Synthesis and antimicrobial activity of new 1,2,3-triazolopyrimidine derivatives and their glycoside and acyclic nucleoside analogs

Article abstract of DOI:10.1002/jhet.832

New [1,2,4-oxadiazolyl]methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin derivatives were synthesized starting from N'-Hydroxy-1-naphthimidamide. The N-substituted acyclic nucleoside analogs as well as the substituted glycosides were also prepared by reaction wit

Full text of DOI:10.1002/jhet.832

May 2012
Synthesis and Antimicrobial Activity of New
1,2,3-Triazolopyrimidine Derivatives and Their Glycoside
and Acyclic Nucleoside Analogs
607
a
b
b
b
*
Wael A. El-Sayed, Omar M. Ali, Merfat S. Faheem, Ibrahim F. Zied, and
b
*
Adel A.-H. Abdel-Rahman
aDepartment of Photochemistry, National Research Centre, Cairo, Egypt
bFaculty of Science, Department of Chemistry, Menoufia University, Shebin El-Koam, Egypt
*
E-mail: waelshendy@gmail.com or adelnassar63@hotmail.com
Received October 15, 2010
DOI 10.1002/jhet.832
View this article online at wileyonlinelibrary.com.
OH
N
O
N
N
N
N
O
NH2
R
5
Steps
N
N
N
New [1,2,4-oxadiazolyl]methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin derivatives were synthesized starting
from N0-Hydroxy-1-naphthimidamide. The N-substituted acyclic nucleoside analogs as well as the substi-
tuted glycosides were also prepared by reaction with the corresponding reagents. The antimicrobial results
indicated that most of the tested compounds exhibited moderate to high antimicrobial activity whereas
few compounds were found to exhibit little or no activity against the tested microorganisms.
J. Heterocyclic Chem., 49, 607 (2012).
INTRODUCTION
related agents that have diverse biological actions and
therapeutic effects including antiviral [37,38] and antitumor
[39–41] activities. The above facts and our interest [38,42–46]
in the attachment of carbohydrate moieties to newly synthe-
sized heterocycles searching for new biologically active leads
promoted us to synthesize new substituted triazolopyrimidine
glycosides and their acyclic analogous and evaluate their
antimicrobial activity.
The 1,2,3-triazole nucleus is found in a large number of
compounds with agrochemical and pharmaceutical uses [1]
and shows activities such as anti-HIV [2], anti-microbial
[3], antibacterial [4], and antitumor [5] properties and has
also found many applications in chemical industries [6].
Pyrimidines and fused pyrimidines, being an integral part
of DNA and RNA in it, play an essential role in several
biological processes. The pyrimidine ring can be found in
nucleoside antibiotics, antibacterials, cardio-vascular, as well
as agrochemical and veterin products [7–9]. Fused pyrimi-
dines are found in a variety of natural products (e.g.,
purines), agrochemicals, and veterinary products [10–12].
Pyrimidine derivatives and heterocyclic annulated pyrimi-
dines continue to attract much interest due to the wide variety
of interesting biological activities observed for these
compounds, such as anticancer [13], antiviral [14], antitumor
[15], anti-inflammatory [16], antimicrobial [17(a,b)], anti-
fungal [18], antihistaminic [19], and analgesic [20] activities.
The study of triazolopyrimidine heterocyclic systems has
known a considerable development due to their varied
effects in diverse domains. Last years, research became
intensified on the synthesis of these compounds [21–25]
and the study of their activities in the pharmacological and
agrochemical fields. These compounds are known for their
anti-tumor [26], antibiotic [27], antifungal, antibacterial
[27–34], anti-inflammatory [35], herbicidal, and CNS
depressant activities [36]. Furthermore, nucleoside analogs
are structurally, metabolically, and pharmacodynamically
RESULTS AND DISCUSSION
In this investigation, 1-naphthonitrile (1) was reacted
with hydroxylamine hydrochloride in presence of 8-
hydroxyquinoline to afford N0-Hydroxy-1-naphthimidamide
(2) in 73% yield. When the oxime derivative 2 was reacted
with chloroacetyl chloride in acetone, the 1,2,4-oxadiazole
derivative 3 was obtained. Conversion of the substituted
1,2,4-oxadiazole derivative 3 to the corresponding azide
derivative 4 was performed by reaction with sodium azide in
DMF at 70ꢀC. The IR spectrum of compound 2 revealed the
presence of absorption bands at 3486 and 3327 cmꢁ1 for the
hydroxyl and amino groups, respectively. The 1H NMR
spectrum of compound 3 showed signals the CH2 in addition
to the aromatic protons. Its IR spectrum of compound 4 showed
characteristic absorption band at 2090 cmꢁ1 for the azide group.
The substituted 1-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-5-
yl]methyl}-1H-1,2,3-triazole derivative 5 was obtained by
reaction of the azide 4 with cyanoacetamide in presence of so-
dium ethoxide at reflux temperature. Its IR spectrum showed
© 2012 HeteroCorporation

608
W. A. El-Sayed, O. M. Ali, M. S. Faheem, I. F. Zied, and A. A.-H. Abdel-Rahman
Vol 49
absorption bands at 3372 and 1679 cmꢁ1 corresponding to the
amino and carbonyl groups, respectively, and its H NMR
Table 1
1
Minimum inhibitory concentrations (MIC-mg/mL) of the title compounds
negative control DMSO, no activity.
spectrum agreed with the assigned structure. Reaction of the
1,2,3-triazole-4-carboxamide derivative 5 with ethyl benzoate
in ethanol at reflux temperature gave the 1,2,3-triazolopyrimidine
derivative 6. Its 1H NMR spectrum showed the presence of the
signals corresponding to CH2, NH, and the aromatic protons
in addition to the disappearance of the NH2 signals.
When the 1,2,3-triazolopyrimidine derivative 6 was
allowed to react with different oxygenated alkyl halides and
bromosugars, the corresponding N-substituted derivatives
was obtained. Thus, reaction of 6 with chloroethylmethyl
ether, 2-(2-chloroethoxy)ethanol, 3-chloropropane-1,2-diol
or ethyl iodide, the corresponding N-substituted acyclic nucle-
oside analogs and alkyl derivatives 7–10, respectively, were
obtained. The structures of these products were confirmed
by their spectral and analytical data (see experimental part)
which agreed with the assigned structures. The 1H NMR spec-
trum of 9 as a representative example showed signals at d 4.55
and 4.68 ppm for the two CH2 and the signals for the hydroxyl
groups at d 4.87 and 4.92 ppm in addition to the aromatic
proton signals at d 7.31–8.26 ppm.
Gram positive Gram negative
Actinomycetes
Bacillus
subtilis
Pseudomonas
aseuginosa
Streptomyces
species
Compound
2
3
4
5
6
7
8
9
10
11
12
13
14
250
100
–
100
250
100
125
75
125
100
250
100
500
250
75
100
100
250
250
100
100
45
500
250
500
125
250
125
100
75
100
125
100
100
75
75
250
125
100
75
Penicillin
31
34
aTotally inactive (MIC > 500 mg/mL).
The result revealed that compounds showed varying
degrees of inhibition against the tested microorganisms.
In general, compounds 9, 10, and 14 displayed the highest
activity against B. subtilis followed by compounds 3, 5, 7,
and 13. Compound 8 displayed the highest inhibition activity
against P. aeruginosa with MIC value of 75 mg/mL while
compounds 9 and 14 revealed the highest activity against
Streptomyces species (Actinomycetes).
The antimicrobial activity results and structure activity
relationship indicated that substitution at N-1 in the pyrimidine
ring in the 1,2,3-triazolyl moiety resulted in an increase in the
antimicrobial activity with respect to the three microorgan-
isms. It is also clear that the acyclic nucleoside analog 8 with
free hydroxyl group showed the highest activity against B.
subtilis and Streptomyces species. Moreover, substitution at
N-1 with long oxygenated alkyl chain with terminal free
hydroxyl group resulted in a marked increase in activity
against P. aeruginosa.
The carboxamide derivative 5 with free two amino groups
showed relatively higher activity than the corresponding azid
derivative Additionally, the antimicrobial activity observed
for the N-substituted 1,2,3-triazolpyrimidine glycosides 13
and 14 indicated the importance of the free hydroxyl
glycopyranosyl moiety as the activity was reduced when this
group was replaced with the corresponding O-acetylated
glycosyles in the protected derivatives as well as the unsub-
stituted precursor. Moreover, the antibacterial activity
observed for the xylopyranosyl derivative was relatively
higher than that of the corresponding glucopyranosyl 13.
In conclusion, new [1,2,4-oxadiazolyl]methyl-3H-[1,2,3]
triazolo[4,5-d]pyrimidin derivatives, their N-substituted acy-
clic nucleoside analogs as well as the substituted glycosides
were prepared and studied for their antimicrobial activity.
When the 1,2,3-triazolopyrimidine derivative 6 was
reacted with 2,3,4,6-tetra-O-acetyl-a-D-gluco- or 2,3,4-
tri-O-acetyl-a-D-xylopyranosyl bromide in DMF in pres-
ence of triethylamine, the corresponding glycosides 11
and 12, respectively, were obtained in 76–78% yields.
The IR spectra of these glycosides showed characteristic
absorption bands at 1738–1740 cmꢁ1 for the acetylcarbonyl
1
groups. The H NMR spectra showed the acetyl methyl
proton signals at d 1.94–2.14 ppm in addition to the signals
of the sugar chain protons. The anomeric proton signal
appeared as doublet at d 5.88 and 5.89 ppm with coupling
constants 10.4 and 10.2 Hz for 11 and 12, respectively,
indicating the b-configuration of the produced glycosides
[45]. The 13C NMR of 11 and 12 showed the acetyl-methyl
signals at 19.30–20.23 (4CH3CO) and those corresponding
to the acetyl-carbonyl at 169.52–171.69. Deacetylation of
the glycoside derivatives 11 and 12 with methanolic
ammonia at room temperature afforded the corresponding
free hydroxyl glycoside derivatives 13 and 14 in 78–79%
yields. The IR spectra showed absorption bands for the
1
hydroxyl groups and the H NMR spectra showed signals
corresponding to the sugar hydroxyls in addition to the rest
of the sugar chain protons (see experimental part).
Antimicrobial activity.
The synthesized compounds
were evaluated for their antimicrobial activity against
three microorganisms; Bacillus subtilis (ATCC 6633)
(Gram-positive), Pseudomonas aeruginosa (ATCC 27853)
(Gram-negative), and Streptomyces species (Actinomycetes).
The values of minimal inhibitory concentrations (MICs) of
the tested compounds are presented in Table 1. The MIC
values of the most active compounds were in accordance
with the results obtained in the primary screening.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis and Antimicrobial Activity of New 1,2,3-Triazolopyrimidine Derivatives
and Their Glycoside and Acyclic Nucleoside Analogs
609
H2O, and the insoluble material was collected by filtration and
purified by recrystallization from ethanol to afford compound 5 as
yellow crystals (2.35 g, 70%), m.p. 186–187ꢀC; IR (KBr) n: 3372
Substitution at the free N-1 in the pyrimidine ring in the
1,2,3-triazolyl moiety afforded compounds with increased
inhibition activities with respect to the three microorganisms.
1
(NH2), 1679 (C¼O), 1614 cmꢁ1 (C¼N); H NMR (DMSO-d6) d
5.10 (s, 2H, CH2), 6.05 (bs, 2H, NH2), 7.31 (m, 2H, Ar-H), 7.45
(m, 2H, Ar-H), 7.70 (d, 1H, J = 8.0 Hz, Ar-H), 7.91 (d, 1H, J = 8.2
Hz, Ar-H), 8.12 (bs, 2H, NH2), 8.27 (d, 1H, J = 7.8 Hz, Ar-H).
Anal. Calcd. for C16H13N7O2 (335.32): C, 57.31; H, 3.91; N, 29.24.
Found: C, 57.11; H, 3.77; N, 29.14.
EXPERIMENTAL
Melting points were determined with a Kofler block apparatus
and are uncorrected. The IR spectra were recorded on a Perkin–
Elmer model 1720 FTIR spectrometer for KBr disc. NMR spectra
were recorded on a varian Gemini 200 NMR Spectrometer at 300
3-{[3-(Naphthalen-1-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-phenyl-
3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one (6). To a solution
of the carboxamide derivative 5 (10 mmol, 3.35 g) in ethanol
(30 mL) was added ethyl benzoate (12 mmol, 1.8 g) and the
reaction mixture was heated under reflux for 6 h. The solvent was
reduced under vacuo and the precipitated solid was filtered off and
recrystallized from ethanol to give 6 as a white solid. (2.9 g, 69%),
m.p. 169–170ꢀC; IR (KBr) n: 3218 (NH), 1671 (C¼O), 1612 cmꢁ1
1
MHz for H and 75 MHz for 13C or on a brucker Ac-250 FT
1
spectrometer at 250 MHz for H and at 62.9 MHz for 13C with
TMS as a standard. The progress of the reactions was monitored
by TLC using aluminum silica gel plates 60 F 245. Elemental
analyses were performed at the Microanalytical data centre at
Faculty of science, Cairo University, Egypt.
1
(C¼N); H NMR (DMSO-d6) d 5.05 (s, 2H, CH2), 7.31 (m, 2H,
N0-Hydroxy-1-naphthimidamide (2). To a solution of 1-
naphthonitrile (1) (10 mmol, 1.53 g) and 8-hydroxyquinoline
(0.3 g) in ethanol (20 mL) were added hydroxylamine
hydrochloride (10 mmol, 0.69 g) and the reaction mixture was
heated under reflux for 4 h (Scheme 1). The solvent was reduced
under vacuum and the precipitated solid was filtered off and
recrystallized from ethanol. White solid (1.36 g, 73%), m.p.
212–213ꢀC; IR (KBr) n: 3486 (OH), 3327 (NH2), 1610 cmꢁ1
Ar-H), 7.45 (m, 3H, Ar-H), 7.64 (m, 2H, Ar-H), 7.82 (m, 2H,
Ar-H), 7.94 (m, 2H, Ar-H), 8.27 (d, 1H, J = 7.8 Hz, Ar-H), 10.02
(s, 1H, NH). Anal. Calcd. for C23H15N7O2 (421.41): C, 65.55; H,
3.59; N, 23.27. Found: C, 65.37; H, 3.32; N, 23.18.
General procedure for the synthesis of compounds 7–10. To a
well stirred solution of compound 6 (5 mmol, 2.11 g) and anhydrous
potassium carbonate (5 mmol, 0.69 g) in N,N-dimethylformamide
(15 mL) was added chloroethylmethyl ether, 2-(2-chloroethoxy)
ethanol, 3-chloropropane-1,2-diol or ethyl iodide (5 mmol) and
stirring was continued at 70ꢀC for 6–9 h (TLC). The solvent was
evaporated under reduced pressure and the residue was recrystallized
from ethanol to give compounds 7–10, respectively.
1
(C¼N); H NMR (DMSO-d6) d 6.18 (s, 2H, NH2), 7.29 (m, 2H,
Ar-H), 7.48 (m, 2H, Ar-H), 7.68 (d, 1H, J = 8.0 Hz, Ar-H), 7.92
(d, 1H, J = 8.2 Hz, Ar-H), 8.24 (d, 1H, J = 7.8 Hz, Ar-H), 9.81
(s, 1H, OH). Anal. Calcd. for C11H10N2O (186.21): C, 70.95; H,
5.41; N, 15.04. Found: C, 70.63; H, 5.28; N, 14.92.
6-(2-Methoxyethyl)-3-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-
5-yl]methyl}5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
(7). Pale yellow solid; (1.79 g, 75%), m.p. 158–159ꢀC; IR (KBr)
5-(Chloromethyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole
(3). To a solution of compound 2 (10 mmol, 1.86 g) in acetone
(30 mL) was added potassium carbonate (10 mmol) and chloroacetyl
chloride (10 mmol, 1.13 g). The solution was heated under reflux for
4 h. The solvent was removed under reduced pressure and the
resulting residue was purified on a column chromatography to give
compound 3 as a pale yellowꢁ1powder (1.84 g, 75%), m.p.
186–187ꢀC; IR (KBr) n: 1610 cm (C¼N); 1H NMR (DMSO-d6)
d 4.58 (s, 2H, CH2), 7.31 (m, 2H, Ar-H), 7.49 (m, 2H, Ar-H), 7.70
(d, 1H, J = 8.0 Hz, Ar-H), 7.92 (d, 1H, J = 8.2 Hz, Ar-H), 8.25
(d, 1H, J = 7.8 Hz, Ar-H). Anal. Calcd. for C13H9ClN2O (244.68):
C, 63.81; H, 3.71; N, 11.45. Found: C, 63.65; H, 3.58; N, 11.29.
1
n: 1670 (C¼O), 1610 cmꢁ1 (C¼N); H NMR (DMSO-d6) d 3.92
(s, 3H, CH3), 4.62 (t, 2H, J = 5.4 Hz, CH2), 4.79 (t, 2H, J = 5.4 Hz,
CH2), 5.21 (s, 2H, CH2), 728 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H),
7.65 (m, 2H, Ar-H), 7.82 (m, 2H, Ar-H), 7.92 (m, 2H, Ar-H), 8.25
(d, 1H, J = 7.8 Hz, Ar-H). Anal. Calcd. for C26H21N7O3 (479.49):
C, 65.13; H, 4.41; N, 20.45. Found: C, 64.91; H, 4.31; N, 20.29.
6-[2-(2-Hydroxyethoxy)ethyl]-3-{[3-(naphthalen-1-yl)-1,2,4-
oxadiazol-5-yl]methyl}-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (8). White solid; (1.89 g, 74%), m.p. 171–172ꢀC; IR
1
(KBr) n: 3481 (OH), 1667 (C¼O), 1612 cmꢁ1 (C¼N); H NMR
5-(Azidomethyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole (4).
A
(DMSO-d6) d 4.65 (t, 2H, J = 5.6 Hz, CH2), 4.74 (t, 2H, J = 5.6
Hz, CH2), 4.86 (t, 2H, J = 5.2 Hz, CH2), 4.91 (t, 1H, J = 5.6 Hz,
OH), 4.97 (t, 2H, J = 5.2 Hz, CH2), 5.12 (s, 2H, CH2), 7.29 (m, 2H,
Ar-H), 7.47 (m, 3H, Ar-H), 7.66 (m, 2H, Ar-H), 7.82 (m, 2H, Ar-H),
7.94 (m, 2H, Ar-H), 8.24 (d, 1H, J = 7.8 Hz, Ar-H). Anal. Calcd. for
C27H23N7O4 (509.52): C, 63.65; H, 4.55; N, 19.24. Found: C, 63.49;
H, 4.41; N, 19.18.
solution of compound 3 (10 mmol, 2.44 g) and sodium azide (10
mmol, 0.65) in DMF (15 mL) was stirred at 70ꢀC for 6 h. The
solvent was removed under reduced pressure and the resulting
residue was triturated with excess diethyl ether to afford 4 as a
white solid. (1.78 g, 71%), m.p. 90–91ꢀC; IR (KBr) n: 2090 (N3),
1612 cmꢁ1 (C¼N); 1H NMR (DMSO-d6) d 4.25 (s, 2H, CH2), 7.29
(m, 2H, Ar-H), 7.44 (m, 2H, Ar-H), 7.69 (d, 1H, J = 8.0 Hz, Ar-H),
7.92 (d, 1H, J = 8.2 Hz, Ar-H), 8.24 (d, 1H, J = 7.8 Hz, Ar-H).
Anal. Calcd. for C13H9N5O (251.24): C, 62.15; H, 3.61; N,
27.87. Found: C, 61.95; H, 3.57; N, 27.69.
5-Amino-1-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-5-yl]methyl}-
1H-1,2,3-triazole-4-carboxamide (5). Cyanacetamide (11 mmol,
0.934 g) was added to a stirred solution of sodium ethoxide (0.253 g,
0.011 g atom of Na) in absolute ethanol (10 mL), and stirring was
continued for 30 min. A solution of compound 4 (10.0 mmol,
2.51 g) in absolute ethanol (10 mL) was slowly added to the
suspension, and then the mixture was heated under reflux for 2 h.
The reaction mixture was concentrated in vacuo and treated with
6-(2,3-Dihydroxypropyl)-3-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-
5-yl]methyl}-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one
(9). Pale yellow solid; (1.88 g, 73%), m.p. 205–206ꢀC; IR (KBr)
n: 3473 (OH), 1668 (C¼O), 1615 cmꢁ1 (C¼N); 1H NMR
(DMSO-d6) d 4.55 (d, 2H, J = 5.6 Hz, CH2), 4.68 (m, 2H, CH2),
4.75 (t, 2H, J = 5.2 Hz, CHOH), 4.87 (t, 1H, J = 6.2 Hz, OH),
4.92 (t, 1H, J = 5.8 Hz, OH), 5.12 (s, 2H, CH2), 7.31 (m, 2H,
Ar-H), 7.50 (m, 3H, Ar-H), 7.9 (m, 2H, Ar-H), 7.84 (m, 2H,
Ar-H), 7.96 (m, 2H, Ar-H), 8.26 (d, 1H, J = 7.8 Hz, Ar-H).
Anal. Calcd. for C26H21N7O4 (495.49): C, 63.02; H, 4.27;
N, 19.79. Found: C, 62.89; H, 4.11; N, 19.62.
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W. A. El-Sayed, O. M. Ali, M. S. Faheem, I. F. Zied, and A. A.-H. Abdel-Rahman
Vol 49
Scheme 1
6-Ethyl-3-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-
1612 cmꢁ1 (C¼N); 1H NMR (DMSO-d6) d 1.48 (t, 3H, J = 4.8 Hz,
CH3), 4.32 (q, 2H, J = 4.8 Hz, CH2), 5.10 (s, 2H, CH2), 7.30
(m, 2H, Ar-H), 7.49 (m, 3H, Ar-H), 7.90 (m, 2H, Ar-H), 7.85
phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one (10). White
solid; (1.78 g, 79%), m.p. 159–160ꢀC; IR (KBr) n: 1669 (C¼O),
Journal of Heterocyclic Chemistry
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May 2012
Synthesis and Antimicrobial Activity of New 1,2,3-Triazolopyrimidine Derivatives
and Their Glycoside and Acyclic Nucleoside Analogs
611
(m, 2H, Ar-H), 7.98 (m, 2H, Ar-H), 8.27 (d, 1H, J = 7.8 Hz, Ar-H).
Anal. Calcd. for C25H19N7O2 (449.46): C, 66.81; H, 4.26; N, 21.81.
Found: C, 66.65; H, 4.14; N, 21.68.
CH2), 5.16 (t, 1H, J = 6.2 Hz, OH), 5.82 (d, 1H, J1,2 = 9.8 Hz, H-1), 7.31
(m, 2H, Ar-H), 7.47 (m, 3H, Ar-H), 7.66 (m, 2H, Ar-H), 7.85 (m, 2H,
Ar-H), 7.96 (m, 2H, Ar-H), 8.24 (d, 1H, J = 7.8 Hz, Ar-H); Anal. Calcd.
for C29H25N7O7 (583.55): C, 59.69; H, 4.32; N, 16.80. Found: C, 59.58;
H, 4.29; N, 16.69.
General procedure for the synthesis of compounds 11 and
12. To a solution of compound 6 (5 mmol, 2.11 g) in DMF (15
mL) was added triethylamine (0.75 mL) and 2,3,4,6-tetra-O-acetyl-a-
D-gluco- or 2,3,4-tri-O-acetyl-a-D-xylopyranosyl bromide (5 mmol).
The reaction mixture was stirred at room temperature until
reaction was judged complete by TLC using chloroform/methanol
(99.5:0.5). The solvent was reduced under reduced pressure and
the residue was washed with distilled water to remove the formed
potassium bromide. The product was dried, and recrystallized
from ethanol to give compounds 11 or 12, respectively.
6-(b-D-Xylopyranosyl)-3-{[3-(naphthalen-1-yl)-1,2,4-oxadiazol-
5-yl]methyl}-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7
(6H)-one (14). Pale yellow solid; (2.16 g, 78%), m.p. 212–213ꢀC;
IR (KBr) n: 3470–3442 (OH), 1665 (C¼O), 1615 cmꢁ1 (C¼N);
1H NMR (DMSO-d6) d 3.41 (m, 2H, H-5,50), 3.78 (m, 2H, H-3,4),
4.24 (t, 1H, J2,3 = 9.2 Hz, H-2), 4.37 (t, 1H, J = 6.4 Hz, OH), 4.48
(m, 1H, OH), 5.02 (m, 1H, OH), 5.08 (s, 2H, CH2), 5.82 (d, 1H,
J1,2 = 9.8 Hz, H-1), 7.33 (m, 2H, Ar-H), 7.48 (m, 3H, Ar-H), 7.65
(m, 2H, Ar-H), 7.84 (m, 2H, Ar-H), 7.98 (m, 2H, Ar-H), 8.25
(d, 1H, J = 7.8 Hz, Ar-H); Anal. Calcd. for C28H23N7O6 (553.53):
C, 60.76; H, 4.19; N, 17.71. Found: C, 60.55; H, 4.11; N, 17.59.
Antimicrobial activity. The synthesized compounds were
tested for their antimicrobial activity against three microorganisms,
and the MICs of the tested compounds were determined by the
dilution method.
6-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-{[3-
(naphthalen-1-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-phenyl-3H-[1,2,3]
triazolo[4,5-d]pyrimidin-7(6H)-one (11).
Pale yellow solid;
(2.93 g, 78%), m.p. 150–151ꢀC; IR (KBr) n: 1738 (C¼O), 1614
1
cmꢁ1 (C¼N); H NMR (DMSO-d6) d 1.94, 2.04, 2.11, 2.15, (4s,
0
12H, 4 CH3CO), 4.07 (m, 1H, H-5), 4.15 (dd, 1H, J6,6 = 11.4 Hz,
J5,6 = 2.8 Hz, H-6), 4.18 (m, 1H, H-60), 4.94 (t, 1H, J3,4 = 9.3 Hz,
H-4), 5.06 (s, 2H, CH2), 5.27 (dd, 1H, J2,3 = 9.6 Hz, J3,4 = 9.3
Hz, H-3), 5.38 (t, 1H, J2,3 = 9.6 Hz, H-2), 5.88 (d, 1H, J1,2 = 10.4
Hz, H-1), 7.32 (m, 2H, Ar-H), 7.46 (m, 3H, Ar-H), 7.65 (m, 2H,
Ar-H), 7.84 (m, 2H, Ar-H), 7.95 (m, 2H, Ar-H), 8.25 (d, 1H,
J = 7.8 Hz, Ar-H); 13C NMR (CDCl3) d 19.30, 19.55, 20.19,
20.23 (4CH3CO), 51.28 (CH2), 62.70 (C-6), 64.24 (C-4), 68.72
(C-3), 71.27 (C-2), 71.94 (C-5), 87.14 (C-1), 119.18–151.14
(Ar-16C, pyrimidine C-5,6), 156.42, 157.15, 159.42 (3C¼N),
168.05, 169.52, 169.64, 170.30, 171.49 (5C¼O). Anal. Calcd. for
C37H33N7O11 (751.70): C, 59.12; H, 4.42; N, 13.04. Found: C,
59.02; H, 4.30; N, 12.89.
Sample preparation. Each of the test compounds and
standards were dissolved in 12.5% DMSO at concentrations of
500 mg/mL. Further dilutions of the compounds and standards
were made in test medium.
Culture of microorganisms. Bacterial strains were supplied from
the Botany Department, Faculty of Science, Menoufia University,
Egypt, namely B. subtilis (ATCC 6633) (Gram-positive),
P. aeruginosa (ATCC 27853) (Gram-negative), and Streptomyces
species (Actinomycetes). The bacterial strains were maintained on
MHA (Mueller—Hinton agar) medium (Oxoid, Chemical Co.) for
24 h at 37ꢀC. The medium was molten on a water bath, inoculated
with 0.5 mL of the culture of the specific microorganism, and
poured into sterile Petri dishes to form a layer of about 3–4 mm.
The layer was allowed to cool and harden. With the aid of cork-
borer, cups of about 10 mm diameter were produced [47].
Agar diffusion technique. Antibacterial activities were tested
against B. subtilis (Gram-positive), P. aeruginosa (Gram-negative),
and Streptomyces species (Actinomycetes) using MH medium (17.5
g casein hydrolysate, 1.5 g soluble starch, 1000 mL beef extract). A
stock solution of each synthesized compound (500 mg/mL) in
DMSO was prepared and incorporated in sterilized liquid MH
medium. Different concentrations of the test compounds in DMF
were placed separately in cups in the agar medium. All plates were
incubated at 37ꢀC overnight. The inhibition zones were measured
after 24 h. The MIC was defined as the intercept of the grave of
logarithm concentrations versus diameter of the inhibition zones [48].
6-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-3-{[3-(naphthalen-
1-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-phenyl-3H-[1,2,3]triazolo
[4,5-d]pyrimidin-7(6H)-one (12).
Pale yellow solid; (2.58 ꢁg1,
76%), m.p. 153–154ꢀC; IR (KBr) n: 1740 (C¼O), 1614 cm
(C¼N); 1H NMR (DMSO-d6) d 1.94, 2.05, 2.12 (4s, 9H, 3 CH3CO),
4.15 (dd, 1H, J5,5 = 11.4 Hz, J4,5 = 2.8 Hz, H-5), 4.18 (m, 1H, H-50),
0
4.94 (m, 1H, H-4), 5.10 (s, 2H, CH2), 5.27 (dd, 1H, J2,3 = 9.6 Hz,
J3,4 = 9.3 Hz, H-3), 5.38 (t, 1H, J2,3 = 9.6 Hz, H-2), 5.89 (d, 1H,
J1,2 = 10.2 Hz, H-1), 7.31 (m, 2H, Ar-H), 7.48 (m, 3H, Ar-H),
7.69 (m, 2H, Ar-H), 7.85 (m, 2H, Ar-H), 7.95 (m, 2H, Ar-H),
8.25 (d, 1H, J = 7.8 Hz, Ar-H); 13C NMR (CDCl3) d 19.28,
19.57, 20.21 (3CH3CO), 51.36 (CH2), 62.70 (C-5), 64.27 (C-4),
68.74 (C-3), 71.27 (C-2), 88.15 (C-1), 119.12-151.39 (Ar-16C,
pyrimidine C-5,6), 156.41, 157.15, 159.45 (3C¼N), 168.42, 169.65,
171.42, 171.59 (4C¼O). Anal. Calcd. for C34H29N7O9 (679.64): C,
60.09; H, 4.30; N, 14.43. Found: C, 59.82; H, 4.26; N, 14.30.
General procedure for the synthesis of compounds 13 and
14. Dry gaseous ammonia was passed through a solution of a
protected glycosides 11 or 12 (5 mmol) in dry methanol (20 mL)
at 0ꢀC for 1 h and then stirring was continued at room
temperature for 5 h. The solvent was evaporated under reduced
pressure at 40ꢀC to give a solid residue, which was recrystallized
from ethanol to afford 13 or 14.
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