Design, synthesis, and biological evaluation of new 1-aryl-4-(β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole derivatives

Article abstract of DOI:10.1007/s10593-018-2319-6

[Figure not available: see fulltext.] New 1-aryl-4-(β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole derivatives have been synthesized by a CuAAC reaction and their antibacterial and antifungal activity has been evaluated. Some of the derivatives showed

Full text of DOI:10.1007/s10593-018-2319-6

DOI 10.1007/s10593-018-2319-6
Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
Design, synthesis, and biological evaluation of new
1-aryl-4-(β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole derivatives
Dinesh Kumar Reddy Vennam1, Ranjith Kumar Thatipamula1,
Sharath Babu Haridasyam1, Shiva Kumar Koppula1*
1 Department of Chemistry, GITAM Deemed to be University,
Hyderabad Campus, Rudraram, Sangareddy 502329, Telangana, India;
e-mail: shivak.koppula78@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(6), 630–637
Submitted January 18, 2018
Accepted after revision May 9, 2018
Copper-Catalyzed Alkyne–Azide Cycloaddition (CuAAC)
Me Me
in vitro antibacterial activity
Me
Me
O
O
O
O
O
O
ArN3, CuI
THF,, 8–12 h
CH
O
O
O
O
70–92%
O
Me
O
Me
N
Ar
N
Me
Me
N
12 examples
New 1-aryl-4-(β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole derivatives have been synthesized by a CuAAC reaction and their
antibacterial and antifungal activity has been evaluated. Some of the derivatives showed remarkable in vitro antibacterial activity against
Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Klebsiella pneumoniae and moderate antifungal
activity. In addition, molecular docking studies of these compounds into the active site of Staphylococcus aureus tyrosyl-tRNA
synthetase were performed. The docking study revealed that all compounds have considerable binding energies and good affinity toward
the active site of the enzyme.
Keywords: arylazide, 1-aryl-4-(β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazoles, 3-O-propargyl-β-D-fructopyranose, antibacterial
activity, antifungal activity, click chemistry, molecular docking simulation.
The importance of 1,2,3-triazole derivatives in biolo-
gical systems has attracted great interest due to the broad
spectrum of their biological activities1–3 and wide use in
pharmaceuticals.4–6 The 1,2,3-triazole core is stable against
acidic and basic hydrolysis as well as against oxidative and
reductive conditions, reflecting a high aromatic stabili-
zation and relative resistance to metabolic degradation.7,8
1,2,3-Triazoles and their derivatives display antimicrobial,
anticancer, antituberculosis, antiviral, anticonvulsant,
antioxidant, and anti-inflammatory activities.9–14 Currently,
there is a number of 1,2,3-triazole moiety-containing drugs
used clinically, such as tazobactam, cefatrizine, and
carboxyamidotriazole (CAI) (Fig. 1).15–17
Here we present our effort at fusion of 1,2,3-triazole and
sugar moiety in one molecule using the Cu(I)-catalyzed
alkyne–azide cycloaddition (CuAAC) in order to obtain
compounds with improved biological activity.
Several synthetic methods have been reported for the
synthesis of 1,2,3-triazoles. A common approach for the
In recent years heterocycle-linked carbohydrates have
emerged as an important class of organic compounds,
displaying a vast spectrum of properties. They are widely
used in materials sciences, organic and medicinal
chemistry.18–30 Among them, 1,2,3-triazole-linked carbo-
hydrate derivatives are of key importance for the synthetic
organic chemistry, and many 1,2,3-triazole-linked carbo-
hydrate derivatives have found medicinal applications.31–36
Figure 1. Some of the 1,2,3-triazole-containing drugs in the market.
0009-3122/18/54(6)-0630©2018 Springer Science+Business Media, LLC
630

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
Me Me
Me Me
Me Me
Scheme 1
MeO
Me
70% HClO4
OMe
Me
OH
Br
O
O
O
O
O
O
ArN3
4a–l
O
OH
6
5
O
O
O
1
6
5
HC
2
1
2
3
Me2CO
CuI, THF
, 8–12 h
NaH, THF
HO
OH
4
O
O
3
O
4
O
O
OH
Ar
N
N
0°C–rt, 6 h
85%
0°C–rt, 6 h
OH
O
O
N
O
CH
Me
Me
Me
60%
-D-Fructose

2
Me
3
5a–l
Me
Me
1
synthesis of 1,4-disubstituted 1,2,3-triazoles is the reaction
of terminal alkynes with azides in the presence of a Cu(I)
catalyst – CuAAC.37–39
Table 1. Substituents and yields of compounds 5a–l
Com-
pound
Yield, Com-
Yield,
%
Ar
Ar
%
90
85
83
81
pound
We used β-D-fructopyranose (1) as a starting compound.
The hydroxyl groups of β-D-fructopyranose (1) were
protected with an acetonide moiety employing 2,2-di-
methoxypropane and HClO4 by a literature method,40 giving
di-O-isopropylidene-β-D-fructopyranose 2, which was
propargylated with propargyl bromide in presence of NaH
in THF to give 1,2:4,5-di-O-isopropylidene-3-O-propargyl-
β-D-fructopyranose (3). Further, terminal alkyne 3 was
reacted with various aromatic azides 4a–l which were
prepared from primary aromatic amines by diazotization
followed by reaction with NaN3.41 The copper-catalyzed
cycloaddition between terminal alkyne 3 and aromatic
azides 4a–l in THF afforded new 1-aryl-4-(1,2:4,5-di-O-iso-
propylidene-β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-tri-
azoles 5a–l in good yields (Scheme 1, Table 1).
C6H5
4-MeC6H4
70
83
86
5a
5b
5c
5d
5e
5f
5g
4-ClC6H4
2-ClC6H4
3-ClC6H4
2,3-(Me)2C6H3
5h
5i
4-n-BuC6H4
2,3-(MeO)2C6H3 89
5j
2,4,6-(Cl)3C6H2 92
4-BrC6H4 71
4-O2NC6H4
1-Naphth
89
87
5k
5l
Scheme 2
Initially, we used the reaction of 1,2:4,5-di-O-iso-
propylidene-3-O-propargyl-β-D-fructopyranose 3 and azide
4a as a test reaction to find the optimal solvent (Scheme 2).
THF proved to be the best solvent, giving the highest yields
in comparison to DMF, MeCN, DMSO, CH2Cl2, and
1,4-dioxane. The reaction was performed using 15 mol %
of CuI as the catalyst under reflux. The results are
summarized in Table 2.
Table 2. Optimization of reaction conditions
for the formation of product 5a
Solvent
Yield, %
Solvent
Yield, %
The newly synthesized derivatives 5a–l were evaluated
for in vitro antibacterial and antifungal activity against
various Gram-positive, Gram-negative bacteria, and fungal
strains. The results are shown in Tables 3 and 4. Penicillin,
DMF
MeCN
DMSO
52
40
48
CH2Cl2
1,4-Dioxane
THF
72
20
83
Table 3. Antibacterial MIC data of compounds 5a–l, µg/ml
Staphylococcus
aureus
Staphylococcus
Pseudomonas
Klebsiella
Compound
Bacillus subtilis
Escherichia coli
epidermidis
37.50
37.50
>150
2.34
aeruginosa
pneumoniae
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
75.00
1.17
2.34
18.75
75.00
9.37
9.37
75.00
18.75
9.37
9.37
9.37
9.37
2.34
1.17
9.37
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
18.75
9.37
9.37
37.50
9.37
5a
9.37
5b
>150
9.37
75.00
18.75
2.34
5c
5d
18.75
>150
37.50
75.00
18.75
75.00
75.00
1.17
1.17
5e
>150
37.50
37.50
9.37
75.00
4.68
5f
5g
>150
4.68
5h
5i
37.50
37.50
9.37
>150
>150
2.34
5j
5k
5l
Penicillin
Streptomycin
4.68
18.75
1.562
9.37
9.37
4.68
4.68
631

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
Table 4. Antifungal activity data of compounds 5a–l
Zone of inhibition, mm
Saccharomyces cerevisiae Aspergillus niger
Candida albicans
100 µg 150 µg
Aspergillus flavus
100 µg 150 µg
12
Compound
100µg
150µg
10
11
6
100 µg
150µg
10
19
14
0
0
0
8
8
6
14
12
0
8
5a
12
12
0
17
17
8
12
14
0
16
18
0
5b
0
5c
0
6
5d
13
13
0
17
18
8
11
13
0
16
17
6
15
11
0
19
16
0
14
13
0
18
19
0
5e
5f
5g
13
12
0
8
6
12
6
8
8
0
6
5h
8
8
0
14
0
12
0
0
5i
8
0
6
0
0
5j
13
0
18
8
13
0
17
6
11
11
25
16
16
25
13
0
19
0
5k
5l
Amphotericin B
23.5
23.5
22
22
25
25
streptomycin, and amphotericin B were used as standard
compounds for comparison. The minimum inhibitory
concentrations (MIC) of synthesized derivatives were
tested against three representatives of Gram-positive
organisms such as Bacillus subtilis, Staphylococcus aureus,
Staphylococcus epidermidis and Gram-negative organisms
such as Escherichia coli, Pseudomonas aeruginosa, and
Klebsiella pneumoniae using broth dilution method,42 with
penicillin and streptomycin as standards. The minimum
inhibitory concentration values are presented in Table 3.
Antibacterial activity results reveal that among all
synthesized derivatives compounds 5e,i,l show potent
activity against Gram-positive bacterial strains Staphylo-
coccus aureus, Staphylococcus epidermidis, and Gram-
negative bacterial strains Pseudomonas aeruginosa,
Klebsiella pneumoniae comparable to penicillin and
streptomycin.
The synthesized derivatives 5a–l were also tested for in
vitro antifungal activity against the Candida albicans,
Saccharomyces cerevisiae, Aspergillus niger, and Asper-
gillus flavus strains by agar well diffusion bioassay.42 The
zone of inhibition values are presented in Table 4. Only
derivatives 5e,f,k showed moderate activity against tested
fungi organisms.
In order to gain insight into the plausible mechanism of
action of derivatives 5a–l, protein docking simulations
were performed. Derivatives 5a–l were docked into active
site of Staphylococcus aureus tyrosyl-tRNA synthetase. The
Staphylococcus aureus tyrosyl-tRNA synthetase has been
reported to be responsible for the translation of the nucleic
acid information into the proteins. Thus, once the enzyme
is inhibited, bacterial cell growth decreases due to the
protein biosynthesis being halted, thus making this enzyme
an attractive target for the new antibacterial agent search.43
Docking of the newly synthesized derivatives into the
active site of tyrosyl-tRNA synthetase revealed well-
established hydrogen bonds between the inhibitors and one
or more amino acids in the active pocket of the receptor,
the closest hydrogen bonds being in the range from 2.3 to
3.0 Å. All the synthesized molecules showed good binding
energy toward the target protein ranging from –9.56 to
–8.24 Kcal·mol–1. Binding energies and inhibition
constants of all derivatives 5a–l are summarized in Table 5.
The binding model of derivative 5l to tyrosyl-tRNA
synthetase is depicted in Figure 2a, surface model of the
active site of the enzyme is shown in Figure 2b, revealing
that the molecule fits quite well into the active pocket.
Figure 2c reveals the closest contacts of molecule 5l with
the amino acid residues in the active site.
Table 5. Binding energy, inhibition constant Ki,
and tyrosyl-tRNA synthetase residues involved
in hydrogen-bonding interaction (within the range of 4.0 Å)
with compounds 5a–l
Residues involved
Com- Binding energy, Inhibition constant,
in the H-bonding
pound
Kcal/mol
Ki, nM
interactions
Phe273, Lys305, Arg58
Phe273, Lys305
–8.57
–8.89
–8.77
–8.24
–8.53
–9.37
–8.61
–8.90
–8.32
–8.52
–8.96
–9.56
522
306
370
913
554
135
489
301
794
570
271
98
5a
5b
5c
5d
5e
5f
Lys84, Gly193
Lys84
Val224
Phe273, Arg58, Lys305
Val224
5g
5h
5i
Phe273
Leu52
Lys226, Val224, Lys231
Phe273, Arg58, Lys305
His57, His50, Lys84
5j
5k
5l
632

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
Figure 2. Interactions between compound 5l and tyrosyl-tRNA synthetase: a) binding model showing hydrogen-bonding interaction;
b) surface area model of the active site; c) 2D model showing amino acid residues in the active site.
In conclusion, twelve 1-aryl-4-(β-D-fructopyranos-3-O-yl)-
methyl-1H-1,2,3-triazole derivatives were synthesized from
the corresponding 3-O-propargyl-β-D-fructopyranose and
their biological activity tested. 1-(2,4,6-Trichlorophenyl)-
4-(1,2:4,5-di-O-isopropylidene-β-D-fructopyranos-3-O-yl)-
methyl-1H-1,2,3-triazole, 1-(4-butylphenyl)-4-(1,2:4,5-di-
O-isopropylidene-β-D-fructopyranos-3-O-yl)methyl-1H-
1,2,3-triazole, and 4-(1,2:4,5-di-O-isopropylidene-β-D-
fructopyranos-3-O-yl)methyl-1-[4-(naphthalen-1-yl)phenyl]-
1H-1,2,3-triazole showed excellent antibacterial activity.
1-(2,4,6-Trichlorophenyl)-4-(1,2:4,5-di-O-isopropylidene-
β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole, 1-(4-bro-
mophenyl)-4-(1,2:4,5-di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1H-1,2,3-triazole, and 4-(1,2:4,5-di-O-iso-
propylidene-β-D-fructopyranos-3-O-yl)methyl-1-(4-nitrophenyl)-
1H-1,2,3-triazole showed moderate antifungal activity.
Docking studies revealed that all the synthesized molecules
exhibited excellent binding energy toward the active site of
the tyrosyl-tRNA synthetase.
meter (400 and 100 MHz or 300 and 75 MHz, respectively)
in CDCl3, with TMS as internal standard. High-resolution
mass spectra were recorded on a Bruker maXis II ESI TOF
spectrometer. Melting points were measured in open
capillaries using a Stuart SMP30 apparatus and are
uncorrected. All the final compounds were purified by
column chromatography on silica gel (60–120 mesh) using
EtOAc–hexane mixtures as eluent.
Reagents and chemicals were obtained from commercial
sources (SD Fine Chemicals, Aldrich) and used without
further purification.
1,2:4,5-Di-O-isopropylidene-β-D-fructopyranose (2) was
synthesized by a literature method.40 The physical and
chemical data of compound 2 are consistent with those in
reported literature .
1,2:4,5-Di-O-isopropylidene-3-O-propargyl-β-D-fructo-
pyranose (3). Hexane-washed 60% NaH dispersion in
mineral oil (0.46 g, 11.5 mmol) was suspended in dry THF
(10 ml) placed on an ice bath. A solution of 1,2:4,5-di-O-
isopropylidene-β-D-fructopyranose (2) (2 g, 7.68 mmol) in
THF (80 ml) was added dropwise using dropping funnel.
After addition, the mixture was stirred at room temperature
for 1 h, then propargyl bromide (1.15 ml, 10.75 mmol) was
added slowly at 0–5°C. The mixture was stirred at room
Experimental
IR spectra were recorded on JASCO FT/IR-5300 and
1
Brucker Tensor-II spectrometers in thin films. H and 13C
NMR spectra were recorded on a Bruker Avance spectro-
633

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
temperature for 6 h then saturated NH4Cl was added slowly
1,6-CH2); 3.61 (1H, d, J = 6.0, 3-CH); 1.56 (3H, s, CH3);
1.50 (3H, s, CH3); 1.40 (6H, s, CH3). 13C NMR spectrum
(100 MHz), δ, ppm: 162.3; 144.4; 139.3; 130.0; 121.6;
120.6; 111.9; 109.1; 104.2; 77.6; 77.3; 74.0; 72.1; 65.4;
60.4; 28.4; 26.9; 26.4; 26.3. Found, m/z: 474.1543 [M+Na]+.
at 0°C. The solution was extracted with CHCl3, dried over
anhydrous Na2SO4, and filtered. The filtrate was con-
centrated under reduced pressure and purified by column
chromatography. Rf 0.7 (EtOAc–hexane, 1:5). Yield 1.94 g
(85%), yellow oil. IR spectrum, ν, cm–1: 3271, 2988, 2934,
2884, 2115, 1452, 1377, 1325, 1220, 1145, 1117, 1019,
C21H26ClN3NaO6. Calculated, m/z: 474.1408
.
1-(2-Chlorophenyl)-4-(1,2:4,5-di-O-isopropylidene-
β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole (5c).
Yield 125 mg (83%), light-yellow solid, mp 119–121°C.
IR spectrum, ν, cm–1: 2986, 2926, 2854, 1596, 1493, 1457,
1372, 1260, 1233, 1210, 1070, 1042, 1026, 857, 786.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 8.00 (1H, s,
H triazole); 7.80–7.79 (1H, m, H-3 Ar); 7.66–7.62 (1H, m,
H-6 Ar); 7.50–7.41 (2H, m, H-4,5 Ar); 5.18 (1H, d,
J = 12.8, OCH2C=CH); 4.93 (1H, d, J = 12.4, OCH2C=CH);
4.40–4.37 (1H, m, 4-CH); 4.25 (1H, dd, J = 5.6, J = 2.0,
5-CH); 4.17–4.12 (2H, m, 1,6-CH2); 4.04 (1H, d, J = 13.6,
6-CH2); 3.96 (1H, d, J = 8.8, 1-CH2); 3.63 (1H, d, J = 7.2,
3-CH); 1.50 (6H, s, CH3); 1.41 (3H, s, CH3); 1.39 (3H, s,
CH3). 13C NMR spectrum (75 MHz), δ, ppm: 146.3; 134.9;
130.8; 128.6, 128.0; 127.8; 124.6; 111.8; 109.4; 104.3; 77.5;
77.2; 73.9; 72.0; 65.4; 60.4; 26.5; 25.3. Found, m/z: 474.1409
1
975, 905, 883, 850, 812. H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 4.55 (1H, dd, J = 16.4, J = 2.4,
OCH2C≡CH); 4.45 (1H, dd, J = 16.4, J = 2.4,
OCH2C≡CH); 4.32 (1H, dd, J = 7.6, J = 5.6, 4-CH); 4.26
(1H, d, J = 8.8, 1-CH2); 4.21 (1H, dd, J = 5.6, J = 2.0,
5-CH); 4.14 (1H, dd, J = 13.6, J = 2.4, 6-CH2); 4.04 (1H, d,
J = 13.6, 6-CH2); 3.96 (1H, d, J = 8.8, 1-CH2); 3.77 (1H, d,
J = 7.6, 3-CH); 2.45 (1H, t, J = 2.4, ≡CH); 1.60 (3H, s,
CH3); 1.51 (3H, s, CH3); 1.43 (3H, s, CH3); 1.39 (3H, s,
CH3). 13C NMR spectrum (100 MHz), δ, ppm: 112.1;
109.1; 104.2; 79.6; 77.6; 74.8; 74.1; 73.9; 71.8; 60.1; 58.3;
28.1; 26.7; 26.3; 26.0. Found, m/z: 321.1318 [M+Na]+.
C15H22NaO6. Calculated, m/z: 321.1314
.
Synthesis of 1H-1,2,3-triazoles 5a–l (General method).
CuI (15 mol %) was added to a solution of alkyne 3 (298 mg,
1 mmol) and azide 4a–l (1.3 mmol) in THF (10 ml). The
reaction mixture was stirred with reflux for 8–12 h.
Completion of the reaction monitored by TLC (EtOAc–
hexane, 1:1). After completion, the reaction mixture was
filtered through a sintered glass funnel and extracted with
EtOAc (2×10 ml). The combined organic layer was dried
over anhydrous Na2SO4, filtered, the solvent evaporated
under reduced pressure, and the crude was purified by
column chromatography (gradient from hexane to hexane–
EtOAc, 3:2).
[M+Na]+. C21H26ClN3NaO6. Calculated, m/z: 474.1408
.
1-(3-Chlorophenyl)-4-(1,2:4,5-di-O-isopropylidene-
β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole (5d).
Yield 98 mg (81%), light-yellow solid, mp 114–116°C.
IR spectrum, ν, cm–1: 2986, 2935, 2885, 1503, 1371, 1218,
1
1116, 1080, 1017, 882, 832. H NMR spectrum (300 MHz),
δ, ppm (J, Hz): 8.00 (1H, s, H triazole); 7.80 (1H, s,
H-2 Ar); 7.67–7.63 (1H, m, H-6 Ar); 7.50–7.42 (2H, m,
H-4,5 Ar); 5.23 (1H, d, J = 12.0, OCH2C=CH); 4.93 (1H,
d, J = 12.3, OCH2C=CH); 4.40–4.35 (1H, m, 4-CH); 4.24–
4.19 (1H, m, 5-CH); 4.17–4.15 (2H, m, 1,6-CH2); 4.06
(1H, d, J = 13.6, 6-CH2); 3.96–3.93 (1H, m, 1-CH2); 3.65
(1H, d, J = 6.6, 3-CH); 1.44 (6H, s, CH3); 1.38 (3H, s,
CH3); 1.34 (3H, s, CH3). 13C NMR spectrum (75 MHz),
δ, ppm: 146.2; 139.0; 134.9; 131.7; 128.8; 127.1; 126.2;
124.6; 112.2; 109.2; 104.5; 77.6; 77.0; 74.0; 72.0; 65.3;
60.4; 28.3; 26.9; 26.4; 26.2. Found, m/z: 474.1413 [M+Na]+.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-phenyl-1H-1,2,3-triazole (5a). Yield 125 mg
(90%), white solid, mp 82–84°C. IR spectrum, ν, cm–1:
3143, 2986, 2927, 1598, 1503, 1456, 1381, 1371, 1218,
1116, 1081, 884, 759. 1H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 8.01 (1H, s, H triazole); 7.74 (2H, d, J = 7.6,
H-2,6 Ph); 7.56–7.44 (3H, m, H-3,4,5 Ph); 5.16 (1H, d,
J
=
12.8, OCH2C=CH); 4.93 (1H, d, J = 12.8,
C21H26ClN3NaO6. Calculated, m/z: 474.1408.
OCH2C=CH); 4.42–4.39 (1H, m, 4-CH); 4.24 (1H, dd,
J = 5.6, J = 2.4, 5-CH); 4.15–4.13 (2H, m, 1,6-CH2); 4.05
(1H, d, J = 13.6, 6-CH2); 3.95 (1H, d, J = 8.8, 1-CH2); 3.64
(1H, d, J = 7.2, 3-CH); 1.58 (3H, s, CH3); 1.51 (3H, s,
CH3); 1.42 (CH3), 1.40 (CH3). 13C NMR spectrum
(100 MHz), δ, ppm: 146.3; 137.1; 129.8; 128.7; 120.7;
120.5; 112.2; 109.2; 104.3; 77.5; 77.4; 76.9; 73.9; 71.9;
65.2; 60.3; 28.2; 26.8; 26.3; 26.1. Found, m/z: 440.1741
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-3-O-
yl)methyl-1-(2,4,6-trichlorophenyl)-1H-1,2,3-triazole (5e).
Yield 160 mg (92%), light-yellow solid, mp 138–139°C.
IR spectrum, ν, cm–1: 2925, 2853, 1483, 1438, 1381, 1260,
1
1210, 1070, 1038, 858. H NMR spectrum (300 MHz),
δ, ppm (J, Hz): 8.04 (1H, s, H triazole); 7.81 (1H, s, H-3 Ar);
7.71 (1H, s, H-5 Ar); 5.17 (1H, d, J = 12.6, OCH2C=CH);
4.92 (1H, d, J = 12.3, OCH2C=CH); 4.41–4.37 (1H, m, 4-CH);
4.23 (1H, dd, J = 5.4, J = 1.8, 5-CH); 4.17–4.10 (2H, m,
1,6-CH2); 4.06 (1H, d, J = 11.1, 6-CH2); 3.93 (1H, d, J = 8.4,
1-CH2); 3.62 (1H, d, J = 7.2, 3-CH); 1.58 (3H, s, CH3);
1.49 (3H, s, CH3); 1.39 (6H, s, CH3). 13C NMR spectrum
(100 MHz), δ, ppm: 134.7; 134.0; 132.5; 131.9; 128.8;
127.0; 112.2; 109.3; 104.3; 77.6; 77.2; 73.9; 71.9; 65.1;
60.3; 28.3; 26.9; 26.3; 26.1. Found, m/z: 542.0629 [M+Na]+.
[M+Na]+. C21H27N3NaO6. Calculated, m/z: 440.1798
.
1-(4-Chlorophenyl)-4-(1,2:4,5-di-O-isopropylidene-
β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole (5b).
Yield 115 mg (85%), light-yellow solid, mp 125–127°C.
IR spectrum, ν, cm–1: 2986, 2935, 2885, 1503, 1371, 1218,
1116, 1080, 1017, 882, 832. 1H NMR spectrum
(300 MHz), δ, ppm (J, Hz): 7.97 (1H, s, H triazole); 7.75–
7.62 (2H, m, H-3,5 Ar); 7.57–7.44 (2H, m, H-2,6 Ar); 5.14
(1H, d, J = 12.6, OCH2C=CH); 4.89 (1H, d, J = 12.4,
OCH2C=CH); 4.44–4.38 (1H, m, 4-CH); 4.28–4.20 (1H, m,
5-CH); 4.19–4.08 (2H, m, 1,6-CH2); 4.07–3.89 (2H, m,
C21H24Cl3N3NaO6. Calculated, m/z: 542.0628
.
1-(4-Bromophenyl)-4-(1,2:4,5-di-O-isopropylidene-
β-D-fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole (5f).
Yield 82 mg (71%), amorphous solid. IR spectrum, ν, cm–1:
634

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
2986, 2933, 1731, 1498, 1381, 1372, 1219, 1116, 1081,
(1H, d, J = 13.6, 6-CH2); 3.93 (1H, d, J = 8.8, 1-CH2); 3.61
(1H, d, J = 7.6, 3-CH); 2.68 (2H, t, J = 7.6, CH2 butyl);
1.57–1.67 (2H, m, CH2 butyl); 1.50 (3H, s, CH3); 1.40 (3H,
s, CH3); 1.39 (3H, s, CH3); 1.39–1.35 (5H, m, CH2 butyl,
CH3); 0.96–0.93 (3H, m, CH3 butyl). 13C NMR spectrum
(100 MHz), δ, ppm: 146.0; 143.9; 135.0; 129.7; 129.6;
120.7; 120.5; 120.4; 112.1; 109.2; 104.3; 77.5; 76.8; 73.8; 71.9;
65.2; 60.2; 35.2; 33.5; 28.2; 26.8; 26.3; 22.3; 13.9. Found,
m/z: 496.2423 [M+Na]+. C25H35N3NaO6. Calculated, m/z:
1015, 883, 829. 1H NMR spectrum (300 MHz), δ, ppm (J, Hz):
7.99 (1H, s, H triazole); 7.75–7.56 (4H, m, H Ar); 5.14
(1H, d, J = 12.0, OCH2C=CH); 4.90 (1H, d, J = 12.3,
OCH2C=CH); 4.38–4.36 (1H, m, 4-CH); 4.24–4.19 (1H, m,
5-CH); 4.16–4.07 (2H, m, 1,6-CH2); 4.04 (1H, d, J = 13.6,
6-CH2); 3.96–3.93 (1H, m, 1-CH2); 3.62 (1H, d, J = 6.6,
3-CH); 1.56 (3H, s, CH3); 1.50 (3H, s, CH3); 1.40 (6H, s,
CH3). 13C NMR spectrum (75 MHz), δ, ppm: 152.0; 133.1;
132.8; 122.6; 122.0; 120.5, 112.3; 109.3; 104.4; 77.6; 77.2;
74.0; 72.0; 65.3; 60.4; 28.3; 26.9; 26.4; 26.2. Found, m/z:
518.0901 [M+Na]+. C21H26BrN3NaO6. Calculated, m/z:
496.2424
.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-(2,3-dimethoxyphenyl)-1H-1,2,3-triazole
(5j). Yield 142 mg (89%), amorphous solid. IR spectrum,
ν, cm–1: 3140, 2986, 2936, 1604, 1519, 1457, 1372, 1261,
518.0903
.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-(4-methylphenyl)-1H-1,2,3-triazole (5g).
Yield 80 mg (70%), amorphous solid. IR spectrum, ν, cm–1:
2985, 2972, 2854, 1732, 1520, 1454, 1445, 1381, 1219,
1
1238, 1116, 1081, 1024, 883, 851, 806, 767. H NMR
spectrum (400 MHz), δ, ppm (J, Hz): 7.93 (1H, s,
H triazole); 7.35 (1H, d, J = 2.4, H-6 Ar); 7.13 (1H, dd,
J = 8.8, J = 2.4, H-5 Ar); 6.95 (1H, d, J = 8.4, H-4 Ar); 5.12
(1H, d, J = 12.4, OCH2C=CH); 4.90 (1H, d, J = 12.4,
OCH2C=CH); 4.39– 4.36 (1H, m, 4-CH); 4.23 (1H, dd,
J = 5.6, J = 2.0, 5-CH); 4.13–4.11 (2H, m, 1,6-CH2); 4.01
(1H, d, J = 13.2, 6-CH2); 3.96 (3H, s, OCH3); 3.94 (3H, s,
OCH3); 3.92 (1H, s, 1-CH2); 3.62 (1H, d, J = 7.6, 3-CH);
1.56 (3H, s, CH3); 1.49 (3H, s, CH3); 1.40 (3H, s, CH3);
1.38 (3H, s, CH3). 13C NMR spectrum (100 MHz), δ, ppm:
149.8; 149.4; 145.9; 130.7; 120.9; 112.3; 112.1; 111.2; 109.2;
105.0; 104.3; 77.4; 77.3; 73.8; 71.9; 65.2; 60.2; 56.2; 28.2;
26.8; 26.3; 26.1. Found, m/z: 500.2010 [M+Na]+.
1
1116, 1081, 1044, 1021, 975, 883, 851, 817. H NMR
spectrum (300 MHz), δ, ppm (J, Hz): 7.95 (1H, s,
H triazole); 7.59 (2H, d, J = 8.1, H-2,6 Ar); 7.31 (2H, d,
J = 7.8, H-3,5 Ar); 5.13 (1H, d, J = 12.3, OCH2C=CH);
4.90 (1H, d, J = 12.3, OCH2C=CH); 4.40–4.36 (1H, m,
4-CH); 4.23–4.22 (1H, m, 5-CH); 4.16–4.12 (2H, m,
1,6-CH2); 4.06–4.04 (1H, d, J = 13.6, 6-CH2); 3.97–3.93
(1H, m, 1-CH2); 3.61 (1H, d, J = 7.2, 3-CH); 2.42 (3H, s,
CH3); 1.56 (3H, s, CH3); 1.50 (3H, s, CH3); 1.40 (3H, s,
CH3); 1.38 (3H, s, CH3). 13C NMR spectrum (75 MHz),
δ, ppm: 141.1; 139.0; 134.9; 130.4; 120.8; 120.5; 112.2;
109.3; 104.5; 77.5; 76.9; 73.9; 71.9; 65.3; 60.3; 28.3; 26.9;
26.4; 26.2; 21.2. Found, m/z: 454.1956 [M+Na]+.
C23H31N3NaO8. Calculated, m/z: 500.2009
.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (5k).
Yield 96 mg (89%), yellow solid, mp 135–137°C (mp 135–
137°C48). IR spectrum, ν, cm–1: 3092, 2987, 2935, 1598,
1526, 1508, 1455, 1380, 1341, 1218, 1181, 1113, 1080,
1016, 883, 854, 750. 1H NMR spectrum (400 MHz),
δ, ppm (J, Hz): 8.43 (2H, d, J = 8.8, H-3,5 Ar); 8.14 (1H, s,
H triazole); 7.98 (2H, d, J = 9.2, H-2,6 Ar); 5.18 (1H, d,
C22H29N3NaO6. Calculated, m/z: 454.1954
.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-(2,3-dimethylphenyl)-1H-1,2,3-triazole (5h).
Yield 74 mg (83%), amorphous solid. IR spectrum, ν, cm–1:
2988, 2928, 2853, 1455, 1382, 1217, 1117, 1081, 906, 753.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 7.71 (1H, s,
H triazole); 7.32 (1H, d, J = 7.2, H-6 Ar); 7.23 (1H, t,
J = 7.6, H-5 Ar); 7.15 (1H, d, J = 7.6, H-3 Ar); 5.17 (1H, d,
J = 12.4 OCH2C=CH); 4.93 (1H, d, J = 12.4, OCH2C=CH);
4.40–4.37 (1H, m, 4-CH); 4.23 (1H, dd, J = 5.6, J = 2.4,
5-CH); 4.13–4.09 (2H, m, 1,6-CH2); 4.02 (1H, d, J = 13.6,
6-CH2); 3.92 (1H, d, J = 8.8, 1-CH2); 3.65 (1H, d, J = 7.6,
3-CH); 2.37 (3H, s, CH3 Ar); 2.03 (3H, s, CH3 Ar); 1.59
(3H, s, CH3); 1.49 (3H, s, CH3); 1.39 (6H, s, CH3).
13C NMR spectrum (100 MHz), δ, ppm: 145.2; 138.8;
136.6; 132.7; 131.3; 126.1; 124.3; 123.9; 112.1; 109.2;
104.3; 77.3; 76.7; 73.8; 71.8; 65.2; 60.2; 28.3; 26.9; 26.3; 26.0;
20.4; 14.3. Found, m/z: 468.2114 [M+Na]+. C23H31N3NaO6.
J
= 12.8, OCH2C=CH); 4.93 (1H, d, J = 12.4,
OCH2C=CH); 4.41–4.37 (1H, m, 4-CH); 4.25 (1H, dd,
J = 5.6, J = 2.0, 5-CH); 4.18–4.13 (2H, m, 1,6-CH2); 4.04
(1H, d, J = 13.6, 6-CH2); 3.96 (1H, d, J = 8.8, 1-CH2); 3.63
(1H, d, J = 7.2, 3-CH); 1.57 (3H, s, CH3); 1.51 (3H, s,
CH3); 1.41 (3H, s, CH3); 1.39 (3H, s, CH3). 13C NMR
spectrum (100 MHz), δ, ppm: 147.2; 141.2; 125.6; 120.4;
119.7; 112.2; 109.2; 104.3; 77.5; 77.4; 73.9; 72.0; 65.2;
60.3; 28.2; 26.7; 26.3; 26.2. Found, m/z: 485.1645 [M+Na]+.
C21H26N4NaO8. Calculated, m/z: 485.1648
.
4-(1,2:4,5-Di-O-isopropylidene-β-D-fructopyranos-
3-O-yl)methyl-1-[4-(naphthalen-1-yl)phenyl]-1H-1,2,3-tri-
azole (5l). Yield 136 mg (87%), white solid, mp 130–133°C.
IR spectrum, ν, cm–1: 2986, 2933, 2888, 1598, 1471, 1446,
1372, 1218, 1182, 1116, 1080, 1041, 1017, 905, 883.
1H NMR spectrum (400 MHz), δ, ppm (J, Hz): 8.03–7.96
(2H, m, H Ar); 7.95 (1H, s, H triazole); 7.62–7.51 (5H, m,
H Ar); 5.24 (1H, d, J = 12.4, OCH2C=CH); 5.01 (1H, d,
J = 12.4, OCH2C=CH); 4.43–4.40 (1H, m, 4-CH); 4.25
(1H, dd, J = 5.6, J = 2.4, 5-CH), 4.18–4.14 (2H, m,
1,6-CH2); 4.04 (1H, d, J = 13.2, 6-CH2); 3.97 (1H, d,
J = 8.4, 1-CH2); 3.69 (1H, d, J = 7.6, 3-CH); 1.60 (3H, s,
Calculated, m/z: 468.2111
.
1-(4-Butylphenyl)-4-(1,2:4,5-di-O-isopropylidene-β-D-
fructopyranos-3-O-yl)methyl-1H-1,2,3-triazole (5i). Yield
109 mg (86%), white solid, mp 110–113°C. IR spectrum,
ν, cm–1: 3143, 2986, 2956, 2871, 1519, 1456, 1445, 1260,
1
1210, 1156, 1059, 1043, 1022, 857. H NMR spectrum
(400 MHz), δ, ppm (J, Hz): 7.96 (1H, s, H triazole); 7.61
(2H, d, J = 8.4, H-2,6 Ar); 7.32 (2H, d, J = 8.4, H-3,5 Ar);
5.14 (1H, d, J = 12.4, OCH2C=CH); 4.91 (1H, d, J = 12.4,
OCH2C=CH); 4.37–4.40 (1H, m, 4-CH); 4.23 (1H, dd,
J = 5.6, J = 2.4, 5-CH); 4.16–4.11 (2H, m, 1,6-CH2); 4.02
635

Chemistry of Heterocyclic Compounds 2018, 54(6), 630–637
CH3); 1.50 (3H, s, CH3); 1.41 (3H, s, CH3); 1.39 (3H, s,
Authors thank Department of Chemistry, GITAM
Deemed to be University for providing lab facilities; Althaf
Hussain, Department of Biotechnology, Kakatiya Univer-
sity, for supporting biological evaluation; Prof. G. A. Ramarao
and Dr. G. Rambabu, Department of Chemistry, GITAM
Deemed to be University for the valuable suggestions.
CH3). 13C NMR spectrum (100 MHz), δ, ppm: 145.5;
134.2; 133.7; 130.4; 128.5; 128.3; 127.9; 127.1; 125.2;
125.0; 123.5; 122.3; 112.2; 109.2; 104.4; 77.5; 77.0; 73.9; 71.9;
65.3; 60.2; 28.3; 26.9; 26.3; 26.1. Found, m/z: 490.1956
[M+Na]+. C25H29N3NaO6. Calculated, m/z: 490.1954
.
Antibacterial activity studies of compounds 5a–l. The
minimum inhibitory concentrations (MIC) of synthesized
derivatives were tested against Gram-positive and Gram-
negative bacteria by the broth dilution method42 recom-
mended by National Committee for Clinical Laboratory
standards. Serial dilutions of the test compounds were
performed at concentrations ranging from 150 to
0.58 μg·ml–1 in a 200 ml culture medium final volume.
Afterward each well was seeded with a 50 μl bacterial
suspension of 0.5 MacFarland density. In each test, a
bacterial culture control and a sterility control (negative)
were performed. The plates were incubated for 24 h at 37°C.
The lowest concentration which inhibited the visible
microbial growth was considered the MIC.
Antifungal activity studies of compounds 5a–l. The
synthesized derivatives were tested by the well diffusion
method.44 All the fungal cultures were adjusted to 0.5
McFarland standards, which is visually comparable to a
fungal suspension of around 1.5 × 108 CFU/ml. Nutrient
agar medium (10 ml) was poured into each petri plate and
plates were swabbed with 100 μl inoculum of the test
microorganisms and kept for 15–30 min for adsorption.
Using sterile cork borer of 10–12 mm diameter, wells were
bored into the seeded agar plates and these were loaded
with a 100 μl volume with concentration of 2.0 mg·ml−1 of
each compounds reconstituted in the DMSO. All the plates
were incubated at 37°C for 24 h. Antifungal activity of
each derivative was evaluated by measuring the zone of
growth inhibition against the test organisms with zone
reader (Hi Antibiotic zone scale).
Molecular docking studies of compounds 5a–l were
carried out using AutoDock version 4.2.45 Binding model
was based on the tyrosyl-tRNA synthetase complex
structure (1jij.pdb, Protein Data Bank http://www.rcsb.org/
pdb).46 AutoGrid component of the program precalculates a
three-dimensional grid of interaction energies based on the
macromolecular target using the AMBER force field. Three-
dimensional structures of derivatives 5a–l were
precalculated using the Chem 3D ultra 8.0 software.47 The
binding site identification was carried out using CASTp
server.48 The parameters were set using the software ADT
(AutoDockTools package, version 1.5.4) on PC which is
associated with AutoDock 4.2. Docking results were
viewed using Maestro elements 1.8 tutorial.49
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This work was funded by the University Grants Comission,
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636

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