Synthesis and antimicrobial activity of new tetrazoles incorporating isoindole-1,3-dione moiety and their sugar derivatives

Article abstract of DOI:10.1002/jhet.1119

New tetrazole derivatives linked to isoindole-1,3-dione were prepared starting from the corresponding nitrile derivatives. The substituted hydrazides, their corresponding sugar hydrazones, and the derived acyclic C-nucleoside analogs were also synthesized

Full text of DOI:10.1002/jhet.1119

Month 2013
Synthesis and Antimicrobial Activity of New Tetrazoles Incorporating
Isoindole-1,3-dione Moiety and Their Sugar Derivatives
Adel A.-H. Abdel-Rahman,* Omar M. Ali, and Amira A.-S. Abdel-Megeed
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
*
E-mail: adelnassar63@yahoo.com
Received May 28, 2011
DOI 10.1002/jhet.1119
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
New tetrazole derivatives linked to isoindole-1,3-dione were prepared starting from the corresponding ni-
trile derivatives. The substituted hydrazides, their corresponding sugar hydrazones, and the derived acyclic
C-nucleoside analogs were also synthesized. The antimicrobial results indicated that most of the tested com-
pounds exhibited moderate to high activity, whereas few compounds were found to exhibit little or no activ-
ity against the tested microorganisms.
J Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
stirring with chloroacetonitrile in DMF at room temperature,
respectively, followed by reaction with sodium azide and
ammonium chloride in DMF. The IR spectra revealed the
disappearance of the CN absorption band present in the
nitrile derivatives 2 and 3 and presence of absorption bands
The synthesis of nitrogen-containing heterocyclic com-
pounds has increasingly been a subject of great interest
because of their importance. Heterocyclic compounds
containing isoindole moiety are of interest because they
show some pharmacological and biological activities [1–4].
Isoindole derivatives have been shown to possess antineo-
plastic and antiviral [5], antimalarial [6], antimycobacterium
tuberculosis activity [7], antitumor [8], and antimicrobial
activities [9]. Tetrazole derivatives found wide applications
as carboxylic surrogates, bioisosteres of carboxylic acids
À1
to the NH group in the region 3446–3470cm (Scheme 1).
When tetrazole derivatives 4 and 5 were stirred with
ethyl chloroacetate in DMF in the presence of potassium
carbonate, they afforded the ethyl ester derivatives 6
and 7. The IR spectrum of the latter ester derivatives
showed the presence of characteristic absorption bands
corresponding to the carbonyl groups in the region 1739
[
10,11] and lipophilic spacers in pharmaceuticals resulting in
À1
À1
and 1746 cm
and (C═N) in 1618–1620 cm . Acid
compounds with antihypertensive, antiallergic, and antibiotic
activities [12]. Many tetrazole derivatives endowed
with a pronounced antimicrobial activity and N-substituted
tetrazoles showed interesting antinociceptive activity [13].
On the other hand, the nucleosides as well as their acyclic
and C-nucleoside analogs possess a wide range of medicinal
properties, including antibiotic, antiviral, and antitumor
activities [14–19]. In view of the reported diverse activities
for isoindole and tetrazole structural moieties, especially
antimicrobial activity, and as continuation of our effort
hydraziedes 8 and 9 were obtained by refluxing the
corresponding ester precursors with hydrazine hydrate
in ethanol. The IR spectra of the produced hydrazides
showed the presence of characteristic absorption bands
corresponding to the NH and NH groups in addition to
2
1
the carbonyl and C═N groups. The H NMR spectra
showed the signals of the NH2 and NH protons and
revealed the absence of the ethyl group signals present in
their corresponding esters (see Experimental Section).
When hydrazide derivatives 8 and 9 were allowed to
react with D-galactose and D-xylose in an aqueous
ethanolic solution and a catalytic amount of glacial acetic
acid, the corresponding sugar hydrazones 10–13 were
obtained in 71–73% yields. The reaction of sugar
hydrazones with acetic anhydride is well known to give
products depending on the applied reaction conditions.
The expected products 14–17 in which per-O-acetylation
of the sugar chain hydroxyls were obtained, in 74.5–
86.7% yields, by carrying out the reaction sugar hydra-
zones 10–13 with acetic anhydride in pyridine at room
[
20–24], to identify new candidates that may be of value in
designing new, potent, selective, and less toxic antimicrobial
agent, we report herein the synthesis and antimicrobial
activity of new tetrazoles incorporating isoindole-1,3-dione
moiety.
RESULTS AND DISCUSSION
The key tetrazole compounds 4 and 5 were synthesized
by refluxing phthalamide with acrylonitrile in ethanol or
©
2013 HeteroCorporation

A. A.-H. Abdel-Rahman, O. M. Ali, and A. A.-S. Abdel-Megeed
Vol 0000
Scheme 1
temperature. The IR spectra of the acetylated hydrazones
4–17 showed characteristic absorption bands corresponding
The result revealed that compounds showed varying
degrees of inhibition against the tested microorganisms. In
general, compounds 4, 10, 13, and 21 displayed the highest
activity with MIC value of 75mg/mL at least against two of
the microorganisms under test. Compound 11 displayed the
highest inhibition activity against Sreptomyces species also
with MIC value of 75 mg/mL. Some of the other compounds
revealed moderate activity, whereas others revealed little
or no activity.
The antimicrobial activity results and structure activity
relationship indicated that the attachment of acyclic sugar
moieties to tetrazole ring system linked through alkyl
linkage to isoindole resulted in increase of antimicrobial
activity. Furthermore, the hydrazones incorporating free
hydroxyl sugar chains showed higher activity than the
corresponding acetylated analogs. In addition, the acyclic
C-nucleoside analog with the five carbon sugar xylose
attached to the oxadiazoline base showed high inhibition
activity against B. subtilis and P. aeruginosa. Furthermore,
the length of the alkyl chain, consisting of one or two
carbon atoms, connecting the isoindole and tetrazole
moieties revealed no effect on inhibition activities of tested
compounds as higher activities were not observed for only
one compound type.
1
to the carbonyl ester and carbonyl amide groups in addition
to the NH absorption bands. On the other hand, when the
reaction with acetic anhydride was carried out using
ꢀ
acetic anhydride only at 100 C, the oxadiazoline acyclic
C-nucleoside analogs 18–21 were obtained [25–28]. The
structures of these derivatives were established by analytical
and spectral data that agreed with the assigned structures. The
1
H NMR spectra of the oxadiazoline derivatives 18–21
showed the signals of the O-acetyl-methyl protons as singlets
in the range 1.95–2.19 ppm and the N-acetyl-methyl protons
in the range 2.27–2.29 ppm. The rest of the sugar chain
protons appeared in the range 3.94–5.89 ppm in addition to
aromatic proton signals as multiplet at 7.71–8.04 ppm. The
disappearance of the chemical shift higher than 7.0 ppm for
the H-1 sugar proton (originally present in their sugar
hydrazone precursors) and instead the appearance of the
doublet signal at d 5.85–5.89 ppm indicated the nature of
the C-1 of the original sugar moiety as -O-CH-N-Ac (C-1
in the original sugar chain moiety and C-2 in the oxadiazoline
ring). These spectral characteristics indicated the N,N-acetal
nature of the this carbon rather than being a C═N, which
indicated that cyclization to the oxadiazoline ring has
taken place and also in agreement with the reporting
literature. This relatively higher chemical shift values (higher
than 7.0 ppm) appeared in their acyclic acetylated hydrazone
derivatives (14–17) [Scheme 2].
In conclusion new tetrazole derivatives incorporating
isoindole-1,3-dione moiety and their sugar hydrazones as
well as acyclic C-nucleoside analogs were prepared and
studied for their antimicrobial activity. The attachment of
acyclic free hydroxyl sugar moieties resulted in higher
antimicrobial activities.
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.
EXPERIMENTAL
Melting points were determined with a kofler block apparatus
(
VEB Wägetechnik Rapido, Germany) and are uncorrected. The
IR spectra were recorded on a perkin-Elmer model 1720 FTIR
spectrometer (Perkin-Elmer, USA) for KBr disk. NMR spectra
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1119

Month 2013
Syntesis of New Isoindolyltetrazoles
Scheme 2
1
were recorded on a Varian Gemini 200 NMR Spectrometer
(C═O). H NMR (CDCl ) d: 3.05 (t, 2H, J=5.6Hz, CH ), 4.16
3
2
1
(
Varian, Palo Alto, CA) at 300 MHz for H NMR with TMS as
(t, 2H, J=5.6Hz, CH ), 7.76–8.05 (m, 4H, Ar-H). Anal. calcd. for
2
a standard. Mass spectra were measured on a Kratos 50 TC
spectrometers (Kratos Analyti-cal Instruments, Ramsey, NJ).
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 Center at Faculty of
Science, Cairo University, Egypt.
11 8 2 2
C H N O : C, 66.00; H, 4.03; N, 13.99. Found: C, 65.86; H,
3.96; N, 13.79.
2-(1,3-Dioxoisoindolin-2-yl)acetonitrile (3). To a solution of
phthalimide (1.47 g, 0.01mol) and potassium carbonate (1.40 g,
0.01 mol) in N,N-dimethylformamide (30 mL), monochloroacetonitrile
(0.76 g, 0.01 mol) was added. The reaction mixture was stirred
overnight at room temperature. The mixture was poured onto cold
water, and the precipitate was filtered off as white crystals. Yield:
3-(1,3-Dioxoisoindolin-2-yl)propanenitrile (2). To a solution
of phthalimide (1) (4.41 g, 0.03 mol) in ethanol (50 mL), triethyl
amine (1.01 g, 0.01 mol) and acrilonitrile (1.59 g, 0.03 mol) were
added. The reaction mixture was reflux for 5 h. The precipitate that
ꢀ
1.5 g (87.2%); mp 130–131 C; IR (KBr) υ: 2246 (CꢁN), 1680
1
(C═O); H NMR (CDCl ) d: 4.56 (s, 2H, CH ), 7.76–7.95 (m,
4H, Ar-H); MS (m/z): 187 (M + 1); Anal. calcd. for C10H N O :
6 2 2
3
2
+
separated on cooling was filtered off as white crystals. Yield:
ꢀ
4
.01 g (66.8%); mp 150–151 C; IR (KBr) υ: 2252 (CꢁN), 1672
C, 64.52; H, 3.25; N, 15.05. Found: C, 64.41; H, 3.17; N, 14.86.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1119

A. A.-H. Abdel-Rahman, O. M. Ali, and A. A.-S. Abdel-Megeed
Vol 0000
Table 1
d: 1.25 (t, 3H, J = 4.8 Hz, CH ), 3.01 (t, 2H, J = 5.5 Hz, CH ),
3 2
4
.09 (t, 2H, J = 5.5 Hz, CH ), 4.22 (q, 2H, J = 4.8 Hz, CH ),
Minimum inhibitory concentrations (MIC-mg/mL) of the title compounds.
2
2
Negative control DMSO, no activity.
5.16 (s, 2H, CH
2
), 7.70–7.96 (m, 4H, Ar-H). MS (m/z): 330
: C, 54.71; H, 4.59; N,
+
(
M + 1); Anal. calcd. for C15
H
15
N
5
O
4
Pseudomonas
aeruginosa
Streptomyces
species
21.27. Found: C, 54.49; H, 4.50; N, 21.19.
Ethyl 2-{5-[(1,3-dioxoisoindolin-2-yl)methyl]-2H-tetrazol-2-
yl}acetate (7). Yield: 2.4 g (76%); mp 114–115 C; IR (KBr)
Bacillus subtilis
Compound (Gram positive) (Gram negative) (actinomycetes)
ꢀ
1
υ: 1739 (C═O), 1675 (C═O), 1620 (C═N); H NMR (CDCl
3
)
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
250
250
75
100
250
250
125
125
75
125
250
100
100
500
500
125
250
75
250
a
d: 1.30 (t, 3H, J = 4.6 Hz, CH
), 4.24 (q, 2H, J = 4.6 Hz, CH
), 7.74–7.86 (m, 4H, Ar-H);
MS (m/z): 316 (M + 1); Anal. calcd. for C H N O : C, 53.33;
2
),
3
—
4
.34 (s, 2H, CH ), 5.16 (s, 2H, CH
2
2
75
125
500
—
100
100
100
75
100
75
125
125
—
250
125
100
250
100
34
+
14 13 5 4
H, 4.16; N, 22.21. Found: C, 53.20; H, 4.09; N, 22.11.
General procedure for the preparation of hydrazide
derivatives 8 and 9. To a solution of the respective ester 6
or 7 (0.01 mol) in absolute ethanol (40 mL), hydrazine hydrate
0
1
2
3
4
5
6
7
8
9
0
1
(
1.5 g, 0.03 mol) was added. The reaction mixture was heated
100
125
75
100
125
100
—
250
250
250
250
100
100
75
under reflux for 3 h. The excess of ethanol was removed under
reduced pressure, and the resulting precipitate was filtered off as
gray powder and crystallized from ethanol.
500
250
500
125
125
100
125
75
2
-{5-[2-(1,3-Dioxoisoindolin-2-yl)ethyl]-2H-tetrazol-2-yl}
ꢀ
acetohydrazide (8). Yield: 3.99 g (94.9%); mp burns at 234–235 C;
IR (KBr) υ: 3441, 3276 (NH
2
and NH), 1690 (C═O), 1658 (C═O),
1
1
615 (C═N); H NMR (DMSO-d ) d: 3.04 (t, 2H, J=5.6Hz, CH ),
6
2
4.15 (t, 2H, J=5.6Hz, CH ), 5.32 (s, 2H, CH ), 5.63 (bs, 2H, NH ),
2 2 2
7
.68–7.99 (m, 4H, Ar-H), 9.18 (bs 1H, NH); MS (m/z): 316
+
Penicillin
31
45
(M +1); Anal. calcd. for C13
13 7 3
H N O : C, 49.52; H, 4.16; N, 31.10.
Found: C, 49.31; H, 4.05; N, 30.88.
a
Totally inactive “—” or (MIC > 500 mg/mL).
2
-{5-[(1,3-Dioxoisoindolin-2-yl)methyl]-2H-tetrazol-2-yl}
ꢀ
acetohydrazide (9). Yield: 2.7 g (89.7%); mp burns at 219–220 C; IR
(
KBr) υ: 3435, 3271 (NH and NH), 1691 (C═O), 1653 (C═O), 1608
2
1
(
C═N); H NMR (DMSO-d
CH ), 5.66 (bs, 2H, NH ), 7.71–8.01 (m, 5H, Ar-H), 9.25 (bs, 1H,
NH); MS (m/z): 302 (M + 1); Anal. calcd. For C H N O : C,
6 2
) d: 4.35 (s, 2H, CH ), 5.36 (s, 2H,
General procedure for the preparation of tetrazole derivatives
2
2
+
4
and 5. A solution of nitrile derivative 2 or 3 (0.01 mol), sodium
12 11 7 3
4
7.84; H, 3.68; N, 32.55. Found: C, 47.68; H, 3.60; N, 32.42.
azide (1.95 g, 0.03 mol), and ammonium chloride (0.53 g, 0.01 mol)
in N,N-dimethyformamide (10 mL) was heated at 120 C for 3h.
ꢀ
General procedure for the synthesis of sugar hydrazones
The solvent was removed under reduced pressure; the residue was
dissolved in water (100 mL) and carefully acidified with conc.
hydrochloric acid at pH = 2 in ice bath. The precipitated tetrazole
that separated was filtered off, dried, and recrystallized.
10–13. A solution of the monosaccharide (0.015 mol) in least
amount of water (1 mL) was treated with a solution of hydrazide
(0.01 mol) in ethanol (60 mL) and few drops of glacial acetic
acid. The mixture was heated under reflux for 2 h. The excess of
ethanol was removed under reduced pressure, and the residue
was triturated with (10 mL) diethyl ether to produce compounds
10–13 as brown viscous material.
2
-[2-(2H-Tetrazol-5-yl)ethyl]isoindoline-1,3-dione (4). Yield:
ꢀ
2
3
.17 g (89.3%) as pale yellow powder; mp 196–197 C; IR(KBr) υ:
446 (NH), 1709 (C═O), 1625 (C═N). H NMR (CDCl ) d: 3.01
1
3
(
t, 2H, J=5.5Hz, CH ), 4.19 (t, 2H, J=5.5Hz, CH ), 7.68–8.01
2
2
D-Galactose-2-{5-[2-(3,1-dioxoisoindolin-2-yl)ethyl]-2H-tetrazol-
(
m, 4H, Ar-H), 9.95 (bs, 1H, NH). Anal. calcd. for C11
C, 54.32; H, 3.73; N, 28.79. Found: C, 54.18; H, 3.66; N, 28.59.
-[(2H-Tetrazol-5-yl)methyl]isoindoline-1,3-dione (5). Yield:
9 5 2
H N O :
2
-yl}acetohydrazone (10). Yield: 3.5 g (73.4%). 3442–3292 (OH
1
and NH), 1688 (C═O), 1661 (C═O), 1615 (C═N); H NMR
DMSO-d ) d 3.09 (t, 2H, J=5.5 Hz, CH ), 3.25–3.44 (m, 3H, H-5,
H-6, H-6′), 3.94–4.18 (m, 2H, H-3, H-4), 4.29 (m, 1H, H-2), 4.35
2
(
6
2
ꢀ
.07 g (90.4%) as white powder; mp 226–227 C; IR (KBr) cm : υ
1
À1
2
3
470 (NH), 1707 (C═O), 1624 (C═N). H NMR (CDCl
), 7.66–7.98 (m, 4H, Ar-H), 10.03 (bs, 1H, NH); Anal.
calcd. for C10 : C, 52.40; H, 3.08; N, 30.56. Found:
3
) d: 4.35
(
t, 2H, J=5.5Hz, CH ), 4.42 (bs, 1H, OH), 4.60 (m, 2H, 2xOH),
2
(s, 2H, CH
2
5
.05 (m, 2H, 2xOH), 5.37 (s, 2H, CH ), 7.44 (d, 1H, J=2.5Hz,
2
7 5 2
H N O
H-1), 7.73–7.97 (m, 4H, Ar-H), 11.60 (bs, 1H, NH); MS (m/z): 478
+
C, 52.24; H, 3.02; N, 30.40.
(M
23 7 8
+ 1); Anal. calcd. for C19H N O : C, 47.80; H, 4.86; N,
General procedure for the preparation of ester derivatives
20.54. Found: C, 47.66; H, 4.81; N, 20.38.
6
and 7. A solution of tetrazole derivative 4 or 5 (0.01 mol) and
potassium carbonate (1.38g, 0.01 mol) in N,N-dimethylformamide
30 mL) was stirred for 2 h. Ethyl chloroacetate (1.24 g, 0.01 mol)
D-Xylose2-{5-[2-(3,1-dioxoisoindolin-2-yl)ethyl]-2H-tetrazol-2-
yl}acetohydrazon (11). Yield: 3.3 g (71.6%). 3448–3297
1
(
(OH and NH), 1685 (C═O), 1660 (C═O), 1618 (C═N);
NMR (DMSO-d ) d 3.07 (t, 2H, J = 5.8 Hz, CH
(m, 3H, H-4, H-5, H-5′), 4.14 (m, 1H, H-3), 4.32 (m, 1H, H-2),
4.39 (t, 2H, J = 5.4 Hz, CH ), 4.50 (bs, 2H, 2xOH), 5.20
(m, 2H, 2xOH), 5.42 (s, 2H, CH ), 7.53 (d, 1H, J = 2.5 Hz,
H-1), 7.73–7.97 (m, 4H, Ar-H), 11.50 (bs, 1H, NH); MS
H
was added, and the mixture was stirred overnight. The mixture
was poured on crushed ice. The precipitate was filtered off as
white powder.
6
2
), 3.25–3.51
2
Ethyl 2-{5-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-2H-tetrazol-2-
2
ꢀ
yl}acetate (6). Yield: 2.2 g (66.9%); mp 83–84 C; IR (KBr)
υ: 1746 (C═O), 1680 (C═O), 1618 (C═N); H NMR (CDCl )
1
+
21 7 7
(m/z): 448 (M + 1); Anal. calcd. For C18H N O : C,
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1119

Month 2013
Syntesis of New Isoindolyltetrazoles
4
8.32; H, 4.73; N, 21.91. Found: C, 48.19; H, 4.64;
N, 21.79.
D-Galactose-2-{5-[(1,3-dioxoisoindolin-2-yl)methyl]-2H-tetrazol-
-yl}acetohydrazone (12). Yield: 3.5 g (75.5%); IR (KBr)
υ: 3393 (OH), 3209 (NH), 1665 (C═O), 1608 (C═N); %).
2,3,4,5-Tetra-O-acetyl-D-(+)-xylose-{2-[(1,3-dioxoisoindolin-2-
yl)methyl]-2H-tetrazol-2-yl}acetylhydrazone (17). Yield: 4.55 g
(75%). IR (KBr) υ: 3411 (NH), 1732 (C═O), 1664 (C═O), 1626
1
2
(C═N); H NMR (DMSO-d
5xCH
6
) d 1.97, 2.04, 2.12, 2.15 (5s, 15H,
), 4.52 (m, 1H,
), 4.72 (m, 1H, H-4), 5.21 (m, 1H, H-3),
3 2
CO), 4.12 (m, 2H, H-6,6′), 4.36 (s, 2H, CH
H-5), 5.44 (s, 2H, CH
1
H NMR (DMSO-d
6
) d 3.25–3.92 (m, 3H, H-5, H-6, H-6′),
2
4
.11–4.15 (m, 1H, H-3,4), 4.32 (s, 2H, CH ), 4.42 (m, 1H,
5.47 (dd, J = 6.4 Hz, J = 8.8 Hz, 1H, H-2), 7.45 (d, 1H, J = 9.2 Hz,
2
H-2), 4.48 (bs, 1H, OH), 4.62 (m, 2H, 2xOH), 5.03 (m, 2H,
H-1), 7.75–7.99 (m, 4H, Ar-H), 11.25 (bs, 1H, NH); MS (m/z):
+
2
7
4
4
xOH), 5.34 (s, 2H, CH
2
), 7.45 (d, 1H, J = 2.5 Hz, H-1),
27 7
602 (M + 1); Anal. calcd. for C25H N O11: C, 49.92; H, 4.52; N,
.70–7.98 (m, 4H, Ar-H), 11.58 (bs, 1H, NH); MS (m/z):
16.30. Found: C, 49.77; H, 4.37; N, 16.19.
+
21 7 8
64 (M + 1); Anal. calcd. for C18H N O : C, 46.65; H,
General procedure for the synthesis oxadiazolin derivatives
.57; N, 21.16. Found: C, 46.51; H, 4.51; N, 21.02.
1
8–21. A solution of sugar hydrazone 10–13 (0.01 mol) in acetic
D-Xylose-2-{5-[(1,3-dioxoisoindolin-2-yl)methyl]-2H-tetrazol-2-yl}
ꢀ
anhydride (30 mL) was heated at 100 C for 3 h. The mixture was
cooled and poured on crushed ice and separated from chloroform
extract in pure form as brown viscous material.
acetohydrazone (13). Yield: 3 g (69%); IR (KBr) υ: 3398 (OH),
1
3
200 (NH), 1661 (C═O), 1612 (C═N); %). H NMR (DMSO-d )
6
d 3.20–3.74 (m, 3H, H-4, H-5, H-5′), 4.12 (m, 1H, H-3), 4.35
s, 2H, CH ), 4.45 (m, 1H, H-2), 4.65 (m, 2H, 2xOH), 5.15 (m, 2H,
4
-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-galactopentitolyl)-5-{2-
(1,3-dioxoisoindolin-2-yl)ethyl)-2H-tetrazol-2-yl)methyl]-2,3-
dihydro}-1,3,4-oxadiazoline (18). Yield: 6.3 g (86.4%); IR
(
2
[
2
xOH), 5.35 (s, 2H, CH ), 7.457 (d, 1H, J= 2.5 Hz, H-1),
2
7
.75–7.99 (m, 4H, Ar-H), 11.18 (bs, 1H, NH); MS (m/z): 434
1
(
(
6
KBr): n 1730 (C = O), 1683 (C = O), 1620 (C = N); H NMR
CDCl ): d 1.95, 1.96, 2.01, 2.10, 2.19, 2.28 (6s, 18H,
xCH CO), 3.02 (t, 2H, J = 4.4 Hz, CH ), 3.98 (m, H, H-5),
+
(M +1); Anal. calcd. for C H N O : C, 47.11; H, 4.42; N, 22.62.
17 19 7 7
3
Found: C, 46.92; H, 4.38; N, 22.50.
3
2
General procedure for the synthesis of O-acetylated sugar
hydrazones 14–17. To a solution of sugar hydrazones 10–13
4.05 (dd, H, J = 2.8 Hz, J = 11.2 Hz, H-5′), 4.21 (t, 2H, J = 4.5
Hz, CH ), 4.86 (m, 1H, H-4), 5.16 (m, 1H, H-3), 5.20 (t, 1H,
J = 7.4 Hz, H-2), 5.30 (s, 2H, CH ), 5.37 (dd, 1H, J = 8.8, 7.4
2
(
0.01 mol) in pyridine (15 mL), acetic anhydride (3.06 g,
2
0
.03 mol) was added. The reaction mixture was stirred for 5 h.
Hz, H-1′), 5.89 (d, 1H, J = 8.8 Hz, oxadiazoline H-5), 7.70-8.01
(m, 4H, Ar-H); MS (m/z): 730 (M + 1); Anal. calcd. for
C H N O14: C, 51.03; H, 4.83; N, 13.44. Found: C, 50.80; H,
31 35 7
4.76; N, 13.32.
4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-D-xylotetritolyl)-5-{2-[(1,3-
dioxoisoindolin-2-yl)ethyl)-2H-tetrazol-2-yl)methyl]-2,3-dihydro}-
+
The mixture was cooled and poured on crushed ice; add
hydrochloric acid with stirring until the odor of pyridine was
removed and extracted by chloroform. The product was
separated in pure form as brown viscous material.
2
,3,4,5,6-Penta-O-acetyl-D-(+)-galactose-{2-[(1,3-dioxoisoindolin-
-yl)ethyl]-2H-tetrazol-2-yl}acetylhydrazone (14). Yield: 5.1 g
74.2%); IR (KBr) υ: 3423 (NH), 1737 (C═O), 1660 (C═N);
2
(
1,3,4-oxadiazoline (19). Yield: 4.9 g (74.5%); IR (KBr): n 1733
1
(C═O), 1680 (C═O), 1618 (C═N); H NMR (CDCl
3
): d 1.97,
1
H NMR (DMSO-d ) d 1.95, 2.02, 2.10, 2.13, 2.16 (5s, 15H,
1.99, 2.03, 2.17, 2.29 (5s, 15H, 5xCH CO), 3.05 (t, 2H,
6
3
5
xCH CO), 3.04 (t, 2H, J=4.8Hz, CH ), 4.09 (m, 2H, H-6,6′), 4.20
J=4.4Hz, CH ), 3.97 (m, 1H, H-4), 4.03 (dd, H, J=2.8Hz,
3
2
2
(
t, 2H, J=4.8Hz, CH
2
), 4.50 (m, 1H, H-5), 4.71 (m, 1H, H-4), 5.18
J= 11.2 Hz, H-4′), 4.24 (t, 2H, J=4.5Hz, CH
H-3), 5.18 (t, 1H, J= 7.4 Hz, H-2), 5.32 (s, 2H, CH
2
), 5.15 (m, 1H,
), 5.39 (dd,
(dd, 1H, J=6.8Hz, J= 9.4 Hz, H-3), 5.40 (s, 2H, CH
2
), 5.48 (t, 1H,
2
J= 9.8 Hz, H-2), 7.46 (d, 1H, J= 9.8 Hz, H-1), 7.74–8.00 (m, 4H,
Ar-H), 11.30 (bs, 1H, NH); MS (m/z): 688 (M +1); Anal. calcd.
1H, J= 8.8, 7.4 Hz, H-1), 5.87 (d, 1H, J= 8.8 Hz, oxadiazoline
H-5), 7.73–7.99 (m, 4H, Ar-H); MS (m/z): 658 (M +1); Anal.
+
+
for C H N O : C, 50.66; H, 4.84; N, 14.26. Found: C, 50.49;
calcd. for C H N O : C, 51.14; H, 4.75; N, 14.91. Found: C,
29
33
7
13
28 31 7 12
H, 4.79; N, 14.14.
,3,4,5-Tetra-O-acetyl-D-(+)-xylose-{2-[(1,3-dioxoisoindolin-2-
yl)ethyl]-2H-tetrazol-2-yl}acetylhydrazone (15). Yield: 4.3 g
50.92; H, 4.68; N, 14.81.
2
4-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-galactopentitolyl)-5-{2-
[(1,3-dioxoisoindolin-2-yl)methyl)-2H-tetrazol-2-yl)methyl]-2,3-
dihydro}-1,3,4-oxadiazoline (20). Yield: 6.5 g (78.3%); IR
À1
À1
(
71.5%); IR (KBr) n 1525 cm
(C═N), 1750 cm
(C═O),
À1
1
1
3
439cm (NH); H NMR (DMSO-d6) d: 1.95, 2.03, 2.11, 2.15
(KBr): n 1734 (C═O), 1683 (C═O), 1621 (C═N); H NMR
(
4s, 12H, 4xCH CO), 3.06 (t, 2H, J = 4.0 Hz, CH ), 4.17 (m, 2H,
(CDCl ): d 1.96, 1.97, 2.06, 2.12, 2.18, 2.27 (6s, 18H,
3
2
3
H-5,5′), 4.29 (t, 2H, J = 4.1 Hz, CH ), 4.39 (m, 1H, H-4), 5.38
6xCH CO), 3.98 (m, 1H, H-5), 4.07 (dd, H, J = 2.8 Hz,
2
3
(
s, 2H, CH
2
), 5.74 (m, 1H, H-3), 5.88 (dd, 1H, J = 6.8 Hz,
J = 11.8 Hz, H-5′), 4.33 (s, 2H, CH
(m, 1H, H-3), 5.14 (t, 1H, J = 7.6 Hz, H-2), 5.32 (s, 2H, CH
2
), 4.93 (m, 1H, H-4), 5.09
),
J = 9.2 Hz, H-2), 7.42 (d, 1H, J = 9.2 Hz, H-1), 7.72–8.02 (m, 4H,
Ar-H), 10.69 (bs, 1H, NH).; MS (m/z): 616 (M + 1); Anal. calcd.
for C H N O : C, 50.73; H, 4.75; N, 15.93. Found: C, 50.50;
2
+
5.37 (dd, 1H, J = 7.4 Hz, 8.6 Hz, H-1), 5.86 (d, 1H, J = 8.6 Hz,
oxadiazoline H-5), 7.69–8.03 (m, 4H, Ar-H); MS (m/z): 716
26 29 7 11
+
H, 4.70; N, 15.76.
,3,4,5,6-Penta-O-acetyl-D-(+)-galactose-{2-[(1,3-dioxoisoindolin-
-yl)methyl]-2H-tetrazol-2-yl}acetylhydrazone (16). Yield: 4.75 g
70.5%). IR (KBr) υ: 3411 (NH), 1722 (C═O), 1662 (C═O), 1627
(M + 1); Anal. calcd. for C H N O : C, 50.35; H, 4.65; N,
3
0 33 7 14
2
13.70. Found: C, 50.01; H, 4.57 N, 13.49.
4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-D-xylotetritolyl)-5-{2-[(1,3-
dioxoisoindolin-2-yl)methyl)-2H-tetrazol-2-yl)methyl]-2,3-
dihydro}-1,3,4-oxadiazoline (21).Yield: 5.2 g (80.8%); IR (KBr):
n 1739 (C═O), 1672 (C═O), 1618 (C═N); H NMR (CDCl
2
(
1
(
1
1
C═N); H NMR (DMSO-d
5H, 5xCH CO), 4.10 (m, 2H, H-6,6′), 4.37 (s, 2H, CH
H, H-5), 5.42 (s, 2H, CH ), 4.69 (m, 1H, H-4), 5.17 (m, 1H, H-3),
6
) d 1.96, 2.04, 2.11, 2.14, 2.17 (5s,
1
3
2
), 4.51 (m,
3
):
d 1.95, 1.96, 2.11, 2.15, 2.28 (5s, 15H, 5xCH CO), 3.94 (m, 1H,
2
3
5
.45 (dd, J=6.4Hz, J= 8.8 Hz, 1H, H-2), 7.42 (d, 1H, J=9.2Hz,
H-1), 7.72-8.01 (m, 4H, Ar-H), 11.27 (bs, 1H, NH); MS (m/z): 674
H-4), 4.07 (dd, H, J = 2.8 Hz, J = 11.6Hz, H-4′), 4.39 (s, 2H,
CH
2
), 5.02 (m, 1H, H-3), 5.12 (t, 1H, J = 7.6 Hz, H-2), 5.39
), 5.35 (dd, 1H, J = 7.4 Hz, 8.6 Hz, H-1), 5.85 (d, 1H,
+
(M +1), Anal. calcd. for C28
H
31
N
7
O
13: C, 49.93; H, 4.64; N, 14.56.
(s, 2H, CH
2
Found: C, 49.71; H, 4.58; N, 14.38.
J = 8.6Hz, oxadiazoline H-5), 7.71–8.04 (m, 4H, Ar-H); MS
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1119

A. A.-H. Abdel-Rahman, O. M. Ali, and A. A.-S. Abdel-Megeed
Vol 0000
+
(
4
m/z): 644 (M + 1); Anal. calcd. for C H N O : C, 50.39; H,
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S. S.; Bdzhola, V. G.; Yarmoluk, S. M. Biochim Biophys Acta (BBA) –
Proteins Proteomics 2008, 1784, 143.
2
7 29 7 12
.54; N, 15.24. Found: C, 50.22; H, 4.41; N, 15.08.
Antimicrobial activity. The synthesized compounds were
[6] Gomes, P.; Araujo, M. J.; Rodrigues, M.; Vale, N.; Azevedo, Z.;
tested for their antimicrobial activity against three microorganisms,
and the minimal inhibitory concentrations (MICs) of the tested
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Sample preparation. Each of the test compounds and
standards was dissolved in 12.5% DMSO at concentrations of
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Awad, A. R. Bioorg Med Chem 2008, 16, 9708.
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5
00 mg/mL. Further dilutions of the compounds and standards
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4 h at 37 C. The medium was molten on a water bath, incubated
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Agar diffusion technique. Antibacterial activities were tested
using MH medium (17.5 g case in hydrolysate, 1.5 g soluble
starch, 1000 mL beef extract). A stock solution of each synthesized
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in sterilized liquid MH medium. Different concentrations of the
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[
[
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ꢀ
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[
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[
[
[
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[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1119