Synthesis of 1,2,3-triazole glycoconjugates as inhibitors of α-glucosidases

Article abstract of DOI:10.1016/j.carres.2011.12.026

Ten new 1,2,3-triazole glycoconjugates were synthesized from d-glucose and evaluated in in vitro assays for their ability to inhibit the enzyme α-glucosidase. Most of the compounds had low activity or were inactive when compared with acarbose. However, the derivative 1,2-O-isopropylidene-3- phenyl-5-(4-phenyl-1H-1,2,3-triazole-1-yl)-α-d-ribofuranose (19i) possessed activity comparable with the standard drug. The influence of the phenyl group on carbon 3 of the carbohydrate framework is discussed.

Full text of DOI:10.1016/j.carres.2011.12.026

Carbohydrate Research 350 (2012) 14–19
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of 1,2,3-triazole glycoconjugates as inhibitors of
a-glucosidases
David R. da Rocha a, Wilson C. Santos b,d, Emerson S. Lima c, Vitor F. Ferreira a,
⇑
a Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, CEG, Campus do Valonguinho, 24210-141 Niterói, RJ, Brazil
b Universidade Federal Fluminense, Faculdade de Farmácia, Programa de Pós-Graduação em Ciências Aplicadas a Produtos Para Saúde (PPG-CAPS),
Rua Mário Viana, 523, 24241-000 Niterói, Brazil
c Universidade Federal do Amazonas, Faculdade de Ciências da Saúde, 69010-300 Manaus, AM, Brazil
d Instituto Teófilo Hernando, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Avda Arzobispo Morcillo, 4, 28029, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Ten new 1,2,3-triazole glycoconjugates were synthesized from D-glucose and evaluated in in vitro assays
Received 3 November 2011
Received in revised form 22 December 2011
Accepted 25 December 2011
Available online 3 January 2012
for their ability to inhibit the enzyme
inactive when compared with acarbose. However, the derivative 1,2-O-isopropylidene-3-phenyl-5-(4-
phenyl-1H-1,2,3-triazole-1-yl)- -ribofuranose (19i) possessed activity comparable with the standard
a-glucosidase. Most of the compounds had low activity or were
a
-D
drug. The influence of the phenyl group on carbon 3 of the carbohydrate framework is discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Triazole
Glycoconjugates
a-Glucosidase
1. Introduction
nes strain SE 50 and is used as a potent sucrase inhibitor (Fig. 1).10
Acarbose consists of
derivative (valienamine) that is linked via its nitrogen atom to
6-deoxyglucose, which is -(1?4)-linked to a maltose moiety
a polyhydroxylated aminocyclohexene
A glycosidic bond is a covalent chemical bond between the
anomeric carbon atom of a saccharide and some other group or mol-
ecule. Many polysaccharides are formed from the union of monosac-
a
(Fig. 1). This compound inhibits pig intestinal sucrase with an
IC50 of 0.5 mM.11 After many clinical investigations, acarbose was
introduced in the market in 1990 for the treatment of type 2
charides by
these bonds are hydrolyzedby specific glycosidase enzymes that lib-
erate the carbohydrate units as nutrients.1 For instance,
-amylase
enzymes are produced in the digestive system to break down the
a- or b-glycosidic bonds. During the digestion process,
a
diabetes mellitus.7 The inhibition of pancreatic
a
-amylase and
intestinal
a-glucosidases has demonstrated great value in the con-
a
-glycosidic bonds of starch. Several glycosidase enzymes are
trol of blood glucose levels by slowing down the starch digestion
involved in important biological processes,2 such as intestinal diges-
tion and the lysosomal catabolism of glycoconjugates. Additionally,
these enzymes are involved in virus production3,4 and cancer metas-
tasis5–7 and are targets for anti-hyperglycemic pharmacological
rate.12–16 The strong inhibition of human amylases by acarbose
(IC50 108.8 12.3 lM) is attributed both to the partial planarity
of the valienamine ring and to the presence of strong electrostatic
interactions between the carboxyl groups at the active site and the
protonated nitrogen atom of the inhibitor.
agents. In this regard, digestive
a-glucosidases control rapid in-
creases in blood glucose and therefore are therapeutically useful
for the treatment of metabolic diseases such as diabetes mellitus.8
Many organisms have endogenous inhibitors that control the
activity of glycosidases and glycosyl transferases. For instance,
nojirimycin (1) and deoxynojirimycin (2) are potent inhibitors for
Polysubstituted five-membered azaheterocycles have been de-
scribed as potent glycosidase inhibitors. These heterocycles mimic
the sugars moieties, and notable structural scaffolds include pyr-
role-, imidazole-,17,18 [1,2,3]-triazole-19–24, and tetrazolo-glyco-
derivatives.25,26
a
- and b-glucosidases and are produced by several natural sources.
The importance of triazolic compounds is of particular interest
for medicinal chemistry, and many of them have been employed
as pharmaceutically active compounds or as prototypes for poten-
tial drugs. In this regard, [1,2,3]-triazoles have gained increasing
attention due to the ease of their incorporation into molecules
via ‘click’ chemistry.27,28 These heterocycles can actively partici-
pate in hydrogen bonding and dipole–dipole interactions due to
their strong dipole moments. Additionally, they are extremely sta-
ble against hydrolysis and oxidative/reductive conditions. They are
Since the discovery of these compounds, several other glycosidase
inhibitors have been isolated from plants and microorganisms.9
The search for a-glucosidase inhibitors led to the isolation of acar-
bose (3), marketed as GlucobayÒ and Precose, from the Actinopla-
⇑
Corresponding author.
E-mail address: cegvito@vm.uff.br (V.F. Ferreira).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.12.026

D. R. da Rocha et al. / Carbohydrate Research 350 (2012) 14–19
15
OH
OH
H
N
HO
HO
OH
HO
HO
H3C
HO
R
O
OH
H
O
OH
O
N
1, R = OH, Nojirimycin
2, R = H, Deoxynojirimycin
HO
O
O
H
OH
HO
HO
O
HO
OH
3, Acarbose (IC50108.8 12.3)
HO
HO
Me
OH
H3C
N
N
O
OH
HO
N
O
HO
OH
O
N
HO
N
HO
4
OMe
O
H
O
N
OH
OH
O
HO
HO
O
HO
5
OAc
AcO
AcO
OH
N
O
N
N
Ph
HO
O
N
HO
N
OAc
N
OH
Fmoc
H
N
HN
6
7
COOtBu
Figure 1. Some examples of
O
a
-glucosidases inhibitors.
significantly active against various biological targets29 such as
tuberculostatic,12,30 antiplatelet agents,31 dopamine D2 receptors
related to schizophrenia,32 and anticonvulsant,33 anti-inflamma-
tory,34,35 anti-allergic,36–39 antiviral,40–43 and antimicrobial
agents.19,44–47 Several 1,2,3-triazoles are described in the literature
was distilled before use. Reagents were purchased from Aldrich
or Acros Chemical Co. Column chromatography was performed
on silica gels (Acros Organics 0.035–0.070 mm, pore diameter
6 nm). Yields refer to the chromatographically and spectroscopi-
cally homogeneous materials. Reactions were monitored by thin
layer chromatography (TLC) and were carried out on 0.25 mm E.
Merck silica gel plates (60F-254) using UV light as the visualizing
agent and an ethanolic solution of sulfuric acid. Infrared spectra
were recorded on a Perkin–Elmer FT-IR Spectrum One spectropho-
tometer was calibrated relative to the 1601.8 cmꢀ1 absorbance of
polystyrene. Optical rotation measurements were obtained using
an Acatec PDA 9300 polarimeter. NMR spectra were recorded on
a Varian Unity Plus VXR (300 MHz) instrument in DMSO-d6 and
CDCl3 solutions, and tetramethylsilane was used as the internal
standard (d = 0 ppm). Elemental analysis was used to determine
the purity of the compounds for which biological data were
determined.
as glycoconjugates for the inhibition of
a-glucosidases (4–7,
Fig. 1).19–24
Compounds with triazole as the core system have promising a-
glucosidase inhibition activity. Our research group recently re-
ported the synthesis of 1,2,3-glycotriazole derivatives, and two of
them displayed a high degree of inhibition of the
a-glucosidase en-
zyme.48 Notably, b-
D-ribosyl triazoles 8 and 9 showed the greatest
activity (Fig. 2). In a continuing effort to find new glycotriazole
analogues and to better understand the relationship between
structural changes and the activities of these substances, we inves-
tigated structural changes in these compounds by introducing a
phenyl group at the C-3 carbon of the carbohydrate and moving
the isopropylidene moiety to the C-1 and the C-2 positions as indi-
cated in Figure 2.
To obtain the triazoles planned in this work, we followed the
synthetic route from
D-glucose (10) as described in Scheme 1.
The route consisted of a series of simple reactions involving the ini-
tial formation of a diacetonide (11),50 followed by the oxidation of
the hydroxyl group at the C-3 position and the addition of the phe-
nyl group to the carbonyl, which occurs selectively at the si face,51
producing 12. The selective removal of the isopropylidene group
2. Results
Melting points were observed on a Fischer–Jones apparatus and
are uncorrected. Analytical grade solvents were used.49 Dioxane
N
N
N
N
N
OCH3
R1
N
OCH3
N
O
O
N
N
O
O
O
O
R2
9 (I
C503,8 0,5 µM)
8,
(IC5014.9 4.2 µM)
Aromatic ring
N
R2
N
OCH3
N
N
O
N
N
O
R1
3
R1
O
O
O
OH
O
19a-j
Isopropylidene transposition
Figure 2. Planning concepts for the synthesis of glycotriazoles 19a–j.

16
D. R. da Rocha et al. / Carbohydrate Research 350 (2012) 14–19
HO
O
O
O
OH
O
O
1) DMSO, (COCl)2,
CH2Cl2, -78 °C, 1.5h
OH
O H
O
O
OH
acetone / I2
reflux, 6h
O
O
O
2) Et3N, -78 °C, 0.5h
O
OH
O
12, 75%
11, 72%
D-glucose(10)
O
Ph
O
HO
HO
OHC
Ph
O
Ph
O
O
PMA/SiO2 1 mol%
PhMgCl
NaIO4
EtOH 90%
rt, 12h
O
MeCN, rt
3h
O
THF, 0 °C to rt
5h
O
OH
O
OH
O
OH
15
O
13, 64%
, 92%
14, 82%
HO
Ph
O
TosO
N3
Ph
Ph
O
O
NaBH4
TsCl, DMAP
NaN3
O
EtOH 80%
rt, 12h
piridine, rt, 3h
O
O
DMF, 120°C
20h
OH
16,
O
OH
O
OH
O
85%
17
, 90%
18
, 75%
N
N
N
Ph
O
R
H
R
CuSO4 / sodium ascorbate
CH2Cl2/H2O, rt, 12h
O
OH
O
19a-j
Scheme 1. Synthetic route used for the preparation of 1,2,3-glycotriazoles 19a–j.
from the hydroxyl groups attached to C-5 and C-6, followed by the
oxidative cleavage of the diol and the reduction of the aldehyde,
led to the formation of 16. Then, the introduction of a tosyl group
at the C-5 position followed by the nucleophilic displacement by
an azide group led to the key intermediate 18. Finally, the 1,3-dipo-
lar cycloaddition reaction was carried out with a series of terminal
in 80% EtOH (50 mL). Next, NaBH4 (720 mg, 2 equiv) was dissolved
in 80% EtOH (30 mL) and added to the reaction mixture. The reac-
tion proceeded for 12 h and then was neutralized with a saturated
solution of NH4Cl, and the EtOH was removed under reduced pres-
sure. The resulting mixture was extracted with CH2Cl2, and the or-
ganic layer was washed with water, dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure to yield
16 (85%, 2.1 g, 7.9 mmol) as a white solid (mp: 112–114 °C). IR mmax
(cmꢀ1; film): 1377 ([C(CH3)2]), 3506 (OH). 1H NMR (300 MHz,
CDCl3) d (J in Hz): 7.38–7.31 (5H, m, phenyl), 6.13 (1H, d, J = 3.9,
H-1), 4.44 (1H, d, J = 4.1, H-2), 4.18 (1H, dd, J = 7.8, 3.4, H-4), 3.46
(1H, dd, J = 12.0, 3.4, H-5a or H-5b), 3.22 (1H, dd, J = 12.0, 7.8, H-
5a or H-5b), 1.67 (3H, s, CH3), 1.41 (1H, s, CH3). 13C NMR
(75 MHz, CDCl3) d: 138.4 (C-1–phenyl), 128.3, 127.8, 124.9 (C-2–
C-6-phenyl), 112.9 [C(CH3)2], 104.9 (C-1), 84.6 (C-4), 84.4 (C-2),
alkynes to generate the desired 1,2,3-triazoles 19a–j linked to D-ri-
bose unit at carbon. All of the 1,2,3-glycotriazoles were obtained
with improved yields, were fully characterized by 1H NMR, 13C
NMR, IR (infrared) spectroscopy, and elemental analysis and are
depicted at Figure 3. Preparation of intermediate 15 from 11 and
all data related to compounds 12–15 can be found in a previous
work of our research group.52
2.1. 1,2-O-Isopropylidene-3-C-phenyl-a-D-ribofuranose (16)
79.8 (C-3), 61.6 (C-5), 26.6, 26.5 (CH3). ½a D20
ꢁ
+51 (c 1.2, CH2Cl2).
A round-bottomed flask equipped with a magnetic stirring bar
Anal. Calcd for C14H18O5: C, 63.15; H, 6.81. Found: C, 63.98; H, 7.16.
was loaded with 15 (2.5 g, 9.7 mmol, 1 equiv) and was dissolved
2.2. 1,2-O-Isopropylidene-3-C-phenyl-5-O-tosyl-a-D-
ribofuranose (17)
N
N
N
Ph
O
R
A round-bottomed flask equipped with a magnetic stirring bar
was loaded with 16 (2.0 g, 7.7 mmol, 1 equiv) and was dissolved
in dry pyridine (6.0 mL). The mixture was placed in an ice bath be-
fore the addition of tosyl chloride (1.8 g, 1.2 equiv) and 1 crystal of
DMAP. The reaction proceeded for 30 min in an ice bath and then
for 3 h at room temperature. Then, 1.0 mL of water was added to
the reaction. The resulting mixture was dissolved in EtOAc
(20 mL) and washed with a 10% CuSO4 aqueous solution and with
water. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to yield 17 (90%,
2.8 g, 6.7 mmol) as a white solid (mp: 122–124 °C).53 IR mmax (cm
ꢀ1; film): 1358 ([C(CH3)2]), 3480 (OH). 1H NMR (300 MHz, CDCl3)
d (J in Hz): 7.28–7.71 (9H, m, phenyl and tosyl), 6.07 (1H, d,
J = 4.0, H-1), 4.37 (1H, d, J = 4.0, H-2), 4.18 (1H, dd, J = 8.3, 2.5, H-
4), 3.93 (1H, dd, J = 11.3, 2.5, H-5a or H-5b), 3.55 (1H, dd, J = 11.0,
8.3, H-5a or H-5b), 2.43 (3H, s, CH3-tosyl), 1.61 (3H, s, CH3), 1.38
(3H, s, CH3). 13C NMR (75 MHz, CDCl3) d: 144.7 (C-1-tosyl), 132.8
O
OH
19a-j
O
O
O
OH
R =
OH
OH
O
c, 86%
d, 85%
b, 90%
a, 90%
Cl
OH
h, 86%
g, 92%
f, 89%
e, 90%
H2N
j, 93%
i, 90%
Figure 3. Structures and yields of the 1,2,3-glycotriazoles 19a–j.

D. R. da Rocha et al. / Carbohydrate Research 350 (2012) 14–19
17
(C-1-phenyl), 129.7, 128.5, 128.1, 127.9, 124.8 (C-2–C-6-phenyl
dd, J = 4.4 and 2.4, H-4), 4.35 (1H, dd, J = 9.3, 2.4, H-5a or H-5b),
3.65 (1H, dd, J = 14.4, 9.3, H-5a or H-5b), 3.38 (1H, s, OH), 1.60
(3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3) d: 158.2
(C-1-phenoxy), 144.2 (C-triazole), 137.7 (C-1 phenyl), 129.4 (C-5-
triazole), 128.7, 128.3, 125.0, 123.6, 121.1, 114.7 (C-2–C-6-phenyl
and phenoxy), 113.2 [C(CH3)2], 105.1 (C-1), 84.1 (C-4), 82.5 (C-2),
and tosyl), 113.5 [C(CH3)2], 105.0 (C-1), 84.1 (C-2), 81.6 (C-4),
79.8 (C-3), 68.7 (C-5), 26.5, 26.4 (CH3), 21.6 (CH3-tosyl). ½a D20
ꢁ
+22
(c 1.1, CH2Cl2). Anal. Calcd for C21H24O7S: C, 59.99; H, 5.75. Found:
C, 60.30; H, 5.80.
2.3. 1,2-O-Isopropylidene-3-C-phenyl-5-azido-
a-
D-ribofuranose
80.2 (C-3), 61.9 (CH2), 50.2 (C-5), 26.5, 26.4 (CH3). ½a D20
ꢁ
+39 (c
(18)
1.1, CH2Cl2). MS m/z Calcd for C23H25N3O5: 423.1788. Found:
424.1871 (M+Å+1). Anal. Calcd for C23H25N3O5: C, 65.24; H, 5.95;
N, 9.92. Found: C, 65.42; H, 6.20; N, 9.98.
A round-bottomed flask equipped with a magnetic stirring bar
was loaded with 17 (2.5 g, 6.1 mmol), sodium azide (2.3 g), and
dry DMF (21 mL). The mixture was heated to 120 °C and the reac-
tion proceeded for 12 h. The organic solvent was concentrated un-
der reduced pressure, and the crude product was dissolved in
EtOAc (20 mL) and washed with water. The organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure to yield 18 (75%, 1.3 g, 4.5 mmol) as a yellow
2.4.3. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(hydroxymethyl)-
1H-1,2,3-triazole-1-yl)-
The reaction produced 19c in an 86% yield as a yellow oil. IR
mmax (cmꢀ1 film): 1377 ([C(CH3)2]), 3476 (OH). 1H NMR
a-D-ribofuranose (19c)
;
(300 MHz, CDCl3) d (J in Hz): 7.55 (1H, s, H-triazole), 7.35–7.47
(5H, m, phenyl), 6.15 (1H, d, J = 4.1, H-1), 4.74 (2H, s, CH2), 4.50
(1H, d, J = 3.9, H-2), 4.42 (1H, dd, J = 14.4, 2.4, H-4), 4.34 (1H, dd,
J = 9.5, 2.4, H-5a or H-5b), 3.65 (1H, dd, J = 14.4, 9.5, H-5a or H-
5b), 1.58 (3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d: 147.7 (C-4-triazole), 137.7 (C-1-phenyl), 128.7, 128.3, 125.1,
122.6 (C-2–C-6-phenyl and C-5-triazole), 113.2 [C(CH3)2], 105.2
(C-1), 56.2 (CH2), 50.2 (C-5), 84.1 (C-4), 82.4 (C-2), 80.3 (C-3),
oil.54 IR max(cmꢀ1; film): 1377 ([C(CH3)2]), 2101 (N3), 3522 (OH).
m
1H NMR (300 MHz, CDCl3) d (J in Hz): 7.30–7.42 (5H, m, phenyl),
6.14 (1H, d, J = 3.9, H-1), 4.45 (1H, d, J = 3.9, H-2), 3.49 (1H, dd,
J = 13.4, 3.2, H-5a or H-5b), 3.29 (1H, s, H-4), 2.85 (1H, dd,
J = 13.2, 8.8, H-5a or H-5b), 1.68 (3H, s, CH3), 1.42 (3H, s, CH3).
13C NMR (75 MHz, CDCl3) d: 138.0 (C-phenyl), 128.5, 128.0, 124.9
(C-2–C6-phenyl), 113.0 [C(CH3)2], 105.0 (C-1), 84.2 (C-2), 82.9 (C-
26.4, 26.4 (CH3). ½a D20
ꢁ
+49 (c 1.0, CH2Cl2). MS m/z Calcd for
4), 80.0 (C-3), 50.6 (C-5), 26.6, 26.5 (CH3). ½a D20
ꢁ
+57 (c 1.0, CH2Cl2).
C
17H21N3O5: 347.1475. Found: 348.1522 (M+Å+1).
2.4. General procedures for preparing glucotriazoles 19a–j
2.4.4. 1,2-O-Isopropylidene-3-C-phenyl-5-((4-(tetrahydro-2H-
pyran-2-yloxi)methyl)-1H-1,2,3-triazole-1-yl)-a-D-ribofuranose
(19d)
A round-bottomed flask equipped with a magnetic stirring bar
was loaded with 18 (1 mmol), the corresponding alkyne (0.9 mmol),
CuSO4ꢂ5H2O (11.2 mg, 0.048 mmol), sodium ascorbate (26.5 mg,
0.13 mmol), CH2Cl2 (0.85 mL), and water (0.85 mL). The reaction
proceeded for 12 h at room temperature, and then the reaction
media was dissolved in CH2Cl2 (10 mL) and water (10 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure, and the crude product
was purified by column chromatography on silica-gel and eluted
with an increasing polarity gradient mixture of hexane and EtOAc
to afford the corresponding 1,2,3-glucotriazole.55
The reaction produced 19d in an 85% yield as a white solid. Mp:
136–138 °C. IR mmax (cmꢀ1; film): 1372 ([C(CH3)2]), 3400 (OH). 1H
NMR (300 MHz, CDCl3) d: 7.56 (1H, d, J = 1.9, H-triazole), 7.35–
7.45 (5H, m, phenyl), 6.16 (1H, d, J = 3.9, H-1), 4.83 (1H, dd,
J = 12.4, 2.9, CH2), 4.71–4.74 (1H, m, H-2-tetrahydropyran), 4.61
(1H, dd, J = 12.4, 5.6, CH2), 4.50 (1H, d, J = 3.9, H-2), 4.42 (1H, dd,
J = 14.4, 2.2, H-4), 4.34 (1H, dd, J = 9.3, 2.2, H-5a or H-5b), 3.84–
3.92 (1H, m, H-6a or H-6b-tetrahydropyran), 3.63 (1H, dd, J = 9.3,
4.4, H-5a or H-5b), 3.51–3.59 (1H, m, H-6a or H-6b-tetrahydropy-
ran), 3.40 (1H, s, OH), 1.60 (3H, s, CH3), 1.49–1.57, 1.68–1.84 (6H,
m, H-3-H-5-tetrahydropyran), 1.40 (3H, s, CH3). 13C NMR (75 MHz,
CDCl3) d: 145.1 (C-4-triazole00), 137.7 (C-1-phenyl), 128.6, 128.3,
125.0 (C-2–C-6-phenyl), 123.4 (C-5-triazole), 113.2 [C(CH3)2],
105.0 (C-1), 98.0, 98.1 (C-2-tetrahydropyran), 84.1 (C-4), 82.5 (C-
2), 80.2 (C-3), 62.0, 62.2 (CH2), 60.4 (C-3-tetrahydropyran), 50.1
(C-5), 30.3, 30.4 (C-6-tetrahydropyran), 26.5 (CH3), 26.4 (CH3),
2.4.1. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(1-
hydroxycyclohexyl)-1H-1,2,3-triazole-1-yl)-a-D-ribofuranose
(19a)
The reaction produced 19a in a 90% yield as a white solid. Mp:
189–191 °C. IR mmax (cmꢀ1; film): 1375 ([C(CH3)2]), 3493 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.37–7.46 (m, 6H, phenyl and
H-triazole), 4.50 (d, 1H, J = 3.9, H-2), 6.16 (d, 1H, J = 3.9, H-1),
4.42–4.35 (m, 2H, H-4, H-5a or H-5b), 3.59–3.67 (m, 1H, H-5a or
H-5b), 3.52 (s, 1H, OH), 1.52–1.92 (m, 10H, cyclohexyl), 1.59 (s,
3H, H-7), 1.40 (s, 3H, H-8). 13C NMR (75 MHz, CDCl3) d: 137.8 (C-
1-phenyl; C-4-triazole); 128.6, 125.1 (C-2–C-6-phenyl), 128.3 (C-
5-triazole), 113.2 [C(CH3)2], 105.0 (C-1), 84.2 (C-4), 82.4 (C-2),
80.3 (C-3), 69.3 (C-2-cyclohexyl), 50.2 (C-5), 38.1 (C-6-cyclohexyl),
37.9 (C-5-cyclohexyl), 26.5, 26.4 (CH3), 25.3 (C-4-cyclohexyl), 21.9
25.3 (C-4-tetrahydropyran), 19.1, 19.2 (C-5-tetrahydropyran). ½a D20
ꢁ
+30 (c 1.1, CH2Cl2). MS m/z Calcd for C22H29N3O6: 431.2050. Found:
432.2229 (M+Å+1). Anal. Calcd for C22H29N3O6: C, 61.24; H, 6.77; N,
9.74. Found: C, 61.39; H, 6.92; N, 10.08.
2.4.5. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(2-hydroxy-4-
methylpentan-2-yl)-1H-1,2,3-triazole-1-yl)-a-D-ribofuranose
(19e)
(C-3-cyclohexyl). ½a D20
ꢁ
+41 (c 1.1, CH2Cl2). MS m/z Calcd for
The reaction produced 19e in a 90% yield as a white solid. Mp:
143–144 °C. IR mmax (cmꢀ1; film): 1375 ([C(CH3)2]), 3465 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.36–7.44 (6H, m, phenyl and
H-triazole), 6.16 (1H, d, J = 3.9, H-1), 4.49 (1H, d, J = 3.9, H-2),
4.32–4.43 (2H, m, H-4, H-5a or H-5b), 3.60–3.68 (1H, m, H-5a or
H-5b), 3.41 (1H, s, OH), 1.77 (2H, dd, J = 6.6, 5.9, CH2), 1.59 (3H,
s, CH3), 1.57 (3H, d, J = 3.2, CH3), 1.40 (3H, s, CH3), 0.82 (3H, dd,
J = 6.6, 1.2, CH3), 0.81 (3H, dd, J = 6.6, 5.3, CH3). 13C NMR
(75 MHz, CDCl3) d: 155.2 (C-4-triazole), 137.8 (C-1-phenyl),
128.6, 128.3, 125.1 (C-2–C-6-phenyl), 120.5 (C-5-triazole00), 113.1
[C(CH3)2], 105.0 (C-1), 84.1 (C-4), 82.5 (C-2), 80.3 (C-3), 71.3, 71.1
(COHCH3), 51.6, 51.5 (CH2), 50.1 (C-5), 29.2, 28.8 (CH3), 26.5, 26.4
C
C
22H29N3O5: 415.2101. Found: 416.2168 (M+Å+1). Anal. Calcd for
22H29N3O5: C, 63.60; H, 7.04; N, 10.11. Found: C, 63.79; H, 7.09;
N, 10.31.
2.4.2. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(phenoxymethyl)-
1H-1,2,3-triazole-1-yl)-a-D-ribofuranose (19b)
The reaction produced 19b in a 90% yield as a white solid. Mp:
129–130 °C. IR mmax (cmꢀ1; film): 1377 ([C(CH3)2]), 3476 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.61 (1H, s, H-triazole), 7.35–
7.45 (5H, m, phenyl), 6.93–7.30 (5H, m, phenoxy), 6.16 (1H, d,
J = 4.1, H-1), 5.17 (2H, s, CH2), 4.50 (1H, d, J = 3.9, H-2), 4.42 (1H,

18
D. R. da Rocha et al. / Carbohydrate Research 350 (2012) 14–19
(CH3), 24.4 (CH3), 24.2 (C-CH3). ½a D20
ꢁ
+48 (c 1.0, CH2Cl2). MS m/z
7.78 (1H, s, triazole), 7.31–7.50 (8H, m, phenyl), 6.19 (1H, d,
Calcd for C22H31N3O5: 417.2258. Found: 418.2310 (for M+Å+1). Anal.
Calcd for C22H31N3O5: C, 63.29; H, 7.48; N, 10.06. Found: C, 63.46;
H, 7.55; N, 10.12.
J = 3.9, H-1), 4.52 (1H, d, J = 3.6, H-2), 4.50 (1H, dd, J = 13.7, 2.2,
H-5a or H-5b), 4.39 (1H, dd, J = 9.3, 2.2, H-4), 3.68 (1H, dd,
J = 14.6, 9.5, H-5a or H-5b), 3.5 (1H, s, OH), 1.58 (3H, s, CH3), 1.40
13
(3H, s, CH3). C NMR (75 MHz, CDCl3) d: 147.7 (C-10-phenyl),
2.4.6. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-cyclohexenyl-1H-
1,2,3-triaze-1-yl)-a-D-ribofuranose (19f)
137.8 (C-1-phenyl), 130.5 (C-40-phenyl), 128.7, 128.3, 128.0,
125.7, 125.1 (C-2–C-6-phenyl and C-20–C-60-phenyl), 120.6 (C-5-
triazole), 113.2 [C(CH3)2], 105.1 (C-1), 84.2 (C-4), 82.4 (C-2), 80.3
The reaction produced 19f in an 89% yield as a white solid. Mp:
185–187 °C. IR mmax (cmꢀ1; film): 1375 ([C(CH3)2]), 3493 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.36–7.46 (6H, m, phenyl and
triazole), 6.45–6.49 (1H, m, H-2-cyclohexenyl), 6.16 (1H, d,
J = 4.1, H-1), 4.50 (1H, d, J = 3.9, H-2), 4.42 (1H, dd, J = 14.6, 2.4,
H-4), 4.32 (1H, dd, J = 9.5, 2.4, H-5a or H-5b), 3.59 (1H, dd,
J = 14.6, 9.5, H-5a or H-5b), 3.46 (1H, s, OH), 2.20–2.15 (4H, m, H-
4 and H-6-cyclohexenyl), 1.76–1.63 (4H, m, H-3 and H-5-cyclohex-
enyl), 1.58 (3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d: 149.4 (C-1-cyclohexenyl), 137.8 (C-4-triazole), 127.2 (C-1-phe-
nyl), 128.6, 128.2, 127.2, 124.8 (C-2–C-6-phenyl), 125.1 (C-2-cyclo-
hexenyl), 119.3 (C-5-cyclohexenyl), 113.2 [C(CH3)2], 105.1 (C-1),
84.1 (C-4), 82.5 (C-2), 80.3 (C-3), 50.1 (C-5), 26.5, 26.4 (CH3),
(C-3), 50.3 (C-5), 26.5, 26.4 (CH3). ½a D20
ꢁ
+52 (c 1.0, CH2Cl2). MS
m/z Calcd for C22H23N3O4: 393.1683. Found: 394.1790 (M+Å+1).
Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68. Found: C,
60.31; H, 5.97; N, 10.82.
2.4.10. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(3-aminophenyl)-
1H-1,2,3-triazole-1-yl)-
The reaction produced 19j in a 93% yield as a yellow solid. Mp:
85–87 °C. IR
max (cmꢀ1; film): 1376 [C(CH3)2], 3367 (OH). 1H NMR
a-D-ribofuranose (19j)
m
(300 MHz, CDCl3) d (J in Hz): 7.73 (1H, s, triazole), 7.38–7.46 (5H,
m, phenyl), 7.10–7.20 (4H, m, aniline), 6.19 (1H, d, J = 3.8, H-1),
4.51 (1H, d, J = 3.8, H-2), 4.47 (1H, dd, J = 14.5, 2.2, H-5a or H-5b),
4.37 (1H, dd, J = 9.4, 2.2, H-4), 3.64 (1H, dd, J = 14.5, 9.4, H-5a or
H-5a), 1.59 (3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d: 147.8 (C-3-aniline), 146.7 (C-4-aniline), 137.8 (C-1-phenyl),
131.4 (C-1-aniline), 129.6, 128.7, 128.3, 125.1 (C-2–C-6-phenyl),
120.6 (C-5-triazole), 116.0, 114.8, 112.2 (C-2, C-4–C-6-aniline),
113.2 [C(CH3)2], 82.5 (C-2), 105.0 (C-1), 84.1 (C-4), 80.3 (C-3),
26.2, 25.2, 22.4, 22.2 (C-3–C-6-cyclohexenyl). ½a D20
ꢁ
+39 (c 1.1,
CH2Cl2). MS m/z Calcd for C22H27N3O4: 397.1996. Found:
398.2059 (M+Å+1). Anal. Calcd for C22H27N3O4: C, 66.48; H, 6.85;
N, 10.57. Found: C, 66.71; H, 6.97; N, 10.61.
2.4.7. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(3-chloropropyl)-
1H-1,2,3-triazole-1-yl)-
a-
D
-ribofuranose (19g)
50.2 (C-5), 26.5, 26.4 (CH3). ½a D20
ꢁ
+37 (c 1.1, CH2Cl2). MS m/z Calcd
The reaction produced 19g in a 92% yield as a white solid. Mp:
108–109 °C. IR mmax (cmꢀ1; film): 1376 [C(CH3)2], 3449 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.79–7.82 (2H, m, H-3 and H-
5-phenyl), 7.31–7.50 (3H, m, H-2, H-4 and H-6-phenyl), 7.33 (1H,
s, triazole), 6.16 (1H, d, J = 3.9, H-1), 4.50 (1H, d, J = 3.9, H-2),
4.39 (1H, dd, J = 14.4, 2.4, H-5a or H-5b), 4.33 (1H, dd, J = 9.0, 2.4,
H-4), 3.62 (1H, dd, J = 14.4, 9.0, H-5a ou H-5b), 3.53–3.60 (2H, m,
CH2), 3.42 (1H, s, OH), 2.85 (2H, t, J = 7.3, CH2), 2.08–2.18 (2H, m,
CH2), 1.60 (3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3)
d: 146.3 (C-4-triazole), 137.8 (C-1-phenyl), 128.6, 128.2, 125.0 (C-
2–C-6-phenyl), 122.0 (C-5-triazole), 113.1 [C(CH3)2], 105.0 (C-1),
84.1 (C-4), 82.5 (C-2), 80.2 (C-3), 50.5 (C-5), 44.1 (CH2), 31.7
for C22H24N4O4: 408.1792. Found: 409.1816 (M+Å+1). Anal. Calcd for
C22H24N4O4: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.82; H, 6.01; N,
13.90.
2.5. a-Glucosidase inhibition
All compounds were initially screened for
a
-glucosidase inhibi-
-glu-
tion as described by Matsui and co-workers.56 The enzyme
a
cosidase from Saccharomyces cerevisiae used was obtained from
Sigma Aldrich Chemical Co., USA (EC. 3.2.1.20, Cat. No. G0660).
The activity of
a-glucosidase was determined by monitoring the
release of p-nitrophenol from p-nitrophenyl
a-D-glucopyranoside
(CH2), 26.5, 26.4 (CH3), 22.6 (CH2). ½a D20
ꢁ
+39 (c 1.1, CH2Cl2). MS
at 405 nm. The compounds were initially evaluated for their ability
to inhibit in a fixed concentration of 580 mM, and the results are
expressed in percentage inhibition against the test performed in
the absence of the inhibitor. The active compounds were then
characterized with respect to the concentration required to inhibit
m/z Calcd for C19H24ClN3O4: 393.1449. Found: 394.1455 (M+Å+1).
Anal. Calcd for C19H24ClN3O4: C, 57.94; H, 6.14; N, 10.67. Found:
C, 58.08; H, 6.24; N, 10.80.
2.4.8. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-(2-hydroxypropan-
2-yl)-1H-1,2,3-triazole-1-yl)-a-D-ribofuranose (19h)
50% of the activity of
a-glucosidase under the test conditions. In
these tests, acarbose was used as standard for comparison. Most
of the compounds were found to be inactive against yeast maltase
except for glycotriazoles 19i and 19f. Next, the determination of
The reaction produced 19h in an 86% yield as a white solid. Mp:
120–122 °C. IR mmax (cmꢀ1; film): 1385 [C(CH3)2], 3369 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.39–7.44 (6H, m, phenyl and
triazole), 6.16 (1H, d, J = 3.9, H-1), 4.50 (1H, d, J = 3.9, H-2), 4.35-
4.43 (2H, m, H-4, H-5a or H-5b), 3.58–3.66 (1H, m, H-5a or
H-5b), 3.52 (1H, s, OH), 1.61 (3H, s, CH3), 1.60 (3H, s, CH3), 1.60
(3H, s, CH3), 1.40 (3H, s, CH3). 13C NMR (75 MHz, CDCl3) d: 155.4
(C-4-triazole), 137.8 (C-1-phenyl), 128.6, 128.3, 125.1 (C-2–C-
6-phenyl), 113.1 [C(CH3)2], 105.0 (C-1), 85.7 (C-5-triazole), 84.1
(C-4), 82.4 (C-2), 80.3 (C-3), 68.2 (C(CH3)2OH), 50.2 (C-5), 30.3
the IC50 for these compounds revealed that 19i (119.5 0.1
had a similar potency to acarbose (IC50 108.8 12 M), but 19f
(247.4 34 M) was twofold less active.
lM)
l
l
3. Discussion
Our results showed that glycotriazoles 19f and 19i were the
most potent in the inhibition assay on the -glucosidase enzyme.
(C-H3), 30.2 (CH3), 26.5, 26.4 (CH3). ½a D20
ꢁ
+50 (c 1.0, CH2Cl2). MS
a
m/z Calcd for C19H25N3O5: 375.1788. Found: 376.1867 (M+Å+1).
Anal. Calcd for C19H25N3O5: C, 60.79; H, 6.71; N, 11.19. Found: C,
60.89; H, 6.81; N, 11.22.
However, their IC50 values were higher than those of acarbose,
which was used in our test as the standard drug. The other com-
pounds prepared in this series showed no significant inhibitory
activity. The comparison of these new compounds with previously
synthesized 1,2,3-triazoles 8 and 9 (Fig. 2)48 revealed that the
introduction of the phenyl group at the C-3 position did not pro-
duce the desired effect of increasing the inhibitory activity.
Although no molecular modeling or docking studies have been
conducted of these substances, we expected that the more rigid li-
2.4.9. 1,2-O-Isopropylidene-3-C-phenyl-5-(4-phenyl-1H-1,2,3-
triazole-1-yl)-a-D-ribofuranose (19i)
The reaction produced 19i in a 90% yield as a white solid. Mp:
192–193 °C. IR mmax (cmꢀ1; film): 1374 [C(CH3)2], 3484 (OH). 1H
NMR (300 MHz, CDCl3) d (J in Hz): 7.79–7.82 (2H, m, phenyl),

D. R. da Rocha et al. / Carbohydrate Research 350 (2012) 14–19
22. Tatsuta, K.; Ikeda, Y.; Miura, S. J. Antibiot. 1996, 49, 836–839.
19
gands would be less affected by entropic issues at the active site of
the enzyme than the more flexible ones; therefore, they should
have a more favorable energy profile. However, the results in this
series did not follow this trend, which leads us to believe that
the volume of the phenyl ring offset the negatively entropic gain
in question.
The results obtained so far showed that the carbohydrate unit
present in the compounds in this series plays an important role
in the inhibitory activity against the enzyme because the introduc-
tion of the phenyl group at the C-3 position of the carbohydrate
significantly altered the interaction with the enzyme.
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We developed a synthetic route in nine steps to synthesize new
1,2,3-triazole glycoconjugates (19a–j) from
overall yield. These 1,2,3-triazoles were evaluated in in vitro assays
and for their ability to inhibit the enzyme -glucosidase. Most of
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