Synthesis and anti-Helicobacter pylori activity of 4-(coumarin-3-yl) thiazol-2-ylhydrazone derivatives

Article abstract of DOI:10.1002/jhet.464

A novel class of coumarin-thiazole conjugated systems (1-31) were synthesized by Hantzsch condensation between α-bromo-3-acetyl coumarin and several thiosemicarbazone intermediates. This scaffold was also evaluated for selective antibacterial activity against 20 isolates of H. pylori clinical strains, including four metronidazole resistant ones.

Full text of DOI:10.1002/jhet.464

November 2010
Synthesis and Anti-Helicobacter pylori Activity of
4-(Coumarin-3-yl)thiazol-2-ylhydrazone Derivatives
1269
Franco Chimenti,a Bruna Bizzarri,a* Adriana Bolasco,a Daniela Secci,a
Paola Chimenti,a Arianna Granese,a Simone Carradori,a Melissa D’Ascenzio,a
M. Maddalena Scaltrito,b and Francesca Sistob
aDipartimento di Chimica e Tecnologie del Farmaco, University ‘‘La Sapienza,’’ P.le A. Moro 5,
00185 Rome, Italy
b
` `
Dipartimento di Sanita Pubblica-Microbiologia-Virologia, Universita degli Studi di Milano,
via Pascal 36, 20133 Milan, Italy
*E-mail: bruna.bizzarri@uniroma1.it
Received January 13, 2010
DOI 10.1002/jhet.464
Published online 20 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A novel class of coumarin-thiazole conjugated systems (1–31) were synthesized by Hantzsch conden-
sation between a-bromo-3-acetyl coumarin and several thiosemicarbazone intermediates. This scaffold
was also evaluated for selective antibacterial activity against 20 isolates of H. pylori clinical strains,
including four metronidazole resistant ones.
J. Heterocyclic Chem., 47, 1269 (2010).
INTRODUCTION
anti-H. pylori agents [6], we have pointed out that the
coumarin ring might play an important role in determin-
ing activity and seemed to be crucial for the selective
antimicrobial activity of such compounds. Recently, we
have synthesized and chemically and biologically char-
acterized some new conjugated coumarin-thiazole sys-
tems, which were endowed with interesting industrial
properties and especially antimicrobial activity on H.
pylori clinical strains [7].
Furthermore, interest in these structures has renewed
due to the recent discovery of their promising antibacte-
rial, antifungal, and antimycobacterial activity [8–11].
Moving from these indications, in this report we
described the synthesis and selective antimicrobial evalu-
ation of a new series of 4-(coumarin-3-yl)thiazol-2-ylhy-
drazone derivatives which differ for the electronic and
steric characteristics on the hydrazone nitrogen (aliphatic
chains, cycloaliphatic moiety, and heterocyclic rings).
Helicobacter pylori are spiral-shaped Gram-negative
bacteria with polar flagella that live near the surface of
the human gastric mucosa. They have evolved specific
mechanisms to avoid the bactericidal acid environment
in the gastric lumen to survive near, to attach to, and to
communicate with the human gastric epithelium and host
immune system. This interaction sometimes results in
severe gastric pathology. In fact, H. pylori infection is
indeed the most known risk factor for the development
of gastroduodenal ulcers, gastric adenocarcinoma, and
gastric mucosa-associated lymphoid tissue lymphoma.
H. pylori infections are difficult to cure and success-
ful treatment generally requires the simultaneous som-
ministration of several antibacterial agents. Antibiotic
resistance has resulted in unsatisfactory eradication
with dual and now triple therapy in many countries.
Newer antibiotics and changes in dosing and duration
of therapy may overcome resistant strains but may only
provide limited improvement in eradication rates [1–3].
In our previous works [4,5] and from the analysis of
the structure of natural coumarins reported as potent
RESULTS AND DISCUSSION
The coumarin-thiazole derivatives (1–30) were pre-
pared in high yields (69–99%) according to a protocol
C
V
2010 HeteroCorporation

1270
F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese,
S. Carradori, M. D’Ascenzio, M. Maddalena Scaltrito, and F. Sisto
Vol 47
1600 cmꢀ1 due to the presence of a d-lactone C¼¼O and
C¼¼N group, respectively.
1
give rise to isomeric geometry E/Z. The H NMR (in
Table 1
Structure of derivatives 1–31.
Moreover, the presence of a C¼¼N double bond can
Comp
R
R1
CDCl3) spectra analysis revealed that the E isomer was
more favored and stable than the Z-configuration. The
amounts of both conformers were measured by area
integration of the signal relative to the CH3 (R1) protons
(area ratio of proton signals E:Z was generally 6:1). The
low-field signal was assigned to the E isomer, as it is
widely accepted in thiosemicarbazone derivatives [17].
Our choice, as reaction medium, of a polar alcoholic
solvent appeared to be preferred to obtain the E-configu-
ration and limit the interconversion according to the
results of our previous theoretical and chromatographic
study for similar compounds [18].
1 [ref. 12]
2
3
4
5
6
7
8
9
10
CH3
CH2CH3
CH3
CH3
CH(CH3)2
(CH2)2CH3
CH3
CH3
CH2CH3
(CH2)2CH¼CH2
CH2CH3
CH3
CH3
(CH2)4CH3
(CH2)3CH3
(CH2)5CH3
CH2CH3
CH3
2-CH3-Cyclopentyliden
3-CH3-Cyclopentyliden
Cyclooctyliden
Cyclohexyl
Fur-2-yl
Fur-2-yl
Tiophen-2-yl
Tiophen-2-yl
Phenyl
11
12
13
14[ref. 11]
15
16
17
18[ref. 13]
19
20
21
22
23
24
25[ref. 14]
26
27
28[ref. 15]
29
30
CH3
H
CH3
H
Then, all compounds were evaluated, as mixture of E/
Z conformers, against 20 clinical strains of H. pylori,
which are more resistant to conventional therapy. Metro-
nidazole was used as standard antibacterial drug (Table
2).
CH3
CH3
CH3
H
CH3
H
CH3
H
H
Pyridin-2-yl
Pyridin-3-yl
Pyridin-3-yl
Pyridin-4-yl
Pyridin-4-yl
1H-indol-3-yl
3,4-Methylendioxophenyl
Naphtalen-1-yl
Naphtalen-2-yl
Coumarin-3-yl
2-COOH-9H-fluoren-5-yliden
Thiazol-2-yl
H
Most of the assayed compounds showed no anti-H.
pylori activity or comparable activity with respect to
Metronidazole (MIC ꢁ 16 lg/mL). Only some com-
pounds (14, 21, and 26), bearing a specific heterocyclic
ring (furan, pyridine, and naphthalene) on the hydrazone
nitrogen, possessed MIC values slightly inferior to the
reference drug (MIC ¼ 8 lg/mL) against some clinical
H. pylori strains. Unfortunately, it was not possible to
correlate this biological activity with lipophilicity
(ClogP).
H
CH3
CH3
CH3
H
31[ref. 16]
used in our laboratory (Table 1). Different carbonyl
compounds reacted directly with thiosemicarbazide in
ethanol with catalytic amounts of acetic acid, and the
obtained thiosemicarbazones were subsequently con-
verted into 4-(coumarin-3-yl)-2-thiazolylhydrazones by
reaction with a-bromo-3-acetyl coumarin in the same
solvent at room temperature (Hantzsch condensation). a-
Bromo-3-acetyl coumarin has been synthesized by direct
halogenation of 3-acetyl coumarin with bromine in chlo-
roform. Moreover, knowing that all reported structures
possess an imine bond, which could be hydrolyzed in
the acidic environment of the stomach (reproduced in
the biological assay), we also synthesized and assayed
their common intermediate (31) by direct reaction
between thiosemicabazide and a-bromo-3-acetyl couma-
rin in ethanol at room temperature.
EXPERIMENTAL
The chemicals, solvents for synthesis and spectral grade sol-
vents were purchased from Aldrich (Italy) and used without
further purification. Melting points are uncorrected and were
determined automatically on an FP62 apparatus (Mettler-Tol-
1
edo). H NMR spectra were recorded at 400 MHz on a Bruker
spectrometer. Chemical shifts are expressed as d units (parts
per millions) relative to the solvent peak. Coupling constants J
are valued in Hertz (Hz). IR spectra were registered on a Per-
kin Elmer FTIR Spectrometer Spectrum 1000 in KBr. Elemen-
tal analysis for C, H, and N were recorded on a Perkin-Elmer
240 B microanalyzer and the analytical results were within
60.4% of the theoretical values for all compounds. All reac-
tions were monitored by TLC performed on 0.2-mm-thick
silica gel plates (60 F254 Merck). Lipophilicity parameter,
ClogP, has been calculated for each molecule by using Chem-
Draw ultra 8.0. The synthesis of some compounds has been
described in previous references (Table 1) and was performed
with slight changes. Their analytical and spectral data were in
full agreement with those reported in the literature.
All synthesized products were purified with petroleum
ether and diethyl ether and, if requested, by chromatog-
raphy before characterization by spectroscopic methods
(IR and 1H NMR) and elemental analysis. The com-
pounds, correctly analyzed for their molecular formula,
showed in the IR spectrum strong bands at 1710 and
Typical
synthesis. The appropriate carbonylic compound (50 mmol)
procedure
for
the
thiosemicarbazones
was dissolved in 100 mL of ethanol and stirred vigorously at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis and Anti-Helicobacter pylori Activity of
4-(Coumarin-3-yl)thiazol-2-ylhydrazone Derivatives
1271
1
Table 2
173ꢂC; H NMR (CDCl3): d 0.95–0.97 (d, J ¼ 6.6 Hz, 6H, 2
ꢃ CH3), 1.98–2.11 (m, J ¼ 6.6 Hz, 1H, CH), 2.17 (s, 3H,
CH3), 7.35–7.38 (m, J7-6 ¼ J7-8 ¼ 7.3 Hz, J7-5 ¼ 1.8 Hz, 1H,
C7H-chrom.), 7.39–7.41 (dd, J5-6 ¼ 7.3 Hz, J5-7 ¼ 1.8 Hz, 1H,
C5H-chrom.), 7.61–7.65 (m, J6-5 ¼ J6-7 ¼ 7.3 Hz, J6-8 ¼ 1.8
Hz, 1H, C6H-chrom.), 7.79–7.82 (dd, J8-7 ¼ 7.3 Hz, J8-6 ¼ 1.9
Hz, 1H, C8H-chrom.), 7.84 (s, 1H, C5H-thiaz.), 8.54 (s, 1H,
C4H-chrom.), 12.00 (br s, 1H, NH, D2O exch.); Anal. Calcd.
for C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83. Found: C,
62.41; H, 5.24; N, 12.82.
MIC values (lg/mL) of derivatives 1–31 and M (metronidazole)
against 20 H. pylori strains.
Metronidazole sensitive Metronidazole resistant
strains (4 strains)
Compound
strains (16 strains)
1
2
3
4
5
6
7
8
9
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
8–ꢁ16
ꢁ16
>16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
8–ꢁ16
ꢁ16
ꢁ16
>16
ꢁ16
8–ꢁ16
ꢁ16
>16
ꢁ16
>16
ꢁ16
0.5–16
>16
>16
>16
>16
>16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
>16
8–ꢁ16
ꢁ16
ꢁ16
ꢁ16
>16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
ꢁ16
>16
>16
>16
>16
>16
3-(2-(2-(2-Pentanylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
men-2-one (4). Orange crystals, 82% yield, mp 186–187ꢂC;
1H NMR (CDCl3): d 0.97–1.03 (t, J ¼ 7.4 Hz, 3H, CH3),
1.59–1.65 (m, J ¼ 7.4 Hz, J ¼ 5.6 Hz, 2H, CH2), 2.18 (s, 3H,
CH3), 2.33–2.38 (t, J ¼ 5.6 Hz, 2H, CH2), 7.34–7.37 (m, J7-6
¼ J7-8 ¼ 7.6 Hz, J7-5 ¼ 2.1 Hz, 1H, C7H-chrom.), 7.62–7.65
(dd, J5-6 ¼ 7.6 Hz, J5-7 ¼ 2.2 Hz, 1H, C5H-chrom.), 7.68–7.75
(m, J6-5 ¼ J6-7 ¼ 7.7 Hz, J6-8 ¼ 2.1 Hz, 1H, C6H-chrom.),
7.77–7.81 (dd, J8-7 ¼ 7.8 Hz, J8-6 ¼ 2.1 Hz, 1H, C8H-chrom.),
7.85 (s, 1H, C5H-thiaz.), 8.62 (s, 1H, C4H-chrom.), 11.90 (br
s, 1H, NH, D2O exch.); Anal. Calcd. for C17H17N3O2S: C,
62.36; H, 5.23; N, 12.83. Found: C, 62.39; H, 5.22; N, 12.83.
3-(2-(2-(3-Pentanylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
men-2-one (5). Yellow crystals, 82% yield, mp 180–183ꢂC;
1H NMR (CDCl3): d 1.16–1.19 (t, J ¼ 7.3 Hz, 6H, 2 ꢃ CH3),
2.40–2.46 (m, 4H, 2 ꢃ CH2), 7.35–7.37 (m, J7-6 ¼ J7-8 ¼ 6.8
Hz, J7-5 ¼ 1.4 Hz, 1H, C7H-chrom.), 7.38–7.41 (dd, J5-6 ¼ 6.8
Hz, J5-7 ¼ 1.4 Hz, 1H, C5H-chrom.), 7.59–7.63 (m, J6-5 ¼ J6-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
M
¼ 6.8 Hz, J6-8 ¼ 1.4 Hz, 1H, C6H-chrom.), 7.78–7.80 (dd, J8-
7
¼ 6.8 Hz, J8-6 ¼ 1.4 Hz, 1H, C8H-chrom.), 7.84 (s, 1H,
7
C5H-thiaz.), 8.61 (s, 1H, C4H-chrom.), 12.01 (br s, 1H, NH,
D2O exch.); Anal. Calcd. for C17H17N3O2S: C, 62.36; H, 5.23;
N, 12.83. Found: C, 62.38; H, 5.24; N, 12.82.
3-(2-(2-(5-Hexen-2-ylidene)hydrazynyl)thiazol-4-yl)-2H-
chromen-2-one (6). Light yellow crystals, 73% yield, mp
1
195–197ꢂC; H NMR (CDCl3): d 2.19 (s, 3H, CH3), 2.38–2.45
(t, J ¼ 6.5 Hz, 2H, CH2), 2.48–2.53 (m, J ¼ 6.5 Hz, J ¼ 7.2
Hz, 2H, CH2), 5.05–5.08 (dd, Jcis ¼ 8.8 Hz, Jgem ¼ 1.7 Hz,
1H, CH¼¼), 5.09–5.13 (dd, Jtrans ¼ 17.7 Hz, Jgem ¼ 1.7 Hz,
1H, CH¼¼), 5.78–5.85 (m, Jcis ¼ 8.8 Hz, Jtrans ¼ 17.8 Hz, J ¼
room temperature with an equimolar amount of thiosemicarba-
zide for 24 h with catalytic amount of acetic acid. The desired
thiosemicarbazone precipitated from reaction mixture was fil-
tered and crystallized from suitable solvent and dried.
Typical procedure for the Hantzsch protocol for the
preparation of derivatives 1–30. Equimolar amounts of the
prepared thiosemicarbazones (50 mmol) and freshly synthe-
sized 3-a-bromo-acetyl coumarin (50 mmol), both dissolved in
ethanol, were reacted at room temperature under magnetic stir-
ring for 4 h. The precipitate was filtered and dried to give
compounds 1–30 in 69–99% yield.
7.2 Hz 1H, CH¼¼), 7.36–7.40 (m, J7-6 ¼ J7-8 ¼ 7.5, J7-5
¼
1.5, 1H, C7H-chrom.), 7.41–7.43 (dd, J5-6 ¼ 7.5, J5-7 ¼ 1.5,
1H, C5H-chrom.), 7.62–7.64 (m, J6-5 ¼ J6-7 ¼ 7.5, J6-8 ¼ 1.4,
1H, C6H-chrom.), 7.79–7.81 (dd, J8-7 ¼ 7.6, J8-6 ¼ 1.4, 1H,
C8H-chrom.), 7.86 (s, 1H, C5H-thiaz.), 8.61 (s, 1H, C4H-
chrom.), 12.00 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C18H17N3O2S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.75;
H, 5.04; N, 12.38.
3-(2-(2-(2-Heptanylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
men-2-one (7). Yellow crystals, 99% yield, mp 198–201ꢂC;
1H NMR (DMSO-d6): d 0.93–0.95 (m, 3H, CH3), 1.22–1.30
(m, 2H, CH2), 1.32–1.38 (m, 2H, CH2), 1.55–1.61 (m, 2H,
CH2), 2.18 (s, 3H, CH3), 2.36–2.40 (m, 2H, CH2), 7.37–7.39
(m, J7-6 ¼ J7-8 ¼ 7.1 Hz, J7-5 ¼ 3.7 Hz, 1H, C7H-chrom.),
7.40–7.42 (dd, J5-6 ¼ 7.16, J5-7 ¼ 3.8, 1H, C5H-chrom.),
7.61–7.66 (m, J6-5 ¼ J6-7 ¼ 7.2 Hz, J6-8 ¼ 3.8 Hz, 1H, C6H-
chrom.), 7.79–7.81 (dd, J8-7 ¼ 7.1, J8-6 ¼ 3.7, 1H, C8H-
chrom.), 7.84 (s, 1H, C5H-thiaz.), 8.61 (s, 1H, C4H-chrom.),
12.06 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C19H21N3O2S: C, 64.20; H, 5.95; N, 11.82. Found: C, 64.15;
H, 5.93; N, 11.84.
3-(2-(2-Butylidenehydrazynyl)thiazol-4-yl)-2H-chromen-2-
1
one (2). Light brown crystals, 96% yield, mp 205–210ꢂC; H
NMR (CDCl3): d 1.15–1.18 (t, 3H, J ¼ 7.2, CH3), 2.20 (s, 3H,
CH3), 2.42–2.47 (q, 2H, J ¼ 7.2, CH2), 7.35–7.39 (m, 1H, J7-6
¼ J7-8 ¼ 7.8 Hz, J7-5 ¼ 2.3 Hz, C7H-chrom), 7.41–7.43 (dd,
1H, J5-6 ¼7.9, J5-7 ¼ 2.4 Hz, C5H-chrom), 7.62–7.65 (m, 1H,
J6-5 ¼ J6-7 ¼ 7.8 Hz, J6-8 ¼ 2.3 Hz, C6H-chrom), 7.68 (s, 1H,
C5H-thiaz.), 7.77–7.83 (dd, 1H, J8-7 ¼ 7.8 Hz, J8-6 ¼ 2.2 Hz,
C8H-chrom.), 10.75 (bs, 1H, NH, D2O exch.); Anal. Calcd. for
C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found: C, 60.13;
H, 4.37; N, 14.06.
3-(2-(2-(3-Methyl-2-butylidene)hydrazynyl)thiazol-4-yl)-2H-
chromen-2-one (3). Yellow crystals, 99% yield, mp 170–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1272
F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese,
S. Carradori, M. D’Ascenzio, M. Maddalena Scaltrito, and F. Sisto
Vol 47
3-(2-(2-(3-Heptanylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
3-(2-(2-(1-(Cyclohexyl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (13). Yellow crystals, 69% yield, mp
men-2-one (8). Yellow crystals, 77% yield, mp 175–180ꢂC;
1H NMR (CDCl3): d 0.95–0.98 (m, 3H, CH3), 1.13–1.19 (m,
2H, CH2), 1.34–1.40 (m, 2H, CH2), 1.55–1.62 (m, 3H, CH3),
2.39–2.42 (m, 2H, CH2), 2.45–2.51 (m, 2H, CH2), 7.36–7.38
(m, 1H, C7H-chrom.), 7.39–7.41 (m, 1H, C5H-chrom.), 7.60–
7.64 (m, 1H, C6H-chrom.), 7.79–7.82 (m, 1H, C8H-chrom.),
7.83 (s, 1H, C5H-thiaz.), 8.61 (s, 1H, C4H-chrom.), 12.14 (br
s, 1H, NH, D2O exch.); Anal. Calcd. for C19H21N3O2S: C,
64.20; H, 5.95; N, 11.82. Found: C, 64.25; H, 5.95; N,
11.81.
1
195–200ꢂC; H NMR (DMSO-d6): d 1.48–1.52 (m, 2H, cyclo-
hexyl), 1.75–1.79 (m, 4H, cyclohexyl), 2.41–2.45 (m, 4H,
cyclohexyl), 7.37–7.41 (m, J7-6 ¼ J7-8 ¼ 7.5 Hz, J7-5 ¼ 1.8
Hz, 1H, C7H-chrom.), 7.41–7.43 (dd, J5-6 ¼ 7.6, J5-7 ¼ 1.9,
1H, C5H-chrom.), 7.53–7.57 (m, J6-5 ¼ J6-7 ¼ 7.5 Hz, J6-8
1.8 Hz, 1H, C6H-chrom.), 7.68–7.70 (dd, J8-7 ¼ 7.9, J8-6
¼
¼
1.7, 1H, C8H-chrom.), 7.85 (s, 1H, C5H-thiaz.), 8.54 (s, 1H,
C4H-chrom.), 11.75 (br s, 1H, NH, D2O exch.); Anal. Calcd.
for C20H21N3O2S: C, 65.37; H, 5.76; N, 11.44. Found: C,
65.33; H, 5.77; N, 11.45.
3-(2-(2-(2-Octanylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
men-2-one (9). Yellow crystals, 74% yield, mp 149–150ꢂC;
1H NMR (DMSO-d6): d 0.84–0.88 (m, 3H, CH3), 1.25–1.32
(m, 6H, 3 ꢃ CH2), 1.47–1.51 (m, 2H, CH2), 1.88–1.91 (m,
3H, CH3), 2.19–2.23 (m, 2H, CH2), 7.37–7.39 (m, 1H, C7H-
chrom.), 7.42–7.44 (m 1H, C5H-chrom.), 7.60–7.64 (m, C6H-
chrom.), 7.68 (s, 1H, C5H-thiaz.), 7.77–7.80 (m, 1H, C8H-
chrom.), 8.53 (s, 1H, C4H-chrom.), 10.71 (br s, 1H, NH, D2O
exch.); Anal. Calcd. for C20H23N3O2S: C, 65.01; H, 6.27; N,
11.37. Found: C, 65.06; H, 6.28; N, 11.35.
3-(2-(2-(2-Methylcyclopentylidene)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (10). Yellow crystals, 79% yield, mp 143–
145ꢂC; 1H NMR (CDCl3): d 1.21–1.23 (m, 3H, CH3), 1.31–
1.39 (m, 1H, cyclopentyl), 1.71–1.77 (m, 1H, cyclopentyl),
1.95–2.02 (m, 1H, cyclopentyl), 2.05–2.12 (m, 1H, cyclopen-
tyl), 2.25–2.33 (m, 1H, cyclopentyl), 2.37–2.46 (m, 1H, cyclo-
3-(2-(2-(1-(Furan-2-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (15). Light green crystals, 77% yield, mp
1
218–220ꢂC; H NMR (DMSO-d6): d 2.25 (s, 3H, CH3), 6.57–
6.58 (d, J3-4 ¼ 1.7 Hz, 1H, C3H-furan), 6.84–6.86 (dd, J4-5
¼
3.3 Hz, J4-3 ¼ 1.7 Hz, 1H, C4H-furan), 7.37–7.41 (m, J7-6
¼
J7-8 ¼ 7.6 Hz, J7-5 ¼ 2.9 Hz, 1H, C7H-chrom.), 7.44–7.47 (dd,
J5-6 ¼ 7.6 Hz, J5-7 ¼ 2.6 Hz, 1H, C5H-chrom.), 7.61–7.63 (m,
J6-5 ¼ J6-7 ¼ 7.2 Hz, J6-8 ¼ 2.9 Hz, 1H, C6H-chrom.), 7.73–
7.75 (d, J5-4 ¼ 3.3 Hz, 1H, C5H-furan), 7.76 (s, 1H, C5H-
thiaz.), 7.80–7.83 (dd, J8-7 ¼ 7.6 Hz, J8-6 ¼ 2.9 Hz, 1H, C8H-
chrom.), 8.56 (s, 1H, C4H-chrom.), 11.25 (br s, 1H, NH, D2O
exch.); Anal. Calcd. for C18H13N3O3S: C, 61.53; H, 3.73; N,
11.96. Found: C, 61.56; H, 3.72; N, 11.98.
3-(2-(2-(Thiophen-2-ylmethylen)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (16). Yellow crystals, 99% yield, mp
230–235ꢂC; 1H NMR (DMSO-d6): d 7.08–7.12 (m, 1H, thio-
phene), 7.37–7.40 (m, 1H, thiophene), 7.41 (s, 1H, C5H-thiaz.),
7.43–7.48 (m, J7-6 ¼ J7-8 ¼ 6.8 Hz, J7-5 ¼ 3.4 Hz, 1H, C7H-
chrom.), 7.58–7.62 (dd, J5-6 ¼ 6.3 Hz, J5-7 ¼ 3.3 Hz, 1H,
C5H-chrom.), 7.63–7.68 (m, 1H, thiophene), 7.75–7.78 (m, 1H,
C8H-chrom.), 7.82–7.87 (m, J6-5 ¼ J6-7 ¼ 6.3 Hz, J6-8 ¼ 3.4
Hz, 1H, C6H-chrom.), 8.24 (s, 1H, CH¼¼N), 8.53 (s, 1H, C4H-
chrom.), 12.10 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C17H11N3O2S2: C, 57.77; H, 3.14; N, 11.89. Found: C, 57.72;
H, 3.15; N, 11.90.
3-(2-(2-(1-(Thiophen-2-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (17). Yellow crystals, 92% yield, mp 221–
223ꢂC; 1H NMR (DMSO-d6): d 2.31 (s, 3H, CH3), 7.03–7.06
(m, 1H, thiophene), 7.37–7.40 (m, 1H, C7H-chrom.), 7.45–7.47
(dd, J5-6 ¼ 7.4 Hz, J5-7 ¼ 2.1 Hz, 1H, C5H-chrom.), 7.52–7.55
(m, 1H, thiophene), 7.57–7.60 (m, 1H, thiophene), 7.61–7.64
(m, 1H, C6H-chrom.), 7.77 (s, 1H, C5H-thiaz.), 7.81–7.84 (dd,
J8-7 ¼ 7.4, J8-6 ¼ 2.5, 1H, C8H-chrom.), 8.57 (s, 1H, C4H-
chrom.), 11.20 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C17H11N3O2S2: C, 57.61; H, 3.41; N, 11.86. Found: C, 57.60;
H, 3.42; N, 11.86.
pentyl), 2.58–2.64 (m, 1H, cyclopentyl), 7.27–7.33 (m, J7-6
¼
J7-8 ¼ 7.7 Hz, J7-5 ¼ 3.63 Hz, 1H, C7H-chrom.), 7.34–7.37
(dd, J5-6 ¼ 7.8, J5-7 ¼ 3.6, 1H, C5H-chrom.), 7.50–7.54 (m,
J6-5 ¼ J6-7 ¼ 7.7 Hz, J6-8 ¼ 3.7 Hz, 1H, C6H-chrom.), 7.57–
7.60 (dd, J8-7 ¼ 7.7, J8-6 ¼ 3.6, 1H, C8H-chrom.), 7.88 (s, 1H,
C5H-thiaz.), 8.49 (s, 1H, C4H-chrom.), 12.00 (br s, 1H, NH,
D2O exch.); Anal. Calcd. for C18H17N3O2S: C, 63.70; H, 5.05;
N, 12.38. Found: C, 63.75; H, 5.04; N, 12.39.
3-(2-(2-(3-Methylcyclopentylidene)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (11). Light yellow crystals, 99% yield, mp
214–216ꢂC; 1H NMR (CDCl3): d 1.10–1.12 (m, 3H, CH3),
1.49–1.56 (m, 1H, cyclopentyl), 2.10–2.12 (m, 1H, cyclopen-
tyl), 2.14–2.17 (m, 1H, cyclopentyl), 2.19–2.22 (m, 1H, cyclo-
pentyl), 2.54–2.62 (m, 1H, cyclopentyl), 2.64–2.73 (m, 1H,
cyclopentyl), 2.75–2.81 (m, 1H, cyclopentyl), 7.35–7.38 (m,
J7-6 ¼ J7-8 ¼ 7.9 Hz, J7-5 ¼ 3.3 Hz, 1H, C7H-chrom.), 7.38–
7.40 (dd, J5-6 ¼ 8.0, J5-7 ¼ 3.2, 1H, C5H-chrom.), 7.63–7.67
(m, J6-5 ¼ J6-7 ¼ 7.9 Hz, J6-8 ¼ 3.3 Hz, 1H, C6H-chrom.),
7.77–7.79 (dd, J8-7 ¼ 7.9, J8-6 ¼ 3.4, 1H, C8H-chrom.), 7.84
(s, 1H, C5H-thiaz.), 8.59 (s, 1H, C4H-chrom.), 11.80 (br s, 1H,
NH, D2O exch.); Anal. Calcd. for C18H17N3O2S: C, 63.70; H,
5.05; N, 12.38. Found: C, 63.65; H, 5.06; N, 12.38.
3-(2-(2-(1-(Pyridin-2-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (19). Orange crystals, 99% yield, mp
258–262ꢂC; 1H NMR (DMSO-d6): d 2.41 (s, 3H, CH3),
7.37–7.40 (m, 1H, C7H-chrom.), 7.42–7.47 (dd, J5-6 ¼ 7.5
3-(2-(2-(Cyclooctylidene)hydrazynyl)thiazol-4-yl)-2H-chro-
men-2-one (12). Yellow crystals, 69% yield, mp 143–145ꢂC;
1H NMR (CDCl3): d 1.47–1.50 (m, 2H, cyclooctyl), 1.52–1.58
(m, 4H, cyclooctyl), 1.79–1.84 (m, 4H, cyclooctyl), 2.43–2.46
(m, 4H, cyclooctyl), 7.27–7.30 (m, J7-6 ¼ J7-8 ¼ 7.5 Hz, J7-5
Hz, J5-7 ¼ 1.9 Hz, 1H, C5H-chrom.), 7.50–7.54 (m, J6-5
¼
J6-7 ¼ 7.3 Hz, J6-8 ¼ 1.2 Hz, 1H, C6H-chrom.), 7.55–7.61
(m, 1H, C5H-pyridine), 7.81 (s, 1H, C5H-thiaz.), 7.82–7.84
(dd, J8-7 ¼ 7.3 Hz, J8-6 ¼ 1.3 Hz, 1H, C8H-chrom.), 8.05–
8.10 (m, 1H, C4H-pyridine), 8.11–8.13 (m, 1H, C3H-pyri-
dine), 8.58 (s, 1H, C4H-chrom.), 8.63–8.65 (m, 1H, C6H-pyri-
dine), 11.77 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C19H14N4O2S: C, 62.97; H, 3.89; N, 15.46. Found: C, 62.95;
H, 3.88; N, 15.45.
¼ 1.6 Hz, 1H, C7H-chrom.), 7.38–7.40 (dd, J5-6 ¼ 7.4, J5-7
¼
1.7, 1H, C5H-chrom.), 7.50–7.54 (m, J6-5 ¼ J6-7 ¼ 7.4 Hz, J6-8
¼ 1.7 Hz, 1H, C6H-chrom.), 7.69–7.71 (dd, J8-7 ¼ 7.4, J8-6
¼
1.7, 1H, C8H-chrom.), 7.87 (s, 1H, C5H-thiaz.), 8.51 (s, 1H,
C4H-chrom.), 11.97 (br s, 1H, NH, D2O exch.); Anal. Calcd.
for C20H21N3O2S: C, 65.37; H, 5.76; N, 11.44. Found: C,
65.33; H, 5.76; N, 11.45.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis and Anti-Helicobacter pylori Activity of
4-(Coumarin-3-yl)thiazol-2-ylhydrazone Derivatives
1273
240–242ꢂC; 1H NMR (DMSO-d6): 7.40–7.44 (m, 1H, C7H-
chrom.), 7.49–7.51 (dd, J5-6 ¼ 7.8 Hz, J5-7 ¼ 1.5 Hz, 1H,
C5H-chrom.), 7.53–7.55 (m, 1H, C6H-chrom.), 7.56 (s, 1H,
C5H-thiaz.), 7.57–7.60 (dd, J8-7 ¼ 7.8 Hz, J8-6 ¼ 1.3 Hz, 1H,
C8H-chrom.), 7.77–7.81 (m, 2H, naphtalene), 7.82–7.85 (m,
1H, naphtalene), 7.97–8.02 (m, 2H, naphtalene), 8.08–8.10 (m,
1H, naphtalene), 8.12 (s, 1H, CH¼¼N), 8.22–8.24 (m, 1H,
naphtalene), 8.60 (s, 1H, C4H-chrom.), 11.54 (br s, 1H, NH,
D2O exch.); Anal. Calcd. for C24H17N3O2S: C, 70.05; H, 4.16;
N, 10.21. Found: C, 70.00; H, 4.15; N, 10.22.
3-(2-(2-(1-(Naphthalen-2-yl)ethyliden)hydrazynyl)thiazol-4-
yl)-2H-chromen-2-one (27). Yellow crystals, 91% yield, mp
244–245ꢂC; 1H NMR (DMSO-d6): 7.38–7.42 (m, 1H, C7H-
chrom.), 7.46–7.48 (dd, J5-6 ¼ 7.4 Hz, J5-7 ¼ 1.8 Hz, 1H,
C5H-chrom.), 7.49–7.53 (m, 1H, C6H-chrom.), 7.54 (s, 1H,
C5H-thiaz.), 7.58–7.60 (dd, J8-7 ¼ 7.3 Hz, J8-6 ¼ 1.4 Hz, 1H,
C8H-chrom.), 7.77–7.82 (m, 2H, naphtalene), 7.90–7.94 (m,
2H, naphtalene), 7.98–8.01 (m, 1H, naphtalene), 8.08–8.10 (m,
1H, naphtalene), 8.21–8.23 (m, 1H, naphtalene), 8.59 (s, 1H,
C4H-chrom.), 11.50 (br s, 1H, NH, D2O exch.); Anal. Calcd.
for C24H17N3O2S: C, 70.05; H, 4.16; N, 10.21. Found: C,
70.00; H, 4.15; N, 10.22.
3-(2-(2-(1-(Pyridin-3-yl)methylen)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (20). Yellow crystals, 99% yield, mp
257–258ꢂC; 1H NMR (DMSO-d6): 7.32–7.35 (m, 1H, C7H-
chrom.), 7.38–7.41 (dd, J5-6 ¼ 7.5 Hz, J5-7 ¼ 1.3 Hz, 1H,
C5H-chrom.), 7.60–7.64 (m, 1H, C6H-chrom.), 7.80–7.83 (dd,
J8-7 ¼ 7.6 Hz, J8-6 ¼ 1.4 Hz, 1H, C8H-chrom.), 7.84 (s, 1H,
C5H-thiaz.), 7.85–7.88 (m, 1H, C5H-pyridine), 8.17 (s, 1H,
CH¼¼N), 8.48–8.52 (m, 1H, C4H-pyridine), 8.56 (s, 1H, C4H-
chrom.), 8.73–8.75 (m, 1H, C6H-pyridine), 9.01 (s, 1H, C2H-
pyridine), 12.75 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C18H12N4O2S: C, 62.06; H, 3.47; N, 16.08. Found: C, 62.07;
H, 3.48; N, 16.10.
3-(2-(2-(1-(Pyridin-3-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (21). Yellow crystals, 99% yield, mp
1
269–270ꢂC; H NMR (DMSO-d6): d 2.41 (s, 3H, CH3), 7.40–
7.44 (m, 1H, C7H-chrom.), 7.48–7.50 (dd, J5-6 ¼ 7.8 Hz, J5-7
¼ 1.7 Hz, 1H, C5H-chrom.), 7.58–7.62 (m, 1H, C6H-chrom.),
7.80–7.83 (dd, J8-7 ¼ 7.7 Hz, J8-6 ¼ 1.7 Hz, 1H, C8H-chrom.),
7.84 (s, 1H, C5H-thiaz.), 7.87–7.90 (m, 1H, C5H-pyridine),
8.52 (s, 1H, C4H-chrom.), 8.55–8.58 (m, 1H, C4H-pyridine),
8.72–8.74 (m, 1H, C6H-pyridine), 9.07 (s, 1H, C2H-pyridine),
11.75 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C19H14N4O2S: C, 62.97; H, 3.89; N, 15.46. Found: C, 62.98;
H, 3.90; N, 15.46.
9-(2-(4-(2H-2-oxo-chromen-3-yl)thiazol-2-yl)hydrazono)-9H-
fluorene-2-carboxylic acid (29). Yellow crystals, 99% yield,
1
mp 190–192ꢂC; H NMR (DMSO-d6): 7.28–7.30 (m, 1H, fluo-
3-(2-(2-(1-(Pyridin-4-yl)methylen)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (22). Orange crystals, 99% yield, mp >
rene), 7.38–7.42 (m, 1H, C7H-chrom.), 7.45–7.47 (dd, J5-6
¼
1
300ꢂC; H NMR (DMSO-d6): 7.40–7.43 (m, 1H, C7H-chrom.),
7.7 Hz, J5-7 ¼ 1.3 Hz, 1H, C5H-chrom.), 7.49–7.53 (m, 1H,
C6H-chrom.), 7.56 (s, 1H, C5H-thiaz.), 7.57–7.61 (m, 2H, fluo-
rene), 7.62–7.64 (dd, J8-7 ¼ 7.4 Hz, J8-6 ¼ 1.4 Hz, 1H, C8H-
chrom.), 7.78–7.82 (m, 2H, fluorene), 8.33–8.38 (m, 2H, fluo-
rene), 8.57 (s, 1H, C4H-chrom.), 11.77 (br s, 1H, COOH, D2O
exch.), 12.50 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C26H15N3O4S: C, 67.09; H, 3.25; N, 9.03. Found: C, 67.13; H,
3.25; N, 9.04.
7.48–7.50 (dd, J5-6 ¼ 7.9 Hz, J5-7 ¼ 1.4 Hz, 1H, C5H-chrom.),
7.59–7.63 (m, 1H, C6H-chrom.), 7.85–7.88 (dd, J8-7 ¼ 7.6 Hz,
J8-6 ¼ 1.5 Hz, 1H, C8H-chrom.), 7.91 (s, 1H, C5H-thiaz.),
8.07–8.10 (d, J ¼ 4.1 Hz, 2H, pyridine), 8.16 (s, 1H, CH¼¼N),
8.55 (s, 1H, C4H-chrom.), 8.81–8.83 (d, J ¼ 4.5 Hz, 2H, pyri-
dine), 13.00 (br s, 1H, NH, D2O exch.); Anal. Calcd. for
C18H12N4O2S: C, 62.06; H, 3.47; N, 16.08. Found: C, 62.05;
H, 3.46; N, 16.08.
3-(2-(2-(1-(Thiazol-2-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (30). Light brown crystals, 99% yield, mp
3-(2-(2-(1-(Pyridin-4-yl)ethyliden)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (23). Yellow crystals, 98% yield, mp
1
256–260ꢂC; H NMR (DMSO-d6): d 2.43 (s, 3H, CH3), 7.39–
1
215–220ꢂC; H NMR (DMSO-d6): d 2.41 (s, 3H, CH3), 7.42–
7.43 (m, 1H, C7H-chrom.), 7.46–7.48 (dd, J5-6 ¼ 8.0 Hz, J5-7
7.46 (m, 1H, C7H-chrom.), 7.48–7.50 (dd, J5-6 ¼ 7.4 Hz, J5-7
¼ 1.6 Hz, 1H, C5H-chrom.), 7.64–7.68 (m, 1H, C6H-chrom.),
7.76–7.78 (dd, J8-7 ¼ 7.5 Hz, J8-6 ¼ 1.9 Hz, 1H, C8H-chrom.),
7.85 (s, 1H, C5H-thiaz.), 8.45–8.48 (d, J ¼ 5.8 Hz, 2H, pyri-
dine), 8.67 (s, 1H, C4H-chrom.), 8.78–8.81 (d, J ¼ 5.8 Hz,
2H, pyridine), 10.75 (br s, 1H, NH, D2O exch.); Anal. Calcd.
for C19H14N4O2S: C, 62.97; H, 3.89; N, 15.46. Found: C,
62.95; H, 3.98; N, 15.45.
¼ 1.6 Hz, 1H, C5H-chrom.), 7.63–7.67 (m, 1H, C6H-chrom.),
7.79 (s, 1H, C5H-thiaz.), 7.83–7.85 (dd, J8-7 ¼ 7.9 Hz, J8-6
¼
1.8 Hz, 1H, C8H-chrom.), 7.86–7.89 (m, 2H, thiazole), 8.72 (s,
1H, C4H-chrom.), 11.75 (br s, 1H, NH, D2O exch.); Anal.
Calcd. for C17H12N4O2S2: C, 55.42; H, 3.28; N, 15.21. Found:
C, 55.47; H, 3.28; N, 15.24.
Procedure for the synthesis of derivative 31. 3-a-Bromo-
acetyl coumarin (50 mmol) was dissolved in 2-propanol and
reacted with an equimolar amount of thiosemicarbazide at
room temperature under magnetic stirring for 4 h. The precipi-
tate was filtered and dried to give intermediate 31.
H. pylori culture. The H. pylori strains used in this study
were maintained at ꢀ80ꢂC in Wilkins Chalgren broth with
10% (v/v) horse serum (Seromed) and 20% (v/v) glycerol
(Merck) until required for the experiments. Before being used
the bacteria were subcultured twice on Columbia agar base
(Difco Laboratories) supplemented with 10% horse serum and
0.25% Bacto yeast extract (Difco). Plates were incubated for
72 h at 37ꢂC in an atmosphere of 10% CO2 in a gas incubator.
Anti-Helicobacter pylori activity. Antimicrobial activity
against H. pylori was determined by the agar dilution standard
method [19]. The strains were inoculated onto Columbia agar
base (Difco) supplemented with 10% horse serum and 0.25%
3-(2-(2-(1-(1H-indol-4-yl)methylen)hydrazynyl)thiazol-4-yl)-
2H-chromen-2-one (24). Yellow crystals, 90% yield, mp 248–
1
250ꢂC; H NMR (DMSO-d6): 6.95–6.98 (t, J ¼ 3.5, 1H, C5H-
indole), 7.12–7.15 (t, J ¼ 3.7, 1H, C6H-indole), 7.32 (s, 1H, C2H-
indole), 7.39–7.43 (m, J7-6 ¼ J7-8 ¼ 7.3 Hz, J7-5 ¼ 1.7 Hz, 1H,
C7H-chrom.), 7.44–7.46 (d, J ¼ 3.7, 1H, C7H-indole), 7.48–7.50
(dd, J5-6 ¼ 7.3 Hz, J5-7 ¼ 1.7 Hz, 1H, C5H-chrom.), 7.49–7.53
(m, 1H, C6H-chrom.), 7.55 (s, 1H, C5H-thiaz.), 7.58–7.60 (dd, J8-
¼ 7.3 Hz, J8-6 ¼ 1.3 Hz, 1H, C8H-chrom.), 7.62–7.64 (d, J ¼
7
3.5, 1H, C4H-indole), 8.16 (s, 1H, CH¼¼N), 8.57 (s, 1H, C4H-
chrom.), 10.79 (br s, 1H, NH, D2O exch.), 11.51 (br s, 1H, NH,
D2O exch.); Anal. Calcd. for C21H14N4O2S: C, 65.27; H, 3.65; N,
14.50. Found: C, 65.25; H, 3.64; N, 14.51.
3-(2-(2-(1-(Naphthalen-1-yl)methylen)hydrazynyl)thiazol-4-
yl)-2H-chromen-2-one (26). Yellow crystals, 70% yield, mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1274
F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese,
S. Carradori, M. D’Ascenzio, M. Maddalena Scaltrito, and F. Sisto
Vol 47
[6] Kawase, M.; Motohashi, N. Curr Med Chem Anti-Infect
Agents 2004, 3, 89.
bacto yeast extract (Difco) and were incubated for 72 h at
37ꢂC in an atmosphere of 10% CO2 in a gas incubator. Colo-
nies were suspended in Wilkins Chalgren broth to achieve a
turbidity equivalent to 0.5 Mc Farland. Columbia agar plates
with 10% horse serum were prepared by using twofold dilu-
tions of the antimicrobial agents (128–0.0039 lg/mL). The
inoculum was delivered to the surface of the agar plates with a
Steer’s replicator to obtain ꢄ5 ꢃ 105 CFU per spot. Growth
control plates without antibiotics were inoculated in each se-
ries of tests. All plates were incubated at 37ꢂC for 72 h under
conditions (10% CO2 in a gas incubator). The minimal inhibi-
tory concentration was defined as the lowest concentration of
drug inhibiting visible bacterial growth.
[7] Chimenti, F.; Carradori, S.; Secci, D.; Bolasco, A.; Chi-
menti, P.; Granese, A.; Bizzarri, B. J Heterocycl Chem 2009, 46, 575.
[8] Raghu, M.; Nagaraj, A.; Reddy, Ch. S. J Heterocycl Chem
2009, 46, 261.
[9] Rao, V. R.; Reddy, M. M. M. Indian J Heterocycl Chem
2003, 13, 69.
[10] Kalluraya, B.; Isloor, A. M.; Shenoy, S. Indian J Heterocycl
Chem 2001, 11, 159.
[11] Kalluraya, B.; Vishwanatha, P.; Isloor, A. M.; Rai, G.;
Kotian, M. Bollettino Chimico Farmaceutico 2000, 139, 263.
[12] Rao, V. R.; Kumar, V. R.; Vardhan, V. A. Phosphorus Sul-
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[13] Srimanth, K.; Rao, V. R. Indian J Chem B 1999, 38B, 473.
[14] Gursoy, A. J Fac Pharm Istanbul U 1974, 10, 57.
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DOI 10.1002/jhet