Synthesis and biological activity of 5-nitrofuran-containing (1,3,4-thiadiazol-2-yl)piperazine moieties as a new type of anti-Helicobacter pylori heterocycles

Article abstract of DOI:10.2298/JSC100324013M

In order to find new and potent drug candidates for the treatment of Helicobacter pylori infections, in this study attention was focused on the synthesis and anti-H. pylori activity of a series of 5-(5-nitrofuran-2-yl)-1,3, 4-thiadiazoles containing piperazinyl functionality at the C-2 position of the 1,3,4-thiadiazole ring. The synthesis of 1-[5-(5-nitrofuran-2-yl)-1,3,4- thiadiazol-2-yl]piperazine derivatives 3a-h and pyrrolidine derivative 3i was achieved with a versatile and efficient synthetic route via 2-chloro-5-(5- nitrofuran-2-yl)-1,3,4-thiadiazole. The inhibitory activity of the new derivatives 3a-i against twenty clinical H. pylori strains was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole. Resulting biological data indicated that most compounds exhibited strong inhibitory activity even at doses lower than 2 μg/disc (average zone of inhibition >20 mm) while metronidazole had little or no growth inhibition at this dose. Compound 3c containing the N-benzoylpiperazin-1- yl moiety showed the most potent inhibitory activity.

Full text of DOI:10.2298/JSC100324013M

J. Serb. Chem. Soc. 76 (2) 201–210 (2011)
JSCS–4112
UDC 547.722+546.17:542.913+547.78+
547.861.3:579.8
Original scientific paper
Synthesis and biological activity of 5-nitrofuran-containing
(1,3,4-thiadiazol-2-yl)piperazine moieties as a new type of
anti-Helicobacter pylori heterocycles
MOHAMMAD HASSAN MOSHAFI1, AZADEH YAHYA-MEYMANDI2, SEYED
ESMAEIL SADAT-EBRAHIMI2, SAEED EMAMI3, MARYAM NAKHJIRI2, FARIDEH
SIAVOSHI4, MARYAM OMRANI4, MOHSEN VOSOOGHI2, ESKANDAR ALIPOUR5,
2
2
*
ABBAS SHAFIEE and ALIREZA FOROUMADI
1Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Kerman University of
Medical Sciences, Kerman, 2Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran,
3Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty
of Pharmacy, Mazandaran University of Medical Sciences, Sari, 4Microbiology Department,
Faculty of Sciences, University of Tehran, Tehran and 5Department of Chemistry, Islamic
Azad University, Tehran-North Branch, Zafar St., Tehran, Iran
(Received 24 March, revised 18 October 2010)
Abstract: In order to find new and potent drug candidates for the treatment of
Helicobacter pylori infections‚ in this study attention was focused on the syn-
thesis and anti-H. pylori activity of a series of 5-(5-nitrofuran-2-yl)-1,3,4-thia-
diazoles containing piperazinyl functionality at the C-2 position of the 1,3,4-
-thiadiazole ring. The synthesis of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-
-yl]piperazine derivatives 3a–h and pyrrolidine derivative 3i was achieved with
a versatile and efficient synthetic route via 2-chloro-5-(5-nitrofuran-2-yl)-1,3,4-
-thiadiazole. The inhibitory activity of the new derivatives 3a–i against twenty
clinical H. pylori strains was evaluated by the disc diffusion method and com-
pared with the commercially available standard drug metronidazole. Resulting
biological data indicated that most compounds exhibited strong inhibitory acti-
vity even at doses lower than 2 μg/disc (average zone of inhibition >20 mm)
while metronidazole had little or no growth inhibition at this dose. Compound
3c containing the N-benzoylpiperazin-1-yl moiety showed the most potent inhi-
bitory activity.
Keywords: synthesis; 1,3,4-thiadiazole; 5-nitrofuran; antibacterial activity; He-
licobacter pylori.
*Corresponding author. E-mail: aforoumadi@yahoo.com
doi: 10.2298/JSC100324013M
201
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MOSHAFI et al.
INTRODUCTION
Helicobacter pylori is considered the major causative bacterium responsible
in gastric ulcer, and other gastro-duodenal inflammatory symptoms and com-
1
plications. Eradication of these pathogens leads to a significant reduction of
gastric ulcers, which may also lead to the prevention of mucosa associated lym-
2
phoid tissue (MALT) malignancies. Several regimens are arranged under dual,
triple and quadruple therapy aiming at higher treatment and eradication rates. The
most effective treatment regimens include a combination of antibiotics (beta-
-lactams, macrolides and quinolones), bactericidal agents (bismuth salts) and anti-
3,4
protozoal agents (metronidazole). The most significant risk factor in the treat-
5
ment protocols are the emergence of resistant strains. The pattern of local pre-
valence of antimicrobial resistant strains varies in different regions of the world.
There are reports on the activity of furazolidone (a nitrofuran analog) on H. py-
lori strains resistant to metronidazole (a nitroimidazole analog) in Iran and neigh-
6
boring countries. Thus, the search for new types of nitroheterocyclic com-
pounds, including nitrofurans, is an attractive therapeutic target to find new and
potent drug candidates for the treatment of H. pylori infections.
Recently‚ as part of an ongoing research program to find new and potent
drug candidates for the treatment of H. pylori infection‚ attention was focused on
the synthesis and anti-H. pylori activity of a series of 5-(nitroaryl)-1,3,4-thia-
7–11
diazoles.
With this point of view and the potent biological activity of 2-(5-
-nitrofuran-2-yl)-1,3,4-thiadiazoles, the synthetic strategy is now focused on the
introduction of a cyclic amine functionality at the C-2 position of the 1,3,4-thia-
diazole ring. Accordingly, it was decided to synthesize and evaluate a series of
1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine derivatives.
RESULTS AND DISCUSSION
Chemistry
The synthesis of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine
derivatives 3a–h and the pyrrolidine derivative 3i was achieved employing a
versatile and efficient synthetic route via 2-chloro-5-(5-nitrofuran-2-yl)-1,3,4-
-thiadiazole (2) (Scheme 1). The intermediate 2 was prepared from commercially
available 5-nitrofurfurylidene diacetate (1) according to previously described
12,13
methods.
Nucleophilic substitution of the chloro- compound 2 with (un)sub-
stituted piperazines in refluxing ethanol afforded compounds 3a and 3d–h in
good yields. Similarly, the reaction of compound 2 with pyrrolidine in refluxing
ethanol yielded compound 3i. N-Acetylation of the unsubstituted piperazine
derivative 3a with acetic anhydride produced compounds 3b. Reaction of pipe-
razine derivative 3a with benzoyl chloride in benzene/pyridine afforded the N-
benzoyl piperazine derivative 3c.
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SYNTHESIS AND ANTI-H. pylori ACTIVITY OF NITROFURANS
203
Scheme 1. Synthesis of compounds 3a–i. a) Ref. 11: i) thiosemicarbazide, EtOH, reflux, 1h;
ii) NH4Fe(SO4)2⋅12H2O, H2O, reflux, 16 h; iii) NaNO2, HCl, Cu, 0 °C→r.t, 3 h; b) piperazine,
EtOH, reflux, 3h; c) substituted piperazine or pyrrolidine, EtOH, reflux, 2–3 h; d) acetic
anhydride, acetic acid, reflux, 20 min, r.t, 12 h; or benzoyl chloride, benzene, pyridine, 24 h.
Analytic and spectral characterization
1
The structures of compounds 3a–i were confirmed using IR, H-NMR and
mass spectrometry.
1-[5-(5-Nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3a). Yield: 73 %;
m.p.: 214–216 °C; Anal. Calcd. for C H N O S: C, 42.70; H, 3.94; N, 24.90 %.
10 11
5 3
–1
Found: C, 42.77; H, 3.80; N, 25.06 %. IR (KBr, cm ): 3431 (N–H), 1551 and
1
1347 (NO ). H-NMR (80 MHz. CDCl , δ / ppm): 7.85 (1H, d, 4-H furan, J =
2
3
= 4.0 Hz), 7.42 (1H, d, 3-H furan, J = 4.0 Hz), 3.82–3.30 (5H, m, 2CH and NH
2
+
piperazine), 3.19–2.99 (4H, m, piperazine). MS (m/z, %): 281 (M , 10), 225 (10),
82 (18), 69 (71), 67 (100).
1-Acetyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3b). Yield:
66 %; m.p.: 221–223 °C; Anal. Calcd. for C H N O S: C, 44.58; H, 4.05; N,
12 13
5 4
–1
21.66 %. Found: C, 44.55; H, 3.88; N, 21.53 %. IR (KBr, cm ): 1664 (C=O),
1
1556 and 1352 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.41 (1H, d, 4-H
2
3
furan, J = 4.0 Hz), 7.2 (1H, d, 3-H furan, J = 4.0 Hz), 3.95–3.45 (8H, m,
+
piperazine), 2.17 (3H, s, CH ). MS (m/z, %): 323 (M , 10), 165 (12), 239 (12),
3
110 (19), 100 (23), 237 (25), 224 (35), 53 (100).
1-Benzoyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3c). Yield:
63 %, m.p.: 225–227 °C; Anal. Calcd. for C H N O S: C, 52.98; H, 3.92; N,
17 15
5 4
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MOSHAFI et al.
–1
18.17 %. Found: C, 53.08; H, 3.90; N, 18.11 %. IR (KBr, cm ): 1639 (C=O),
1
1555 and 1362 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.42 (1H, d, 4-H
2
3
furan, J = 4.0 Hz), 7.24 (1H, d, 3-H furan, J = 4.0 Hz), 7.30–7.10 (5H, m,
+
phenyl), 3.95–3.65 (8H, m, piperazine). MS (m/z, %): 385 (M , 5), 236 (10), 148
(10), 166 (20), 77 (63), 105 (100).
1-Methyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3d). Yield:
46 %; m.p.: 199–202 °C; Anal. Calcd. for C H N O S: C, 44.74; H, 4.44; N,
11 13
5 3
–1
23.71 %. Found: C, 44.80; H, 4.27; N, 23.70 %. IR (KBr, cm ): 1551 and 1352
(NO ). H-NMR (80 MHz, CDCl ,) δ / ppm): 7.45 (1H, d, 4-H furan, J = 4.0 Hz),
1
2
3
7.15 (1H, d, 3-H furan, J = 4.0 Hz), 3.80–3.55 (4H, m, piperazine), 2.65–2.48
+
(4H, m, piperazine), 2.35 (3H, s, N–Me piperazine). MS (m/z, %): 295 (M , 10),
83 (42), 68 (100).
1-[5-(5-Nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]-4-phenylpiperazine (3e). Yield:
42 %; m.p.: 202–205 °C (dec); Anal. Calcd. for C H N O S: C, 53.77; H,
16 15
5 3
–1
4.23; N, 19.60 %. Found: C, 53.94; H, 4.26; N, 19.44 %. IR (KBr, cm ): 1555
and 1357 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.45 (1H, d, 4-H furan,
1
2
3
J = 4.0 Hz), 7.4–7.2 (5H, m, phenyl), 6.98 (1H, d, 3-H furan, J = 4.0 Hz), 3.94–
+
–3.73 (4H, m, piperazine), 3.45–3.29 (4H, m, piperazine). MS (m/z, %): 357 (M ,
8), 77 (6), 161 (9), 143 (22), 102 (60), 132 (100).
3-Methyl-1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3f). Yield:
52 %; m.p.: 124–125 °C; Anal. Calcd. for C H N O S: C, 44.74; H, 4.44; N,
11 13
5 3
–1
23.71 %. Found: C, 44.67; H, 4.30; N, 23.64 %. IR (KBr, cm ): 3421 (N–H),
1
1556 and 1349 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.42 (1H, d, 4-H
2
3
furan, J = 4.0 Hz), 7.15 (1H, d, 3-H furan, J = 4.0 Hz), 4.05–3.75 (5H, m, 2CH
2
and NH piperazine), 3.28–2.85 (3H, m, CH and CH piperazine), 1.16 (3H, d,
2
13
CH , J = 5.8 Hz). C-NMR (125 MHz, CDCl , δ / ppm): 19.3, 45.1, 50.1, 50.5,
57.2, 124.7, 128.8, 140.5, 149.5, 151.6, 172.6. MS (m/z, %): 295 (M , 8), 83
(22), 70 (100).
3
3
+
3,5-Dimethyl-1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3g).
Yield: 30 %; m.p.: 126–129 °C; Anal. Calcd. for C H N O S: C, 46.59; H,
12 15
5 3
–1
4.89; N, 22.64 %. Found: C, 46.60; H, 5.03; N, 22.71 %. IR (KBr, cm ): 3431
1
(N–H), 1549 and 1347 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.40 (1H, d,
2
3
4-H furan, J = 4.0 Hz), 7.47 (1H, d, 3-H furan, J = 4.0 Hz), 4.05–3.75 (2H, m,
2CH piperazine), 3.15–2.75 (5H, m, 2CH and NH piperazine), 1.16 (6H, d,
2
13
2CH , J = 5.8 Hz,). C-NMR (125 MHz, CDCl , δ / ppm): 19.2, 50.2, 56.6,
102.3, 113.8, 145.5, 148.5, 153.1, 172.8. MS (m/z, %): 309 (M , 7), 252 (7), 223
(7), 130 (8), 95 (15), 84 (42), 81 (90) ,70 (100).
3
3
+
1-Benzyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3h). Yield:
50 %; m.p.: 151–154 °C (dec); Anal. Calcd. for C H N O S: C, 54.97; H,
17 17
5 3
–1
4.61; N, 18.86 %. Found: C, 55.04; H, 4.69; N, 18.72 %. IR (KBr, cm ): 1547
and 1352 (NO ). H-NMR (80 MHz, CDCl , δ / ppm): 7.44 (1H, d, 4-H furan,
1
2
3
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SYNTHESIS AND ANTI-H. pylori ACTIVITY OF NITROFURANS
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J = 4.0 Hz), 7.40–7.20 (5H, m, phenyl), 7.14 (1H, d, 3-H furan, J = 4.0 Hz),
13
3.80–3.49 (6H, m, piperazine and CH –Ph), 2.75–2.40 (4H, m, piperazine). C-
2
-NMR (125 MHz, CDCl , δ / ppm): 50.1, 51.9, 62.8, 124.8, 127.4, 128.4, 128.7,
3
+
129.1, 137.3, 140.4, 149.7, 151.6, 172.4. MS (m/z, %): 371 (M , 8), 166 (8), 159
(20), 132 (20), 55 (24), 146 (70), 89 (80), 91 (100).
2-(5-Nitrofuran-2-yl)-5-pyrrolidin-1-yl-1,3,4-thiadiazole (3i). Yield: 58 %;
m.p.: 247–249 °C; Anal. Calcd. for C H N O S: C, 45.11; H, 3.79; N, 21.04
10 10
4 3
–1
%. Found: C, 45.50; H, 3.61; N, 21.00 %. IR (KBr, cm ): 1541 and 1349 (NO );
H-NMR (80 MHz, , δ / ppm): 7.40 (1H, d, 4-H furan, J = 4.0 Hz), 7.15 (1H, d,
2
1
3-H furan, J = 4.0 Hz), 3.88–3.38 (4H, m, pyrrolidine), 2.35–1.93 (4H, m, pyrro-
13
lidine). C-NMR (125 MHz, CDCl , δ / ppm): 25.7, 51.1, 109.9, 113.9, 144.5,
3
+
148.9, 153.1, 169.1. MS (m/z, %): 266 (M , 50), 147 (6), 132 (15), 237 (15), 114
(30), 192 (39), 100 (39), 70 (100).
Anti-Helicobacter pylori activity
The growth inhibitory activity of the nitrofuran derivatives 3a–i against H.
14,15
pylori was evaluated using the paper disc diffusion method.
The diameters of
the inhibition zone of title compounds were compared with the commercially
available antibacterial metronidazole. Different doses of the compounds were
loaded on standard discs (6 mm diameter), which were then placed on a Muller–
–Hinton agar plate, previously inoculated with bacterial suspension. After incu-
bation for 3–5 days at 37 °C, the inhibition zone around each disc was recorded.
All tests were performed in triplicate and the antibacterial activity is given as the
mean of inhibition diameters (mm) produced by the title compounds. The com-
pounds 3a–i were initially evaluated against three H. pylori strains at a high dose
of 32 μg/disc and the results are summarized in Table I. Generally, the anti-
bacterial activity of compounds can be classified as follows: strong response,
zone diameter >20 mm; moderate response, zone diameter 16–20 mm; weak
response, zone diameter 11–15 mm; and little or no response, zone diameter <10
mm. The results given in Table I revealed that all the synthesized nitrofuran ana-
logs 3a–i, exhibited strong antimicrobial activity against H. pylori strains at a do-
se of 32 μg/disc (inhibition zone diameter >20 mm).
Due to the strong inhibitory activity of compounds 3a–i at 32 μg/disc, all
compounds were further tested at the doses lower than 32 μg/disc against a
broader panel of H. pylori strains (twenty clinical isolates). The antibacterial acti-
vities of the target compounds at doses of 16, 8, 4, 2, 1, 0.5 and 0.25 μg/disc
against 20 clinical isolates of H. pylori are given in Table II as the average dia-
meters of the inhibition zones.
The inhibition zone diameters of compounds at different doses indicate that
all compounds exhibit higher inhibitory activity against the clinical isolates of H.
pylori compared to the standard drug, metronidazole. The inhibition zone dia-
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MOSHAFI et al.
meters of all compounds were on average more than 20 mm at 8 μg/disc, which
is greater than that of metronidazole. Compounds 3a–d showed strong growth
inhibitory activity at doses of 4 and 2 μg/disc, while metronidazole had very
weak activity at these doses. The N-benzoylpiperazine derivative 3c had strong
activity even at 0.5 μg/disc (inhibition zone = 20 mm). The inhibition zone dia-
meters at the lowest dose (0.25 μg/disc), indicated that the N-acetyl and N-ben-
zoyl compounds (3b and 3c, respectively) still had a weak growth inhibition
while the remaining compounds showed little or no activity at this dose.
TABLE I. In vitro antibacterial activity of compounds 3a–i at 32 μg/disc against H. pylori
using the disc diffusion method
N N
O2N
R
O
S
Compound
3a
R
Inhibition zone diametera, mm (range)
50 (44–60)
N
NH
O
3b
3c
45.3 (45–48)
42.6 (44–47)
N
N
CH3
O
N
N
Ph
3d
3e
3f
48.6 (47–51)
23 (19–33)
42 (42–44)
N
N
CH3
N
N
Ph
CH3
N
NH
CH3
3g
41 (40–46)
N
NH
CH3
3h
28 (25–31)
46 (46–48)
N
N
Ph
3i
N
a
The anti-Helicobacter pylori activity was determined by the paper disc diffusion bioassay. All tests were per-
formed in triplicate and the antibacterial activity is expressed as the mean of the inhibition diameters produced
by the title compounds
The comparison of inhibition zone diameters produced by title compounds
revealed that substitution of piperazine moiety by N-phenyl, N-benzyl, 3-methyl
and 3,5-dimethyl diminished the inhibitory activity against clinical isolates of H.
pylori. In contrast, N-benzoylation of the piperazine ring increased the anti-H.
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SYNTHESIS AND ANTI-H. pylori ACTIVITY OF NITROFURANS
207
pylori activity. In addition, the introduction of N-methyl or N-acetyl groups on
the piperazine ring did not improve the antibacterial activity against H. pylori.
TABLE II. Inhibition zone diameters of compounds 3a–i at different doses against 20 clinical
H. pylori isolates. Antibacterial activities are expressed as the mean of inhibition zone dia-
meters (mm). Range of inhibition zone diameters against 20 clinical H. pylori isolates are
given in parenthesis
Concentration, μg/disc
Compound
0.25
7.9
0.5
12.6
1
2
4
8
16
3a
17.9
23.8
29. 6
33. 6
43.5
(6–10)
11.8
(6–19)
15.1
(6–20)
8.2
(6–11)
6.5
(6–9)
6
(6–15)
16.7
(6–22)
20.1
(11–30) (14–40) (17–50) (21–57) (28-60)
19.7 23.1 29.7 34.8 40.4
(14–30) (15–50) (15–60) (20–60) (24–60)
24.1 28.8 35.2 41.2 49.1
3b
3c
(11–30) (14–30) (11–43) (18–49) (20–55) (34–60)
3d
14.8
(6–20)
7.6
(6–10)
7.1
18.1
22.9
28.2
34.1
40.6
(10–28) (14–38) (15–60) (21–60) (30–60)
3e
12.3
(6–16)
8.5
(6–10)
12.7
17.3
18.4
21.4
23.9
(10–30) (11–40) (12–40) (15–41)
3f
13.0
(6–20)
17.8
19.3
(8–30)
20.7
23.1
(12–37) (18–50)
20.5 21.5
30.8
(6)
6
(6–10)
8.4
3g
(6)
7.7
(6–9)
6.7
(6–15)
11.1
(6–17)
8.5
(6–16)
15.2
(8–20)
13.2
(15–22) (15–25) (15–25) (18–25)
3h
19.8
(6–28)
19.9
22.6
(10–26) (15–30) (18–30)
25.3 33.3 38.1
23.5
24.8
3i
(6–9)
6
(6–12)
6
(6–17)
9.2
(12–26) (18–33) (24–39) (26–49)
Metronidazole
13.1
16.0
19.8
24.1
(4–21)
(6–19)
(8–26)
(11–27) (17–32)
EXPERIMENTAL
The purity of the synthesized compounds was confirmed by thin layer chromatography
(TLC) using various solvents of different polarities. Merck silica gel 60 F254 plates were ap-
plied for the analytical TLC. Melting points were measured using a Kofler hot-stage apparatus
and are uncorrected. The IR spectra were obtained on a Shimadzu 470 (Shimadzu, Tokyo, Ja-
pan) spectrophotometer (potassium bromide disks). Nuclear magnetic resonance spectra were
determined in CDCl3 containing TMS as an internal standard using Bruker 80 or 500 spectro-
meters. The mass spectra were recorded on a Finnigan MAT TSQ-70 spectrometer at 70 eV.
Elemental analyses were realized on a CHN-O-rapid elemental analyzer (Heraeus GmbH, Ha-
nau, Germany) for C, H and N, and the results were within ±0.4 % of the theoretical values.
All reagents were purchased from Merck and Aldrich and used as such without purification.
The solvents employed in the reactions were previously distilled.
General procedure for the synthesis of 1-[5-(5-nitrofuran-2-yl)-1,3,4 thiadiazol-2-yl]pipera-
zine derivatives
To a mixture of 2-chloro-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (2, 231 mg, 1.0 mmol)
in ethanol (15 ml), appropriate substituted piperazine (1.0 mmol) was added and refluxed for 3 h.
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MOSHAFI et al.
The completion of reaction was monitored by TLC. After cooling, the separated solid was fil-
tered off and re-crystallized from ethanol.
Synthesis of 1-acetyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3b)
Acetic anhydride (3 ml) was added to a mixture of 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadia-
zol-2-yl]piperazine (3a, 280 mg, 1.0 mmol) in acetic acid (12.5 ml) and refluxed for 20 min.
The mixture was stirred at room temperature overnight and then poured in to ice-water. The
yellow precipitate was separated and washed with water and crystallized from ethanol to give
pure compound 3b.
Synthesis of 1-benzoyl-4-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine (3c)
Benzoyl chloride (70.5 mg, 0.5 mmol) was added under stirring to a suspension of 1-[5-
-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl] piperazine (3a, 140 mg, 0.5 mmol) in benzene (1 ml)
and pyridine (0.5 ml) at 0–5 °C and then, the reaction mixture was stirred at room temperature
for 24 h. After evaporation of solvents under reduced pressure, the residue was washed with
water and crystallized from ethanol to give compound 3c.
Synthesis of 2-(5-nitrofuran-2-yl)-5-pyrrolidin-1-yl-1,3,4-thiadiazole (3i)
A mixture of 2-chloro-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (2, 231 mg, 1.0 mmol) and
pyrrolidine (70 mg, 1.0 mmol) in ethanol (10 ml) was refluxed for 1 h. After completion of the
reaction, the orange precipitate was filtered and crystallized from ethanol.
CONCLUSIONS
In this study, attention was focused on the synthesis and anti-Helicobacter
pylori activity of a series of 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazoles containing a
piperazinyl functionality at the C-2 position of the 1,3,4-thiadiazole ring. The
synthesis of the 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperazine deriva-
tives 3a–h and the pyrrolidine derivative 3i was achieved using a versatile and
efficient synthetic route via 2-chloro-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole.
Based on the resulting biological data, compound 3c containing the N-benzoyl-
piperazin-1-yl moiety showed the most potent inhibitory activity against H.
pylori strains. The potent activity and straightforward synthesis of these nitro-
furans suggest that they are potential candidates for the development of new anti-
H. pylori agents.
Acknowledgments. This work was supported by grants from the Research Council of
Tehran University of Medical Sciences and the Iran National Science Foundation (INSF).
Available online at www.shd.org.rs/JSCS/
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2011 Copyright (CC) SCS

SYNTHESIS AND ANTI-H. pylori ACTIVITY OF NITROFURANS
209
И З В О Д
СИНТЕЗА И БИОЛОШКА АКТИВНОСТ 5-НИТРОФУРАНА, КОЈИ САДРЖЕ
(1,3,4-ТИАДИАЗОЛ-2-ИЛ)ПИПЕРАЗИНСКУ СТРУКТУРУ, КАО НОВИ ТИП
АНТИ-Helicobacter pylori ХЕТЕРОЦИКЛА
MOHAMMAD HASSAN MOSHAFI1, AZADEH YAHYA-MEYMANDI2, SEYED ESMAEIL SADAT-EBRAHIMI2,
SAEED EMAMI3, MARYAM NAKHJIRI2, FARIDEH SIAVOSHI4, MARYAM OMRANI4, MOHSEN VOSOOGHI2,
ESKANDAR ALIPOUR5, ABBAS SHAFIEE2 и ALIREZA FOROUMADI2
1Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Kerman University of Medical Sciences,
Kerman, 2Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran, 3Department of Medicinal Chemistry and Pharma-
ceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari,
4Microbiology Department, Faculty of Sciences, University of Tehran, Tehran и 5Department of Chemistry,
Islamic Azad University, Tehran-North Branch, Zafar St., Tehran, Iran
У циљу проналажења новог ефикасног лека за лечење од инфекција изазваних Helico-
bacter pylori нашу пажњу усмерили смо према синтези и испитивању анти-H. pylori актив-
ности серије 5-(5-нитрофуран-2-ил)-1,3,4-тиадиазола који садрже пиперазинилни структурни
фрагмент у положају C-2 1,3,4-тиjадиазолског прстена. Синтеза деривата 1-[5-(5-нитрофу-
ран-2-ил)-1,3,4-тиадиазол-2-ил]пиперазина 3a–h и пиролидинског деривата 3i постигнута је
преко интермедијера 2-хлор-5-(5-нитрофуран-2-ил)-1,3,4-тиадиазола. Користећи диск-дифуз-
иону методу испитана је инхибиторна активност нових деривата 3a–i према двадесет клини-
чких сојева H. pylori и извршено је поређење добијених резултата са резултатима активности
метронидазола, комерцијалног стандарда. Добијени резултати показују да већина једињења
показује јаку инхибиторну активност чак и при дозама мањим од 2 μg/диск (просечна зона
инхибиције је >20 mm), док метронидазол показује малу инхибицију или потпуно одсуство
инхибиције при истим дозама. Највећу инхибицију показује једињење 3c које садржи N-
бензоилпиперазин-1-ил фрагмент.
(Примљено 24. марта, ревидирано 18. октобра 2010)
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