Synthesis, CI-MS analyses and preliminary biological evaluation of a novel library of hydrophobic persulfide-spacers α-alkyl glycosides

Article abstract of DOI:10.2174/157017810790796372

We report the synthesis of novel polyether-based polyols derived from simple glycosides that bear sulfur spacers in the attempt to potentially provide new antibiotics. The CI-MS demonstrated the stepwise and successive fission of the sulfide-spacer groups; however, it does not distinguish between the alditols having different arrangement of O- (CH₂)₃-S(CH ₂)₂OH groups. The investigated compounds exhibited antimicrobial activities against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and antifungal activities against Candida albicans at a concentration of 1 mg /ml in DMF.

Full text of DOI:10.2174/157017810790796372

Letters in Organic Chemistry, 2010, 7, 127-135
127
Synthesis, CI-MS Analyses and Preliminary Biological Evaluation of a
Novel Library of Hydrophobic Persulfide-Spacers ꢀ-Alkyl Glycosides
Hammed H.A.M. Hassan*
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426 Ibrahimia, 21321-Alexandria, Egypt
Received January 21, 2009: Revised December 25, 2009: Accepted December 31, 2009
Abstract: We report the synthesis of novel polyether-based polyols derived from simple glycosides that bear sulfur
spacers in the attempt to potentially provide new antibiotics. The CI-MS demonstrated the stepwise and successive fission
of the sulfide-spacer groups; however, it does not distinguish between the alditols having different arrangement of O-
(CH2)3-S(CH2)2OH groups. The investigated compounds exhibited antimicrobial activities against Staphylococcus aureus,
Pseudomonas aeruginosa, Escherichia coli and antifungal activities against Candida albicans at a concentration of 1 mg /
ml in DMF.
Keywords: Carbohydrates, perallyl glycosides, AIBN, sulfide spacer, antimicrobial.
Antibiotics play a major role in modern medicine’s battle
against bacterial infections. Unfortunately, overuse and
misuse of antibiotics unintentionally produced new strains of
resistant bacteria and increased our vulnerability to
untreatable bacterial infections. Most antibiotics destroy
bacteria by attacking their metabolic structures. Sometimes
the stronger bacteria survive the treatment and pass on their
resistance to future generations. Over time, resistance
spreads and the medicine becomes less effective.
Mammalian cell surfaces expose wide arrays of complex
glycoconjugates that are playing critical roles in multiple key
cellular events [1], several of which have been characterized
by multivalent carbohydrate-protein interactions [2]. The
innate immune system recognizes the structure of
carbohydrate on bacteria through their carbohydrate binding
protein as the first defense mechanism against this type of
infectious agents [3]. Alternatively, bacteria possess proteins
that also recognize and bind to the carbohydrate of host
human tissues as the premise for bacterial infections [4].
This diverse utility has long suggested the power of
carbohydrates in therapeutic approaches. Dendrons such as 1
and 2 (Scheme 1) mediated the transfection of Cos-7 [5] and
BHK-21 cells [6] with plasmid DNA. In addition, human
cells (D-407) were successfully transfected with an
oligodeoxynucleotide, in vitro, using a related dendron as a
vector [7]. Dendrons 3 and 4 were reported as pentration
enhancers for the oral administration of heparin in rats [8].
mannose 5 and a series of synthetic mannoside derivatives 6-
13 (Scheme 1) against E. coli K12 as measured by surface
plasmon resonance are compiled in Table 1 [11]. It is
believed that the hydrophobic aglycones are the most potent
candidates; in particular those constructed using the best
monosaccharide structures mounted on dendritic structures
having optimized scaffolds and linker distances [12]. We
have previously described the synthesis of bioactive
molecules containing carbohydrates such as sulfated
disaccharides [13], tetrasaccharides [14], their mimetic
analogues [15-17], nucleosides [18] and nucleotides [19]. In
this work, the synthesis of a new series of persulfide-spacer
pentyl- and heptyl glycosides having gluco-, galacto- and
manno configurations and their microbial evaluation against
Staphylococcus
aureus,
Pseudomonas
aeruginosa,
Escherichia coli and Candida albicans are described. We
postulated that radical addition of 2-mercaptoethanol, as a
spacer arm, to the double bonds in perallyl glycosides
accessible from ꢀ-allyl-, ꢀ-pentyl- and ꢀ-heptyl glycosides
of different monosaccharides could be used for the
construction of a novel library of lipophilic sulfide-spacer
dendrons 14. Such types of spacer arms contain two
functional groups which can interact with receptors
independently. The hydroxyl group of these spacers can
either be used directly or first be converted into another
functional group for subsequent coupling to the protein [20].
Alkyl glycosides are very useful as antimicrobial agents,
non-ionic detergents in the isolation of membrane proteins,
drug carriers, food emulsifiers and textile lubricants [21].
The natural receptor for E. coli is a highly mannosylated
glycoprotein present on the surface of the endothelial lining
of urinary tissues [9]. The crystal structure of the
enterobacteria from uropathogenic E. coli, primarily causing
pyelonephritis, has been solved with methyl ꢀ-D-mannopyr-
anoside 6 [10] as well as with the more hydrophobic alkyl ꢀ-
D-mannopyranoside [11]. The relative affinities of ꢀ-D-
As a model reaction, the tetraallyl derivative 15 was
prepared by reaction of the commercial 6 with allyl bromide
/ NaH in DMF [22] in 60 % yield, Scheme 1. Elongation of
tetraallyl ꢀ-mannoside 15 by heating with 2-mercaptoethanol
in 1,4-dioxane in the presence of azobisisobutyronitrile
(AIBN) as a radical initiator furnished the corresponding
sulfide-spacer glycoside 16 in 90 % yield [23].
*Address correspondence to this author at the Chemistry Department,
Faculty of Science, Alexandria University, P.O. Box 426 Ibrahimia, 21321-
Alexandria, Egypt; Tel: + 2 012 5888 595; Fax: + 203 5932488; E-mail:
hassan10@safwait.com
As longer chain ꢀ-type alkyl glycosides with different
structure of the carbohydrate moieties are desired for the
study, D-galactose 17, D-mannose 5 and D-glucose 18 have
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

128 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Hammed H.A.M. Hassan
R
H3C (CH2)9
R
R
Lys
O
H
Lys
NH2
N
N
N
H
H
O
Lys
R
O
H3C (CH2)9
1
2
R = Lysine
R = Arginine
R
O
S
S
O
N
H
R
N
H3C
O
(
O
CH2)14
H
O
H
NH2
S
O
HN
N
R
N
N
N
H
H
H
S
O
O
O
O
R
(
H3C CH2)14
N
H
R6
R5
OH
3
4
R = Lysine
R = Arginine
R2
OH
O
O
R4
HO
HO
R3
R1
14
OR
R
R = -O-(CH2)6CH3
R = -O-(CH2)4CH3
R
R
R = -O-(CH2)3S(CH2)2OH
5
6
7
8
9
H
CH3-
CH3CH2-
CH3CH2CH2-
CH3(CH2)2CH2-
10 CH3(CH2)3-CH2-
11 CH3(CH2)4-CH2-
12 CH3(CH2)5-CH2-
13 CH3(CH2)6-CH2-
R1, R3, R4, R6 = -O-(CH2)3S(CH2)2OH
R2, R3, R4, R6 = -O-(CH2)3S(CH2)2OH
R1, R3, R5, R6 = -O-(CH2)3S(CH2)2OH
Scheme 1.
Table 1. The Relative Affinities of ꢀ-D-Mannosides Against E. coli K12 [13]
R
Rel. Affinity
5
6
H
0.96
1.00
CH3-
7
CH3CH2-
1.80
8
CH3CH2CH2-
CH3(CH2)2CH2-
CH3(CH2)3-CH2-
CH3(CH2)4-CH2-
CH3(CH2)5-CH2-
CH3(CH2)6-CH2-
7.30
9
15.0
10
11
12
13
88.0
220.0
440.0
100.0
been used. The allyl ꢀ-glycosides 19, 23 and 27 were
prepared by refluxing the corresponding sugar with allyl
alcohol in the presence of Dowex-50X8 (H+) ion exchange
resin as described by Lee and Lee [24]. Thiol addition to 19,
23 and 27 with mercaptoethanol proceeded smoothly and
gave spacers 20, 24 and 28, respectively, in good yield. For
the purpose of preparing fully sulfide-spacer glycosides with
different sugar moieties, the perallyl ꢀ-glycosides 21, 25 and
29 were prepared in moderate yields from 19, 23 and 27,
respectively, using standard chemistry procedure.
Mercaptoethanol / AIBN mixture reacted efficiently with the
olefins 21, 25 and 29 to produce sulfide-spacer glycosides
22, 26 and 30, respectively, in good yield.
dondrons. Regarding the relative affinities mentioned in
Table 1, ꢀ-pentyl- and ꢀ-heptylglycosides are considered
valuable tools for the study. ꢀ-Pentyl glycosides 31, 37 and
43, (Scheme 3), were prepared in 30 % yields by direct O-
glycosylation of 17, 5 and 18, respectively, with 1-pentanol
in the presence of FeCl3 [25]. Under similar condition, ꢀ-
heptyl glycosides 32, 38 and 44 were obtained in 30 % yields
from reaction of the unprotected sugars 17, 5 and 18,
respectively, with 1-heptanol. A slight increase in reactions
yields was observed when the ꢀ-O-alkyl glycosylation
reactions of the readily available ꢁ-peracetates analogues of
17, 5, and 18 with pentan-1-ol or heptan-1-ol in the presence
of Lewis acid [26], followed by de-O-acetylation to produce
the target glycosides in 33-36 % overall yields. Tetraallyl ꢀ-
pentylglycosides 33, 39, 45 and tetraallyl ꢀ-heptylglycosides
35, 41, 47 were prepared in 60 % average yields by reaction
Our next target was to examine the effect of the alkyl
chain length increase on the properties of the resulted

Antimicrobial Persulfide-Spacer ꢀ-Alkyl Glycosides
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
129
OR1
OR1
OH
OH
OR
OR
O
O
O
R1O
a)
HO
HO
RO
b)
R1O
OMe
16
RO
OR
OR
60%
90%
OMe
OMe
15
6
D-Galactose
17
22
OR1
c)
44%
b)
OR
OH
OH
OR
OR1
OH
OH
O
88 %
O
O
O
a)
R1O
OR
RO
OR1
HO
HO
19
21
OR
OR1
OR1
OH
OH
60 %
b)
90 %
21
19
20
22
20
D-Mannose
OR1
OH
OH
5
OR OR
OR1
OH
26
OH
O
O
O
O
R1O
R1O
RO
RO
HO
HO
HO
HO
c)
b)
40%
84 %
OR1
OR1
OR
a)
25
23
24
26
23
25
60 %
b)
90 %
24
D-Glucose
18
30
OR
OR1
OH
OH
c)
O
b)
O
O
O
R1O
R1O
RO
RO
HO
HO
HO
HO
40%
84 %
a)
OR
OR1
OH
OR1
OH
OR
OR1
OR
27
29
60 %
29
27
28
30
b)
92 %
R =
R1 =
28
S
OH
Scheme 2. Reagents: a) NaH, DMF, allylbromide; b) 2-mercaptoethanol, AIBN, 1,4-dioxane, 80oC; c) allyl alcohol, Dowex 15 (H+), reflux,
2h.
of pentyl glycosides 31, 37 and 43 or heptyl glycosides 32,
38 and 44, respectively, with NaH / allyl bromide in DMF.
Compounds 33, 39, 45 and 35, 41, 47 were treated with 2-
mercaptoethanol in the presence of AIBN at 75oC to give
sulfide spacers pentylglycosides 34, 40, 46 and sulfide
spacers heptylglycosides 36, 42, 48, respectively, in good
yields (75-92 %) [27].
analysis. IR spectra (film, NaCl) showed a broad band
around ꢀ 4000 cm-1 correspond to the free terminal OH
groups and a strong band atꢀ 2923 cm-1 due to the alkyl
groups. 1H-NMR spectra of either mono- or persulfide-
spacer glycosides revealed the presence of signals at ꢁ 2.20-
2.60 (m, -CH2SCH2-), 2.61 (m, -CH2-), 2.77-2.70 (m, -CH2-),
3.77-3.70 (m, -CH2OH) correspond to thiospacer protons,
whereas protons of the carbohydrates were resonated at 3.98-
Elongated persulfide-spacer glycosides exhibited similar
spectroscopic behaviors and interesting mass spectral

130 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Hammed H.A.M. Hassan
OR
OR1
OH
OH
OR
OR1
O
O
O
HO
RO
R1O
a)
b)
31
32
D-Galactose
OR
OH
OR1
O
O
O
33 %
O
31 %
17
31
33
34
c)
60 %
c)
OH
OR1
OR1
OR
OH
OR
60 %
O
O
O
HO
R1O
RO
d)
d)
33
35
34
36
OR1
O
OH
OR
O
79 %
80 %
36
32
35
R1
=
R =
S
OH
OH
OR1
OH
O
OR
OR
OR1
a)
O
b)
O
D-Mannose
R1O
R1O
HO
HO
RO
RO
38
37
35 %
35 %
5
O
O
O
O
37
39
40
c)
60 %
c)
60 %
OR
OH
OR
OR1
OH
O
OR1
O
O
R1O
R1O
HO
HO
RO
RO
d)
d)
41
39
40
42
89 %
82 %
O
O
38
41
42
R1
=
R =
S
OH
OH
OR1
OR
a)
b)
O
O
44
D-Glucose
43
O
R1O
R1O
HO
HO
RO
RO
30 %
30 %
18
OR
OH
OR1
O
O
O
c)
c)
60 %
43
45
46
60 %
OR
OH
OR1
O
d)
d)
O
47
45
O
48
46
R1O
R1O
HO
HO
RO
RO
84 %
80 %
OH
OR
OR1
O
O
O
44
47
48
R1
=
R =
S
OH
Scheme 3. Reagents: a) amylalcohol, FeCl3, reflux; b) heptylalcohol, FeCl3, reflux; c) NaH, DMF, allylbromide; d) 2-mercaptoethanol,
AIBN, 1,4-dioxane, 80 oC, 3h.
3.90 (d, 2H, H-4, H-5), 3.90-3.80 (m, 2H, H-2, H-3), 3.80-
3.60 (m, 2H, 2x H-6), 4.66 (d, J = 3.2 Hz, H-1), respectively.
The CI-MS analyses of 34 and 36 as two models of
persulfide-spacer alkyl glycosides using methane as the
ionizing gas are presented in Scheme 4. The molecular ion
peaks (M+, M++1) of low intensities were observed whereas
those charged ions originate from the methane gave larger
fragment-ions. However, use of methane as the ionizing gas
gives many fragment ions and thus the mass spectral data of
all derivatives were obtained by using selected mass range
300-700 atomic mass units rather than scanning the entire
Mass spectrometry analyses of numerous mono- and
oligosaccharides derivatives have been reported [28]. The
partially methylated alditol acetates showed very
characteristic mass spectra, especially for methylation
analyses [29]. Position-dependent, characteristic fragments
were observed for O-(hydroxyethyl)glucitol acetates [30]. In
addition, many of the stereoisomers of methylated hexitol
acetates having the same arrangements of O-methyl and O-
acetyl groups exhibited markedly different analyses [31].

Antimicrobial Persulfide-Spacer ꢀ-Alkyl Glycosides
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
131
m/z +644
m/z +336
OH
S
OH
S
O
O
O
S
O
O
OH
O
O
O
OR
O
S
S
O
S
O
OH
HO
RO
HO
(m/z +644)
S
49
S
OH
34B
OH
+136
OH
36B (m/z +672)
+78
SH
+
(m/z +586)
(m/z +614)
34D
36D
S
H2O
D
HO
+44
OH
B
S
SH
m/z +652
OH
OH
S
OH
OH
O
O
O
S
S
S
O
O
O
O
O
O
+70
E1
+98
E2
O
+
O
O
O
HO
CH2
or
OR
S
S
A
O
S
HO
O
OH
HO
O
S
S
S
(m/z +678)
34A
36A
HO
R
OH
OH
m/z +722
34 R = C5H11
m/z +750
HO
(m/z +706)
50
+118
OH
+88
F1
+116
F2
+
H2C
or
S
m/z +634
36 R = C7H15
C
OH
m/z +604
OH
OH
S
OH
S
S
S
m/z +500
O
O
O
+136
OH
O
O
OH
O
OH
O
S
+
S
S
H2O
OH
D
O
O
O
O
S
OR
O
S
S
HO
O
OH
HO
S
(m/z +604)
34C
51
52
OH
36C (m/z +632)
+136
OH
+
S
+70
H2O
D
CH2
E1
E2
+
m/z +365
OH
+98
m/z +229
OH
CH2
+
OH
S
S
+136
OH
S
+88
F1
F2
O
S
OH2
+
O
O
HO
D
O
O
+116
OH2
+
+
54
53
Scheme 4.
mass range 50-1000 atomic mass units. Interestingly, within
the selected mass range, the major quantitative differences in
the CIMS of all of the persulfide-spacer alkyl glycosides
occur in the relative intensities of the M-78(B), M-118(C)
and M-136(D). The CIMS spectral data proved that the
cleavage of the ꢀ-glycoside linkages take place through two
possible mechanisms either by fission of the alkyl group (ꢀ-
pentyl- or ꢀ-heptyl-)[M+-70(E1) or M+-98(E2), respectively]
as identified by the ion derivative 50 at m/e 652 or by
elimination of the glycosidic group (HO-pentyl- or HO-

132 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Hammed H.A.M. Hassan
Table 2. Prominent Fragments (m/z) in Mass Spectra of the Persulfide-Spacer Glycosides [32]
No.
m/z
336
365
500
586
604
632
614
634
644
652
672
16
22
26
30
34
36
40
42
46
48
--
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
--
--
--
--
+
--
--
--
--
+
--
--
--
--
--
+
--
--
--
--
--
+
+
+
+
+
+
+
+
+
+
+
--
--
--
--
+
--
+
+
+
+
+
+
+
+
+
--
--
--
--
--
+
--
+
--
+
--
+
--
+
--
+
--
+
--
+
--
+
--
+
--
+
--
--
--
+
--
--
--
heptyl-)[M+-88(F1) or M+-116(F2), respectively] as
demonstrated by the ion derivative 51 at m/e 634. Further
successive eliminations of m/e 136 (D) ion from 51 were
identified by the ion derivative 52 (m/e 500), 53 (m/e 365)
and 54 (m/e 229). All of the compounds studied yield these
ions (Table 2). These results derive us to conclude that the
CI mass spectrometry under methane as ionizing gas
demonstrated the stepwise and successive fission of the
sulfide-spacer groups in one hand but it does not distinguish
between the alditols having different arrangement of O-
(CH2)3-S(CH2)2OH groups on the other hand.
37°C for 18-48h. Three standard compounds Imipenam (10
μg / disc), Ampicillin (10 μg / disc) and Clotrimazole (0.01g
/ ml) were used as control. After incubation, the plates were
examined visually and the zone of inhibition was measured
in millimetres with an accuracy of 0.5 mm using a ruler.
Each inhibition zone diameter was measured three times
(three different plates) and the average was taken.
The antimicrobial screening against test strains shows
that most perallylated glycosides and their persulfide-spacers
analogues have more significant effect on inhibition of gram-
negative bacteria than on gram-positive bacteria. This is due
to the structural difference in cell wall composition of gram-
positive and gram-negative bacteria. The gram-negative
bacteria have a layer of lipopolysaccharides at the exterior,
Biological Activity
The prepared perallylated and persulfide-spacer
glycosides were screened in vitro against one Gram-positive
bacteria Staphylococcus aureus ATCC6538P and two Gram-
negative bacteria Pseudomonas aeruginosa ATCC9027 and
Escherichia coli ATCC8739. The compounds were also
screened against Candida albicans ATCC2091 fungi.
followed underneath by
a thin (~7–8 nm) layer of
peptidoglycan [34]. Although the lipopolysaccharides are
composed of covalently linked lipids and polysaccharides;
there is a lack of strength and rigidity. On the other hand, the
cell wall in gram-positive bacteria is principally composed of
a thick layer (~20–80 nm) of peptidoglycan consisting of
linear polysaccharide chains cross-linked by short peptides
to form a three-dimensional rigid structure [35]. The rigidity
and extended cross-linking endow the cell walls with fewer
interaction sites and make them difficult to penetrate. The
reported compounds were designed to act as penetration
enhancers by forming lipophilic ion-pairs with the negatively
charged lipopolysaccharides. Ion-pairing has been used as a
means to enhance the absorption of various drugs [36]. The
antibiotic molecules contain many active groups such as
hydroxyl and amido groups, which reacts easily with the
charged lipopolysaccharides forming matched ion-pairs. This
ion-pair model of absorption assumes that the antibiotics are
absorbed via a complex formation with the lipopolysac-
charides. In the current study, the reported persulfide-spacers
polyols can attack the gram-negative bacteria forming
matched ion-pair which enhance the absorption through their
thin peptidoglycan layer. On the other hand, the fewer
interaction sites in case of gram-positive bacteria may
produce a mismatched ion-pair with the persulfide-spacers
and accordingly the difficult penetration of their relatively
thick layer. This may explain the negative antimicrobial
Screening results are summarized in Table 3. All the
synthesized compounds were dissolved to prepare a stock
solution of 1 mg / ml using DMF. Stock solution was
aseptically transferred and two-fold diluted to have solutions
of different concentrations. The antibacterial and antifungal
activities of test compounds were done by filter paper disc
method [33] and the activities were determined by measuring
the diameters of the inhibition zone (mm). Media with DMF
was set up as control. All cultures were routinely maintained
on NA (nutrient agar) and incubated at 37°C. The inoculums
of bacteria were performed by growing the culture in NA
broth at 37°C for overnight. Approximately, 0.1 ml of
diluted bacterial or fungal culture suspension was spread
with the help of spreader on NA plates uniformly. Solutions
of the tested compounds and reference drugs were prepared
by dissolving 10 mg of the compound in 10 ml DMF. A 100
μL volume of each sample was pipetted into a hole (depth 3
mm) made in the centre of the agar. Sterile 8 mm discs (Hi-
media Pvt. Ltd.) were impregnated with test compounds. The
disc was placed onto the plate. Each plate had one control
disc impregnated with solvent. The plates were incubated at

Antimicrobial Persulfide-Spacer ꢀ-Alkyl Glycosides
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
133
results of most tested substrates against S. aureus
ATCC6538P; however, the persulfide-spacer glycosides 42
and 48 showed moderate inhibitory results against this
bacterial strain. In addition, the perslfide-spacer 48 showed
relatively good activity against E. coli ATCC8739 while no
activity was noticed for its perallylated glycosides analogue
47. The relatively higher inhibition results were obtained
against C. albicans by 21, 22, 30, 36 and the unsubstituted
ꢀ-heptyl glucoside 44. Thus the data revealed that all
compounds have produced the marked enhancement in the
potency of these analogues as antibacterial and antifungal
agents.
18, 22, 26, ꢀ-pentyl- 30, 36, 42 and ꢀ-heptyl- 31, 37, 43
glycosides led to a library of sulfide-spacers 21, 25, 29 and
33, 39, 45 and 35, 41, 47 in good yields. The CI mass
spectrometry under methane as ionizing gas demonstrated
the stepwise and successive fission of the sulfide-spacer
groups, however, it does not distinguish between the alditols
having different arrangement of O-(CH2)3-S(CH2)2OH
groups. The microbiological screening revealed that all
compounds showed moderate inhibition relative to the
standard drug and the nature of substituents and basic
skeleton of molecule do not have strong influence on the
activities. The glycosides 42 and 48 showed moderate
inhibitory results against S. aureus while all other tested
compounds were inactive against this bacterial strain. In
addition, the persulfide-spacer 48 showed relatively good
activity against E. coli while no activity was noticed for its
perallylated glycosides analogue 47. The relatively higher
inhibition results were obtained against C. albicans by 21,
22, 30, 36 and the unsubstituted ꢀ-heptyl glucoside 44.
Table 3. In Vitro Antimicrobial and Antifungal Activities of
the Prepared Perallylated and Persulfide-Spacer
Glycosides. (Average Inhibition Zone Diameter in
mm)
Compound
S
C
Ps
EC
Imipenam (10 mcg/disc)
30
30
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
16
---
---
---
---
16
---
---
40
16
16
20
20
19
16
18
20
17
14
18
20
19
18
17
17
20
18
16
18
16
30
---
---
16
17
16
16
16
16
16
17
16
16
16
18
16
20
16
16
16
15
16
17
17
26
---
---
14
14
15
14
16
16
16
17
18
16
16
18
16
16
16
17
15
15
18
---
15
Ampicillin (10 mcg/disc)
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Clotrimazole (0.01 g/ml)
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21
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Strain
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EC
Strain NO
Staphyllococcus aureus
ATCC6538P
Pseudomonas aeruginosa ATCC9027
[10]
Candida albicans
ATCC2091
Escherischia Coli
ATCC8739
In conclusion, the syntheses of a new series of persulfide-
spacer ꢀ-pentyl- and ꢀ-heptyl glycosides having gluco-,
galacto- and manno configurations are described. Radical
addition of 2-mercapto-ethanol to the perallyl glycosides 20,
24, 28 and 32, 38, 44 and 34, 40, 46 accessible from ꢀ-allyl-
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Bouckaert, J.; Berglund, J.; Schembri, M.; De Genst, E.; Cools, L.;
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a
spectrophotometer. 1H-NMR and 13C- NMR were recorded on
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standard. Chemical ionization mass spectrometry (CIMS)
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disaccharides for modular synthesis of heparin sulfate fragments:
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a Finnigan SSQ 7000
spectrometer attached to digital DEC 300 work station at the
central scientific services unit, National Research Center, Dokki,
Cairo, Egypt. Methane, the ionizing gas, was introduced directly
into the source of the mass spectrometer and the pressure of the gas
in the source was approximately 0.5 torr. Under these conditions,
essentially all of the charged ions originate from the methane.
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Cairo University, Giza, Egypt. Antimicrobial and antifungal
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(1ꢁ4)Glcp-b-D-(1ꢁ4)GlcpN3”. Org. Chem. Ind. J., 2008, 4(1),
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ii-General Procedure for perallylation reaction. To a cold (0oC)
solution of ꢂ-alkyl glycoside (0.1 mmol) dissolved in DMF (25
ml), NaH (8x equiv.) was added portion wise. Stirring was
continued at 0oC for 15 min, 45 min at rt then the salty solution was
cooled to 0oC again. Allyl bromide (8x equiv) in DMF was added
slowly and the clear mixture was allowed to stir at rt for 15 h. The
organic solvent and volatiles were removed under high vacuum and
the crude product was purified on column chromatography (1:2
EtOAc / hexane).
iii-General Procedure for radical elongations. ꢃsolution of ꢂ-alkyl
perallyl glycoside (0.5 mmol), AIBN (0.1-0.2 mmol) and 2-
mercaptoethanol (10 mmol) in 1,4-dioxane (10 ml) was degassed
[19]
Hassan, H. H. A. M. Chemical Synthesis of UDP-GlcpA from the
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from Lactose. Asian J. Chem., 2010, 22(3), 2117.
o
by bubbling N2 gas in solution before heating at 75 C (preheated
oil bath). Stirring was continued for 4- 6 hours then concentrated to
dryness. Co-evaporation twice with toluene and the residue was
purified on silica gel column chromatography.
[20]
[21]
R. Roy. In Carbohydrate Chemistry; Boons G.J., Ed.; Blackie
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Lambert, O.; Levy, D.; Ranck, J. L. Use of detergents in two-
dimensional crystallization of membrane proteins. Biochem.
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partially methylated alditol acetates. Carbohydr. Res., 1967, 5, 433.
rapid permethylation of glycolipid and
polysaccharide catalyzed by methylsulfinyl carbanion in dimethyl
sulfoxide. J. Biochem. (Tokyo), 1964, 55, 205.
polyglycosides-properties and applications of
a new class of
surfactants. Angew. Chem. Int. Ed. Engl., 1998, 37, 1328. e)
Wegner, M.; von Rybinski, W. Surfactant systems for
microemulsions and their importance for applications. Tenside
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[22]
[23]
Tamura, J. -I.; Horito, S.; Yoshimura, J.; Hashimoto, H. Effect of
complexation of silver ion with the glycosyl donor and acceptor on
the region- and stereoselectivity in the ꢀ-manno-pyranosylation of
Hakomori, S.
A
1,3-di-N-benzyloxycarbonyl-2-deoxystreptamine
using
silver
triflate as a promoter in tetrahydrofuran. Carbohydr. Res., 1990,
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van Seeventer, P.B.; van Dorst, J.A.L.M.; Siemerink, J.F.;
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[31]
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McNeil, M.; Albersheim, P. Chemical ionization mass
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56, 239.
Selected spectroscopic data: Methyl 2, 3, 4, 6-tatra-O-[3-
(hydroxythioethyl)-propyl]-ꢀ-D-mannopyranoside 16: IR (Film,
NaCl): 3788-3400, 2923, 1661, 1565, 1438, 1308, 1289, 1247,
1123, 1088, 1062, 919, 907, 858, 807, 794, 767, 707, 670. 1H-NMR
(500 MHz, CDCl3): 1.84-1.80 (m, 8H, 4x CH2), 2.66-2.56 (m, 16H,
4x CH2SCH2-), 3.30-3.28 (m, 10H, 2x H-6, 4x OCH2), 3.59-
3.51(m, 8H, 4x CH2OH), 3.69-3.67 (m, 5H, OCH3, H-4, H-5),
3.84-3.80 (m, 2x H-2, H-3), 4.69 (d, J = 3.0 Hz, 1H, H-1). CIMS:
Calculated for C27H54O10S4 (666): Found: 694(M+ +1+ 2CH4) (82),
693 (M+ + 2CH4) (25), 666(M+) (11), 649 (M+ + 1-H2O) (100), 648
(M+-H2O) (80), 647 (M+-H3O+) (65), 635 (M-CH4O)(76), 633 (35),
621 (M-C2H6O)(3), 616 (70), 588(M-C2H6OS) (17), 571(55), 557
(64), 556 (72), 548 (M-C5H10OS) (2), 531 (M-C5H10O2S) (13),
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Lee, R.T.; Lee, Y. C. Synthesis of 3-(2-aminoethylthio)propyl
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Res., 1998, 311, 25.
[26]
(a) Zorica, P.; Stanimir, K.; Aleksandra, S. BF3 etherate-induced
formation of C7-C16-alkyl ꢀ-D glucopyranosides. Ind. J. Chem.
Sect. B, 2004, 43B, 132. (b) Konstantinovic, S.; Dimitrijevic, B.;
Radulovic, V. Synthesis of C7-C16-alkyl glycosides: Part III-
Synthesis of alkyl D-galactopyranosides in the presence of tin (IV)
chloride as a Lewis acid catalyst. Ind. J. Chem. Sect. B, 2002, 41B,
598. (c) Chatterjee, S. K.; Nuhn, P. Stereoselective ꢁ-glycosidation
using FeCl3 as a Lewis acid catalyst. Chem. Commun., 1998, 16,
1729.
500(M-C6H14O3S) (8), 396 (2). 3-(Hydroxythioethyl) -propyl-ꢀ-D-
galactopyranoside 20: IR (Film, NaCl): ꢄ 3400, 2990, 2940, 2910,
1660, 1569, 1443, 1300, 1289, 1247 cm-1. 1H-NMR (500 MHz,
CD3OD): ꢅ 2.24-2.55 (m, 4H, -CH2SCH2-), 2.55-2.61 (m, 2H, -
CH2-), 2.65-2.70 (m, 2H, -CH2-), 3.98-3.93 (m, 2H, H-4, H-5),
3.90-3.84 (m, 2H, H-2, H-3), 3.77-3.70 (m, 2H, -CH2OH), 3.80-
3.60 (m, 2H, 2x H-6), 4.25 (d, J = 3.4 Hz, H-1). 13C-NMR (125
MHz, CD3OD): 96.1 (C-1), 67.0, 68.2, 67.4, 69.6, 61.4, 35.4, 32.9,
30.4, 30.2. CIMS: Calculated for C11H22O7 S (298): Found; 62 (43),
79(7), 82(7), 83(6), 84(1), 85(1), 87(1), 89(1), 91(1), 92(2), 93(1),
94(1), 100(6), 103(11), 105(24), 109(14), 110 (23), 111(5),
119(26), 121(1), 128(2), 129(1), 137(D)(100), 138(2), 139(9),
[27]
General Procedures: i- All moisture-sensitive reactions were
performed under
a nitrogen atmosphere using oven-dried
glassware. AIBN was recrystallized in dry methanol before use.
Evaporation was performed under vacuum with a water bath
temperature below 40oC. Reactions were monitored by TLC on
Silica Gel 60 F254 plates with detection by UV at 254 nm and by
charring with 5 % ethanolic H2SO4. Column chromatography was
performed on silica gel 60 (EM Science, 70-230 mesh). IR spectra

Antimicrobial Persulfide-Spacer ꢀ-Alkyl Glycosides
Letters in Organic Chemistry, 2010, Vol. 7, No. 2
135
142(3), 146 (3),155(3),156(1), 166(7), 175(9), 166(2), 177(2),
183(1), 195(1), 209 (10), 239(5), 262 (M+-D)(6), 278(2), 282 (2),
298(M+)(1).1,2,3,4,6-Penta-O-[3-(hydroxythioethyl)-propyl]-ꢀ-D-
galactopyranoside 22: (88 % yield, colorless oil). IR (Film, NaCl):
ꢀ 3700-3300, 2990-2900 cm-1. 1H NMR (500 MHz, CDCl3): 1.74–
1.83 (m, 10 H), 2.20–2.35 (m, 10 H), 2.53–2.63 (m, 10 H), 3.19–
2.53–2.63 (m, 8H), 2.70–2.76 (m, 8H), 3.19–3.28 (m, 8H), 3.35–
3.41 (m, 8H), 3.42–3.90 (m, 6H), 5.01-5.90 (m, 5H), 6.03 (br s,
1H). CIMS: m/z (%):Calculated for C33H66O10S4 (750): Found;
350(2), 437(3), 439(1), 446(3), 448(3), 453(2), 467(5), 501(2),
512(2), 520(3), 527(8), 529(6), 533(2), 534(4), 538(2), 539(2),
545(4), 547(0.22), 548(5), 553(5), 557(6), 558(12), 559(2), 560(6),
561(7), 562(8), 563(13), 564(18), 565(7), 566(21), 567(14), 575(7),
576(6), 577(8), 583(8), 588(13), 590(29), 591(21), 594(M+-2x
B)(2) 595(15), 596(11), 598(12), 599(68), 600(54), 601(100),
602(65), 603(84), 604(88), 605(53), 606(37), 607(87), 608(87),
609(89), 610(80), 611(76), 612(M+-2x B+CH4) (21), 614(M+-
D)(47), 615(35), 617(60), 618(M+-3x A) (65), 619(87), 620(28),
621(18), 621(42), 623(35), 623(11), 625(29), 626(11), 628(19),
631(23), 632(15), 633(M+-C) (21), 633(21), 635(M+-F2) (34),
636(62), 637(77), 638(65), 639(41), 640(52), 644(18), 646(17),
648(13), 648(52), 650(50), 651(M+-E2) (27), 653(6), 653(36),
654(15), 655(15), 657(13), 658(5), 660(8), 661(30), 662(M+-2x
A)(76), 664(62), 666(22), 667(7), 668(9), 670(M+-E2+CH4) (7),
673(M+-B)(16), 674(3), 675(18), 676(1), 677(16), 678(5), 679(30),
680(M+-2x A+CH4)(8), 681(25), 682(3), 683(14), 684(8), 684(24),
686(15), 688(14), 690(M+-B+CH4) (4), 691(11), 693(9), 696(11),
697(18), 699(4), 700(3).
3.28 (m, 11H), 3.35–3.41 (m, 4 H), 3.42–
3.90 (m, 10 H),
4.90-5.01 (m, 2H), 5.40 (br s, 1H). Calculated for
C31H62O11S5ꢁ2H2O (734): % C: 50.68; % H: 7.90; Found; C: 50.89,
H: 6.79. CIMS: m/z (%): 497(4), 499 (M+-2x D) (99), 501(5),
515(7), 516 (M+-2x D + CH4) (13), 517(5), 543(26), 544(22),
545(12), 547(13), 551(5), 555(42), 557(M+-C-D) (100), 558 (10),
559(26), 560(12), 561(10), 563(11), 575 (M+-C-D+CH4) (20),
577(14), 587(13), 589(13), 591(15), 598(8), 601(17), 602(13),
604(17), 607(14), 615 (M++1-2x B) (27), 616(55), 619(20),
620(11), 621(21), 631(8), 632(M+ -2x B+CH4)(67), 633 (M+-1-D)
(99), 634(M+-D) (70), 636(63), 637(13), 640(11), 650(36), 651(M+-
1-C) (58), 652 (M+-C) (22), 654(6), 659(28), 661(18), 669(M+-
C+CH4) (5), 675(29), 677(32), 679(12), 684(7), 691(6), 692(M+-B)
(9),
694(6),
695(27),697(9),699(4).Pentyl-2,3,4,6-tatra-O-[3-
(hydroxythioethyl)-propyl]-ꢀ-D-mannopyranoside 40: (89 % yield,
colorless oil). CIMS: m/z (%): Calculated for C31H62O10S4 (723):
Found; 499(M+-C10H21O3S) (6), 500(M+-C10H22O3S) (3), 515(3),
517(M+-C10H21O3S + CH4) (7), 530(38), 557(34), 568(14), 571(94),
577(16), 585(M+-1-C5H12O2S) (4), 589(M++1-C5H10O2S) (3),
590(6), 604(7), 605(M+-1-C5H10O2S+CH4) (13), 607(M++1-
C5H10O2S+CH4) (2), 615(24), 617(60), 624(8), 629(29), 631(16),
633(77), 635(M++1-C5H10O)(M-F) (100), 638(20), 644(M+-
C2H6OS) (4), 646(77), 648(31), 649(57), 651(M+-1-C5H10) (29),
[33]
[34]
[35]
[36]
Finegold, S. M.; Martin, W.J. Diagnostic Microbiology, 6th ed.;
Louis S.: London, 1982; p. 450.
Madigan M, Martinko J. Brock Biology of Microorganisms. 11th
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Baron S. Medical microbiology. 4th ed. Galveston: University of
Texas Medical Branch; 1996.
a) Quintanar-Guerrero, D.; Allemann, E.; Fessi, H.; Doelker, E.
Applications of the Ion-Pair Concept to Hydrophilic Substances
with Special Emphasis on Peptides. Pharm. Res., 1997, 14, 119. b)
Jonkman, J. H. G.; Hunt, C. A. Ion pair absorption of ionized drugs
-fact or fiction? Pharm. Weekbl. Sci., 1983, 5, 41. c) Neubert, R.
Ion pair transport across membranes. Pharm. Res., 1989, 6, 743.
653(M++1-C5H10) (5), 654(7), 662(M+- C2H6OS
+ CH4) (9),
663(10), 665(20), 678(M+-C2H4O) (6), 681(4), 686(16), 692(29),
693(M+-1-C2H6O + CH4) (90), 694(3), 695(M+-1-C2H4O +CH4)
(62),
698(13).
Heptyl-2,3,4,6-tatra-O-[3-(hydroxythioethyl)-
propyl]-ꢀ-D-glucopyranoside 48: (84 % yield, colorless oil). 1H
NMR: 1.62–1.83 (m, 9H), 2.20–2.26 (m, 2H), 2.32–2.35 (m, 2H),