, 12Н, 4 CH3CO), 3.07
CHCl3). Found, %: C 47.05; H 7.49; N 5.53; P 5.98.
C20H37N2O11P. Calc., %: C 46.87; H 7.28; N 5.47; P
1
6.04. H NMR: 1.36 [t, 9H, J 7.30, N+(CH2CH3)3],
1.97, 2.01, 2.07 (all s, 12Н, 4CH3CO), 3.08 [q, 6Н, J
[q, 6Н, J 7.33, N+(CH2CH3)3], 3.85–3.94 (m, 2H,
H1'), 4.05–4.11 (m, 1H, H2), 4.17–4.27 (m, 2H, H6a,
H6b), 4.32–4.40 (m, 1H, H5), 5.16 (t, 1H, J 9.68,
H4), 5.29 (t, 1H, J 9.96, H3), 5.51 (dd, 1H, J1,P 7.18,
J1,2 3.53, H1), 7.17 (d, 1H, J2,NH 9.64, NHC(O)CH3).
7.3, N+(CH2CH3)3], 4.09–4.27 (m, 3H, H2, H6a, H6b),
4.36–4.46 (m, 1H, H5), 5.17 (t, 1H, J 9.62, H4),
5.27–5.35 (m, 1H, H3), 5.61–5.69 (m, 1H, H1), 6.90
(d, 1H, J1,P 668.04, P–H), 6.90–7.05 [m, 1H,
NHC(O)CH3], 11.73 (br s, 1H, HN+). 13C NMR: 8.7
(CH3CH2N+), 20.7, 20.8 [3 C(O)CH3], 23.0
(CH3C(O)NH), 45.9 (CH2N+), 52.1 (C2), 61.9 (C6),
68.4 (C4), 69.0 (C3), 71.2 (C5), 93.1 (C1, J 3.9), 169.6,
170.9, 171.1, 171.2 (4 C=O). 31P NMR: +1.93.
13C NMR: 8.8 (CH3CH2N+), 14.2 (C16'), 20.8, 20.9
[3 C(O)CH3, NHC(O)CH3], 22.8, 25.9, 27.4, 29.5,
29.8, 32.0 (C2'–C15'), 45.8 (CH2N+), 52.3 (C2),
62.0 (C6), 63.6 (C1'), 68.7 (С3, C4, С5), 94.2 (C1),
169.5, 170.9, 182.6 (4 C=O). 31P NMR: –2.43.
General procedure for the synthesis of (XII) and
(XIV). Decan-1-ol or hexadecane-1-ol (2 eq) and a
solution of pivaloyl chloride (4.3 eq) in pyridine (5 mL)
were successively added to a solution of H-phosphonate
(X) (1 eq) in pyridine (10 mL) cooled to –20°C. The
mixture was stirred for 1 h and water (1 mL) and iodine
(1 eq) were added. The mixture was stirred for 2 h and
1M Na2S2O3 was added dropwise until the iodine
color disappeared. The pale yellow reaction mixture
was evaporated to dryness and the residue was chro-
matographed on silica gel eluting with CH2Cl2–
CH3OH (40 : 1 → 5 : 1 and 1 vol % Et3N) to give decyl
glycophosphate (XII) (23%) as colorless oil and hexa-
decyl glycophosphate (XIV) (10%) as a colorless oil.
2,3,4,6-Tetra-О-acetyl-α-D-glucopyranosyl Н-phos-
phonate, triethylammonium salt (XVIII). Salicyl chlo-
rophosphite (IX) (3.23 g, 16 mmol) [13] was added
under stirring to a solution of glucopyranose tetraace-
tate (XVII) (6.2 g, 17.8 mmol) [15] and triethylamine
(17.3 mL, 124.6 mmol) in dry THF (35 mL) and the
mixture was stirred for 9 h. Water (15.4 mL) was added
and the reaction mixture was stirred for 1 h. The mix-
ture was evaporated to dryness, and the residue was
chromatographed on silica gel eluting with CH2Cl2–
CH3OH (50 : 1 and 1 vol % Et3N) to give 4 g (44%) of
compound (XVIII) as a hygroscopic white powder,
α 2D0
+ 48.4 (c 0.9, CHCl3). Found, %: C 46.82; H
[ ]
2-Acetamido-2-deoxy-3,4,6-tri-О-acetyl-α-D-
7.11; N 2.81; P 6.00. C20H36NO12P. Calc., %: C 46.78;
H 7.07; N 2.73; P 6.03. MALDI-TOF MS: m/z 513.2
[M]. Calc. М 513.2 (C20H36NO12P). 1H NMR: 1.28 [t,
9H, J 7.30, N+(CH2CH3)3], 1.96, 1.98, 2.01, 2.04 (all
glucopyranosyl decyl phosphate, triethylammonium salt
20
(XII).
+ 26.6 (c 0.642, CH3OH). Found, %: C
[α]D
54.09; H 8.78; N 4.21; P 4.55. C30H57N2O12P. Calc.,
%: C 53.88; H 8.59; N 4.19; P, 4.63. MALDI-TOF s, 12Н, 4CH3CO), 3.0 [q, 6Н, J 7.30, N+(CH2CH3)3],
MS: m/z 566.4 [M]–. Calc. М– 566.2 (C24H41NO12P–). 4.07 (dd, 1H, J6a,6b 12.4, J6a,5 2.3, H6a), 4.19 (dd, 1H,
1H NMR: 0.86 (t, 3H, J 7.0, H10'), 1.18 (br s, 4H, H-
J6a,6b 12.4, J6b,5 3.39, H6b), 4.26–4.30 (m, 1H, H5),
9', H-8'), 1.21–1.28 (m, 10H, H3'–H-7'), 1.32 [t, 9H, 4.90–4.94 (m, 1H, H2), 5.07 (t, 1H, J 9.8, H4), 5.50
J 7.30, N+(CH2CH3)3], 1.56–1.64 (m, 2H, H2'), 1.94,
(t, 1H, J 9.8, H3), 5.75 (dd, 1H, J1,P 8.9, J1,2 3.4, H1),
1.98, 1.99, 2.06 (all s, 12Н, 4 CH3CO), 3.06 [q, 6Н, J 6.91 (d, 1H, J1,P 638.9, P–H). 13C NMR: 8.5
7.31, N+(CH2CH3)3], 3.83–3.94 (m, 2H, H1'), 4.05– (CH3CH2N+), 20.49, 20.57, 20.59, 20.61 [4
C(O)CH3], 45.7 (CH2N+), 61.6 (C6), 68.2 (C3), 68.3
(C4), 70.1 (C5), 70.5 (C2), 91.1 (C1), 169.5, 169.8,
169.9, 170.6 (4 C=O). 31P NMR: +0.77.
General procedure for the synthesis of glycophos-
phates (XX), (XXII). Decan-1-ol or hexadecane-1-ol
(2 eq) and a solution of pivaloyl chloride (4.3 eq) in
pyridine (5 mL) were successively added under stirring
4.10 (m, 1H, H2), 4.18–4.25 (m, 2H, H6a, H6b),
4.30–4.40 (m, 1H, H5), 5.16 (t, 1H, J 9.80, H4),
5.26–5.32 (m, 1H, H3), 5.51 (dd, 1H, J1,P 7.34, J1,2
3.22, H1), 7.06 [d, 1H, J2,NH 9.35, NHC(O)CH3],
11.98 (br s, 1H, HN+). 13C NMR: 8.7 (CH3CH2N+),
14.1 (C10'), 20.8, 22.7, 23.0 [3 C(O)CH3,
CH3C(O)NH], 25.9, 27.4, 29.4, 29.5, 29.6, 29.7, 31.9
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
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SYNTHESIS AND BIOLOGICAL ACTIVITY
163
to a solution of H-phosphonate (XVIII) (1 eq) in pyr- Dibenzyl phosphate (1.71 g, 6.16 mmol) was added to a
idine (10 mL) cooled to –20°C. The mixture was solution of oxazoline (XXIII) [17] (1.69 g, 5.13 mmol) in
stirred for 1 h and water (1 mL) and iodine (1 eq) were 1,2-dichloroethane (37 mL) and the reaction mixture
added. The mixture was stirred for 2 h and 1M was stirred at room temperature for 19 h. The mixture was
Na2S2O3 was added dropwise until the iodine color concentrated and dried in vacuum. The resulting (XXIV)
was used without further purification.
disappeared. The pale yellow reaction mixture was
evaporated to dryness and the residue was chromato-
graphed on silica gel to give glycophosphates (XX)
(53%, colorless oil) and (XXII) (35%, colorless oil).
2,3,4,6-Tetra-О-acetyl-α-D-glucopyranosyl decyl
phosphate, triethylammonium salt (XX). Phosphate (XX)
was isolated as colorless oil in a yield of 53% by flash
chromatography on silica gel eluting with
CH2Cl2/CH3OH (100 : 1 → 100 : 2, and 1 vol % Et3N);
Phosphate (XXIV) (1.7 g, 2.8 mmol) was dissolved
in methanol (50 mL) and 10% Pd/C (1.6 g) was added
in an argon atmosphere. The solution was hydroge-
nated at room temperature under vigorous stirring for
3 h and filtered through celite. Celite was washed with
hot methanol (10 mL) and trimethylamine (0.4 mL)
and the solvents were removed in vacuum. The residue
was washed with a CH2Cl2–ether mixture, filtered,
and the filtrate was evaporated in vacuum to give 0.4 g
20
[α]2D0
+ 18.2° (с 1.00, CH2Cl2). Found, %: C 53.79;
(27%) of compound (XXV) as colorless syrup,
+
[α]D
H 8.49; N 2.05; P 4.68. C30H56NO13P. Calc., %:
C 53.80; H 8.43; N 2.09; P 4.62. MALDI-TOF MS:
m/z 567.1 [M]–. Calc. М– 567.2 (C24H40O13P–).
34.4 (c 0.9, CH3OH). Found, %: C 45.51; H 7.01; N
5.23; P 5.89. C20H37N2O12P. Calc., %: C 45.45; H
7.06; N 5.30; P 5.86. MALDI-TOF MS: m/z 426.3
[M]– . Calc. М– 426.1 (C14H21NO12P–). 1H NMR: 1.17
[t, 9H, J 7.3, N+(CH2CH3)3], 1.86, 1.87, 1.89, 1.95 (all
1H NMR: 0.86 (t, 3Н, J 6.9, H10'), 1.18–1.23 (m,
14Н, H3'–H-7'), 1.31 [t, 9H, J 7.3, N+(CH2CH3)3],
1.39–1.44 (m, 2Н, H-8'), 1.56–1.65 (m, 2Н, H2'),
1.98, 1.99, 2.02, 2.05 (all s, 12Н, 4CH3CO), 3.07 [q,
s, 12Н, CH3CO), 2.95 (q, 6Н, J 7.3, N+(CH2CH3)3),
3.91–3.99 (m, 1Н, H6a), 4.05–4.17 (m, 3H, H2, H5,
H6b), 4.98 (t, 1H, J 9.5, H4), 5.08 (d, 1H, J 3.2, H3),
5.18 (t, 1H, J 10, H1), 6.44 (d, 1H, J2,NH 9.5, NH),
6Н, J 7.3, N+(CH2CH3)3], 3.84–3.95 (m, 2H, H1'),
4.05–4.34 (m, 3H, H5, H6a, H6b), 4.89–4.96 (m,
1H, H2), 5.11 (t, 1H, J 9.8, H4), 5.52 (t, 1H, J 9.8,
H3), 5.72 (dd, 1H, J1,P 7.8, J1,2 3.3, H1). 13C NMR: 8.5
9.37 (br s, 1H, N+H). 13C NMR: 8.7 (CH3CH2N+),
20.7, 20.8, 22.8 [3 C(O)CH3 ], 23.2 (CH3C(O)NH),
45.5 (CH2N+), 52.6 (C2), 62.4 (C6), 67.3 (C4), 68.7
(C3), 71.6 (С5), 91.6 (d, J 6.7, C1), 169.6 (NHC=O),
170.7, 170.9, 171.4 (3 C=O). 31P NMR: +1.94.
(CH3CH2N+), 14.1 (C10'), 20.6, 20.7 [4 C(O)CH3],
22.6, 25.7, 27.1, 29.3, 29.4, 29.6, 30.8, 31.9 (C2'–C9'),
45.6 (CH2N+), 61.6 (C6), 67.9 (C1'), 68.3 (C4), 68.3
(C3), 70.2 (C5), 70.3 (C2), 91.9 (C1), 169.6, 170.1,
170.7 (4 C=O). 31P NMR: –2.69.
Biological activity. Antimicrobial activity of com-
pounds (VI), (XII), (XIV), (XX), (XXII), (XXV), and
(XXVI) was studied using serial dilutions in liquid
nutrient media as described in [24, 25] followed by
calculations of MIC values impeding the growth and
development of the test microorganisms. Particularly,
Staphylococcus aureus АТСС 209p and Bacillus cereus
АТСС 8035 were used as Gram-positive cultures;
Escherichia coli CDC F-50 and Pseudomonas aerugi-
nosa ATCC 9027 as Gram-negative cultures; and
Aspergillus niger BKMF-1119, Trichophyton mentagro-
phytes var. gypseum 1773, and Candida albiсans 855-
653 as fungi. Antibiotic chloramphenicol was used as a
control.
The study of antituberculosis activity of com-
pounds (VI), (X), (XII), (XIV), (XX), (XXII), (XXV),
and (XXVI) was conducted by the method of vertical
diffusion [26] on a thick nutrient medium “New”
using the laboratory MBT strain H37Rv. The nutrient
medium was poured into tubes, 5 mL in each, seeded
with suspensions of mycobacteria (0.1 mL per each)
diluted in accordance with the opacity standard of
10 GKI units. The tubes were placed in a thermostat
for 24 h to grow MBT. In a day, the tubes were verti-
cally positioned and 12.5, 6.2, 3.1, 1.5, 0.7, 0.35,
2,3,4,6-Tetra-О-acetyl-α-D-glucopyranosyl cetyl
phosphate, triethylammonium salt (XXII). Phosphate
(XXII) (35%, colorless oil) was isolated by flash chro-
matography on silica gel eluting with CH2Cl2/CH3OH
α 2D0
+ 11.2°
[ ]
(100 : 1 → 100 : 1.5, 1 vol % Et N);
3
(с 1.00, CH2Cl2). Found, %: C 57.41; H 9.01; N 1.78;
P 4.15. C36H68NO13P. Calc., %: C 57.35; H 9.09; N
1.86; P 4.11. MALDI-TOF MS: m/z 675.2 [M + Na]+.
1
Calc. [M + Na]+ 675.3 (C30H53NaO13P+). H NMR:
0.75 (t, 3Н, J 7.0, H16'), 1.03–1.23 (m, 26Н, H3'–
H15'), 1.28 [t, 9H, J 7.3, N+(CH2CH3)3], 1.45–1.53
(m, 2Н, H2'), 1.88, 1.90, 1.92, 1.95 (all s, 12Н,
4CH3CO), 3.07 [q, 6Н, J 7.3, N+(CH2CH3)3], 3.52–
3.76 (m, 2H, H1'), 3.96–4.16 (m, 3H, H5, H6a, H6b),
4.76–4.80 (m, 1H, H2), 4.98 (t, 1H, J 9.7, H4), 5.38
(t, 1H, J 9.6, H3), 5.57 (dd, 1H, J1,P 7.9, J1,2 3.5, H1).
13C NMR: 8.7 (CH3CH2N+), 14.2 (C10'), 20.8
[C(O)CH3], 22.8, 25.9, 27.4, 29.5, 29.6, 29.8, 30.1,
30.8, 32.0 (C2'–C15'), 45.9 (CH2N+), 61.8 (C6), 66.2
(C1'), 68.5 (C4), 68.9 (C3), 70.3 (C5), 70.8 (C2), 92.0
(C1), 169.8, 170.3, 170.9 (4 C=O). 31P NMR: –2.31.
2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glu- 0.1 μg/mL suspensions of compounds (VI), (X),
copyranosyl-О-phosphate, triethylammonium salt (XXV). (XII), (XIV), (XX), (XXII), (XXV), and (XXVI) in
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 45 No. 2 2019

164
SHARIPOVA et al.
10. Cao, Z., Qu, Y., Zhou, J., Liu, W., and Yao, G., J. Car-
bohydr. Chem., 2015, vol. 34, pp. 28–40.
aqueous DMSO were dropped in the tubes following
their free edges. The tubes were placed in a thermostat
and stored at sterile conditions at 37°С for 10 days. 11. Gorityala, B.K., Lu, Z., Leow, M.L., Ma, J., and
Liu, X.-W., J. Am. Chem. Soc., 2012, vol. 134,
The MBT growth was evaluated using a standard
approach, according to which the appearance of areas
of the MBT delayed growth exceeding 10 mm evi-
denced the tuberculostatic properties. Antituberculo-
sis drugs isoniazid and pyrazinamide inhibiting the
MBT growth at MIC 0.1 and 12 μg/mL, respectively,
were used as controls.
pp. 15229–15232.
12. Izmest’ev, E.S., Andreeva, O.V., Sharipova, R.R.,
Kravchenko, M.A., Garifullin, B.F., Strobykina, I.Yu.,
Kataev, V.E., and Mironov, V.F., Russ. J. Org. Chem.,
2017, vol. 53, pp. 51–56.
13. Young, R.W., J. Am. Chem. Soc., 1952, vol. 74,
pp. 1672–1673.
14. Filice, M., Guisan, J.M., Terreni, M., and Palomo, J.M.,
ACKNOWLEDGMENTS
Nat. Protoc., 2012, vol. 7, pp. 1783–1796.
15. Fusari, M., Fallarini, S., Lombardi, G., and Lay, L.,
The study of antituberculosis activity of the com-
pounds was supported by the Russian Science Foun-
dation, project no. 14-50-00014. The authors grate-
fully acknowledge the Assigned Spectral–Analytical
Center of FRC Kazan Scientific Center of RAS.
Bioorg. Med. Chem., 2015, vol. 23, pp. 7439–7447.
16. Chen, C., Liu, B., Xu, Y., Utkina, N., Zhou, D., Dani-
lov, L., Torgov, V., Veselovsky, V., and Feng, L., Carbo-
hydr. Res., 2016, vol. 430, pp. 36–43.
17. Saneyoshi, H., Yamamoto, Y., Kondo, K., Hiyoshi, Y.,
and Ono, A., J. Org. Chem., 2017, vol. 82, pp. 1796–
1802.
COMPLIANCE WITH ETHICAL STANDARDS
18. Wang, S., Czuchry, D., Liu, B., Vinnikova, A.N., Gao, Y.,
Vlahakis, J.Z., Szarek, W.A., Wang, L., Feng, L., and
Brockhausen, I., J. Bacteriol., 2014, vol. 196, pp. 3122–
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The authors declare that they have no conflict of
interest. This article does not contain any studies
involving animals or human participants performed by
any of the authors.
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RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Vol. 45
No. 2
2019