Synthesis and Antimicrobial Evaluation of Some New 4,5′-Bisthiazoles

Article abstract of DOI:10.1002/jhet.2054

Thiazole and bisthiazole derivatives represent a prevalent scaffold in the antimicrobial drug discovery. Therefore, we have decided to synthesize some new series of 4,5′-bisthiazoles. A total of 17 compounds were synthesized, their structural elucidation

Full text of DOI:10.1002/jhet.2054

Month 2014
Synthesis and Antimicrobial Evaluation of Some New 4,5′-Bisthiazoles
a
b
a
a
c
a
a
*
Tibor Rozsa, Mihaela Duma, Laurian Vlase, Ioana Ionuţ, Adrian Pîrnău, Brînduşa Tiperciuc, and Ovidiu Oniga
aDepartment of Pharmaceutical Chemistry, Iuliu Haţieganu University of Medicine and Pharmacy, 12 Ion Creangă Street,
400010 Cluj Napoca, Romania
bState Veterinary Laboratory for Animal Health and Food Safety, 400572 Cluj-Napoca, Romania
cNational Institute for Research and Development of Isotopic and Molecular Technologies, 400293 Cluj Napoca, Romania
*
E-mail: ionut.ioana@umfcluj.ro
Received December 18, 2012
DOI 10.1002/jhet.2054
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Thiazole and bisthiazole derivatives represent a prevalent scaffold in the antimicrobial drug discovery.
Therefore, we have decided to synthesize some new series of 4,5′-bisthiazoles. A total of 17 compounds
were synthesized, their structural elucidation being based on elemental analysis (C,H,N,S) and spectroscopic
data (MS and 1H NMR). Their in vitro antimicrobial activities were assessed against several Gram-positive
and Gram-negative bacteria strains and also against one fungal strain (Candida albicans) using the
difusimetric method. Some of the compounds showed modest to good antibacterial activity against
Gram-negative Escherichia coli and Salmonella typhimurium and Gram-positive Staphylococcus aureus and
Bacillus cereus bacterial strains. All of the synthesized compounds showed moderate to very good antifungal
activity against C. albicans.
J. Heterocyclic Chem., 00, 00 (2014).
insecticidal, schistosomicidal, and anthelmintic activities
[20]. More recently, thiazole compounds have been
found to possess analgesic [21] and fibrinogen receptor
antagonism [22], they being considered also new inhib-
itors of bacterial DNA gyrase B [23]. In addition,
thiazoles are common substructures in numerous
biologically active compounds. Thus, the thiazole
nucleus has been much studied in the field of organic
and medicinal chemistry.
The treatment of bacterial and fungal infectious
diseases remains a challenging problem because of the
increasing number of multi-drug resistant microbial
pathogens. Nowadays, the design of new compounds,
capable to deal with resistant bacteria, having new
structures and new targets of action, has become one
of the most important areas in the antibacterial and
antifungal research purpose. Prompted by these findings
and as a part of our efforts to discover potentially active
new antimicrobial agents, we report in the present work
the synthesis of 17 variously substituted 4,5′-bisthiazoles
and the evaluation of their antibacterial and antifungal
activities.
INTRODUCTION
In the current context of increasing resistance of
microorganisms to antibiotics, particularly pathogenic
bacteria and fungi, development of new antibacterial
and antifungal agents is an important issue. Although
the anti-infective therapeutic arsenal may be consid-
ered rich by the number of molecules existing in
therapy, the emergence of the so-called “super bacte-
ria,” whose main characteristic is the high level of
resistance to antibiotics, currently creates big problems
to physicians.
Thiazoles and their derivatives have attracted continu-
ing interest over the years due to their different biolog-
ical activities [1–8]. For example, the coenzyme of
vitamin B1, which contains a thiazolium ring, is
important for the decarboxylation of alpha-ketoacids
[9]. This heterocyclic system has found broad applica-
tion in drug development for the treatment of inflamma-
tion [10], convulsion [11], tumors [12–15], hypertension
[16], bacterial [17], fungal [18], and HIV infections
[19]. Some thiazole derivatives also exhibit herbicidal,
© 2014 HeteroCorporation

T. Rozsa, M. Duma, L. Vlase, I. Ionuţ, A. Pîrnău, B. Tiperciuc, and O. Oniga
Vol 000
RESULTS AND DISCUSSION
All newly synthesized compounds were characterized by
melting point, elemental analysis, and spectroscopic data
(1H NMR and MS). All of them gave very good C,H,N,S
quantitative elemental analysis results. All spectral data were
in accordance with the assumed structures. The physical
data, the yields, and the spectral characterizations of the
synthesized compounds are presented in the Experimental
section, along with the details of the synthetic procedures.
The mass spectra of the synthesized compounds gave idea
about the fragmentation of the final compounds, with their
corresponding mass, and showed the correct molecular ions
(M+ or M+1), as suggested by their molecular formulas. The
structures of the final compounds are presented in Table 1.
Chemistry.
The target molecules (Scheme 1) were
obtained via the classical Hantzsch thiazole synthesis
through the condensation of bromoketone II with various
thioamides (Scheme 2), in anhydrous acetone. The
synthesis of bromoketone II was achieved starting from
the corresponding ketone I by bromination with molecular
bromine. Ketone I was easily obtained by the Hantzsch
condensation of thiobenzamide with 3-chloroacetylacetone
in 96% EtOH at reflux (Scheme 3).
Thioamide IV, with a thiazole nucleus in its structure,
was obtained via a two-step synthesis involving a Hantzsch
reaction and a nitrile to thioamide transformation using
hydrogen sulfide gas. Thioamides Va–c, which have a
simple thiosemicarbazone structure, were obtained from
thiosemicarbazide and various aldehydes or cyclohexanone
in refluxing ethanol. Thioamide VI was synthesized from
thiosemicarbazide and phenylisocyanate in ethanol at reflux.
Antimicrobial activity.
The in vitro antimicrobial
activities were evaluated by the agar disk diffusion
method according to the National Committee for Clinical
Laboratory Standards guidelines. The antibacterial
activities of the synthesized bisthiazoles were evaluated
against various pathogenic Gram-negative (Salmonella
typhimurium ATCC 13311 and Escherichia coli ATCC
25922) and Gram-positive (Listeria monocytogenes ATCC
35152, Staphylococcus aureus ATCC 25923, and Bacillus
cereus ATCC 13061) strains. The antifungal activities of
the previously mentioned compounds were evaluated
against a strain of Candida albicans (ATCC 90028).
Scheme 1. Synthesis of bisthiazoles VIIa–e, VIIa–i, IXa–c; anhydrous
acetone, RT, 24 h.
For the antibacterial assay, Mueller-Hinton agar medium
was used. For the antifungal assay, this medium was
supplemented with 2% glucose (providing adequate growth
of yeasts) and 0.5 mg/mL methylene blue (providing a better
definition of the inhibition zone). The inoculum was prepared
by suspending five representative colonies, obtained from an
18–24 h culture on non-selective nutritive agar medium, in
sterile distilled water. The cell density was adjusted to the
density of a 0.5 McFarland standard by measuring the absor-
bance with a spectrophotometer at a wavelength of 530 nm
and adding sterile distilled water as required (corresponding
to a population of 1–5 × 10 6 CFU/mL). Six-millimeter diam-
eter wells were cut from the agar using a sterile cork-borer,
and a predetermined volume of each compound solution
was delivered into the wells. A sterile swab was soaked in
suspension and then the Mueller-Hinton agar plates were
inoculated by streaking the entire surface. After drying for
10–15 ([A-Za-z0-9,10–15 min, the 6 mm diameter wells were
inoculated with 50 μL from 1 mg/mL solution in dimethyl
sulfoxide (DMSO) (Merck, Germany) of each compound
(50 μL/well). Ciprofloxacin (50 μL/well) and Fluconazole
(50 μL/well) were used as standard drugs. The plates were
incubated at 35°C. The diameters of the zone of inhibition
were measured to the nearest whole millimeter at a
point in which there will be no visible growth after
24–48 h. DMSO, the solvent used for the preparation of
the newly synthesized compound solutions, did not show
any inhibition against the tested bacterial and fungal
strains. The assays were executed in duplicate.
Scheme 2. Synthesis of some of the thiomide components. iii: PhCSN2,
EtOH, reflux, 3 h; iv: H2S, EtOH, TEA, 48 h, v. ArCHO, EtOH, AcOH cc,
reflux 2 h; vi. PhNCO, EtOH, TEA, reflux, 2 h.
Scheme 3. Synthesis of bromoketone II; i: EtOH, reflux, 4 h; ii: Br2/CCl4,
HCI cc. (cat.), reflux, 2 h.
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Synthesis and Antimicrobial Evaluation of Some New 4,5′-Bisthiazoles
Table 1
The structures of the synthesized bisthiazoles.
Ph
S
S
N
N
X
Me
Compound
VIIa
X
X
VIIIe
VIIIf
N
H
N
VIIb
O
N
CH3
CH3
N
H
VIIc
VIId
VIIIg
VIIIh
Br
N
H
S
H
N
N
VIIe
VIIIi
IXb
HO
H
H
N
N
N
H
O
VIIIa
H
S
NH
N
N
VIIIb
IXc
IXa
NH2
HN
Br-
+
NH2
VIIIc
VIIId
O
O
H
N
N
N
H
N
H
Cl
O
N
NH
The results of the antifungal and antibacterial activities
of the compounds are presented in Table 2, in comparison
with ciprofloxacin and fluconazole, the reference drugs.
a bulky substituent in position 2 of the bisthiazole (4-(2-
phenylthiazol-5-yl)phenyl and 6-chlorochromenyl) have
an increased activity against C. albicans. Compound
VIIIg, with methylamino in position 2 of the heterocyclic
system, showed superior antifungal activity compared with
fluconazole. Against B. cereus compounds VIIb, VIIIa,
VIIIb, VIIIh, IXb, and IXc showed higher activity than
the standard ciprofloxacin. Therefore, we could assume that
the activity against this strain in series VIII is increased
RESULTS
All of the bisthiazoles showed good antifungal activities,
representative for the three series being VIId, VIIIg, and
IXc. This is consistent with the fact that compounds with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Rozsa, M. Duma, L. Vlase, I. Ionuţ, A. Pîrnău, B. Tiperciuc, and O. Oniga
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Table 2
Antimicrobial evaluation (diameter of inhibition zone/mm).
Compound
I
II
III
IV
V
VI
VIIa
VIIb
VIIc
VIId
VIIe
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
VIIIf
VIIIg
VIIIh
VIIIi
IXa
13
10
12
12
12
16
14
10
10
12
12
12
16
14
12
12
16
26
-
10
12
8
8
8
10
22
6
12
10
12
15
12
15
18
10
10
14
10
14
18
12
12
14
15
16
-
8
12
10
6
16
16
14
10
8
10
8
12
14
10
6
10
16
12
10
14
24
26
10
10
10
10
14
26
16
8
15
12
12
20
16
14
25
10
22
22
15
30
14
12
12
12
20
-
6
16
15
20
16
14
8
10
12
12
-
IXb
IXc
C
F
12
16
26
-
24
24
14
-
28
-, Agar diffusion technique, diameter of inhibition (mm). Solutions of compounds: 1 mg/mL (DMSO) (50 μL/well). Microbial strains I = Salmonella
typhimurium ATCC 13311; II = Staphylococcus aureus ATCC 25923; III = Listeria monocytogenes ATCC 35152; IV = Escherichia coli; ATCC 25922;
V = Bacillus cereus ATCC 13061; VI = Candida albicans ATCC 90028.
when the radical R from the –NHR substituent is aromatic
(phenyl, α-naphthyl) or amidino. The most active com-
pounds from series IX were those with a bulky substituent
and antifungal activities, and some structure-activity
relationships have been made. The best activity has been
found against C. albicans and Gram-positive bacteria
(B. cereus, S. aureus, and L. monocytogenes). These classes
of compounds, especially those belonging to series VIII,
may constitute potential antimicrobial agents against certain
drug-resistant strains.
in position
2 (6-chlorochromenyl and ethylvanilyl).
Compounds VIIIb and VIIIh also showed high activities
against L. monocytogenes, which were slightly higher than
the activity of the standard antibiotic. All compounds
showed modest activity against E. coli, lower than that of
ciprofloxacin. S. aureus showed a good sensitivity toward
compounds VIIIb and VIIIg, which were more active
compared with the standard. The compounds from series
VIII were also the most active against S. typhimurium from
all the synthesized compounds.
The newly synthesized 4,5′-bisthiazoles showed an
interesting antifungal activity as well as very good
antibacterial activity against B. cereus and two of them
(VIIIb and VIIIg) also against S. aureus. The most promising
compounds were found to be those from series VIII,
respectively the aminobisthiazoles with an –NHR type
of substituent in position 2 of the heterocyclic system.
EXPERIMENTAL
Chemistry.
The melting points were taken with an
Electrothermal melting point meter (Hamburg, Germany) and
were uncorrected. Analytical thin layer chromatography (TLC)
was used to monitor the reaction progress and to confirm the
purity of the compounds being carried out on precoated Silica
Gel 60F254 sheets (Darmstadt, Germany). We used heptane–
ethyl-acetate (3:7) as mobile phase and UV absorbtion for
1
visualization. Yields were not optimized. The H NMR spectra
were recorded at room temperature on a Bruker Avance NMR
spectrometer (Karlsruhe, Germany) operating at 500 MHz and
were in accordance with the assigned structures. Chemical shift
values were reported relative to tetramethylsilane (TMS) as
internal standard. The samples were prepared by dissolving the
compounds in DMSO-d6 (δH = 2.51 ppm) as solvent, and the
spectra were recorded using a single excitation pulse of 12 μs
(1H NMR). Elemental analysis was registered with a Vario El
CHNS instrument (Hanau, Germany).
Reagents and solvents were purchased from Sigma-Aldrich
(St. Louis, MO) and used without further purification.
1-(4-Methyl-2-phenylthiazol-5-yl)ethanone (I). The synthesis
was performed according to literature [24,25]. Thiobenzamide
(3.425 g, 25 mmol) was dissolved in 96% EtOH (40 mL); and after
total dissolution by refluxing for 5 min, 3-chloroacetylacetone was
CONCLUSIONS
In conclusion, a series of 17 new 4,5′-bisthiazoles were
synthesized, with promising antimicrobial activities. The
formation of the second thiazole nucleus in this type of
compounds has occurred very easily in mild condition
reactions, respectively in anhydrous acetone at room
temperature. All compounds were characterized with the
help of analytical techniques: 1H NMR, mass, and elemental
analysis. They were evaluated for their in vitro antibacterial
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Synthesis and Antimicrobial Evaluation of Some New 4,5′-Bisthiazoles
added (3.625 g, 27.5 mmol) and refluxed for 4 h. After cooling, the
precipitated ketone hydrochloride was suction-filtered. The
product was dissolved in distilled water/ice (30 mL) and
neutralized with a 10% Na2CO3 solution to pH 9–10. The product
was recrystallized from 96% ethanol. Yield (77%, 4.18 g), white
solid, mp 66–67°C.
(DMSO-d6, 500 MHz) δ ppm: 8.24 (m, 1H, ¼CH), 7.16 (m,
1H, Ar–H), 6.88–6.92 (m, 1H, Ar–H), 6.78 (s, 4H, –OH, –NH,
–NH2), 6.75–6.78 (m, 1H, Ar–H), 3.98–4.06 (q, 2H, –CH2),
1.47–1.50 (t, 2H, –CH3); MS (EI, 70 eV) m/z (%): 240 (M + 1)
Anal. Calcd. (%) for C10H13N3O2S: C, 50.19; H, 5.48; N,
17.56; S, 13.40 Found: C, 50.17; H, 5.52; N, 17.53; S, 13.44.
2-((6-Chloro-4-oxo-4H-chromen-3-yl)methylene)hydrazine-
2-Bromo-1-(4-methyl-2-phenylthiazol-5-yl)ethanone (II).
The synthesis was performed according to literature [24,25], with
a slight modification, in order to improve the yield and to shorten
the reaction time. 1-(4-methyl-2-phenylthiazol-5-yl)ethanone
(4.34 g, 20 mmol) was dissolved in dry carbon tetrachloride
(20 mL), and a few drops of concentrated hydrochloric acid
were added. A 10% solution of bromine in CCl4 (10 mL) was
gradually added while stirring at 0°C for 30 min. The mixture
was refluxed for 2 h, with continued stirring. At the end of the
reaction, the solvent was evaporated under vacuo and the
obtained residue was recrystallized from absolute ethanol. The
product was washed with a cold (0°C) 10% solution of
NaHCO3 for neutralization, until no bromide ions could be
detected in the filtrate and then with cold distilled water until
neutral pH. Yield (80%, 4.80 g), beige crystalline solid, mp:
108–110°C.
carbothioamide (Vb).
The 6-chloro-4-oxo-4H-chromene-3-
carbaldehyde (0.417 g, 2 mmol) was suspended in absolute
ethanol (10 mL) and brought to reflux for 5 min.
Thiosemicarbazide (0.182 g, 2 mmol) and three drops of glacial
AcOH were added, and reflux was continued for 2 h. After
cooling, the product was suction-filtered and recrystallized
from absolute ethanol. Yield (73%, 0.41 g), yellow
1
microcrystalline powder, mp: 193–195°C. H NMR (DMSO-d6,
500 MHz) δ ppm: 8.15 (d, 1H, Chromene-H), 8.04 (d, 1H, CH),
7.59–7.61 (dd, 1H, Chromene-H), 7.51–7.53 (dd, 1H, Chromene-
H), 6.47 (s, 3H, NH, NH2); MS (EI, 70eV) m/z (%): 282 (M + 1)
Anal. Calcd. (%) for C11H8ClN3O2S: C, 46.90; H, 2.86; N, 14.92;
S, 11.38 Found: C, 46.88; H, 2.89; N, 14.87; S, 11.41.
2-(Thiophen-2-ylmethylene)hydrazinecarbothioamide (Vc).
This compound has been previously reported [26,27]. Yield
(83%, 0.77 g), white microcrystalline powder, mp: 192–194°C.
2-Carbamothioyl-N-phenylhydrazinecarboxamide (VI). This
compound has been previously reported [28]. Yield (45%, 0.283 g),
white microcrystalline powder, mp: 195–196°C.
4′-Methyl-2′-phenyl-2-(pyridin-3-yl)-4,5′-bisthiazole (VIIa). II
(0.296 g, 1 mmol) was dissolved in 96% EtOH (4 mL), and then
pyridine-3-carbothioamide (0.138 g, 1 mmol) was added, and the
mixture was refluxed for 2 h. After cooling, the mixture was
poured into ice-cold water (20 mL) and the formed precipitate was
suction-filtered. The product was neutralized with a 10% solution
of Na2CO3 and then washed with distilled water until neutral pH.
The product was recrystallized from 96% ethanol. Yield
(45%, 0.150 g), brown powder, mp: 114°C.
4-(2-Phenylthiazol-4-yl)benzonitrile (III).
The 4-(2-
bromoacetyl)benzonitrile (4.48 g, 20 mmol) was introduced
into a round-bottom flask, absolute ethanol (20 mL) was
added and the mixture was brought to reflux. Thiobenzamide
was then gradually added (2.74 g, 20 mmol) and refluxing
was continued for 3 h. The mixture was then cooled, and the
precipitate was suction-filtered. The product was washed
with a cold 10% solution of Na2CO3 for neutralization, until
no bromide ions could be detected in the filtrate and then with
cold distilled water until neutral pH. The product was
recrystallized from 96% ethanol. Yield (92.5%, 4.85 g), white
powder, mp: 137–139°C. 1H NMR (DMSO-d6, 500MHz) δ ppm:
7.68–7.72 (m, 4H, Ar–H), 7.61 (s, 1H, Thiazole-CH), 7.25–7.41
(m, 5H, Ar–H); MS (EI, 70 eV) m/z (%): 263 (M+ 1) Anal. Calcd.
(%) for C16H10N2S: C, 73.26; H, 3.84; N, 10.68; S, 12.22 Found:
C, 73.22; H, 3.88; N, 10.72; S, 12.25.
4-(2-Phenylthiazol-4-yl)benzothioamide (IV). Compound III
(2.62 g, 10mmol) was added in a round bottomed flask and was
suspended in absolute EtOH (30 mL). Triethylamine (TEA, 2 mL)
was added, and the flask was introduced into an ice cold water
bath. Hydrogen sulfide gas (44.8L, 2000 mmol) was slowly
passed through the suspension for 48h. The precipitated product
was suction-filtered and recrystallized from absolute ethanol.
Hydrogen sulfide was generated from iron (II) sulfide and
concentrated hydrochloric acid, using a Kipp apparatus. Yield
(80%, 2.37g), yellow crystalline powder, mp: 178–179°C. 1H
NMR (DMSO-d6, 500MHz) δ ppm: 8.06–8.09 (m, 2H, Ar–H),
7.62–7.64 (m, 2H, Ar–H), 7.58 (s, 1H, Thiazole-CH), 7.39–7.42
(m, 1H, Ar–H), 7.32–7.34 (m, 2H, Ar–H), 7.31 (s, 2H, –CSNH2),
7.24–7.28 (m, 2H, Ar–H); MS (EI, 70eV) m/z (%): 297 (M + 1)
Anal. Calcd. (%) for C16H12N2S2: C, 64.83; H, 4.08; N, 9.45; S,
21.64 Found: C, 64.79; H, 4.05; N, 9.49; S, 21.67.
VIIa was also prepared according to the general procedure in
anhydrous acetone, as described for VIIId, using pyridine-3-
carbothioamide (1 mmol) as a thioamide component. The product
was recrystallized from 96% ethanol. Yield (38%, 0.127 g),
1
brown powder, mp: 114°C. H NMR (DMSO-d6, 500 MHz) δ
ppm: 9.19 (m, 1H, Ar–H), 8.71–8.73 (m, 1H, Ar–H), 8.35–8.38
(m, 1H, Ar–H), 8.08 (s, 1H, Thiazole-CH), 7.97–7.99 (m, 2H,
Ar–H), 7.58–7.61 (m, 1H, Ar–H), 7.51–7.52 (m, 3H, Ar–H),
2.71 (s, 3H, CH3); MS (EI, 70 eV) m/z (%): 336 (M + 1) Anal.
Calcd (%) for C18H13N3S2: C, 64.45; H, 3.91; N, 12.53; S,
19.12 Found: C, 64.49; H, 3.86; N, 12.46; S, 19.17.
4′-Methyl-2′-phenyl-2-(pyridin-4-yl)-4,5′-bisthiazole (VIIb).
The synthesis was performed in 96% EtOH at reflux according to
the first procedure described for VIIa. The product was
recrystallized from 96% ethanol. Yield (60%, 0.200 g), gray
powder, mp: 175–176°C. 1H NMR (DMSO-d6, 500 MHz) δ ppm:
8.52–8.54 (m, 2H, Ar–H), 7.83–7.85 (m, 2H, Ar–H), 7.49
(s, 1H, Thiazole-CH), 7.39–7.42 (m, 1H, Ar–H), 7.29–7.31
(m, 2H, Ar–H), 7.23–7.26 (m, 2H, Ar–H), 2.72 (s, 3H, CH3);
MS (EI, 70 eV) m/z (%): 336 (M + 1) Anal. Calcd. (%) for
C18H13N3S2: C, 64.45; H, 3.91; N, 12.53; S, 19.12 Found: C,
64.48; H, 4.00; N, 12.50; S, 19.16.
2-(3-Ethoxy-4-hydroxybenzylidene)hydrazinecarbothioamide
(Va). Thiosemicarbazide (0.455 g, 5 mmol) was suspended in
absolute EtOH (10 mL). The mixture was brought to reflux for
5 min, then ethylvaniline (0.831 g, 5 mmol) and three drops of
glacial AcOH were added. Refluxing was continued for an
additional 4 h. After cooling, the white crystalline precipitate
was suction-filtered and recrystallized from absolute ethanol.
2-(4-Bromophenyl)-4′-methyl-2′-phenyl-4,5′-bisthiazole (VIIc).
The synthesis was performed according to the general procedure
described for VIIId by using 4-bromobenzothioamide (0.108 g,
0.5 mmol) as
a thioamide component. The product was
1
Yield (82%, 0.98 g), white crystals, mp: 198–200°C. H NMR
recrystallized from 96% ethanol. Yield (70%, 0.143 g), beige
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1
powder, mp: 152–153°C. H NMR (DMSO-d6, 500MHz) δ ppm:
7.39–7.42 (m, 2H, Ar–H), 7.83 (Thiazole-CH), 7.28–7.31 (m, 4H,
Ar–H), 7.22–7.26 (m, 2H, Ar–H), 7.06–7.08 (m, 2H, Ar–H), 2.49
(s, 3H, CH3); MS (EI, 70eV) m/z (%): 413 (M + 1), 415 (M + 1)
—corresponding to the two isotopes of bromine. Anal. Calcd. (%)
for C19H13BrN2S2: C, 55.21; H, 3.17; N, 6.78; S, 15.51 Found: C,
55.25; H, 3.14; N, 6.74; S, 15.56.
for C14H14N5S2Br: C, 42.43, H, 3.56, N, 17.67, S, 16.18.
Found: C, 42.41, H, 3.52, N, 17.70, S, 16.16.
N′-(4′-Methyl-2′-phenyl-4,5′-bisthiazol-2-yl)benzohydrazide
(VIIIc). 2-Benzoylhydrazinecarbothioamide (0.195 g, 1 mmol)
and II (0.296 g, 1 mmol) were separately dissolved in minimum
amounts of anhydrous acetone. The solutions were mixed and
stirred at room temperature for 24 h. The precipitate was then
filtered, suspended in distilled water, neutralized with a 10%
solution of Na2CO3 and then washed again with water until
neutral pH. The product was recrystallized from 96% ethanol.
4′-Methyl-2′-phenyl-2-(4-(2-phenylthiazol-5-yl)phenyl)-4,5′-
bisthiazole (VIId). The synthesis was performed according to
the general procedure described for VIIId. The product was
recrystallized from absolute ethanol. Yield (77.5%, 0.38 g),
yellow powder, mp: 221–223°C. 1H NMR (DMSO-d6,
500 MHz) δ ppm: 8.37 (s, 1H, Thiazole-CH), 8.22–8.24 (m, 2H,
Ar–H), 8.10–8.12 (m, 2H, Ar–H), 8.06–8.08 (m, 2H, Ar–H),
8.02 (s, 1H, Thiazole-C7-H), 7.99–8.00 (m, 2H, Ar–H),
7.52–7.54 (m, 6H, Ar–CH), 2.72 (s, 3H, –CH3); MS (EI,
70eV) m/z (%): 494 (M + 1). Anal. Calcd. (%) for C28H19N3S3:
C, 68.12; H, 3.88; N, 8.51; S, 19.49. Found: C, 68.15; H, 3.82; N,
8.47; S, 19.50.
2-(4′-Methyl-2′-phenyl-4,5′-bisthiazol-2-yl)phenol (VIIe).
The synthesis was performed according to the general procedure
described for VIIId by using II (0.148 g, 0.5 mmol) and 2-
hydroxybenzothioamide (0.077 g, 0.5 mmol) as the thioamide
component. The product was recrystallized from 96% ethanol.
Yield (16%, 0.028 g), light beige powder, mp: 170–172°C. 1H
NMR (DMSO-d6, 500 MHz) δ (ppm): 7.60 (s, 1H, Thiazole-
CH), 7.47–7.49 (m, 1H, Ar–H), 7.39–7.42 (m, 1H, Ar–H),
7.29–7.31 (m, 2H, Ar–H), 7.22–7.26 (m, 2H, Ar–H), 7.13–7.16
(m, 1H, Ar–H), 6.83–6.86 (m, 1H, Ar–H), 6.66–6.68 (m, 1H,
Ar–H), 4.39 (s, 1H, –OH), 2.53 (s, 3H, –CH3); MS (EI, 70 eV)
m/z (%): 352 (M + 1) Anal. Calcd. for C19H14N2OS2: C, 65.12;
H, 4.03; N, 7.99; O, 4.57; S, 18.30 Found: C, 65.07; H, 4.05;
N, 7.94; S, 18.33.
1
Yield (71%, 0.236 g), white powder, mp: 211–212°C; H NMR
(DMSO-d6, 500MHz) δ ppm: 11.42 (s, 1H, NH), 9.49 (s, 1H,
NH), 7.68–7.71 (m, 2H, Ar–H), 7.62–7.65 (m, 2H, Ar–H),
7.56–7.58 (m, 1H, Ar–H), 7.39–7.42 (m, 1H, Ar–H), 7.22–7.26
(m, 2H, Ar–H), 7.29–7.31 (m, 2H, Ar–H), 7.37 (s, 1H,
Thiazole-CH), 2.67 (s, 3H, CH3); MS (EI, 70 eV) m/z (%): 393
(M + 1) Anal. Calcd. (%) for C20H16N4OS2: C, 61.20; H, 4.11;
N, 14.27; S, 16.34. Found: C, 61.22; H, 4.09; N, 14.30; S, 16.30.
2-(2-Cyclohexylidenehydrazinyl)-4′-methyl-2′-phenyl-4,5′-
bisthiazole(VIIId). 2-Cyclohexylidenehydrazinecarbothioamide
(0.171 g, 1 mmol) was suspended in anhydrous acetone (10 mL),
and then II (0.296 g, 1 mmol) was added. The mixture was
stirred for 24 h at room temperature. The precipitate was
then filtered, washed with dry diethyl ether, and neutralized
with a 10% solution of Na2CO3. The product was then
washed with distilled water until neutral pH and dried
overnight at room temperature. The product was recrystallized
from absolute ethanol. Yield (80%, 0.298 g), light beige powder,
1
mp: 177–178°C. H NMR (DMSO-d6, 500MHz) δ ppm: 11.02 (s,
1H, NH), 7.91–7.93 (m, 2H, Ar–H), 7.48–7.50 (m, 3H, Ar–H),
7.08 (s, 1H, Thiazole-CH), 2.61 (s, 3H, CH3), 2.44–2.46 (m, 2H,
CH2), 2.25–2.27 (m, 2H, CH2), 1.58–1.64 (m, 6H, CH2); MS
(EI, 70 eV) m/z (%): 369 (M + 1) Anal. Calcd. for C19H20N4S2:
C, 61.92; H, 5.47; N, 15.20; S, 17.40. Found: C, 61.89; H, 5.48;
N, 15.17; S, 17.45.
4′-Methyl-N-(naphthalen-1-yl)-2′-phenyl-4,5′-bisthiazol-2-
amine (VIIIa).
II (0.148 g, 0.5 mmol) was dissolved in the
minimum amount of anhydrous acetone, and α-
naphthylthiourea (0.101g, 0.5 mmol) was added. The mixture was
stirred for 24 h at room temperature, and the formed precipitate
was suction-filtered. The product was refluxed with a mixture of
CH2Cl2: Acetone 1:1 (10mL) for 5 min, and the precipitate was
rapidly suction-filtered. Finally, it was neutralized with a 10%
solution of Na2CO3 solution and washed with distilled water until
neutral pH. Yield (58%, 0.115 g), gray powder, mp: 213–215°C;
1H NMR (DMSO-d6, 500MHz) δ (ppm): 10.56 (s, 1H, NH)
7.53–7.55 (m, 1H, Ar–H), 7.39–7.43 (m, 3H, Ar–H), 7.29–7.31
(m, 2H, Ar–H), 7.18–7.28 (Ar–H), 7.24 (s, 1H, Thiazole-CH),
2.67 (s, 3H, CH3); MS (EI, 70 eV) m/z (%): 400 (M + 1); Anal.
Calcd (%) for C23H17N3S2: C, 69.14; H, 4.29; N, 10.52; S,
16.05. Found: C, 69.23; H, 4.22; N, 10.61; S, 15.95.
N-Allyl-4′-methyl-2′-phenyl-4,5′-bisthiazol-2-amine (VIIIe).
The synthesis of this compound has been previously reported by
using EtOH as solvent in reflux conditions, although its biological
activity has not been determined [29]. II (0.148 g, 0.5mmol) was
dissolved in the minimum amount of anhydrous acetone, and
allylthiourea (0.058g, 0.5 mmol) was added. The precipitate was
then filtered, washed with dry diethyl ether, and neutralized with a
10% solution of Na2CO3. The product was then washed with
distilled water until neutral pH and dried overnight at room
temperature. The product was recrystallized from absolute
methanol. Yield (54.4%, 0.085g), yellow solid, mp: 112–113°C.
1H NMR (DMSO-d6, 500 MHz) δ ppm: 10.60 (s, 1H, NH), 7.41
(m, 1H, Ar–H), 7.29 (m, 2H, Ar–H), 7.22–7.26 (m, 2H, Ar–H),
7.32 (s, 1H, Thiazole-CH), 5.92–6.00 (m, 1H, CH), 5.12–5.17 (m,
1H, CH), 5.02–5.05 (m, 1H, CH), 3.51 (m, 2H, CH2), 2.68 (s, 3H,
CH3); MS (EI, 70eV) m/z (%): 314 (M + 1) Anal. Calcd. (%) for
C16H15N3S2: C, 61.31; H, 4.82; N, 13.41; S, 20.46. Found: C,
61.36; H, 4.79; N,13.34; S, 20.41.
N-(4′-Methyl-2′-phenyl-4,5′-bisthiazol-2-yl)acetamide (VIIIf).
The synthesis was performed according to the general procedure
described for VIIId by using N-carbamothioylacetamide
(0.118 g, 1 mmol) as a thioamide component. The product was
recrystallized from 96% ethanol. Yield (73%, 0.23 g), yellow
powder, mp: 269–270°C. 1H NMR (DMSO-d6, 500 MHz) δ
ppm: 9.47 (s, 1H, NH), 7.39–7.42 (m, 1H, Ar–H), 7.28–7.31
(m, 2H, Ar–H), 7.23–7.26 (m, 2H, Ar–H), 7.22 (s, 1H,
Thiazole-CH), 2.40 (s, 3H, –CH3), 2.70 (s, 3H, CH3); MS (EI,
Amino(4′-methyl-2′-phenyl-4,5′-bisthiazol-2-ylamino)
methaniminium bromide (VIIIb).
II (0.296 g, 1 mmol) was
dissolved in anhydrous acetone (5 mL), and a solution of 2-
imino-4-thiobiuret (0.118 g, 1 mmol) in acetone (5 mL) was
gradually added with continuous stirring at 0°C, over 30 min.
Stirring was continued for 24 h, and the formed precipitate was
suction-filtered and washed with dry diethyl ether (5 mL). The
product was recrystallized from absolute ethanol. Yield (59%,
0.234 g), light-yellow crystalline powder, mp: 282–284°C. 1H
NMR (DMSO-d6, 500MHz) δ ppm: 7.39–7.42 (m, 1H, Ar–H),
7.22–7.26 (m, 2H, Ar–H), 7.29–7.31 (m, 2H, Ar–H), 7.84 (s,
1H, Thiazole-CH), 5.60 (s, 5H, guanidino-H), 2.71 (s, 3H,
CH3); MS (EI, 70 eV) m/z (%): 316 (M + 1) Anal. Calcd. (%)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Antimicrobial Evaluation of Some New 4,5′-Bisthiazoles
70 eV) m/z (%): 316 (M + 1) Anal. Calcd. (%) for C15H13N3OS2:
C, 57.12; H, 4.15; N, 13.32; S, 20.33. Found: C, 57.14; H, 4.11;
N, 13.27; S, 20.29.
(M+ 1) Anal. Calcd. (%) for C18H14N4S3: C, 56.52; H, 3.69; N,
14.65; S, 25.15. Found: C, 56.46; H, 3.73; N, 14.52; S, 25.05.
2-Ethoxy-4-((2-(4′-methyl-2′-phenyl-4,5′-bisthiazol-2-yl)
N-4′-Dimethyl-2′-phenyl-4,5′-bisthiazol-2-amine (VIIIg).
The synthesis was performed according to the general procedure
described for VIIId by using II (0.148 g, 0.5 mmol) and 1-
methylthiourea (0.045 g, 0.5 mmol) as a thioamide component.
The product was recrystallized from 96% ethanol. Yield
(74%, 0.106 g), yellow powder, mp: 153–154°C. 1H NMR
(DMSO-d6, 500 MHz) δ ppm 9.13 (s, 1H, NH), 7.39–7.42
(m, 1H, Ar–H), 7.28–7.31 (m, 2H, Ar–H), 7.23–7.26 (m, 2H,
Ar–H), 7.25 (s, 1H, Thiazole-CH), 2.95 (s, 3H, CH3), 2.50
(s, 3H, –CH3); MS (EI, 70 eV) m/z (%): 288 (M + 1) Anal.
Calcd. (%) for C14H13N3S2: C, 58.51; H, 4.56; N, 14.62; S,
22.31. Found: C, 58.49; H, 4.58; N, 14.57; S, 22.36.
4′-Methyl-N,2′-diphenyl-4,5′-bisthiazol-2-amine (VIIIh).
The synthesis of this compound has been previously reported,
although its biological activity has not been determined [30].
II (0.296 g, 1 mmol) was dissolved in 96% EtOH (5 mL).
1-phenylthiourea (0.152 g, 1 mmol) was added and the mixture
was refluxed for 3 h. After cooling, the formed precipitate was
suction-filtered, neutralized with a 10% solution of Na2CO3,
and washed with distilled water until neutral pH. The product
was recrystallized from 96% ethanol. Yield (51%, 0.180 g),
yellow powder, mp 122–123°C;
VIIIh was also prepared according to the general procedure
described for VIIId by using II (0.296 g, 1 mmol) and 1-
phenylthiourea (0.152 g, 1 mmol) as a thioamide component.
The product was recrystallized from 96% ethanol. Yield
(60%, 0.208 g), yellow powder, mp 122–123°C; 1H NMR
(DMSO-d6, 500 MHz) δ ppm: 10.41 (s, 1H, NH), 7.95–7.97
(m, 2H, Ar–H), 7.68–7.70 (m, 2H, Ar–H), 7.50 (m, 3H, Ar–
H), 7.35–7.38 (m, 2H, Ar–H), 7.12 (s, 1H, Thiazole-CH),
2.66 (s, 3H, CH3); MS (EI, 70 eV) m/z (%): 350 (M + 1) Anal.
Calcd. (%) for C19H15N3S2: C, 65.30; H, 4.33; N, 12.02; S,
18.35. Found: C, 65.25; H, 4.26; N, 11.96; S, 18.32.
hydrazono)methyl)phenol (IXb).
Synthesis was performed
according to the general procedure described for VIIId by using
2-(3-ethoxy-4-hydroxybenzylidene)hydrazinecarbothioamide
(0.119 g, 0.5 mmol) as a thioamide component. The product
was recrystallized from absolute ethanol. Yield (80%,
0.180 g), brown-reddish powder, mp; 240–242°C; 1H NMR
(DMSO-d6, 500 MHz) δ ppm: 8.85 (s, 2H, –OH and –NH),
8.17–8.18 (m, 1H, ¼CH), 7.39–7.42 (m, 1H, Ar–H), 7.29–7.31
(m, 2H, Ar–H), 7.23–7.26 (m, 2H, Ar–H), 6.93–6.95 (m, 1H,
Ar–H), 7.20 (s, 1H, Thiazole-CH); 6.74–6.76 (m, 1H, Ar–H);
3.99–4.0 (q, 2H, CH2); 2.62 (s, 3H, CH3); 1.47–1.50 (t, 3H,
CH3); MS (EI, 70 eV) m/z: 437 (M + 1) Anal. Calcd. (%) for
C22H20N4O2S2: C, 60.53; H, 4.62; N 12.83; S, 14.69. Found:
C, 60.55; H, 4.63; N, 12.79; S, 14.84.
6-Chloro-3-((2-(4′-methyl-2′-phenyl-4,5′-bisthiazol-2-yl)
hydrazono)methyl)-4H-chromen-4-one (IXc).
2-((6-Chloro-4-
oxo-4H-chromen-3-yl)methylene)hydrazinecarbothioamide
(0.282g, 1 mmol) was suspended in anhydrous acetone (20 mL),
and II (0.296g, 1 mmol) was added. After stirring for 24 h at
room temperature, the product was filtered, washed with diethyl
ether (5 mL), and neutralized with a 10% solution of Na2CO3.
The compound was recrystallized from absolute ethanol. Yield
(83%, 0.400g), white powder, mp: 225–226°C; 1H NMR
(DMSO-d6, 500MHz) δ ppm: 9.70 (s, 1H, –NH–), 7.77 (d, 1H,
Ar–H), 7.58–7.59 (dd, 1H, Chromone-CH), 7.50–7.52 (dd, 1H,
Chromone-CH), 7.35–7.37 (m, 1H Chromone-CH), 7.39–7.42 (m,
1H, Ar–H), 7.29–7.31 (m, 2H, Ar–H), 7.22–7.26 (m, 2H, Ar–H),
7.16 (s, 1H, Thiazole-CH), 5.72 (d, 1H, Chromone-CH), 2.76
(s, 3H, –CH3); MS (EI, 70 eV) m/z (%): 479 (M + 1), 481
(M + 1)—corresponding to the two isotopes of chlorine. Anal.
Calcd. (%) for C23H15ClN4O2S2: C, 57.67; H, 3.16; N 11.70;
S, 13.39. Found: C, 57.59; H, 3.11; N 11.61; S, 13.51.
2-(4′-Methyl-2′-phenyl-4,5′-bisthiazol-2-yl)-N-phenylhydrazine-
carboxamide (VIIIi). Synthesis was performed according to the
general procedure described for VIIId by using II (0.296 g,
1 mmol) and 2-carbamothioyl-N-phenylhydrazinecarboxamide
(0.21 g, 1 mmol) as a thioamide component. The product was
recrystallized from absolute ethanol. Yield (86%, 0.349 g), yellow
Acknowledgments. This research was financially supported by
the Iuliu Haţieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania, Grant 22714/2011.
1
REFERENCES AND NOTES
powder, mp 245–246°C; H NMR (DMSO-d6, 500 MHz) δ ppm:
8.80 (s, 1H, –NH), 8.51 (d, 1H, –NH), 7.69 (d, 1H, –NH),
7.37–7.42 (m, 3H, Ar–H), 7.28–7.31 (m, 2H, Ar–H), 7.22–7.26
(m, 2H, Ar–H), 7.17–7.21 (m, 2H, Ar–H), 6.92–6.96 (m, 1H,
cAr–H), 6.67 (s, 1H, Thiazole-CH), 2.61 (s, 3H, –CH3); MS
(EI, 70 eV) m/z (%): 408 (M+ 1); Anal. Calcd. for C20H17N5OS2:
C, 58.95; H, 4.20; N 17.19; S, 15.74. Found: C, 59.03; H, 4.17;
N, 17.11; S, 15.80.
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1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet