Design, Synthesis, and in vitro Antimicrobial Activity of New Furan/Thiophene-1,3-Benzothiazin-4-one Hybrids

Article abstract of DOI:10.1002/jhet.2429

This study presents the design, synthesis, spectral analysis, and in vitro antimicrobial evaluation of a new series of furan/thiophene-1,3-benzothiazin-4-one hybrids (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). New compounds were obtained by cyclization reaction of N-substituted furan/thiophene-2-carboxamide derivatives (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) with thiosalicylic acid. All synthesized compounds were screened for their in vitro antimicrobial activities using the broth microdilution method. Nine of the synthesized compounds showed good activity against Gram-positive, Gram-negative bacteria, and yeasts belonging to Candida spp. (MIC = 7.81-500 μg/mL), especially against Staphylococcus spp. (MIC = 15.62-62.5 μg/ml), Bacillus spp. (MIC = 7.81-62.5 μg/mL), Bordetella bronchiseptica ATCC 4617 (MIC = 62.5-125 μg/mL), and fungistatic activity against Candida spp. (MIC = 62.5-125 μg/mL).

Full text of DOI:10.1002/jhet.2429

March 2016
Design, Synthesis, and in vitro Antimicrobial Activity of New
479
Furan/Thiophene-1,3-Benzothiazin-4-one Hybrids
a
b
b
*
Łukasz Popiołek, Anna Biernasiuk, and Anna Malm
aDepartment of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin,
4A Chodźki Street, 20-093 Lublin, Poland
bDepartment of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Faculty of Pharmacy with
Medical Analytics Division, Medical University of Lublin, 1 Chodźki Str, 20-093 Lublin, Poland
*
E-mail: lukasz.popiolek@umlub.pl
Additional Supporting Information may be found on the online version of this article
Received January 28, 2015
DOI 10.1002/jhet.2429
Published online 21 April 2015 Wiley Online Library (wileyonlinelibrary.com).
This study presents the design, synthesis, spectral analysis, and in vitro antimicrobial evaluation of a new
series of furan/thiophene-1,3-benzothiazin-4-one hybrids (17–32). New compounds were obtained by cycli-
zation reaction of N-substituted furan/thiophene-2-carboxamide derivatives (1–16) with thiosalicylic acid.
All synthesized compounds were screened for their in vitro antimicrobial activities using the broth
microdilution method. Nine of the synthesized compounds showed good activity against Gram-positive,
Gram-negative bacteria, and yeasts belonging to Candida spp. (MIC = 7.81–500 μg/mL), especially against
Staphylococcus spp. (MIC = 15.62–62.5 μg/ml), Bacillus spp. (MIC = 7.81–62.5 μg/mL), Bordetella
bronchiseptica ATCC 4617 (MIC = 62.5–125 μg/mL), and fungistatic activity against Candida spp. (MIC
= 62.5–125 μg/mL).
J. Heterocyclic Chem., 53, 479 (2016).
INTRODUCTION
spectrum of antimicrobial activity, reduced their toxicity
to the human body, and above all, with a reduction in op-
portunities for microbial drug resistance [1].
Review of the literature shows that the synthesis of a
hybrid compounds is a classic design and strategy for
new biologically active compounds. It is based on a
combination of two or more bioactive molecules in
one molecule, to obtain the corresponding hybrid com-
pound [1].
The growing problem of multi-drug resistance caused
by micro-organisms has reached alarming levels in many
countries around the world. Microbial resistance not only
contributed to the increase in mortality associated with
infections and the incidence of infections but also
significantly contributed to raise the financial costs of
health care related to the treatment of drug-resistant in-
fections [1].
In this paper, we decided to combine two different bio-
logically active heterocyclic moieties: furan or thiophene
derivatives with benzothiazines. The benzothiazine deriva-
tives are widely reported for their biological properties like
antibacterial [3–5], antifungal [6,7], antitubercular [8], an-
timalarial [9], antiviral [10], anti-inflammatory [11–13],
analgesic [13], and antiproliferative activities [14–16].
Because of the aforementioned facts, the purpose of this
research is to provide a series of hybrid compounds
consisting of furane/thiophene derivatives combined with
1,3-benzothiazin-4-one derivatives as new potential anti-
microbial agents.
Many recent publications indicate that, despite the grow-
ing problem of resistance to antimicrobial agents among
the most common pathogens, the number of new antibi-
otics introduced into medicine is steadily declining in re-
cent years. For example, when considering the matter, the
Infectious Diseases Society of America, in 2010, proposed
the initiative “10 × 20” calling for a global effort to dis-
cover and implement 10 new antibiotics by 2020 [2].
In order to overcome the rapidly increasing microbial re-
sistance to currently used drugs is necessary to search for
new antimicrobial agents that should significantly differ
structurally and show a different mechanism of action than
currently used chemotherapeutic agents.
RESULTS AND DISCUSSION
It seems appropriate to combine two or more systems
with different pharmacophoric groups, which exhibit com-
plementary mechanism of antimicrobial activity. This
would imply an increase in its potency, broadening the
Chemistry. New furan/thiophene-1,3-benzothiazin-4-
one conjugates were synthesized according to the synthetic
route presented in Scheme 1. The synthesis followed the
© 2015 HeteroCorporation

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Ł. Popiołek, A. Biernasiuk, and A. Malm
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Scheme 1. Reactions leading to new furan/thiophene-1,3-benzothiazin-4-one hybrids.
Microbiology
general pathway. First, the hydrazides of furan-2-
carboxylic acid or thiphene-2-carboxylic acid were
subjected to condensation reactions with various
aromatic aldehydes in ethanol as a solvent. Second,
obtained N-substituted furan/thiophene-2-carboxamide
derivatives (1–16) were reacted with thiosalicylic acid
in the presence of 1,4-dioxane to give new furan/
thiophene-1,3-benzothiazin-4-one hybrids (17–32).
Antibacterial activity. According to the data presented
in Table 1, on the basis of minimal inhibitory
concentration values obtained by the broth microdilution
method [17], it was shown that among the examined
compounds, the widest spectrum of antibacterial activity
possessed compounds 14, 15, 16, 22, 24, 29, and 31
against all investigated strains of Gram-positive bacteria:
staphylococci (MIC =15.62–1000 μg/mL, MBC = 125–>
1000 μg/mL), micrococci (MIC=125–1000 μg/mL, MBC
>1000 μg/mL), and Bacillus spp. (MIC= 7.81–1000 μg/mL,
MBC >1000μg/mL).
Among them, compounds 15, 16, and 31 exhibited the
highest bactericidal or bacteriostatic activity against Staph-
ylococcus spp. (MIC = 15.62–62.5 μg/mL, MBC = 125 to
>1000 μg/mL) and Bacillus spp. ATCC (MIC = 7.81–
62.5 μg/mL, MBC 62.5 to >1000 μg/mL). Compound 15
showed especially strong antibacterial activity against Staphy-
lococcus aureus ATCC 25923, S. aureus ATCC 6538, and
Bacillus cereus ATCC 10876 (MIC = 15.62 μg/mL). More-
over, very strong activity was found for compound 16 against
B. cereus ATCC 10876 (MIC = 7.81 μg/mL) (Table 1).
The remaining compounds 1, 7, 9, 17, 18, 23, 25, 26, 28,
and 30 exhibited slightly weaker antibacterial activity (MIC =
125–1000μg/mL) or no activity to Gram-positive bacteria.
Some of the tested compounds (14, 17, 18, 24, 25, 26, 29,
and 31) inhibited the growth of reference strains of Gram-
negative bacteria, for example, Bordetella bronchiseptica
ATCC 4617, especially compounds 25 and 26 with good
antibacterial activity (MIC = 62.5–125μg/mL) or Escherichia
coli ATCC 25922 (compounds 17 and 18 with mild bioac-
tivity; MIC = 1000 μg/mL) (Table 1).
All the newly obtained compounds are air stable solids
and soluble in dimethyl sulfoxide (DMSO) at ambient tem-
perature. Structure of all obtained derivatives was
established on the basis of elemental and spectral analysis
(1H NMR, 13C NMR). The purity of the synthesized com-
1
pounds was checked by thin layer chromatography. H
NMR spectral results for all compounds together with
hydrogen assignments, and 13C NMR spectra results are
presented in the Experimental Section.
The 1H NMR spectra of the derivatives 1–16
showed one proton singlet signal typical for the NH
group in the δ 8.26–12.19 ppm range and one proton
singlet signal for the ¼CH group at δ 7.91–8.79 ppm,
what confirmed the successful formation of the desired
products. The 1H NMR of 17–32 compounds con-
firmed the adequate cyclization to appropriate new
furan/thiophene-1,3-benzothiazin-4-one hybrids. The
singlet signal for NH group was observed in the δ
8.79–14.23 ppm range and for the CH group at δ
5.01–8.80 ppm. The 13C NMR spectra of compounds
1–16 also confirmed the presence of C¼O group at δ
156.3–161.7 ppm and ¼CH group in the range of δ
136.9–157.2 ppm. Whereas for compounds 17–32 in
13C NMR, the characteristic signals for two C¼O
groups at δ 155.2–164.8 ppm and for CH group in
the range of δ 50.7–58.1 ppm were observed. All other
aliphatic and aromatic signals for obtained compounds
were observed at expected regions.
The remaining compounds had no inhibitory effect on
the growth of reference strains of Gram-negative bacteria
even at maximal concentration used (2000 μg/mL) by pre-
liminary agar dilution method. Moreover, all tested strains
of bacteria were insensitive to compounds 2–6, 8, 10–13,
19–21, and 27 (Table 1).
All of synthesized compounds (1–32) were subjected to
in vitro antimicrobial assays.
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Antifungal activity.
Compounds 25 and 26 showed
solution was cooled at room temperature. The obtained
precipitate was filtered off and crystallized from ethanol.
N-[2-(1H-pyrrol-2-yl)ethenyl]furan-2-carboxamide (1). Yield:
good fungistatic activity with MIC = 62.5–125 μg/mL
against both strains of Candida albicans and good or
moderate activity with MIC =62.5–500μg/mL against
Candida parapsilosis ATCC 22019. In turn, compounds
24, 27, 28, 29, 30, and 31 inhibited the growth of yeasts
with MIC values ranging from 250 to 1000 μg/mL or had
no activity to reference strains. The MFC (Minimal
Fungicidal Concentration) of tested compounds for these
yeasts was >1000μg/mL. The remaining compounds had
no antifungal activity (Table 1).
1
94.6%; mp: 240–242°C. H NMR (DMSO-d6) δ (ppm)
= 6.13–6.14 (m, 1H, ArH), 6.46–6.48 (m, 1H, ArH),
6.67–6.69 (m, 2H, ArH), 6.90–6.92 (m, 1H, ArH), 7.23–
7.24 (m, 1H, ArH), 7.91 (s, 1H, ¼CH), 8.28 (s, 1H, NH),
11.54 (s, 1H, NHpyrrole); 13C NMR (DMSO) δ (ppm)
= 110.8, 112.6, 116.2, 118.5, 119.5, 124.7 (6Car), 136.9
(¼CH), 144.0, 144.9 (2Car), 156.8 (C¼O). Analysis for
C10H9N3O2 (203.20) Calculated: C, 57.28%; H, 7.67%;
N, 11.56%. Found: C, 57.34%; H, 7.82%; N, 11.61%.
N-[2-(1H-pyrrol-2-yl)ethenyl]thiophene-2-carboxamide (2).
CONCLUSIONS
1
Yield: 92.3%; mp: 236–238°C. H NMR (DMSO-d6) δ
In this research we designed, synthesized, and analyzed
16 new furane/thiophene-1,3-benzothiazin-4-one hybrids
(17–32) and subjected them to in vitro antimicrobial assays.
Our antibacterial activity results indicate that among the
synthesized compounds, the highest antimicrobial activity
possesses compounds 15, 16, and 31 against reference
strains of Gram-positive bacteria (MIC=7.81–125μg/mL)
and compounds 25 or 26 against reference yeasts species
(MIC=62.5–500μg/mL).
(ppm) = 6.15–6.16 (m, 1H, ArH), 6.50–6.56 (m, 1H,
ArH), 6.92–6.97 (m, 1H, ArH), 7.19–7.22 (m, 1H, ArH),
7.82–7.87 (m, 2H, ArH), 8.14 (s, 1H, ¼CH), 8.26 (s,
1H, NH), 11.55 (s, 1H, NHpyrrole); 13C NMR (DMSO) δ
(ppm) = 110.9, 116.2, 119.5, 124.7, 127.4, 130.0, 133.1
(7Car), 136.9 (¼CH), 138.6 (Car), 161.7 (C¼O).
Analysis for C10H9N3OS (219.26) Calculated: C,
54.78%; H, 4.14%; N, 19.16%. Found: C, 54.82%; H,
4.11%; N, 19.19%.
N-[2-(2,3-dimethoxyphenyl)ethenyl]furan-2-carboxamide (3).
Yield: 94.2%; mp: 89–91°C. 1H NMR (DMSO-d6) δ
(ppm)=3.85 (s, 3H, CH3), 3.89 (s, 3H, CH3), 6.76–6.78
(m, 1H, ArH), 7.16–7.20 (m, 2H, ArH), 7.37–7.39 (m,
1H, ArH), 7.50–7.53 (m, 1H, ArH), 7.99–8.01 (m, 1H,
ArH), 8.79 (s, 1H, ¼CH), 11.96 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)=56.8 (CH3), 60.6 (CH3), 112.6, 114.4,
118.5, 122.0, 123.3, 127.5, 144.0, 144.9, 149.7, 149.9
(10Car), 150.7 (¼CH), 156.8 (C¼O). Analysis for
C14H14N2O4 (274.27) Calculated: C, 61.31%; H, 5.14%;
EXPERIMENTAL
Chemistry. All reagents were purchased from Sigma-
Aldrich (Munich, Germany) and Merck Co. (Darmstadt,
Germany) and used without further purification. Melting
points were determined in Fisher-Johns blocks (Fisher
Scientific, Schwerte, Germany) and presented without
1
any corrections. The H NMR spectra were recorded on a
Bruker Avance 300 apparatus (Bruker BioSpin GmbH,
Rheinstetten/Karlsruhe, Germany) in DMSO-d6 with
tetramethylsilane as internal standard. The 13C NMR
spectra were recorded on a Bruker Avance 300 apparatus.
Chemical shifts are given in ppm (δ-scale). The purity of
obtained compounds was checked by thin layer
chromatography on aluminum oxide 60 F254 plates
(Merck Co. Whitehouse Station, New Jersey, USA), in a
CHCl3/C2H5OH (10:1, v/v) solvent system. The spots
were detected by exposure to a UV lamp at 254nm.
Elemental analyses of the obtained compounds were
performed for C, H, N on AMZ 851 CHX analyser (PG,
Gdańsk, Poland). The maximum percentage differences
between calculated and found values for each element
were within the error and amounted to 0.4%.
N, 10.21%. Found: C, 61.35%; H, 5.19%; N, 10.28%.
N-[2-(2,3-dimethoxyphenyl)ethenyl]thiophene-2-carboxamide
(4). Yield: 75.6%; mp: 180–182°C. 1H NMR (DMSO-d6)
δ (ppm)=3.85 (s, 3H, CH3), 3.90 (s, 3H, CH3), 7.17–7.31
(m, 2H, ArH), 7.53–7.68 (m, 1H, ArH), 7.93–8.10 (m,
2H, ArH), 8.47–8.48 (m, 1H, ArH), 8.77 (s, 1H, ¼CH),
11.86 (s, 1H, NH); 13C NMR (DMSO) δ (ppm)=59.8
(CH3), 60.6 (CH3), 114.4, 122.0, 122.3, 127.4, 130.0,
133.1, 138.6, 149.7, 149.9 (10Car), 150.7 (¼CH), 161.7
(C¼O). Analysis for C14H14N2O3S (290.34) Calculated:
C, 57.92%; H, 4.86%; N, 9.65%. Found: C, 57.98%; H,
4.82%; N, 9.61%.
N-[2-(2,4-dimethoxyphenyl)ethenyl]furan-2-carboxamide (5).
Yield: 88.5%; mp: 176–178°C. 1H NMR (DMSO-d6) δ
(ppm)=3.80 (s, 3H, CH3), 3.84 (s, 3H, CH3), 6.59–6.68 (m,
3H, ArH), 7.26–7.27 (m, 1H, ArH), 7.75–7.90 (m, 2H,
ArH), 8.68 (s, 1H, ¼CH), 11.70 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)= 56.0 (CH3), 56.8 (CH3), 100.3, 107.1,
112.6, 117.5, 118.5, 129.7, 144.1, 144.9 (8Car), 151.6
(¼CH), 156.8 (C¼O), 160.9, 162.8 (2Car). Analysis for
C14H14N2O4 (274.27) Calculated: C, 61.31%; H, 5.14%; N,
10.21%. Found: C, 61.35%; H, 5.17%; N, 10.18%.
Synthesis of N-substituted furan/thiophene-2-carboxamide
derivatives (1–16)
General procedure.
To a solution of furan-2-
carbohydrazide or thiophene-2-carbohydrazide (10 mmol)
in ethanol (20 mL), an equimolar amount of various
aldehydes (10mmol) was added. The suspension was heated
until clear solution was obtained, and then the solution was
refluxed for 2 h. After the completion of the reaction, the
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N-[2-(2,4-dimethoxyphenyl)ethenyl]thiophene-2-carboxamide
(6). Yield: 79.2%; mp: 122–124°C. H NMR (DMSO-
(C¼O). Analysis for C12H10N2O2S (246.28) Calculated: C,
1
58.52%; H, 4.09%; N, 11.37%. Found: C, 58.55%; H,
d6) δ (ppm)=3.88 (s, 3H, CH3), 3.92 (s, 3H, CH3),
6.71–6.75 (m, 2H, ArH), 7.25–7.29 (m, 1H, ArH),
7.84–8.01 (m, 2H, ArH), 8.09–8.10 (m, 1H, ArH), 8.75
(s, 1H, ¼CH), 11.73 (s, 1H, NH); 13C NMR (DMSO) δ
(ppm)=56.0 (CH3), 56.8 (CH3), 100.3, 107.1, 117.5,
127.4, 129.7, 130.0, 133.1, 138.6 (8Car), 151.6 (¼CH),
160.9 (Car), 161.7 (C¼O), 162.8 (Car). Analysis for
C14H14N2O3S (290.34) Calculated: C, 57.92%; H,
4.86%; N, 9.65%. Found: C, 57.87%; H, 4.89%; N,
4.11%; N, 11.34%.
N-[2-(5-bromo-2-hydroxyphenyl)ethenyl]furan-2-carboxamide
1
(11). Yield: 96.9%; mp: 198–200°C. H NMR (DMSO-
d6) δ (ppm)=6.77–6.79 (m, 1H, ArH), 6.94–6.98 (m, 1H,
ArH), 7.39–7.40 (m, 1H, ArH), 7.47–7.48 (m, 1H, ArH),
7.50–7.51 (m, 1H, ArH), 7.83–8.03 (m, 1H, ArH), 8.67 (s,
1H, ¼CH), 11.19 (s, 1H, OH), 12.25 (s, 1H, NH); 13C
NMR (DMSO) δ (ppm)= 112.6, 114.6, 118.5, 118.9,
119.3, 130.4, 130.5, 144.0, 144.9 (9Car), 150.4 (¼CH),
156.3 (Car), 156.3 (C¼O). Analysis for C12H9BrN2O3
57.80%.
N-[2-(2-ethoxy-4-hydroxyphenyl)ethenyl]furan-2-carboxamide
(309.11) Calculated: C, 46.63%; H, 2.93%; N, 9.06%.
Found: C, 46.69%; H, 2.91%; N, 9.10%.
(7). Yield: 96.5%; mp: 118–120°C. 1H NMR (DMSO-d6)
δ (ppm)=1.39–1.45 (t, 3H, CH3, J=7.5Hz), 4.09–4.16 (q,
2H, CH2, J= 7.5 Hz), 6.73–6.75 (m, 1H, ArH), 6.90–6.93
(m, 1H, ArH), 7.11–7.15 (m, 1H, ArH), 7.32–7.34 (m, 2H,
ArH), 7.43–7.48 (m, 1H, ArH), 8.38 (s, 1H, ¼CH), 9.57
(s, 1H, OH), 11.73 (s, 1H, NH); 13C NMR (DMSO) δ
(ppm)=13.8 (CH3), 64.5 (CH2), 103.5, 110.1, 112.6,
116.7, 118.5, 130.2, 144.0, 144.9 (8Car), 151.6 (¼CH),
156.8 (C¼O), 157.6, 162.2 (2Car). Analysis for
C14H14N2O4 (274.27) Calculated: C, 61.31%; H, 5.14%;
N-[2-(5-bromo-2-hydroxyphenyl)ethenyl]thiophene-2-carboxamide
(12). Yield: 97.1%; mp: 180–182°C. H NMR (DMSO-
1
d6) δ (ppm) = 6.89–6.92 (m, 1H, ArH), 7.22–7.25 (m, 1H,
ArH), 7.41–7.44 (m, 1H, ArH), 7.69–7.84 (m, 1H, ArH),
7.89–7.94 (m, 2H, ArH), 8.60 (s, 1H, ¼CH), 11.16 (s,
1H, OH), 12.19 (s, 1H, NH); 13C NMR (DMSO) δ
(ppm) = 114.6, 118.9, 119.3, 127.4, 130.0, 130.4, 130.6,
133.1, 138.6 (9Car), 150.4 (¼CH), 156.3 (Car), 161.7
(C¼O). Analysis for C12H9BrN2O2S (325.18) Calculated:
C, 44.32%; H, 2.79%; N, 8.61%. Found: C, 44.35%; H,
N, 10.21%. Found: C, 61.35%; H, 5.12%; N, 10.25%.
N-[2-(2-ethoxy-4-hydroxyphenyl)ethenyl]thiophene-2-carboxamide
2.80%; N, 8.59%.
1
(8). Yield: 60.9%; mp: 160–162°C. H NMR (DMSO-
N-[2-(3-bromo-4-hydroxyphenyl)ethenyl]furan-2-carboxamide
1
d6) δ (ppm) = 1.43–1.47 (t, 3H, CH3, J = 5 Hz), 4.09–4.18
(q, 2H, CH2, J =7.5 Hz), 6.91–6.94 (m, 1H, ArH), 7.14–
7.24 (m, 1H, ArH), 7.26–7.29 (m, 1H, ArH), 7.36–7.46
(m, 1H, ArH), 7.90–7.95 (m, 1H, ArH), 8.01–8.09 (m,
1H, ArH), 8.37 (s, 1H, ¼CH), 9.58 (s, 1H, OH), 11.75
(s, 1H, NH); 13C NMR (DMSO) δ (ppm) = 13.8 (CH3),
64.5 (CH2), 103.5, 110.1, 116.6, 127.4, 130.0, 133.1,
138.6 (8Car), 151.6 (¼CH), 158.2 (C¼O), 157.6, 162.2
(2Car). Analysis for C14H14N2O3S (290.34) Calculated:
C, 57.92%; H, 4.86%; N, 9.65%. Found: C, 57.89%; H,
(13). Yield: 54.0%; mp: 220–222°C. H NMR (DMSO-
d6) δ (ppm)=6.69–6.70 (m, 1H, ArH), 7.01–7.03 (m, 1H,
ArH), 7.28–7.29 (m, 1H, ArH), 7.53–7.58 (m, 1H, ArH),
7.84–7.94 (m, 2H, ArH), 8.31 (s, 1H, ¼CH), 10.81 (s, 1H,
OH), 11.78 (s, 1H, NH); 13C NMR (DMSO) δ (ppm)
=109.9, 112.6, 116.3, 118.5, 127.2, 128.4, 130.4, 144.0,
144.9 (9Car), 148.6 (¼CH), 153.7 (Car), 158.6 (C¼O).
Analysis for C12H9BrN2O3 (309.11) Calculated: C,
46.63%; H, 2.93%; N, 9.06%. Found: C, 46.60%; H,
2.94%; N, 9.09%.
4.85%; N, 9.67%.
N-[2-(3-bromo-4-hydroxyphenyl)ethenyl]thiophene-2-carboxamide
N-[2-(2-hydroxyphenyl)ethenyl]furan-2-carboxamide (9).
(14). Yield: 49.4%; mp: 193–195°C. 1H NMR (DMSO-d6)
1
Yield: 83.5%; mp: 163–165°C. H NMR (DMSO-d6) δ
δ (ppm)= 7.02–7.06 (m, 1H, ArH), 7.20–7.23 (m, 1H, ArH),
7.56–7.66 (m, 1H, ArH), 7.87–8.03 (m, 3H, ArH), 8.29 (s,
1H, ¼CH), 10.82 (s, 1H, OH), 11.81 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)= 109.9, 116.3, 127.2, 127.4, 128.4, 130.0,
130.4, 133.1, 138.6 (9Car), 148.6 (¼CH), 153.7 (Car), 161.7
(C¼O). Analysis for C12H9BrN2O2S (325.18) Calculated: C,
44.32%; H, 2.79%; N, 8.61%. Found: C, 44.39%; H, 2.75%;
(ppm)=6.77–6.79 (m, 1H, ArH), 6.95–7.01 (m, 2H, ArH),
7.33–7.39 (m, 2H, ArH), 7.58–7.61 (m, 2H, ArH),
7.58–7.61 (m, 1H, ArH), 8.01–8.02 (m, 1H, ArH), 8.70 (s,
1H, ¼CH), 11.20 (s, 1H, OH), 12.19 (s, 1H, NH); 13C
NMR (DMSO) δ (ppm)=112.6, 117.4, 118.5, 120.4,
121.1, 128.5, 129.7, 144.0, 144.9 (9Car), 152.1 (¼CH),
156.8 (C¼O), 158.3 (Car). Analysis for C12H10N2O3
(230.22) Calculated: C, 62.60%; H, 4.38%; N, 12.17%.
N, 8.65%.
N-[2-(3-bromo-4-methoxyphenyl)ethenyl]furan-2-carboxamide
(15). Yield: 62.7%; mp: 109–111°C. 1H NMR (DMSO-d6)
Found: C, 62.64%; H, 4.39%; N, 12.19%.
N-[2-(2-hydroxyphenyl)ethenyl]thiophene-2-carboxamide (10).
δ (ppm) =3.90 (s, 3H, CH3), 6.70–6.71 (m, 1H, ArH), 7.18–
7.21 (m, 1H, ArH), 7.29–7.30 (m, 1H, ArH), 7.67–7.68 (m,
1H, ArH), 7.70–7.71 (m, 1H, ArH), 7.92–7.94 (m, 1H,
ArH), 8.36 (s, 1H, ¼CH), 11.86 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)=56.8 (CH3), 112.6, 114.3, 114.4, 118.5,
126.9, 132.3, 144.0, 144.9 (9Car), 148.6 (¼CH), 156.8
(C¼O), 157.2 (Car). Analysis for C13H11BrN2O3 (323.14)
Yield: 69.5%; mp: 165–167°C. 1H NMR (DMSO-d6) δ
(ppm) = 6.95–7.01 (m, 2H, ArH), 7.28–7.39 (m, 2H, ArH),
7.61–7.65 (m, 1H, ArH), 7.95–8.11 (m, 2H, ArH), 8.50 (s,
1H, ¼CH), 8.68 (s, 1H, OH), 9.06 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)= 117.4, 120.4, 121.2, 127.4, 128.5, 129.7,
130.0, 133.1, 123.6 (9Car), 152.0 (¼CH), 158.3 (Car), 161.7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

484
Ł. Popiołek, A. Biernasiuk, and A. Malm
Vol 53
N-[2-(2,3-dimethoxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
Calculated: C, 48.32%; H, 3.43%; N, 8.67%. Found: C,
48.35%; H, 3.41%; N, 8.71%.
yl]thiophene-2-carboxamide (20). Yield: 95.1%; mp: 148–
1
150°C. H NMR (DMSO-d6) δ (ppm)=3.78 (s, 3H, CH3),
N-[2-(3-bromo-4-methoxyphenyl)ethenyl]thiophene-2-carboxamide
(16). Yield: 60.0%; mp: 183–185°C. 1H NMR (DMSO-d6) δ
3.83 (s, 3H, CH3), 5.01 (s, 1H, CH), 7.16–7.27 (m, 4H,
ArH), 7.52–7.68 (m, 2H, ArH), 7.88–8.10 (m, 2H, ArH),
8.48–8.50 (m, 1H, ArH), 8.74–8.75 (m, 1H, ArH), 11.94 (s,
1H, NH); 13C NMR (DMSO) δ (ppm)=54.5 (CH), 56.8
(CH3), 60.6 (CH3), 114.9, 120.7, 121.4, 127.1, 127.4, 129.0,
129.2, 129.4, 129.5, 130.0, 130.4, 134.8, 136.8, 139.2,
145.2, 151.6 (16Car), 156.3 (C¼O), 163.9 (C¼O). Analysis
for C21H18N2O4S2 (426.51) Calculated: C, 59.14%; H,
(ppm) = 3.97 (s, 3H, CH3), 7.27–7.37 (m, 2H, ArH), 7.76–8.10
(m, 4H, ArH), 8.40 (s, 1H, ¼CH), 11.94 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm) =56.8 (CH3), 114.3, 114.4, 126.9, 127.4,
129.1, 130.0, 132.3, 133.1, 138.6 (9Car), 157.2 (¼CH), 158.2
(Car) 161.7 (C¼O). Analysis for C13H11BrN2O2S (339.21)
Calculated: C, 46.03%; H, 3.27%; N, 8.26%. Found: C,
46.08%; H, 3.23%; N, 8.29%.
4.25%; N, 6.57%. Found: C, 59.18%; H, 4.28%; N, 6.61%.
N-[2-(2,4-dimethoxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
yl]furan-2-carboxamide (21). Yield: 94.5%; mp: 120–122°
Synthesis of 2,3-disubstituted-4-oxo-1,3-benzothiazine derivatives
(17–32)
General procedure.
To a solution of N-substituted
1
C. H NMR (DMSO-d6) δ (ppm)=3.81 (s, 3H, CH3), 3.84
furan/thiophene-2-carboxamide derivatives 1–16 (10mmol)
in 15mL of 1,4-dioxane, thiosalicylic acid (1.54g,
10mmol) was added. The mixture was stirred under reflux
for 3h at 100°C. Then the solvent was removed under
reduced pressure. After that, 15mL of 10% water solution
(s, 3H, CH3), 6.60–6.68 (m, 3H, ArH), 7.23–7.26 (m, 2H,
ArH), 7.53–7.59 (m 2H, ArH), 7.79–7.90 (m, 2H, ArH),
7.99–8.00 (m, 1H, ArH), 8.68 (s, 1H, CH), 11.70 (s, 1H,
NH); 13C NMR (DMSO) δ (ppm)=53.3 (CH), 56.0 (CH3),
56.8 (CH3), 100.4, 106.9, 112.6, 114.5, 121.4, 127.1,
129.2, 129.4, 130.4, 130.5, 134.8, 136.8, 144.0, 145.9
(14Car), 155.2 (C¼O), 156.1, 161.4 (2Car), 163.9 (C¼O).
Analysis for C21H18N2O5S (410.44) Calculated: C,
61.45%; H, 4.42%; N, 6.83%. Found: C, 61.41%; H,
4.41%; N, 6.85%.
of sodium bicarbonate was added. The precipitate was
filtered off and purified by recrystallization from ethanol.
N-[4-oxo-2-(1H-pyrrol-2-yl)-2H-1,3-benzothiazin-3(4H)-yl]furan-
2-carboxamide (17).
Yield: 36.0%; mp: 224–226°C. 1H
NMR (DMSO-d6) δ (ppm)=6.08–6.11 (m, 2H, ArH), 6.27
(s, 1H, CH), 6.43–6.47 (m, 1H, ArH), 6.83–6.85 (m, 1H,
ArH), 7.07–7.07 (m, 1H, ArH), 7.16–7.19 (m, 1H, ArH),
7.35–7.44 (m, 4H, ArH), 9.68 (s, 1H, NH), 14.23 (s, 1H,
NH); 13C NMR (DMSO) δ (ppm)=58.0 (CH), 107.8,
109.7, 112.6, 114.5. 119.9, 127.1, 129.2, 129.4, 130.4,
134.1, 134.8. 136.8, 144.0, 145.9 (14Car), 155.2 (C¼O),
164.7 (C¼O). Analysis for C17H13N3O3S (339.37)
Calculated: C, 60.17%; H, 3.86%; N, 12.38%. Found: C,
N-[2-(2,4-dimethoxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
yl]thiophene-2-carboxamide (22). Yield: 92.3%; mp: 116–
1
118°C. H NMR (DMSO-d6) δ (ppm)=3.81 (s, 3H, CH3),
3.85 (s, 3H, CH3), 5.08 (s, 1H, CH), 6.64–6.68 (m, 2H,
ArH), 6.81–6.86 (m, 1H, ArH), 7.04–7.10 (m, 1H, ArH),
7.1–.21 (m, 1H, ArH), 7.31–7.36 (m, 1H, ArH), 7.52–7.63
(m, 1H, ArH), 7.77–7.91 (m, 3H, ArH), 11.71 (s, 1H, NH);
13C NMR (DMSO) δ (ppm)=53.4 (CH), 56.0 (CH3), 56.8
(CH3), 100.4, 106.9, 121.4, 127.1, 127.4, 129.0, 129.2,
129.4, 130.0, 130.4, 130.5, 134.8, 136.8, 139.2, 156.1
(15Car), 156.3 (C¼O), 161.4 (Car), 163.9 (C¼O). Analysis
for C21H18N2O4S2 (426.51) Calculated: C, 59.14%; H,
60.20%; H, 3.85%; N, 12.40%.
N-[4-oxo-2-(1H-pyrrol-2-yl)-2H-1,3-benzothiazin-3(4H)-
yl]thiophene-2-carboxamide (18). Yield: 54.2%; mp: 214–
1
216°C. H NMR (DMSO-d6) δ (ppm) = 6.21 (s, 1H, CH),
6.65–6.62 (m, 2H, ArH), 7.23–7.28 (m, 4H, ArH), 7.86–
8.32 (m, 4H, ArH), 9.54 (s, 1H, NH), 11.64 (s, 1H, NH);
13C NMR (DMSO) δ (ppm) =58.1 (CH), (CH3), 107.8,
109.4, 119.9, 127.1, 129.0, 129.2, 129.4, 130.0, 130.1,
130.4, 134.1, 134.8, 136.8, 139.2 (14Car), 156.3 (C¼O),
164.8 (C¼O). Analysis for C17H13N3O2S2 (355.43)
Calculated: C, 57.45%; H, 3.69%; N, 11.82%. Found: C,
4.25%; N, 6.57%. Found: C, 59.16%; H, 4.28%; N, 6.59%.
N-[2-(2-ethoxy-4-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]furan-2-carboxamide (23).
Yield: 97.1%; mp:
1
118–120°C. H NMR (DMSO-d6) δ (ppm)=1.36–1.42 (t,
3H, CH3), 4.05–4.13 (q, 2H, CH2), 6.72–6.73 (m, 1H,
ArH), 6.88–6.91 (m, 1H, ArH), 7.10–7.20 (m, 1H, ArH),
7.31–7.40 (m, 3H, ArH), 7.51–7.68 (m, 2H, ArH), 7.96–
7.98 (m, 1H, ArH), 8.09–8.13 (m, 1H, ArH), 8.37 (s, 1H,
CH), 9.53 (s, 1H, OH), 11.71 (s, 1H, NH); 13C NMR
(DMSO) δ (ppm)=13.8 (CH)3, 53.4 (CH), 64.5 (CH2),
103.3, 111.2, 112.6, 114.5, 119.8, 127.1, 129.2, 129.4,
130.4, 131.2, 134.8, 136.8, 144.0, 145.9 (14Car), 155.2
(C¼O), 155.5, 156.4 (2Car), 163.9 (C¼O). Analysis for
C21H18N2O5S (410.44) Calculated: C, 61.45%; H, 4.42%;
57.42%; H, 3.70%; N, 11.85%.
N-[2-(2,3-dimethoxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
yl]furan-2-carboxamide (19). Yield: 44.9%; mp: 147–149°C.
1H NMR (DMSO-d6) δ (ppm)=3.82 (s, 3H, CH3), 3.85
(s, 3H, CH3), 6.69–6.76 (m, 2H, ArH), 7.10–753 (m, 4H,
ArH), 7.95–8.09 (m, 2H, ArH), 8.80 (s, 1H, CH), 11.95
(s, 1H, NH); 13C NMR (DMSO) δ (ppm)= 56.6 (CH), 56.8
(CH3), 60.6 (CH3), 112.6, 114.5, 120.7, 121.4, 127.1, 129.2,
129.4, 129.5, 130.4, 134.8, 136.8, 144.0, 145.2, 145.9 151.6
(16Car), 155.2 (C¼O), 163.9 (C¼O). Analysis for
C21H18N2O5S (410.44) Calculated: C, 61.45%; H, 4.42%;
N, 6.83%. Found: C, 61.41%; H, 4.40%; N, 6.86%.
N, 6.83%. Found: C, 61.48%; H, 4.41%; N, 6.81%.
N-[2-(2-ethoxy-4-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]thiophene-2-carboxamide (24). Yield: 93.8%; mp:
119–121°C. 1H NMR (DMSO-d6) δ (ppm)=1.34–1.42
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
New Furan/Thiophene-1,3-Benzothiazin-4-one Hybrids
485
(t,3H, CH3), 4.09–4.16 (q, 2H, CH2), 6.86–6.89 (m, 1H, ArH),
6.99–7.69 (m, 6H, ArH), 7.87–8.09 (m, 3H, ArH), 8.35 (s, 1H,
CH), 9.54 (s, 1H, OH), 11.74 (s, 1H, NH); 13C NMR (DMSO)
δ (ppm)=13.8 (CH3), 53.4 (CH), 64.5 (CH2), 103.3, 111.2,
119.8, 120.1, 127.4, 129.0, 129.2, 129.4, 130.0, 130.4,
131.2, 134.8, 136.8, 139.2, 155.53 (15Car), 156.3 (C¼O),
156.4 (Car), 161.3 (C¼O). Analysis for C21H18N2O4S2
(426.51) Calculated: C, 59.14%; H, 4.25%; N, 6.57%.
for C19H13BrN2O3S2 (461.35) Calculated: C, 49.46%;
H, 2.84%; N, 6.07%. Found: C, 49.48%; H, 2.82%;
N, 6.09%.
N-[2-(3-bromo-4-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]furan-2-carboxamide (29).
Yield: 37.9%; mp:
212–214°C. 1H NMR (DMSO-d6) δ (ppm)=6.73–6.74
(m, 1H, ArH), 7.03–7.06 (m, 2H, ArH), 7.31–7.32 (m, 1H,
ArH), 7.55–7.59 (m, 2H, ArH), 7.87–8.04 (m, 4H, ArH),
8.34 (s, 1H, CH), 11.02 (s, 1H, OH), 11.81 (s, 1H, NH);
13C NMR (DMSO) δ (ppm)=56.1 (CH), 110.1, 112.6,
114.5, 116.2, 127.1, 127.6, 129.2, 129.4, 130.4, 133.9,
134.8, 136.8, 137.3, 144.0, 145.9, 155.2 (16Car), 155.3
(C¼O), 163.9 (C¼O). Analysis for C19H13BrN2O4S
(445.29) Calculated: C, 51.25%; H, 2.94%; N, 6.29%.
Found: C, 59.18%; H, 4.23%; N, 6.52%.
N-[2-(2-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
yl]furan-2-carboxamide (25). Yield: 40.0%; mp: 96–98°C.
1H NMR (DMSO-d6) δ (ppm)=6.72–6.73 (m, 2H, ArH),
6.88–6.96 (m, 4H, ArH), 7.27–7.33 (m, 3H, ArH),
7.52–7.52 (m, 2H, ArH), 7.96 (s, 1H, CH), 8.65 (s, 1H,
OH), 9.04 (s, 1H, NH); 13C NMR (DMSO) δ (ppm)
= 51.9 (CH), 112.6, 114.5, 118.1, 119.9, 124.7, 127.1,
129.2, 129.3., 129.7, 130.4, 134.8, 136.8, 144.0, 145.9,
148.9 (16Car), 155.2 (C¼O), 163.9 (C¼O). Analysis for
C19H14N2O4S (366.39) Calculated: C, 62.28%; H,
3.85%; N, 7.65%. Found: C, 62.32%; H, 3.83%; N,
Found: C, 51.28%; H, 2.95%; N, 6.27%.
N-[2-(3-bromo-4-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]thiophene-2-carboxamide (30). Yield: 71.4%; mp:
1
190–192°C. H NMR (DMSO-d6) δ (ppm)=6.27 (s, 1H,
NH), 6.71–6.73 (m, 1H, ArH), 7.01–7.03 (m, 1H, ArH),
7.13–7.15 (m, 1H, ArH), 7.21–7.22 (m, 1H, ArH), 7.38–
7.40 (m, 2H, ArH), 7.44–7.46 (m, 1H, ArH), 7.64–7.68
(m, 1H, ArH), 7.78–7.80 (m, 1H, ArH), 7.88–7.90 (m,
1H, ArH), 8.35 (s, 1H, OH), 8.79 (s, 1H NH); 13C NMR
(DMSO) δ (ppm)=50.7 (CH), 110.1, 116.2, 127.1, 127.4,
127.6, 129.0, 129.2, 129.4, 130.0, 130.4, 133.9, 136.8,
137.3, 139.2, 155.2 (16Car), 156.3 (C¼O), 163.9 (C¼O).
Analysis for C19H13BrN2O3S2 (461.35) Calculated: C,
49.46%; H, 2.84%; N, 6.07%. Found: C, 49.49%; H,
7.67%.
N-[2-(2-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-3(4H)-
yl]thiophene-2-carboxamide (26). Yield: 58.1%; mp: 98–
100°C. 1H NMR (DMSO-d6) δ (ppm) = 6.88–6.95 (m, 3H,
ArH), 7.21–7.32 (m, 3H, ArH), 7.51–7.54 (m, 2H, ArH),
7.75–7.89 (m, 3H, ArH), 8.49 (s, 1H, CH), 8.61 (s, 1H,
OH), 9.06 (s, 1H, NH); 13C NMR (DMSO) δ (ppm)
= 51.9 (CH), 119.1, 119.9, 124.7, 127.1, 127.4, 129.0,
129.2, 129.3, 129.4, 130.4, 134.8, 136.8, 139.4, 148.9
(16Car), 156.3 (C¼O), 163.9 (C¼O). Analysis for
C19H14N2O3S2 (382.46) Calculated: C, 59.67%; H,
2.82%; N, 6.10%.
N-[2-(3-bromo-4-methoxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]furan-2-carboxamide (31).
Yield: 95.7%; mp:
1
130–132°C. H NMR (DMSO-d6) δ (ppm)=3.94 (s, 3H,
CH3), 6.74–6.75 (m, 1H, ArH), 7.04–7.09 (m, 1H, ArH),
7.22–7.48 (m, 4H, ArH), 7.60–7.77 (m, 2H, ArH), 7.92–
7.98 (m, 1H, ArH), 8.05–8.08 (m, 1H, ArH), 8.39 (s, 1H,
CH), 11.89 (s, 1H, NH); 13C NMR (DMSO) δ (ppm)
=56.1 (CH), 56.8 (CH3), 111.6, 112.6, 114.5, 114.8,
126.8, 127.1, 129.2, 129.4, 130.4, 134.4, 134.8, 136.8,
138.5, 144.0, 145.9 (15Car), 155.2 (C¼O), 160.2 (Car),
163.9 (C¼O). Analysis for C20H15BrN2O4S (459.31)
Calculated: C, 52.30%; H, 3.29%; N, 6.10%. Found: C,
3.69%; N, 7.32%. Found: C, 59.70%; H, 3.71%; N,
7.30%.
N-[2-(5-bromo-2-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]furan-2-carboxamide (27).
Yield: 69.7%; mp:
196–198°C. 1H NMR (DMSO-d6) δ (ppm)=6.27–6.29
(m, 1H, ArH), 6.46–6.48 (m, 1H, ArH), 6.65–6.67 (m,
1H, ArH), 7.02–7.04 (m, 1H, ArH), 7.16–7.26 (m, 3H,
ArH), 7.34–7.37 (m, 2H, ArH), 7.54–7.57 (m, 1H, ArH),
8.62 (s, 1H, CH), 9.97 (s, 1H, NH); 13C NMR (DMSO) δ
(ppm)=52.2 (CH), 112.4, 112.6, 114.5, 120.0, 127.1,
127.7, 129.2, 129.4, 130.4, 130.8, 131.6, 134.8, 136.8,
144.0, 145.9, 149.5 (16Car), 155.2 (C¼O), 163.9 (C¼O).
Analysis for C19H13BrN2O4S (445.29) Calculated: C,
51.25%; H, 2.94%; N, 6.29%. Found: C, 51.28%; H,
52.34%; H, 3.32%; N, 6.13%.
N-[2-(3-bromo-4-methoxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]thiophene-2-carboxamide (32). Yield: 51.4%; mp:
1
126–128°C. H NMR (DMSO-d6) δ (ppm)=3.94 (s, 3H,
CH3), 7.08–7.14 (m, 1H, ArH), 7.24–7.28 (m, 2H, ArH),
7.31–7.37 (m, 1H, ArH), 7.44–7.51 (m, 1H, ArH), 7.56–
7.68 (m, 1H, ArH), 7.73–7.82 (m, 1H, ArH), 7.96–8.08
(m, 3H, ArH), 8.38 (s, 1H, CH), 11.92 (s, 1H, NH); 13C
NMR (DMSO) δ (ppm)=56.1 (CH), 56.8 (CH3), 111.6,
114.8, 126.8, 127.1, 127.4, 129.0, 129.2, 129.4, 130.0,
130.4, 134.4, 134.8, 136.8, 138.5, 139.2 (15Car), 156.3
(C¼O), 160.2 (Car), 163.9 (C¼O). Analysis for
C20H15BrN2O3S2 (475.38) Calculated: C, 50.53%; H,
3.18%; N, 5.89%. Found: C, 50.50%; H, 3.17%; N, 5.92%.
2.92%; N, 6.31%.
N-[2-(5-bromo-2-hydroxyphenyl)-4-oxo-2H-1,3-benzothiazin-
3(4H)-yl]thiophene-2-carboxamide (28). Yield: 64.7%; mp:
176–178°C. 1H NMR (DMSO-d6) δ (ppm)=6.84–6.87
(m, 2H, ArH), 7.23–7.37 (m, 3H, ArH), 7.53–7.56 (m,
1H, ArH), 7.71–8.06 (m, 4H, ArH), 8.47 (s, 1H, CH),
8.55 (s, 1H, OH), 10.18 (s, 1H, NH); 13C NMR (DMSO)
δ (ppm)=52.2 (CH), 112.4, 120.0, 127.1, 127.4, 127.7,
129.0, 129.2, 129.4, 130.0, 130.8, 134.8, 136.8, 139.2,
149.5 (16Car), 156.3 (C¼O), 163.9 (C¼O). Analysis
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

486
Ł. Popiołek, A. Biernasiuk, and A. Malm
Vol 53
[6] Borate, B. H.; Maujan, S. R.; Sawargave, S. P.; Chandavarkar,
M. A.; Vaiude, S. R.; Joshi, V. A.; Wakharkar, R. D.; Iyer, R.; Kelkar,
R. G.; Chavan, S. P.; Kunte, S. S. Bioorg Med Chem Lett 2010, 20, 722.
[7] Fringuelli, R.; Schiaffella, F.; Bistoni, F.; Pitzurra, L.;
Vecchiarelli, A. Bioorg Med Chem 1998, 6, 103.
[8] Gao, Ch.; Ye, T.-H.; Wang, N.Y.; Zeng, X.-X.; Zhang, L.-D.;
Xiong, Y.; You, X.-Y.; Xia, Y.; Xu, Y.; Peng, C.-T.; Zuo, W.-Q.; Wei, Y.;
Yu, L.-T. Bioorg Med Chem Lett 2013, 23, 4919.
MICROBIOLOGY
In vitro antimicrobial assay. The detailed procedure for
determining the in vitro antimicrobial activity is presented
in the Supporting Information.
Acknowledgments. The project was partially supported by the
Research Grant for Young Scientists (MNmb25).
[9] Barazarte, A.; Camacho, J.; Dominiguez, J.; Lobo, G.;
Gamboa, N.; Rodrigues, J.; Capparelli, M. V.; Álvarez-Larena, Á.;
Andujar, S.; Enriz, D.; Charris, J. Bioorg Med Chem 2008, 16, 3661.
[10] Mizuhara, T.; Oishi, S.; Ohno, H.; Shimura, K.; Matsuoka, M.;
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[11] Zarghi, A.; Zebardast, T.; Daraie, B.; Hedayati, M. Bioorg
Med Chem 2009, 17, 5369.
[12] Chia, E. W.; Pearce, A. N.; Berridge, M. V.; Larsen, L.; Perry,
N. B.; Sansom, C. E.; Godfrey, C. A.; Hanton, L. R.; Lu, G.-L.; Walton, M.;
Denny, W. A.; Webb, V. L.; Copp, B. R.; Harper, J. L. Bioorg Med Chem
2008, 16, 9432.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet