Synthesis and antimicrobial activity of new 2,5-disubstituted 1,3,4-oxadiazoles and 1,2,4-triazoles and their sugar derivatives

Article abstract of DOI:10.1002/cjoc.201100029

A series of new 2,5-disubstituted-1,3,4-oxadiazole and 1,2,4-triazole derivatives were synthesized by heterocyclization of acid hydrazide 1 and thiosemicarbazide derivative 2. Furthermore, the acyclic C-nucleoside analogs were prepared by cyclization of their corresponding sugar hydrazones by reaction with acetic anhydride. The antimicrobial activity of the prepared compounds was evaluated and some of the synthesized compounds revealed good activities against fungi. Copyright

Full text of DOI:10.1002/cjoc.201100029

FULL PAPER
DOI: 10.1002/cjoc.201100029
Synthesis and Antimicrobial Activity of New 2,5-Disubstituted
1,3,4-Oxadiazoles and 1,2,4-Triazoles and
Their Sugar Derivatives
El-Sayed, Wael A.a,b
Ali, Omar M.c
Hendy, Hend A.c
Abdel-Rahman, Adel A.-H.*,b,c
a Department of Photochemistry, National Research Centre, Cairo, Egypt
b Chemistry Department, Northern Border University, Arar, Saudi Arabia
c Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
A series of new 2,5-disubstituted-1,3,4-oxadiazole and 1,2,4-triazole derivatives were synthesized by hetero-
cyclization of acid hydrazide 1 and thiosemicarbazide derivative 2. Furthermore, the acyclic C-nucleoside analogs
were prepared by cyclization of their corresponding sugar hydrazones by reaction with acetic anhydride. The an-
timicrobial activity of the prepared compounds was evaluated and some of the synthesized compounds revealed
good activities against fungi.
Keywords 1,3,4-oxadiazoles, 1,2,4-triazoles, sugar hydrazones, acyclic nucleosides, antimicrobial activity
Introduction
acyclic diacylhydrazines or ring conversion.[36] In view
of the above facts and as continuation of interest in
identification of new valuable candidates in designing
new, potent and less toxic antimicrobial agents,[35,37-41]
we here report the synthesis and antimicrobial activity
of new 2,5-disubstituted 1,3,4-oxadiazoles and 1,2,4-
triazoles as well as their derived acyclic C-nucleoside
analogs incorporating both ring systems.
The chemistry of azoles derived N-bridged hetero-
cycles has received considerable attention in recent
years due to their usefulness in different areas of bio-
logical activities and as industrial intermediates.
1,3,4-Oxadiazole derivatives have been reported to
possess a broad spectrum of biological activity in both
agrochemicals and pharmaceuticals such as antibacte-
rial,[1] antimicrobial,[2] insecticidal,[3] herbicidal, fungi-
cidal,[4] anti-inflammatory,[5] hypoglycemic,[6] hypoten-
sion characteristics,[7] antiviral,[8] and antitumor activi-
ties.[9] 1,2,4-Triazole derivatives are known to exhibit
antimicrobial,[10-14] antitubercular[15], anticancer,[16,17]
anticonvulsant,[18] anti-inflammatory analgesic[19] and
antidepressant properties.[20] The arrangement of three
basic nitrogen atoms in triazole ring induces the anti-
viral activities in the compounds containing triazole
ring.[21] 1,2,4-Triazole nucleus has been incorporated in
a wide variety of therapeutically interesting drug candi-
dates including H1/H2 histamine receptor blockers,
cholinesterase active agents, CNS stimulants, antian-
xiety sedatives[22] and antimycotic activity such as Flu-
conazole, Itraconazole and Voriconazole.[23,24] There are
some known drugs containing 1,2,4-triazole moiety, eg.,
Triazolam,[25] Alprazalam,[26] Etizolam,[27] Furacylin,[28]
Ribavirin[29] and Propiconazole.[30] On the other hand,
the nucleosides as well as their acyclic and C-nucleoside
analogues possess a wide range of medicinal properties,
including antibiotic, antiviral, and antitumor activi-
ties.[31-35] Oxadiazole and triazole ring systems have
been reported to be synthesized either by cyclization of
Experimental
Melting points were determined with a kofler block
apparatus and are uncorrected. The IR spectra were re-
corded on a Perkin-Elmer model 1720 FTIR spectrome-
ter for KBr disc. NMR spectra were recorded on a Var-
1
ian Gemini 200 NMR spectrometer at 300 MHz for H
and 75 MHz for 13C or on a Brucker Ac-250 FT spec-
1
trometer 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. EI-mass spectra were measured on HP D5988
A 1000 MHz spectrometer (Hewlett-Packard, Palo Alto,
CA, USA). Elemental analyses were performed at the
Micro Analytical Data Centre at Faculty of Science,
Cairo University, Egypt. The antimicrobial activity was
measured at Botany Department, Faculty of Science,
Menoufia University, Shebin El-koom, Egypt.
2-(4-Chlorophenyl)-5-[(naphthalen-2-yloxy)methyl]-
1,3,4-oxadiazole (2)
A mixture of the hydrazide 1 (2.16 g, 10 mmol) and
*
E-mail: adelnassar63@yahoo.com
Received June 19, 2011; accepted August 9, 2011; Published online December 23, 2011.
Chin. J. Chem. 2012, 30, 77—83
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77

El-Sayed et al.
FULL PAPER
from ethanol to give the product as white solid. Yield
82%, m.p. 143—144 ℃; H NMR (DMSO-d6, 300
chlorobenzoic acid (10 mmol) was dissolved in phos-
phorus oxychloride (20 mL) and refluxed for 20 h. The
reaction mixture was slowly poured over crushed ice
and kept over night. The solid thus separated out was
filtered, washed with water, dried and recrystallized
from ethanol as yellow solid. Yield 85%, m.p. 108—
110 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 4.83 (s, 2H,
CH2), 7.14—7.17 (m, 2H, ArH), 7.44 (d, J＝8.2 Hz, 1H,
ArH), 7.46—7.49 (m, 2H, ArH), 7.52 (d, J＝7.8 Hz, 1H,
ArH), 7.55 (d, J＝8.5 Hz, 2H, ArH), 7.97 (d, J＝8.5 Hz,
2H, ArH), 8.19 (s, 1H, ArH); IR (KBr) ν: 1617 (C＝N)
1
MHz) δ: 4.82 (s, 2H, CH2), 6.02 (s, 2H, NH2), 7.12—
7.14 (m, 2H, ArH), 7.44 (d, J＝8.2 Hz, 1H, ArH), 7.48
—7.50 (m, 2H, ArH), 7.58 (d, J＝7.8 Hz, 1H, ArH),
8.18 (s, 1H, ArH), 9.02 (brs, 1H, NH), 9.92 (brs, 1H,
NH); IR (KBr) ν: 3359 (NH2), 3311 (NH), 1662 (C＝O)
－
＋
1
cm ; MS m/z (%): 275 (M , 48). Anal. calcd for
C13H13N3O2S: C 56.71, H 4.76, N 15.26; found C 56.55,
H 4.62, N 15.14.
5-[(Naphthalen-2-yloxy)methyl]-2H-1,2,4-triazole-
3(4H)-thione (6)
－
＋
1
cm ; MS m/z (%): 335 (M , 45). Anal. calcd for
C19H13ClN2O2: C 67.76, H 3.89, N 8.32; found C 67.48,
H 3.75, N 8.25.
A solution of compound 5 (2.75 g, 10 mmol) was re-
fluxed in 4% sodium hydroxide (25 mL) for 3 h. The
resulting solution after charcoal treatment and filtration
was acidified with hydrochloric acid to pH 5—6. The
that separated solid was filtered, dried and recrystallized
from dilute ethanol to give the product as yellow solid.
N'-(1-Methylethylidene)-2-(2-naphthyloxy)acetohy-
drazide (3)
A solution of the hydrazide 1 (2.16 g, 10 mmol) and
p-nitroacetophenone (1.65 g, 10 mmol) in glacial acetic
acid (10 mL) was refluxed for 8 h. The solid separated
upon cooling was filtered, washed with cold ethanol and
recrystallized from ethanol to give the product as yellow
solid. Yield 74%, m.p. 138 — 139 ℃ ; 1H NMR
(DMSO-d6, 300 MHz) δ: 2.29 (s, 3H, CH3), 4.86 (s, 2H,
CH2), 7.17—7.19 (m, 2H, ArH), 7.49 (d, J＝8.2 Hz, 1H,
ArH), 7.52—7.55 (m, 2H, ArH), 7.57 (d, J＝7.8 Hz, 1H,
ArH), 7.67 (d, J＝8.5 Hz, 2H, ArH), 7.98 (d, J＝8.5 Hz,
2H, ArH), 8.22 (s, 1H, ArH), 9.79 (brs, 1H, NH); IR
1
Yield 71%, m.p. 156—166 ℃; H NMR (DMSO-d6,
300 MHz) δ: 4.84 (s, 2H, CH2), 7.14—7.17 (m, 2H,
ArH), 7.46 (d, J＝8.2 Hz, 1H, ArH), 7.49—7.51 (m, 2H,
ArH), 7.59 (d, J＝7.8 Hz, 1H, ArH), 8.20 (s, 1H, ArH),
9.14 (brs, 1H, NH), 12.98 (brs, 1H, NH); 13C NMR
(DMSO-d6, 300 MHz) δ: 66.24 (CH2), 112.17—155.40
(10 ArC), 159.93 (triazolyl C-5), 178.66 (C＝S); IR
－
1
(KBr) ν: 3449 (NH), 1622 (C＝N) cm ; MS m/z (%):
257 (M＋, 38). Anal. calcd for C13H11N3OS: C 60.68, H
4.31, N 16.33; found C 60.52, H 4.19, N 16.18.
－
1
(KBr) ν: 3293 (NH), 1659 (C＝O) cm ; MS m/z (%):
363 (M＋, 39). Anal. calcd for C20H17N3O4: C 66.11, H
4.72, N 11.56; found C 65.97, H 4.62, N 11.47.
1-(2-(Naphthalen-2-yloxy)acetyl)-4-phenylsemicarba-
zide (7)
A solution of compound 1 (2.16 g, 10 mmol), and
phenylisocyanate (1.19 g, 10 mmol) in ethanol (50 mL)
was refluxed on steam bath for 10 h. It was then con-
centrated, cooled and kept overnight in a refrigerator.
The solid thus separated out, was filtered, washed with
ethanol, dried and recrystallized from ethanol-DMF (4 :
1) to give the product as white solid. Yield 76%, m.p.
3-Acetyl-5-[(2-naphthyloxy)methyl]-2-(4-nitrophen-
yl)-2,3-dihydro-1,3,4-oxadiazole (4)
A mixture of compound 3 (3.63 g, 10 mmol) and
acetic anhydride (5 mL) was heated under reflux for 1 h.
After the reaction mixture was attained at room tem-
perature, the excess acetic anhydride was decomposed
by water and the mixture was stirred for 30 min. The
separated product was filtered, washed with water, dried
and recrystallized from ethanol to give the product as
1
203—204 ℃; H NMR (DMSO-d6, 300 MHz) δ: 4.83
(s, 2H, CH2), 7.11—7.50 (m, 2H, ArH), 7.45 (d, J＝8.2
Hz, 1H, ArH), 7.48—7.14 (m, 2H, ArH), 7.54 (d, J＝
7.8 Hz, 1H, ArH), 7.67—7.70 (m, 3H, ArH), 7.97—
7.99 (m, 2H, ArH), 8.19 (s, 1H, ArH), 9.02 (brs, 1H,
NH), 9.80 (brs, 1H, NH), 9.98 (brs, 1H, NH); IR (KBr)
1
white solid. Yield 70%, m.p. 164—165 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 2.23 (s, 3H, CH3), 2.30 (s, 3H,
CH3), 4.89 (s, 2H, CH2), 7.19—7.22 (m, 2H, ArH), 7.48
(d, J＝8.2 Hz, 1H, ArH), 7.53—7.56 (m, 2H, ArH),
7.57 (d, J＝7.8 Hz, 1H, ArH), 7.68 (d, J＝8.5 Hz, 2H,
ArH), 7.98 (d, J＝8.5 Hz, 2H, ArH), 8.22 (s, 1H, ArH);
－
1
ν: 3349—3311 (NH), 1682 (C＝O) cm ; MS m/z (%):
335 (M＋, 49). Anal. calcd for C19H17N3O3: C 68.05, H
5.11, N 12.53; found C 68.15, H 4.98, N 12.39.
－
1
IR (KBr) ν: 1681 (C＝O), 1624 (C＝N) cm ; MS m/z
(%): 405 (M＋, 55). Anal. calcd for C22H19N3O5: C 65.18,
H 4.72, N 10.37; found C 65.05, H 4.60, N 10.50.
5-[(Naphthalen-6-yloxy)methyl]-N-phenyl-1,3,4-oxa-
diazol-2-amine (8)
A suspension of compound 7 (1.68 g, 5 mmol) in
ethanol (30 mL) was dissolved in aqueous sodium hy-
droxide (5 mol/L, 1 mL) with cooling and stirring, re-
sulting in a clear solution. To this mixture iodine in po-
tassium iodide solution (5%) was added gradually with
stirring till the color of iodine persisted at room tem-
perature. The reaction mixture was then refluxed for 2 h
on steam bath. The mixture was then cooled and poured
1-(2-(Naphthalen-2-yloxy)acetyl)thiosemicarbazide
(5)
A suspension of the hydrazide 1 (2.16 g, 10 mmol),
potassium thiocyanate (0.97 g, 10 mmol) in 36% hy-
drochloric acid (10 mL) and water (150 mL) was re-
fluxed for 3.5 h. After cooling, the white solid obtained
was filtered, washed with water, dried and recrystallized
78
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Chin. J. Chem. 2012, 30, 77—83

Synthesis and Antimicrobial Activity of New 2,5-Disubstituted 1,3,4-Oxadiazoles
over crushed ice. The separated solid mass was filtered,
dried and recrystallized from ethanol to give the product
as yellow solid. Yield 62%, m.p. 198—199 ℃; H
7.58 (d, J＝7.8 Hz, 1H, ArH), 8.19 (s, 1H, ArH), 9.79
(brs, 1H, NH), 12.94 (brs, 1H, NH); IR (KBr) ν: 331
－
1
1
(NH2), 3302 (NH), 1671 (C＝O), 1620 (C＝N) cm ;
MS m/z (%): 329 (M＋, 48). Anal. calcd for C15H15N5-
O2S: C 54.70, H 4.59, N 21.26; found C 54.61, H 4.38,
N 21.18.
NMR (DMSO-d6, 300 MHz) δ: 4.87 (s, 2H, CH2), 7.17
—7.20 (m, 2H, ArH), 7.48 (d, J＝8.2 Hz, 1H, ArH),
7.54—7.56 (m, 2H, ArH), 7.59 (d, J＝7.8 Hz, 1H, ArH),
7.67—7.70 (m, 3H, ArH), 7.98—8.01 (m, 2H, ArH),
8.21 (s, 1H, ArH), 9.85 (bs, 1H, NH); IR (KBr) ν: 3282
Sugar 2-({5-[(naphthalen-2-yloxy)methyl]-4H-1,2,4-
triazol-3yl}sulfanyl)acetylhydrazones (12, 13)
－
＋
1
(NH), 1620 (C＝N) cm ; MS m/z (%): 317 (M , 59).
Anal. calcd for C19H15N3O2: C 71.91, H 4.76, N 13.24;
found C 71.76, H 4.58, N 13.38.
To a well stirred solution of the respective mono-
saccharide (D-mannose or D-ribose) (10 mmol) in water
(2 mL) and glacial acetic acid (0.3 mL) was added the
hydrazide 11 (3.29 g, 10 mmol) in ethanol (20 mL) and
the mixture was heated under reflux for 9—10 h. The
resulting solution was concentrated and left to cool and
the precipitated solid was filtered, washed with ethanol,
dried and recrystallized from ethanol-DMF (3∶1) to
give compounds 12 and 13.
4-Amino-5-[(naphthalen-6-yloxy)methyl]-N-phenyl-
1,2,4-triazol-2-amine (9)
A solution of compound 8 (1.56 g, 5 mmol) and
hydrazine hydrate (1.3 mol) in absolute ethanol (30 mL)
was refluxed for 10 h. The solution was cooled and the
resulting precipitate was filtered, dried and recrystal-
lized from ethanol to give the product as yellow solid.
D-Mannose-2-({5-[(naphthalen-2-yloxy)methyl]-
4H-1,2,4-triazol-3yl}sulfanyl)acetylhydrazones (12):
The product was obtained as brownish powder. Yield
1
Yield 70%, m.p. 189—190 ℃; H NMR (DMSO-d6,
300 MHz) δ: 4.89 (s, 2H, CH2), 6.08 (brs, 2H, NH2),
7.16—7.19 (m, 2H, ArH), 7.49 (d, J＝8.2 Hz, H, ArH),
7.57—7.59 (m, 2H, ArH), 7.64 (d, J＝7.8 Hz, 1H, ArH),
7.69—7.72 (m, 3H, ArH), 7.99—8.02 (m, 2H, ArH),
8.22 (s, 1H, ArH), 9.97 (brs, 1H, NH); IR (KBr) ν: 3427
1
72%, m.p. 150—151 ℃; H NMR (DMSO-d6, 300
MHz) δ: 3.41—3.44 (m, 2H, H-6, H-6'), 3.53—3.55 (m,
1H, H-5), 4.15—4.17 (m, 2H, H-3,4), 4.45 (t, J＝5.7 Hz,
1H, H-2), 4.58—4.60 (m, 1H, OH), 4.63 (s, 2H, CH2),
4.78 (d, J＝6.3 Hz, 1H, OH), 4.91—4.93 (m, 1H, OH),
4.95 (s, 2H, CH2), 5.02 (t, J＝4.3 Hz, 1H, OH),
5.36—5.38 (m, 1H, OH), 7.24—7.27 (m, 2H, ArH),
7.37 (d, J＝7.6 Hz, 1H, H-1), 7.48 (d, J＝8.2 Hz, 1H,
ArH), 7.52—7.55 (m, 2H, ArH), 7.62 (d, J＝7.8 Hz, 1H,
ArH), 8.19 (s, 1H, ArH), 10.12 (bs, 1H, NH), 11.84 (bs,
1H, NH); IR (KBr) ν: 3431—3360 (OH), 3300 (NH),
－
＋
1
(NH2), 1617 (C＝N) cm ; MS m/z (%): 331 (M , 61).
Anal. calcd for C19H17N5O: C 68.87, H 5.17, N 21.13;
found C 68.70, H 5.05, N 21.02.
Ethyl
{[5-[(naphthalen-2-yloxy)methyl]-4H-1,2,4-
triazol-3-yl]sulfanyl}acetate (10)
A solution of compound 6 (2.57, 10 mmol) and an-
hydrous potassium carbonate (10 mmol) in ethanol (25
mL) was stirred at room temperature for 1 h and ethyl
chloroactate was added (1.22 g, 10 mmol), then the
mixture was refluxed for 6 h. The reaction mixture was
cooled and the resulting precipitate was filtered, dried
and recrystallized from ethanol to give 10 as white solid
－
1
1670 (CONH), 1621 (C＝N) cm ; MS m/z (%): 491
(M＋, 45). Anal. calcd for C21H25N5O7S: C 51.32, H 5.13,
N 14.25; found C 51.24, H 5.05, N 14.11.
D-Ribose-2-({5-[(naphthalen-2-yloxy)methyl]-4H-1,
2,4-triazol-3yl}sulfanyl)acetylhydrazones (13): The
product was obtained as brownish powder. Yield 69%,
1
1
2.64 g (77%) ℃; H NMR (DMSO-d6, 300 MHz) δ:
m.p. 142—143 ℃; H NMR (DMSO-d6, 300 MHz) δ:
1.14 (t, J＝6.4 Hz, 3H, CH3), 4.05 (q, J＝6.4 Hz, 2H,
CH2), 4.81 (s, 2H, CH2), 4.96 (s, 2H, CH2), 7.15—7.18
(m, 2H, ArH), 7.47 (d, J＝8.2 Hz, 1H, ArH), 7.48—
7.50 (m, 2H, ArH), 7.60 (d, J＝7.8 Hz, 1H, ArH), 8.20
(s, 1H, ArH), 11.96 (brs, 1H, NH); IR (KBr) ν: 3309
(NH), 1741 (C＝O) cm ; MS m/z (%): 363 (M , 32).
Anal. calcd for C17H17N3O3S: C 59.46, H 4.99, N 12.24;
found C 59.62, H 4.91, N 12.16.
3.35 (m, 2H, H-5, H-5'), 4.17—4.25 (m, 2H, H-3,4),
4.68—4.70 (m, 1H, H-2), 4.73 (m, 1H, OH), 4.79 (s, 2H,
CH2), 4.88 (d, J＝6.3 Hz, 1H, OH), 4.92—4.94 (m, 1H,
OH), 4.98 (s, 2H, CH2), 5.57—5.60 (m, 1H, OH),
7.21—7.24 (m, 2H, ArH), 7.36 (d, J＝7.6 Hz, 1H, H-1),
7.48 (d, J＝8.2 Hz, 1H, ArH), 7.54—7.56 (m, 2H, ArH),
7.65 (d, J＝7.8 Hz, 1H, ArH), 8.21 (s, 1H, ArH), 10.02
(bs, 1H, NH), 11.88 (bs, 1H, NH); IR (KBr) ν: 3434—
3362 (OH), 3290 (NH), 1667 (CONH), 1619 (C＝N)
－
＋
1
－
＋
2-({5-[(Naphthalen-2-yloxy)methyl]-4H-1,2,4-
triazol-3yl}sulfanyl)-acetohydrazide (11)
1
cm ; MS m/z (%): 461 (M , 42). Anal. calcd for
C20H23N5O6S: C 52.05, H 5.02, N 15.18; found C 51.94,
H 4.95, N 15.02.
A solution of the ester 10 (3.43 g, 10 mmol) and hy-
drazine hydrate (0.5 g, 10 mmol) was refluxed in abso-
lute ethanol (30 mL) for 8 h. The solution was cooled
and the resulting precipitate was filtered, dried and re-
crystallized from ethanol to give the product as white
solid. Yield 76%, m.p. 202 — 203 ℃ ; 1H NMR
(DMSO-d6, 300 MHz) δ: 4.79 (s, 2H, CH2), 4.94 (s, 2H,
CH2), 5.82 (brs, 2H, NH2), 7.16—7.18 (m, 2H, ArH),
7.47 (d, J＝8.2 Hz, 1H, ArH), 7.49—7.52 (m, 2H, ArH),
O-Acetyl-D-sugar-2-({5-[(naphthalen-2-yloxy)meth-
yl]-4H-1,2,4-triazol-3yl}sulfanyl)acetlhydrazones
(14, 15)
To a solution of the sugar hydrazone 13 or 14 (5
mmol) in pyridine (5 mL) was added acetic anhydride
(3 mL) and the mixture was stirred for 6 h. The resulting
solution was poured onto crushed ice, and the separated
Chin. J. Chem. 2012, 30, 77—83
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79

El-Sayed et al.
FULL PAPER
product was filtered off, washed with potassium hydro-
gen carbonate and water then dried. The products were
recrystallized from ethanol.
2H, CH2), 4.95 (s, 2H, CH2), 5.28 (dd, J＝7.8, 7.2 Hz,
1H, H-3), 5.37 (dd, J＝7.8, 9.8 Hz, 1H, H-2), 5.76 (d,
J＝9.8, 1H, oxadiazoline H-2), 7.18—7.21 (m, 2H,
ArH), 7.44 (d, J＝8.2 Hz, 1H, ArH), 7.57—7.59 (m, 2H,
ArH), 7.64 (d, J＝7.8 Hz, 1H, ArH), 8.18 (s, 1H, ArH);
IR (KBr) ν: 1732 (C＝O), 1664 (C＝O), 1620 (C＝N)
cm ; MS m/z (%): 785 (M , 42). Anal. calcd for
C35H39N5O14S: C 53.50, H 5.00, N 8.91; found C 53.32,
H 4.88, N 8.74.
Penta-O-acetyl-D-mannopentitolyl-2-({4-acetyl-5-
[(naphthalen-2-yloxy)methyl]-4H-1,2,4-triazol-3-yl}-
sulfanyl)acetylhydrazones (14): The product was ob-
tained as brownish powder. Yield 79%, m.p. 90—92 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 1.90 (s, 3H, CH3),
1.95 (s, 3H, CH3), 1.98 (s, 3H, CH3), 2.03 (s, 3H, CH3),
2.05 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.98 (dd, J＝11.2,
2.8 Hz, 1H, H-6), 4.11 (dd, J＝11.2, 3.2 Hz, 1H, H-6'),
4.19—4.21 (m, 1H, H-5), 4.21 (t, J＝7.2 Hz, 1H, H-4),
4.68 (s, 2H, CH2), 4.95 (s, 2H, CH2), 5.22 (dd, J＝7.8,
7.2 Hz, 1H, H-3), 5.26 (dd, J＝7.8, 9.8 Hz, 1H, H-2),
7.21—7.24 (m, 2H, ArH), 7.36 (d, J＝7.6 Hz, 1H, H-1),
7.48 (d, J＝8.2 Hz, 1H, ArH), 7.56—7.58 (m, 2H, ArH),
7.67 (d, J＝7.8 Hz, 1H, ArH), 8.20 (s, 1H, ArH), 10.05
(brs, 1H, NH); IR (KBr) ν: 1737 (C＝O), 1680 (C＝O),
－
＋
1
1-{5-[[4-Acetyl-5-[(naphthalen-2-yloxy)methyl]-4H-
1,2,4-triazol-3-ylthio]-methyl]-2-(tetra-O-acetyl-D-ribo-
tetritolyl)-1,3,4-oxadiazol-3(2H)-yl}ethanone (17): The
product was obtained as brownish powder; 60%, m.p.
1
101—102 ℃; H NMR (DMSO-d6, 300 MHz) δ: 1.96
(s, 3H, CH3), 1.99 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.09
(s, 3H, CH3), 2.23 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.96
(dd, J＝11.2, 2.8 Hz, 1H, H-5), 4.10 (dd, J＝11.2, 3.2
Hz, 1H, H-5'), 4.24—4.26 (m, 1H, H-4), 4.66 (s, 2H,
CH2), 4.98 (s, 2H, CH2), 5.24 (dd, J＝7.8, 7.2 Hz, 1H,
H-3), 5.36 (dd, J＝7.8, 9.8 Hz, 1H, H-2), 5.78 (d, J＝
9.8 Hz, 1H, oxadiazoline H-2), 7.25—7.28 (m, 2H,
ArH), 7.45 (d, J＝8.2 Hz, 1H, ArH), 7.57—7.60 (m, 2H,
ArH), 7.65 (d, J＝7.8 Hz, 1H, ArH), 8.20 (brs, 1H,
ArH); IR (KBr) ν: 1738 (C＝O), 1671 (C＝O), 1618
－
＋
1
1618 (C＝N) cm ; MS m/z (%): 743 (M , 40). Anal.
calcd for C33H37N5O13S: C 53.29, H 5.01, N 9.42; found
C 53.18, H 4.94, N 9.28.
Tetra-O-acetyl-D-ribotetritolyl-2-({4-acetyl-5-[(naph-
thalen-2-yloxy)methyl]-4H-1,2,4-triazol-3yl}sulfanyl)-
acetylhydrazones (15): The product was obtained as
1
－
＋
1
brownish powder. Yield 76%; m.p. 96—97 ℃; H
(C＝N) cm ; MS m/z (%): 713 (M , 29). Anal. calcd
for C32H35N5O12S: C 53.85, H 4.94, N 9.81; found C
53.59, H 4.84, N, 9.77.
NMR (DMSO-d6, 300 MHz) δ: 1.92, 1.98, 2.02, 2.05,
2.25 (5s, 15H, 5CH3), 3.97 (dd, J＝11.2, 2.8 Hz, 1H,
H-5), 4.14 (dd, J＝11.2, 3.2 Hz, 1H, H-5'), 4.24—4.26
(m, 1H, H-4), 4.62 (s, 2H, CH2), 4.94 (s, 2H, CH2), 5.20
(dd, J＝7.8, 7.2 Hz, 1H, H-3), 5.28 (dd, J＝7.8,
Results and Discussion
9.8 Hz, 1H, H-2), 7.24—7.27 (m, 2H, ArH), 7.38 (d,
J＝7.6 Hz, 1H, H-1), 7.45 (d, J＝8.2 Hz, 1H, ArH),
7.58—7.61 (m, 2H, ArH), 7.67 (d, J＝7.8 Hz, 1H, ArH),
8.21 (s, 1H, ArH), 10.14 (brs, 1H, NH); IR (KBr) ν:
1736 (C＝O), 1669 (C＝O), 1614 (C＝N) cm ; MS
m/z (%): 671 (M＋, 39). Anal. calcd for C30H33N5O11S: C
53.65, H 4.95, N 10.43. found: C 53.42, H 4.90, N
10.35.
Reaction of the acetohydrazide derivative 1 with
chlorobenzoic acid in phosphorus oxychloride at reflux
temperature afforded 2,5-disubstituted-1,3,4-oxadiazole
derivative 2 in 85% yield.
－
1
When the hydrazide 1 was reacted with p-nitro-
acetophenone in presence of acetic acid at reflux tem-
perature, it afforded the arylidinacetohydrazide deriva-
tive 3. The IR spectrum of the produced arylidine 3
showed the carbonyl absorption band at 1659 cm－ and
1
1-{5-[[5-[(Naphthalen-2-yloxy)methyl]-4H-1,2,4-tri-
azol-3-ylthio]-methyl]-2-(O-acetylsugar)-1,3,4-oxadi-
azol-3(2H)-yl}ethanone (16, 17)
1
its H NMR spectrum agreed with the assigned struc-
ture.
Treatment of the arylidinehydrazide 3 with acetic
anhydride at reflux temperature afforded the substituted
1,3,4-oxadiazole derivative 4 in 70% yield. The H
NMR spectrum of 4 showed the signals of the methyl
group signals at δ 2.23 and 2.30, each as singlet in addi-
tion to the CH2 at δ 4.89, and the aromatic protons in the
range 7.19—8.22.
A solution of sugar hydrazones 12 or 13 (5 mmol) in
acetic anhydride (5 mL) was heated at 100 ℃ for 2 h.
The resulting solution was poured onto crushed ice, and
the product that separated out was filtered off, washed
with potassium hydrogen carbonate and water then
dried. The products were recrystallized from ethanol.
1-{5-[[4-Acetyl-5-[(naphthalen-2-yloxy)methyl]-4H-
1,2,4-triazol-3-ylthio]-methyl]-2-(penta-O-acetyl-D-
mannopentitolyl)-1,3,4-oxadiazol-3(2H)-yl}ethanone
(16): The product was obtained as brownish powder.
1
When the acetohydrazide 1 was reacted with potas-
sium thiocyanate in acidic medium it afforded the hy-
drazinecarboxylate derivative 5 in 87% yield. Its IR
spectrum showed characteristic absorption bands for the
1
Yield 62%; m.p. 98—99 ℃; H NMR (DMSO-d6, 300
－
1
NH2 and carbonyl groups at 3359 and 1662 cm , re-
spectively. Heating of compound 5 in 4% sodium hy-
droxide solution led to the formation of the substituted
MHz) δ: 1.92 (s, 3H, CH3), 1.98 (s, 3H, CH3), 2.02 (s,
3H, CH3), 2.07 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.23 (s,
3H, CH3), 2.26 (s, 3H, CH3), 3.96 (dd, J＝11.2, 2.8 Hz,
1H, H-6), 4.09 (dd, J＝11.2, 3.2 Hz, 1H, H-6'), 4.17—
4.20 (m, 1H, H-5), 4.22 (t, J＝7.2 Hz, 1H, H-4), 4.64 (s,
1
1,2,4-triazole-3-thiol 6 in 75% yield. Its H NMR spec-
trum showed signals corresponding to NH, and CH2
80
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 77—83

Synthesis and Antimicrobial Activity of New 2,5-Disubstituted 1,3,4-Oxadiazoles
Scheme 1 Synthesis of compounds 2—6
Scheme 2 Synthesis of compounds 7—9
O
N
N
O
H
H
4-Chlorobenzoic acid
O
N
N
O
O
PhNCO
N
Ph
O
R
R
POCl3 / reflux
Cl
1
H
O
EtOH/reflux
2
7
N
CH3
4-nitroacetophenone
N
NaOH/KI
reflux
H
O
O
NH2
3
R
N
NO2
H
N
N
1
Ac2O/reflux
NHPh
O
O
NO2
Ac
N
8
N
EtOH/reflux NH2NH2
CH3
O
O
O
R
R
N
N
4
O
NHPh
O
H
N
KSCN/HCl
reflux
N
NH2
N
H
NH2
9
S
5
sponding sugar hydrazones 12 and 13 were obtained in
65%—70% yields. Their IR spectra showed the pres-
ence of characteristic absorption bands corresponding to
NaOH/reflux
HCl
N
N
R =
－
1
SH
O
the hydroxyl groups in the rang 3462—3431 cm . The
1H NMR spectra showed the signals of the sugar chain
protons at δ 3.35—5.57 and the C-1 methine proton as
doublet in the range δ 7.54—7.57 in addition to the
aromatic protons in the region δ 7.21—8.21. It is well
known that[42-47] reaction of sugar aroylhydrazones with
acetic anhydride could afford different products ac-
cording to the applied reaction conditions. Acetylation
of the sugar hydrazones 12 and 13 with acetic anhydride
in pyridine at room temperature afforded the corre-
sponding per-O-acetyl derivatives 14 and 15. Their
spectral data revealed also that triazole N4-acetylation
had also taken place in addition to acetylation of the
sugar moiety. However, it has been reported[42-48] that
when the reaction was carried out at high temperature in
boiling acetic anhydride, cyclization usually takes place
in addition to per-O-acetylation to afford acyclic
C-nucleoside analogs. We reported previously[38,42] the
synthesis of 1,2,4-triazolo[1,3,4]oxadiazole and N-ace-
tyl-1,3,4-oxadiazoline acyclic nucleoside analogs by the
reaction of hydrazonyl sugars with boiling acetic anhy-
dride. Thus, when the hydrazones 12 and 13 were
heated in acetic anhydride at 100 ℃ they gave the
1,3,4-oxadiazoline acyclic nucleoside analogs 16 and 17,
respectively. The later structures were established on the
basis of their spectral and analytical data which con-
firmed the assigned structures. Their IR spectra showed
absorption bands in the carbonyl frequency region of
1664—1671 cm－1 and 1732—1738 cm－1 corresponding
to the carbonyl amide and the carbonyl ester groups,
respectively, indicating the presence of N-acetyl group
in addition to the O-acetyl groups. The 1H NMR spectra
of 16 and 17 showed the signals of the O-acetyl-methyl
protons each as singlet in the rang δ 1.92—2.12 and the
N
R
H
6
groups in addition to aromatic proton signals (see
experimental part).
When the acetohydrazide 1 was reacted with
phenylisocyanate in ethanol it afforded the phenylhy-
drazine carboxamide derivative 7. Heating of compound
7 in ethanol in presence of sodium hydroxide and iodine
in potassium iodide solution afforded the 2,5-disubsti-
1
tuted-1,3,4-oxadiazole derivative 8. Its H NMR spec-
trum showed the CH2 signal at δ 4.87 in addition to the
aromatic proton signals at 7.18—8.21. Treatment of the
oxadiazole 8 with hydrazine hydrate in ethanol at reflux
temperature afforded N4-amino-1,2,4-triazole derivative
9 in 70% yield. The IR spectrum showed the NH2 ab-
sorption band at 3427 cm－1 and the 1H NMR as well as
MS spectra agreed with the assigned structure (Scheme
2).
When the 1,2,4-triazole-3-thiol (5) was reacted with
ethyl chloroacetate at room temperature, it afforded the
corresponding ethyl ester derivative 10 in 77% yield. Its
IR spectra showed the NH and carbonyl absorption
－
1
bands at 3309 and 1741 cm , respectively. Treatment
of the ester 10 with hydrazine hydrate in ethanol at the
reflux temperature afforded the acetohydrazide 11 in
1
75% yield. The H NMR spectrum of 11 revealed the
disappearance of the ethyl signals present in the ester 10
and instead signals corresponding to the NH and NH2
appeared at δ 5.82 and 9.79.
When the hydrazide 11 was allowed to react with
D-mannose and D-ribose in an aqueous ethanolic solu-
tion and a catalytic amount of acetic acid, the corre-
Chin. J. Chem. 2012, 30, 77—83
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
81

El-Sayed et al.
FULL PAPER
N-acetyl-methyl protons in the range δ 2.23—2.26. The
rest of the sugar chain protons appeared in the region δ
3.96—5.39 in addition to the aromatic protons in the
region δ 7.18—8.20. The low chemical shift (δ 5.76 and
5.78) assigned for the oxadiazoline H-2 (H-1 in the
original sugar chain) proved its N,N-acetal nature rather
than being a C＝N indicating cyclization had taken
place.[42,43,46,47] The chemical shift of H-1 for acetylated
sugar moieties in hydrazonyl sugars was reported to
appear at higher values (δ 7.00—7.35).[43]
The disappearance of the NH signal corresponding
to the N-4 in the triazole ring and presence of a signal
assigned for an N-acetyl methyl group indicated that
N4-acetylation had also taken place in addition to
acetylation of the sugar moiety (Scheme. 3).
that tested compounds did not show high activity
against bacteria under test (Escherichia coli and Bacil-
lus subtilis) while some compounds revealed high activ-
ity against fungi. Compounds 4, 12 and 13 were the
most active against Escherichia coli while 4, 13 and 17
revealed the highest activity against Bacillus subtilis.
Compounds 3, 9, 12 and 17 showed high activity
against the fungus microorganism Aspergillus flavus
while 4, 13 and 17 were the most active among the se-
ries of tested compounds against Candida albicans.
Structure-activity relationship The antimicrobial
activity results and structure-activity relationship indi-
cated that substitution at N-3 and incorporation of
p-nitrophenyl moiety in the 1,3,4-oxadiazole in com-
pound 4 revealed higher activity as the activity was re-
duced in compound 8. Furthermore, the attachment of
acyclic sugar moieties to the substituted hydrazonyl tri-
azole ring system resulted in higher activities.
Additionally, the sugar hydrazones with free hy-
droxyl acyclic sugar moieties showed higher activity
values than the corresponding acetylated analogs. The
methylethylidene derivative with p-nitrophenyl ring
showed high activity against Aspergillus flavus. In addi-
tion, the acyclic nucleoside analog with the acetylated
riptetritolyl moiety attached to the oxadiazoline base
exhibited relatively higher activity than the correspond-
ing mannopentitolyl against Escherichia coli, Asper-
Antimicrobial activity
The synthesized compounds were screened in vitro
for their antimicrobial activities[47] against Escherichia
coli NRRL B-210 (Gram －ve bacteria), Bacillus sub-
tilis NRRL B-543 (Gram ＋ve bacteria), Aspergillus
flavus and Candida albicans NRRL Y-477 (Fungi). The
diameters of zone of inhibition were measured and
compared with that of the standard, and the values were
tabulated. Tetracycline was used as standard for the an-
timicrobial activity and the observed zone of inhibition
is presented in Table 1. The results indicated generally
Scheme 3 Synthesis of compounds 10—17
6
ClCH2COOEt
K2CO3/DMF
r.t.
HN NH2
N
N
NH2NH2
OEt
O
S
N
N
O
R
N
H
EtOH/reflux
O
O
S
O
R
R
N
H
11
R1-CHO/AcOH
EtOH/reflux
10
HN N
R1
HN N
O
N
N
N
Ac2O/pyridine
r.t.
N
O
S
S
O
R2
R
N
N
H
Ac
14,15
12, 13
Ac2O/100 oC
N
N
Ac
N
N
O
S
O
R
N
R2
Ac
16, 17
AcO
AcO
=
HO
HO
OAc
OAc
OAc
OH
OH
OH
R1 =
R2
,
,
R =
OAc
OAc
OH
OH
CH2OAc
CH2OAc
CH2OH
CH2OH
14, 16
15, 17
12
13
82
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 77—83

Synthesis and Antimicrobial Activity of New 2,5-Disubstituted 1,3,4-Oxadiazoles
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15
33
9
17
8
46
—
—
25
8
50
11
13
30
15
11
—
15
20
11
14
30
24
12
11
22
20
Ref.
2
10
12
8
3
4
14
21
—
17
30
—
25
30
27
22
24
28
32
5
10
8
9
11
8
10
8
9
16
—
14
10
18
8
6
7
8
9
10
11
12
13
14
15
16
17
8
10
15
—
8
8
11
15
12
19
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Conclusions
New 2,5-disubstituted-1,3,4-oxadiazole and 1,2,4-
triazole derivatives were synthesized. The derived
acyclic C-nucleoside analogs were also prepared via
cyclization of the corresponding sugar hydrazones. Sub-
stitution at N-3 and incorporation of p-nitrophenyl moi-
ety in the 1,3,4-oxadiazole ring and attachment of free
hydroxyl acyclic sugar moiety to 1,2,4-triazole in-
creased antimicrobial activity.
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Chin. J. Chem. 2012, 30, 77—83
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
83