Synthesis and antibacterial properties of new phenothiazinyl-and phenyl-nitrones

Article abstract of DOI:10.1016/j.crci.2013.12.011

The synthesis of new phenothiazinyl-and phenyl-nitrones under classical versus microwave heating conditions is described. Better yields were obtained under microwave irradiation in the condensation reactions of phenothiazyl-carbaldehyde with hydro-xylamine derivatives. The structures of the new phenothiazinyl-nitrones were assigned on the basis of MS, FT-IR and NMR spectra. The new nitrones and some known phenylnitrones were screened for their antibacterial and antifungal activity against several Candida species, Gram negative bacteria, such as E. coli, Citrobacter spp, Morganella spp, Pseudomonas aeruginosa, Klebsiella pneumoniae (±ESBL), Proteus spp, Acinetobacter spp and the Gram positive bacterium Staphylococcus aureus, with moderate results.

Full text of DOI:10.1016/j.crci.2013.12.011

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Contents lists available at ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
´
Full paper/Memoire
Synthesis and antibacterial properties of new
phenothiazinyl- and phenyl-nitrones
a
a
a
b
´
˘
˘
Hermina Iulia Petkes , Emese Gal , Luiza Gaina , Mihaela Sabou ,
Cornelia Majdik a, Lumini¸ta Silaghi-Dumitrescu a,
*
a Faculty of Chemistry and Chemical Engineering, ‘‘Babes-Bolyai’’ University, Kogalniceanu 1, 400084 Cluj-Napoca, Romania
b Faculty of Medicine, ‘‘Iuliu Hatieganu’’, University of Medicine and Pharmacy, Victor Babes 41, 400012 Cluj-Napoca, Romania
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of new phenothiazinyl- and phenyl-nitrones under classical versus
microwave heating conditions is described. Better yields were obtained under microwave
irradiation in the condensation reactions of phenothiazyl-carbaldehyde with hydro-
xylamine derivatives. The structures of the new phenothiazinyl-nitrones were assigned on
the basis of MS, FT–IR and NMR spectra. The new nitrones and some known phenyl-
nitrones were screened for their antibacterial and antifungal activity against several
Candida species, Gram negative bacteria, such as E. coli, Citrobacter spp, Morganella spp,
Pseudomonas aeruginosa, Klebsiella pneumoniae (ꢀ ESBL), Proteus spp, Acinetobacter spp and
the Gram positive bacterium Staphylococcus aureus, with moderate results.
Received 28 June 2013
Accepted after revision 16 December 2013
Available online xxx
Keywords:
Phenothiazinyl-nitrones
Phenyl-nitrones
Antifungal activity
Microwave-assisted synthesis
Fluorescence
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
with alkynes, alkenes and a,b-unsaturated aldehydes, to
afford carbacephem skeletons [12], isoxazolines [13] and
isoxazolidine [14], or generating new carbon–carbon bonds
by nucleophilic additions [15]. The interest for the nitrone
derivatives is also supported by the antibacterial, antifungal
and antiproliferative effects of the above-mentioned classes
of organic heterocycles as well as their own antioxidant [16]
or antiproliferative properties [17].
The ability of nitrones to trap free radicals and release
nitric oxide in vivo and in vitro is important in the
treatment of cerebral ischemia, of neurodegenerative
diseases, as well as in the prolongation of lifespan
[16,18] – i.e. phenyl-tert-butyl-nitrone (PBN or NXY-
059) is a free radical scavenger with neuroprotective
properties [19].
Phenothiazine, one of the oldest bioactive heterocyclic
compounds, is present as major pharmacophore group in
many types of drugs in clinical use (tranquillizers [1,2],
sedatives, anthelmintic [3,4], anti-inflammatory, antima-
larial, antimicrobial, antiparkinsonian [5,6], anticonvul-
sant [7], antitubercular drugs, etc.), as well as in other
biologically active compounds, such as bactericidal pro-
ducts, pesticides [8], compounds with analytical applica-
tions (redox indicators and reagents in spectrophotometric
determinations) [9,10], high temperature antioxidants for
lubricants and dyes [11].
Nitrones are versatile starting materials, with a wide
range of applications, including cycloaddition reactions
The most popular method for the preparation of
nitrones is the condensation of aldehydes or ketones with
N-monosubstituted hydroxylamines [20,21]. The hydro-
xylamines are generated in situ via the reduction of nitro
compounds with zinc powder in the presence of weak
acids (NH4Cl or AcOH). Other methods are the direct
oxidation of secondary amines to the corresponding
nitrones using various metal salts (copper, silver, lead,
*
Corresponding author.
E-mail addresses: hermina@chem.ubbcluj.ro (H.I. Petkes),
´
˘
˘
emese@chem.ubbcluj.ro (E. Gal), gluiza@chem.ubbcluj.ro (L. Gaina),
Sabou.Carmen@umfcluj.ro (M. Sabou), majdik@chem.ubbcluj.ro
(C. Majdik), lusi@chem.ubbcluj.ro, luminita.silaghi@gmail.com
(L. Silaghi-Dumitrescu).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.12.011
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011

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Scheme 1. Synthesis of mono-phenothiazinyl 3a–3j, and di-phenothiazinyl 4 nitrones. A. MW, 100 8C, 10 min. B. EtOH, 100 8C, 1–6 h.
selenium, mercury, and ruthenium) [22,23] as well as
organic oxidants and transition metal complexes (i.e.
(salen)Mn(III) [24,25]), the oxidation of imines with m-
CPBA, dimethyldioxirane (DMD) or the photochemical
oxidation (l = 350 nm) of aldimines in the presence of O2
over a TiO2 suspension [26].
Microwave irradiation is an excellent alternative for a
wide range of heterocyclic syntheses, due to its well-
known advantages: reaction rate enhancement, reaction
time shortage, better yields, lesser solvent usage [27–30].
According to literature data, the improvements achieved
under microwave irradiation came from different effects
generated by the interaction of electromagnetic waves
during the reaction process as compared to the tempera-
ture effect [31].
The present paper aims at describing an efficient
microwave synthesis of aromatic and heteroaromatic
nitrone derivatives together with their antifungal and
antibacterial activities.
Hydroxylamines containing electron-withdrawing and
electron-donating groups were obtained by reducing the
corresponding nitro compounds with ammonium chloride
and zinc (powder). A comparison of the reaction conditions
and yields after purification by flash chromatography is
presented in Table 1. Irrespective of the reaction conditions
(classical or microwave-activated process), nitrones 3a–3d
and 4 with electron-withdrawing substituents, such as
phenyl, chlorophenyl and bromophenyl, were isolated in
low yields: 16 to 35% with classical heating and 28–50%
under microwave heating (Table 1). Better yields were
obtained for nitrones 3g, 3h, 3j with electron-donating
alkyl groups (65–77% with classical heating and 81–84%
under microwave heating). The shorter reaction time as
well as higher yields obtained under microwave conditions
makes this a more advantageous method than the classical
synthesis (Table 1).
A notable problem associated with many reactive
nitrones is dimerization [32]. In the reactions described
in this work, no dimerization product was obtained, but
the corresponding imines were formed as byproducts
during the reaction as well as the purification by flash
chromatography. The new class of phenothyazinyl N-
substituted nitrones is highly sensitive and decomposes on
heating (120–130 8C) without melting.
2. Results and discussion
The new phenothiazinyl N-aryl or N-alkyl nitrones 3a–
3j, 4 were synthetized with a modified procedure [16] by
condensation reactions of the formyl phenothiazine 1a–d
and hydroxylamines 2a–h in an ethanol/water mixture (5/
1, v/v), with low to good yields (16–84%, Scheme 1).
Our interest in nitrone derivatives is related to their
potential antifungal and/or antibacterial properties.
Table 1
The synthesis of phenothiazinyl-nitrones by microwave irradiation and by convection heating.
Entry
Compound
R1
R2
Convection heating
Microwave
Yield (%)a
Yield (%)a
Reaction time
Reaction time
(min)
(min)
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
C6H5
20
16
21
35
30
41
65
77
52
70
34
120
60
37
30
28
50
44
56
84
81
74
84
61
10
10
10
10
10
10
10
10
10
10
10
2
Me
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
4-acetyl-C6H4
3-acetyl-C6H4
Me
3
Me
60
4
Me
480
90
5
Me
6
Me
60
7
Et
75
8
Et
Et
75
9
Octadecyl
Octadecyl
Me
C6H5
120
75
10
11
3j
Et
4
C6H5
60
a
Isolated yield after column chromatography.
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011

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3
Table 2
According to our goal, a number of previously reported
phenyl-nitrones 5a–d [33,34], 6a, b, f [35] 6d [36], 6e, g, h
[37,38], 6m, o [39], 6k [40], 6j, n, q [41,42] was also
synthesized (see Fig. 1).
Optical properties of phenothiazinyl-nitrones.
b
Compound labs [nm]
molꢃ1cmꢃ1
lem [nm] Stokes shift FF
a
(
e
)
Dn [cmꢃ1
]
The new phenyl-nitrones 6c, 6i, 6l, 6p were prepared by
the one-pot procedure from the corresponding aromatic
amines, nitrobenzene derivatives and zinc powder in
acetic acid.
The structures of the newly-synthesized nitrones were
confirmed by their 1H NMR, MS and FT–IR spectra. In the
1H NMR spectra, the characteristic signal for the phe-
nothiazinyl-nitrones 3a–j and 4 is the singlet generated by
the imine proton at ꢁ 7.15 ppm, (value for nitrone 3g) and
7.79 ppm, for nitrone 4 (see experimental part).
In the UV spectra, the new phenothiazinyl-nitrones 3a–
f, 3i and 4 present three absorption bands, while the
nitrones 3g, 3h and 3j present only two. The intense
3a
3b
3c
3d
3e
3f
3g
3h
3i
315, 272, 393(9517)
316, 274, 385(8277)
551
521
7255
7142
7103
7535
7211
7197
7275
7076
7888
7235
7595
7.83
5.59
5.01
5.43
7.77
8.33
3.50
4.70
1.90
4.20
5.43
316, 275, 380(10048) 518
317, 275, 397(9561)
312, 241, 398(8480)
314, 271, 402(9398)
555
550
542
302, 377(14026) 519
302, 377(21778) 515
314, 275, 382(14010) 569
302, 376(22408) 518
318, 419(16280) 554
3j
4
a
UV–Vis measured in CH2Cl2.
b
Quantum yields against perylene standard in cyclohexane.
the quantum yields (FF) between 1.90 for 3i and 4.7% for
3h.
The quantum yields were calculated [43] using
perylene in cyclohexane as standard, Table 2.
absorption band at 302–318 nm is due to the
p–p*
electronic transition, while the moderate one, in the range
370–400 nm, with the extinction coefficient (
e
) between
8 ꢂ 103 and 2 ꢂ 104, is due to the n–
p* electronic
transitions within the phenothiazinyl-imino chromo-
phore. The band around 270 nm is correlated with the
presence of the phenyl group. The bathochromic shift of
the absorption maxima for compound 4 compared to
compound 3a is due to the presence of the second imine
unit. The presence of the molecular ion, the cleavage of the
N-alkyl bond in the phenothiazine unit and the N–O bond
in the nitrone unit are common features of the mass
spectra of these new nitrones.
3. Biological assay
The antifungal and antibacterial activities of the new
and already reported nitrone derivatives mentioned above
were evaluated against several Candida species Gram
negative bacteria such as E. coli, Citrobacter spp, Morganella
spp, Pseudomonas aeruginosa, Klebsiella pneumoniae
(
ꢀ ESBL), Proteus spp, Acinetobacter spp, and the Gram
positive bacterium Staphylococcus aureus.
All phenothiazinyl-nitrones display light-blue fluores-
cence with large Stokes shifts (Dn = 7076–7888 cmꢃ1) and
Antifungal and antibacterial activities were investi-
gated in triplicate, by the disk diffusion method at 8 mM
nitrone concentration. Low inhibition potentials (diameter
of inhibition area 3–5 mm) were recorded with few
exceptions, two Candida strains (Candida albicans and
Candida krusei), were sensitive to compounds 5a, 6a and
6p, with the diameter of inhibition area at 10–11 mm.
For the phenothiazinyl-nitrones 3a, 3h and 4, the tests
were repeated at higher concentration (25
mg/disk), with
the same standard fluconazole concentration on the disk.
The fluconazole-resistant Candida strains involved in these
tests were Candida parapsilosis, famata and glabrata
(isolated from blood), and albicans and krusei, isolated
from the urine of patients. For the C. glabrata and C. krusei,
the investigated nitrones did not present inhibition
activities. In the case of C. famata, compounds 3a and 4
present minimum inhibition activity (d: 3 mm and 4 mm,
respectively). A limited inhibition activity (d: 3 mm) was
observed for the phenothiazinyl nitrone 3h on C. albicans.
Only the C. parpsilosis was sensitive to phenothiazinyl-
nitrones, with the inhibition diameter of 6 mm for 3a, 7 mm
for nitrone 3h and 6 mm for nitrone 4.
4. Conclusions
In conclusion, a novel class of functionalized phe-
nothiazinyl-nitrones with aromatic and aliphatic chains
was synthesized and structurally characterised. Higher
yields in a shorter reaction time were obtained under
microwave irradiation compared to classical heating. The
Fig. 1. Structure of phenyl mono-, and di-nitrones.
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
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new nitrones and some known phenyl-nitrones were
screened for their antibacterial and antifungal activity
against several Candida species and Gram negative or
positive bacteria, with moderate results.
5.3. General experimental procedures for the synthesis of
phenothiazinyl-nitrones
5.3.1. Preparation of hydroxylamines
The nitro derivative (1 mmol) disolved in ethanol
(5 mL), ammonium chloride (0.053 g, 1 mmol) and water
(1 mL) were mixed under stirring and cooled on an ice bath
to 5 8C, after which zinc dust (0.13 g, 2 mmol) was added
slowly. The suspension thus obtained was used without
further purification.
5. Experimental
5.1. General information
All reagents and solvents were obtained from com-
mercial sources and were used without purification.
Phenyl-nitrones 5a–5d, 6a–6q were prepared by the
classical synthesis method according to the literature data
[29–38].
5.3.1.1. Method A: microwave-assisted synthesis. In a 10-mL
microwave reaction vessel equipped with a stirrer and a
cap, the corresponding hydroxylamine solution (1 mmol)
and sodium acetate (0.123 g, 1.5 mmol) were added to the
corresponding phenothiazine derivative (1 mmol). The
reaction mixture was subjected to microwave irradiation
using a power level of 100 W at 100 8C for 10 min. After
cooling, the mixture was diluted with water and dichlor-
omethane, filtered and the residue washed with the
organic solvent. The organic layer was separated, dried
on anhydrous sodium sulphate and filtered. The solvent
was removed under vacuum and the residue was purified
by flash column chromatography on silica with various
eluent systems.
The infrared spectra were recorded on a Bruker Vector
22 FT–IR spectrometer from 4000 to 600 cmꢃ1 using KBr
pellets. The NMR spectra were recorded at room tempera-
ture on a Bruker Avance instrument (1H/13C: 300 MHz/
75 MHz) using deuterated solvents; chemical shifts are
reported in ppm relative to TMS, J values are given in Hz.
For elemental analyses (C, N, H, S), a Thermo Flash 1112
Series elemental analyser was used. Mass spectra were
measured on a Shimadzu QP-2010 PLUS GC-MS mass
spectrometer (DI, EI-70 eV). The reaction mixtures were
irradiated in a CEM Discover LabMate microwave reactor.
UV–Vis spectra were recorded in dichloromethane with a
PerkinElmer Lambda 35 UV–Vis spectrophotometer;
emission spectra were measured in dichloromethane
using a PerkinElmer FL 55 fluorescence spectrophot-
5.3.1.2. Method B: classical synthesis. Hydroxylamine was
synthesized as described above. To the hydroxylamine
suspension (1 mmol), the corresponding phenothiazine
derivative (1 mmol) and sodium acetate (0.123 g,
1.5 mmol) were added; the reaction mixture was stirred
at 100 8C for 1–6 h. After cooling, the mixture was worked
up as described before for microwave-assisted synthesis.
Synthetic procedures for each phenothiazinyl-nitrones
and copies of 1H NMR, 13C NMR are included as
Supplementary material (S) and are available on the
website of this journal.
ometer. Flash chromatography was performed using silica
˚
mm). The reactions were
gel (60 A, particle size 40–63
monitored by thin-layer chromatography (TLC) on alumi-
nium plates precoated with silica gel (60, F254) and
visualized by UV light. For the microbial identification,
the Vitek 2 bioMerieux system was used.
5.2. Antimicrobial assay
5.3.2. (Z)-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3a
In vitro antifungal and antibacterial activities for the
nitrone derivatives were tested according to the disk
diffusion method using 5-mm-diameter disk papers [44].
The fungi and bacteria isolated from various body fluids
(urine, sputum, wound, blood) were grown [45] onto a
Mueller–Hinton culture medium by incubation at 37 8C for
48 h. After identification, according the CLSI standards
[46], each colony was suspended in 5 mL of a sterile saline
solution. The turbidity of the inoculum was adjusted to
McFarland Turbidity Standard No. 0.5, and the inoculums
were added to different Petri plates filled with a Mueller–
Hinton culture medium, or Mueller–Hinton and methylene
blue culture medium for Candida spp. strains. The five
sterile filter paper disks were aseptically placed on the
inoculated plate, at equal distance from each other. On
each plate, the paper disks were impregnated aseptically
Yellowish–green solid; yield 37% (0.12 g) was obtained
by microwave-assisted heating, and 20% (0.06 g) by
convective heating. Decomposition: 121 8C without melt-
ing. IR (KBr)
(%): 332 (100, [M]+), 317 (18); 1H NMR (CDCl3)
N–CH3), 6.86–6.81 (m, 2H, H1, H9), 6.95 (t, 1H, H7,
n
max/cmꢃ1 3015, 1550, 679; MS (70 eV), m/z
d
3.41 (s, 3H,
JH
¼ 7:9; JH
¼ 7:4), 7.13 (d, 1H, H6, JH
¼ 7:9),
ꢃH
ꢃH
ꢃH
7
6
7
8
7
6
7.19 (t, 1H, H8, JH
3H, Hc, Hd), 7.75 (d, 2H, Hb, JH
8.18 (d, 1H, H4, JH
13C NMR (75 MHz, CDCl3)
¼ 7:4, JH
¼ 8:9), 7.49–7.44 (m,
ꢃH
ꢃH
7
8
8
9
¼ 7:5), 7.78 (s, 1H, H3a),
ꢃH
c
b
¼ 1:7), 8.26 (d, 1H, H2, JH
¼ 7:8);
ꢃH
ꢃH
2
4
1
2
d 147.9, 144.7, 133.6, 133.6,
129.81, 129.3, 129.2, 127.7, 127.6, 127.3, 125.4, 123.4,
123.2, 121.7, 114.5, 113.9, 35.7; anal. calcd. for
C
20H16N2OS: C, 72.26; H, 4.85; N, 8.43; S, 9.65; O, 4.81;
found: C, 72.36; H, 4.89; N, 8.40; S, 9.58.
by pipetting with DMSO (10
reference) or with each one of the investigated compounds
3a–j, 6a–q (10 L, 8 mM solution in DMSO). Agar plates
mL, the solvent was used as a
5.3.3. (Z)-4-chloro-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3b
m
were incubated at 37 8C for 24 h, 48 h and 72 h, respec-
tively, and the diameter of the inhibition area was
measured. Tests were performed in triplicate.
Yellowish–green solid; yield 30% (0.11 g) was obtained
by microwave-assisted heating, and 16% (0.05 g) by
convective heating. Decomposition: 115 8C without melting.
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011

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5
IR (KBr)
(%): 366 (100, [M]+), 351 (32), 350 (21); 1H NMR (CDCl3)
3.42 (s, 3H, N–CH3), 6.87–6.82 (m, 2H, H1, H9), 6.96 (t, 1H,
n
max/cmꢃ1 2894, 1611, 812, 734; MS (70 eV, EI), m/z
13C NMR (75 MHz, CDCl3)
137.7, 134.3, 129.6, 129.4, 127.7, 127.7, 127.3, 124.8, 123.3,
122.7, 121.7, 114.6 113.8, 35.6, 26.8; anal. calcd. for
d
196.8, 151.5, 148.2, 144.4,
d
H7, JH
7.43 (d, 2H, Hb, JH
7.76 (s, 1H, H3a), 8.16 (d, 1H, H4, JH
¼ 7:5; JH
¼ 7:4), 7.18–7.12 (m, 2H, H6, H8),
ꢃH
8
C22H18N2O2S: C, 70.57; H, 4.85; N, 7.48; S, 8.56; O, 8.55;
found: C, 70.59; H, 4.87; N, 7.47; S, 7.57.
ꢃH
7
6
7
¼ 8:8), 7.72 (d, 2H, Hc, JH
¼ 8:8),
ꢃH
ꢃH
c
c
b
b
¼ 1:4), 8.25 (d, 1H,
ꢃH
2
4
H2, JH
¼ 8:4); 13C NMR (75 MHz, CDCl3)
d
153.2, 153.1,
5.3.7. (Z)-3-acetyl-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3f
ꢃH
1
2
148.3, 146.7, 134.2, 133.2, 131.7, 129.3, 127.6, 125.6, 124.9,
122.6, 120.0, 120.1, 119.9, 118.5, 117.3; anal. calcd. for
Orange-red solid; yield 56% (0.21 g) was obtained by
microwave-assisted heating, and 41% (0.14 g) by convective
heating. Decomposition: 123–126 8C without melting. IR
C20H15ClN2OS: C, 65.48; H, 4.12; N, 7.64; S, 8.74; O, 4.36;
found: C, 65.47; H, 4.14; N, 7.63; S, 8.73.
(KBr)
347 (100, [M]+), 359 (32), 358 (22);1H NMR (CDCl3)
3H, CH3), 3.40 (s, 3H, N–CH3), 6.85–6.80 (m, 2H, H1, H9), 6.95
(t, 1H, H7, JH ¼ 7:4), 7.12 (d, 1H, H6,
¼ 7:5, JH
n
max/cmꢃ1 3086, 1811, 1636, 593; MS (70 eV), m/z (%):
5.3.4. (Z)-4-bromo-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3c
Yellowish–green solid; yield 28% (0.11 g) was obtained
by microwave-assisted heating, and 21%, (0.08 g) by
convective heating. Decomposition: 125–127 8C without
melting. IR (KBr)
(70 eV), m/z (%): 410 (100, [M]+), 412 (96), 394 (27), 396
(23); 1H NMR (CDCl3)
3.41 (s, 3H, N–CH3), 6.86–6.82 (m,
2H, H1, H9), 6.96 (t, 1H, H7, JH
d2.65 (s,
ꢃH
ꢃH
8
7
6
7
JH
¼ 7:5), 7.17 (t, 1H, H8, JH
¼ 7:4, JH
¼ 8:0),
ꢃH
ꢃH
ꢃH
7
6
7
8
8
9
7.57 (t, 1H, He, JH
¼ 7:8, JH
¼ 8:0), 7.86 (s, 1H, H3a),
ꢃH
ꢃH
e
e
f
n
max/cmꢃ1 3124, 1542, 757, 593; MS
8.02–7.98 (m, 2H, Hdd, Hf), 8.25–8.22 (m, 2H, Hb, H2), 8.32 (d,
1H, H4, JH
¼ 1:6); 13C NMR (75 MHz, CDCl3)
d 195.9,
ꢃH
1
2
d
170.4, 149, 148.1, 144.5, 137.9, 133.9, 129.7, 129.5, 129.4,
127.7, 127.3, 126, 124.9, 123.4, 123.3, 122.8, 121.1, 114.5,
113.8; anal. calcd. for C22H18N2O2S: C, 70.57; H, 4.85;
N, 7.48; S, 8.56; O, 8.55; found: C, 70.56; H, 4.80; N, 7.50;
S, 8.59.
¼ 7:4, JH
¼ 7:4),
¼ 8:5),
ꢃH
ꢃH
8
7
6
7
7.21–7.11 (m, 4H, H6, H8, Hb), 7.60 (d, 2H, Hc, JH
7.76 (s, 1H, H3a), 8.16 (d, 1H, H4, JH
ꢃH
c
b
¼ 1:7), 8.23 (d, 1H,
ꢃH
2
4
H2, JH
¼ 8:6); 13C NMR (75 MHz, CDCl3)
d 148.1, 144.6,
ꢃH
1
2
133.7, 132.3, 129.4, 129.2, 128.3, 127.7, 127.4, 125.4, 123.2,
114.6, 113.9; anal. calcd. for C20H15BrN2OS: C, 58.40; H,
3.68; N, 6.81; S, 7.80; O, 3.89; found: C, 58.42; H, 3.70; N,
6.82; S, 7.84.
5.3.8. (Z)-N-((10-ethyl-10H-phenothiazin-3-
yl)methylene)methanamine oxide 3g
Green oil; yield 84% (0.22 g) was obtained by micro-
wave irradiation, and 65% (0.17 g) by convective heating.
5.3.5. (Z)-3-bromo-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3d
Decomposition: 126 8C without melting. IR (KBr) nmax
cmꢃ1 2874, 1645, 1468, 670; MS (70 eV), m/z (%): 284 (100,
[M]+), 269 (62), 268 (45); 1H NMR (CDCl3)
1.33 (t, 3H, CH3,
¼ 14), 3.75 (s, 3H, CH3), 3.84 (q, 2H, CH2,
/
Yellowish–green solid; yield 50% (0.21 g) was obtained
by microwave-assisted heating, and 35% (0.14 g) by
convective heating. Decomposition: 127 8C without melt-
ing. IR (cmꢃ1, KBr) nmax 3155, 1608, 762, 593; MS
(70 eV), m/z (%): 410 (100, [M]+), 412 (98), 394 (31), 396
d
JCH
JCH
ꢃCH
ꢃCH
2
3
¼ 14), 6.80–6.74 (m, 2H, H1, H9), 6.85 (t, 1H, H7,
2
3
JH
¼ 7:0, JH
¼ 7:6), 7.02 (d, 1H, H6, JH
¼ 7:0),
ꢃH
ꢃH
ꢃH
7
6
7
8
7
6
7.08 (t, 1H, H8, JH
7.91 (d, 1H, H4, JH
13C NMR (75 MHz, CDCl3)
d 146.3, 143.6, 134.4, 128.2,
¼ 7:6, JH
¼ 7:8), 7.15 (s, 1H, H3a),
ꢃH
ꢃH
7
8
8
9
(26); 1H NMR (CDCl3)
2H, H1, H9), 6.97 (t, 1H, H7, JH
d
3.41 (s, 3H, N–CH3), 6.85–6.82 (m,
¼ 1:7), 7.98 (d, 1H, H2, JH
¼ 8:1);
ꢃH
ꢃH
2
4
1
2
¼ 7:5; JH
¼ 7:4),
¼ 7:4,
¼ 8:0),
¼ 8:1),
ꢃH
ꢃH
8
7
6
7
7.15 (d, 1H, H6, JH
¼ 7:0), 7.19 (t, 1H, H8, JH
¼ 8:0), 7.71 (d,d1H, Hd, J
127.4, 127.3, 127.1, 124.7, 123.5, 123.4, 122.8, 115.1, 114.3,
53.9, 42, 12.8; anal. calcd. for C16H16N2OS: C, 67.58; H,
5.67; N, 9.85; S, 11.28; O, 5.63; found: C, 67.23; H, 5.62; N,
9.8050; S, 11.09.
ꢃH
ꢃH
8
7
6
7
JH
¼ 8:0), 7.33 (t, 1H, He, JH
¼ 8:1, JH
ꢃH ꢃH
ꢃH
e
e
8
9
f
7.76 (d, 1H, Hf, JH
ꢃH
H
ꢃH
e
e
f
d
7.77 (s, 1H, H3a), 7.96 (d, 1H, Hb, JH
¼ 1:7), 8.19 (d, 1H,
ꢃH
b
f
H4, JH
(75 MHz, CDCl3)
¼ 1:6), 8.24 (d, 1H, H2, JH
¼ 7); 13C NMR
ꢃH
ꢃH
2
4
1
2
d
149.3, 148, 144.5, 133.8, 132.7, 130.5,
5.3.9. (Z)-N-((10-ethyl-10H-phenothiazin-3-
yl)ethylene)methanamine oxide 3h
129.4, 127.7, 127.6, 127.3, 125, 124.9, 123.3, 123.2, 122.8,
122.7, 120.2, 114.5, 113.8, 35.6; anal. calcd. for
Green solid; yield 81% (0.23 g) was obtained by micro-
wave irradiation, and 77% (0.18 g) by convective heating.
C20H15BrN2OS: C, 58.40; H, 3.68; N, 6.81; S, 7.80; O,
3.89; found: C, 58.45; H, 3.73; N, 6.78; S, 7.89.
Decomposition: 127 8C without melting. IR (KBr)
3019, 1501, 1468, 751; MS (70 eV), m/z (%): 298 (100, [M]+),
283 (58), 282 (39); 269 (13); 1H NMR (CDCl3)
1.39 (t, 3H,
n
max/cmꢃ1
5.3.6. (Z)-4-acetyl-N-((10-methyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3e
d
CH3, JCH ꢃCH ¼ 14:5), 1.52 (t, 3H, CH3, JCH ꢃCH ¼ 13:9),
2
3
2
3
Orange-red solid; yield 44% (0.16 g) was obtained by
microwave-assisted heating, and 30% (0.10 g) by convec-
tive heating. Decomposition: 123 8C without melting. IR
3.95–3.86 (quin, 4H, CH2), 6.81 (d, 1H, H9, JH
¼ 7:0), 6.82
ꢃH
8
9
(d, 1H, H1, JH
¼ 7:5), 6.90 (t, 1H, H7, JH
¼ 7:6,
ꢃH
ꢃH
1
2
7
6
JH
JH
¼ 7:4), 7.07 (d, 1H, H6, JH
¼ 7:6), 7.11 (t, 1H, H8,
ꢃH
ꢃH
ꢃH
6
7
8
7
(KBr)
374 (100, [M]+), 359 (42), 358 (37); 1H NMR (CDCl3)
(s, 3H, CH3), 3.38 (s, 3H, N–CH3), 6.82–6.79 (m, 2H, H1, H9),
n
max/cmꢃ1 2986, 1721, 1573, 589MS (70 eV), m/z (%):
¼ 7:4, JH
¼ 7:0), 7.24 (s, 1H, H3a), 7.99 (d, 1H,
ꢃH
7
8
8
9
d
2.62
H4, JH
¼ 1:2), 8.05 (d, 1H, H2, JH
¼ 7:9); 13C NMR
ꢃH
2
ꢃH
2
4
1
(75 MHz, CDCl3) d 145.1, 143.5, 132.7, 128.2, 127.2, 127.1,
6.94 (t, 1H, H7, JH
¼ 7:0, JH
¼ 7:6), 7.11 (d, 1H, H6,
127, 124.7, 123.4, 123.2, 122.7, 115, 114.2, 61.3, 41.8,
13.4, 12.6; anal. calcd. for C17H18N2OS: C, 68.42; H, 6.08;
N, 9.39; S, 10.5; O, 5.36; found: C, 68.42; H, 6.03; N, 9.35;
S, 10.09.
ꢃH
ꢃH
8
7
6
7
JH
JH
¼ 7:6), 7.11 (t, 1H, H8, JH
ꢃH
¼ 7:6), 7.85 (d, 2H, Hb,
ꢃH
ꢃH
7
6
7
6
¼ 8:6), 7.84 (s, 1H, H3a), 8.01 (d, 2H, JH ꢃH ¼ 8:6),
c
c
b
b
8.19 (d, 1H, H4, JH
¼ 1:6), 8.23 (d, 1H, H2, JH
¼ 8:3);
ꢃH
ꢃH
2
4
1
2
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011

G Model
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6
H.I. Petkes et al. / C. R. Chimie xxx (2014) xxx–xxx
5.3.10. (Z)-N-((10-octadecyl-10H-phenothiazin-3-
yl)methylene)aniline oxide 3i
H2, H6), 8.55 (dd, 1H, Hf, JH ꢃH ¼ 8:5, JH ꢃH ¼ 2:3), 8.73 (s,
e
f
f
b
1H, CH), 8.90 (d, 1H, Hb), 9.71(d, 1H, He, JH ꢃH ¼ 8:5),
e
f
Green solid; yield 74% (0.42 g) was obtained by
microwave irradiation, and 52% (0.29 g) by convective
heating. Decomposition: 121–124 8C without melting. IR
13C NMR (75 MHz, CDCl3)
d 120.5, 121.8, 126.7, 127.8,
129.5, 129.7, 130.2, 131,4; anal. calcd. for C13H9N3O5:
C, 54.36; H, 3.16; N, 14.63; O, 27.85; found: C, 454.27;
H, 3.20; N, 14.58.
(KBr)
(74, [M]+), 554 (23), 499 (39), 485 (82), 387 (27), 359 (18),
n
max/cmꢃ1 2919, 1457, 756; MS (70 eV), m/z (%): 570
5.3.14. (Z)-3-chloro-N-(4-chlorobenzylidene)aniline oxide 6i
Beige solid, yield 75% (0.19 g); mp 105–106 8C. MS
(70 eV), m/z (%): 265/267/269 (30/7/3, [M]+), 249 (100); 1H
345 (32); 1H NMR (CDCl3)
d
0.88 (t, 3H,
d
CH3,
JCH
JCH
¼ 12:3J), 1.26 (s, 30H, CH2), 1.79 (q, 2H,
bCH2,
ꢃCH
ꢃCH
2
3
¼ 13:4), 3.95–3.86 (quin, 4H, CH2, JCH ꢃCH ¼ 13:1),
2
2
2
2
NMR (CDCl3)
d
7.51–7.40 (mt, 3H, H1, H2, Hd), 7.75 (d, 2H,
3.83 (t, 2H,
H9), 6.90 (t, 1H, H7, JH
(m, 2H, H6, H8), 7.43–7.41 (m, 3H, Hc, Hd), 7.76–7.72 (m, 3H,
a
CH2, JCH ꢃCH ¼ 13:8), 6.85–6.83 (m, 2H, H1,
2
2
H3, H6, JH
¼ 8), 7.90 (s, 1H, CH), 8.17 (t, 1H, Hc,
ꢃH
3
2
¼ 7:4, JH
¼ 7:4), 7.15–7.06
ꢃH
ꢃH
7
6
7
8
JH ꢃH ¼ 8, JH ꢃH ¼ 8), 8.26 (d, 1H, Hb, JH ꢃH ¼ 8), 8.55 (s,
c
c
c
b
d
b
1H, Hf); 13C NMR (75 MHz, CDCl3)
d 123.0, 127.1, 127.2,
H
JH
3a, Hb), 7.13(d, 1H, H4, JH
¼ 1:2), 8.25 (d, 1H, H2,
ꢃH
2
4
128.5, 128.9, 129, 129.5, 129.9, 131.1, 131.9,133.2, 134.8,
136.1; anal. calcd. for C13H9Cl2NO: C, 58.67; H, 3.41; Cl,
26.64; N, 5.26; O 6.01; found: C, 58.72; H, 3.48; N, 5.18.
¼ 8:6); 13C NMR (75 MHz, CDCl3)
d 148.8 8, 147,1,
ꢃH
1
2
143.9, 133.5, 129.6, 129.1, 128.8, 127.7, 127.4, 127.3, 125,
124.2, 123.9, 122.9, 121.5, 115.5, 114.7, 47.7, 31.9, 29.7, 29.5,
29.4, 29.2, 26.8, 26.7, 22.7, 14.1; anal. calcd. for C37H50N2OS:
C, 77.85; H, 8.83; N, 4.91; S, 5.62; O, 2.80; found: C, 77.84; H,
8.89; N, 4.97; S, 5.67.
5.3.15. (Z)-N-(4-chlorobenzylidene)-3-hydroxyaniline oxide
6l
Off-white solid, yield 83% (0.2 g); mp 195–196 8C. MS
(70 eV), m/z (%): 247/249 (70/21, [M]+), 230/232 (100); 1H
5.3.11. (N)-N-((10-octedecyl-10H-phenothiazin-3-
yl)ethylene)methanamine oxide 3j
Yellowish–green solid, yield 84% (0.43 g) was obtained
by microwave irradiation, and 70% (0.36 g) by convective
heating. Decomposition: 125 8C without melting. IR (KBr)
NMR (DMSO-d6)
d
6.90 (dd, 1H, Hd, JH
¼ 8:9,
ꢃH
e
d
JH
¼ 1:7), 7.29 (t, 1H, He, JH
¼ 8:9, JH ꢃH ¼ 7:8),
ꢃH
ꢃH
e
e
d
d
f
7.60 f (d, 2H, H2, H6, JH
¼ 8:8), 7.71 (d, 1H, Hf,,
ꢃH
2
3
JH ꢃH ¼ 7:8), 7.95 (d, 2H, H3, H5, JH
¼ 8:8), 8.16 (s,
ꢃH
e
f
2
3
1H, CH), 8.43 (s, 1H, Hb), 9.68 (broad s, 1H, OH); 13C NMR
n
max/cmꢃ1 3102, 1576, 834; MS (70 eV), m/z (%): 522 (100,
(75 MHz, DMSO)
131.9, 134.1, 134.2, 147.2, 157.2; anal. calcd. for
13H10ClNO2: C, 63.04; H, 4.07; Cl, 14.31; N, 5.66; O,
d 114.8, 118.2, 120.7, 123.4, 129.0, 129.5,
[M]+), 507 (26), 506 (41), 451 (21), 395 (56), 311 (100); 1H
NMR (CDCl3) 0.87 (t, 3H,
CH3, JCH ꢃCH ¼ 12:6), 1.25 (s,
30H, CH2), 1.77 (q, 2H,
CH2, JCH ꢃCH ¼ 13:3), 3.90 (q, 2H,
d
d
C
2
3
b
12.92; found: C, 63.12; H, 4.10; N, 5.62.
2
2
CH2, JCH ꢃCH ¼ 13:3, 6.84–6.80 (m, 2H, H1, H9), 6.89 (t, 1H,
2
2
5.3.16. (Z)-N-(4-bromobenzylidene)-3-hydroxyaniline oxide
6p
Beige solid, yield 80% (0.23 g); mp 188–190 8C. MS
(70 eV), m/z (%): 291/293 (100, [M]+), 275/277 (85); 1H
H7, JH
JH
¼ 6:8, JH
¼ 7:4), 7.07 (d, 1H, H6,
ꢃH
ꢃH
7
6
7
8
¼ 6:8), 7.12 (t, 1H, H8, JH
¼ 7:4), 7.23 (s, 1H,
ꢃH
ꢃH
7
6
7
8
H
JH
3a), 7.95 (d, 1H, H4, JH
¼ 1:8), 8.10 (d, 1H, H2,
ꢃH
2
4
¼ 6:8); 13C NMR (75 MHz, CDCl3)
d 146.6, 144.2,
ꢃH
1
2
NMR (DMSO-d6)
d
6.91 (dd, 1H, Hd, JH
¼ 8:6,
132.7, 128.1, 127.4), 127.3, 127.2, 124.9, 124.3, 124.1, 122.8,
115.5, 114.7, 61.5, 47.6, 29.7, 29.75, 29.6 29.4, 29.3, 26.9,
26.7, 22.7, 14.2, 13.6; anal. cald. for C33H50N2OS: C, 75.81; H,
9.64; N, 5.36; S, 6.13; O, 3.06; found: C, 75.83; H, 9.65; N,
5.33; S, 6.19; anal. calcd. for C33H50N2OS: C, 75.81; H, 9.64; N,
5.36; S, 6.13; O, 3.06; found: C, 75.83; H, 9.65; N, 5.33; S, 6.19.
ꢃH
e
d
JH
¼ 1:7), 7.29 (t, 1H, He, JH
¼ 8:6, JH ꢃH ¼ 7:9),
ꢃH
ꢃH
e
e
d
f
f
7.75–7.69 (m, 3H, H2, H6, Hf)d, 7.89 (d, 2H, H3, H5,
JH
¼ 8:9), 8.15 (s, 1H, CH), 8.44 (s, 1H, Hb), 9.68 (broad
ꢃH
2
3
s, 1H, OH); 13C NMR (75 MHz, DMSO)
d 115, 118.2, 120,
120.7, 122.8, 123.7, 129.5, 131.2, 131.9, 134.1, 147.6,
157.3; anal. calcd. for C13H10NO2: C, 53.45; H, 3.45; Br,
27.35; N, 4.79; O, 10.95; found: C, 53.50; H, 3.49; N, 4.82.
5.3.12. (N,N0Z,N,N0Z)-N,N0-(10-methyl-10H-phenothiazine-
3,7-diyl)bis(methan-1-yl-1-ylidene) dianiline oxide 4
Green solid; yield 61% (0.27 g) was obtained by
microwave irradiation, and 34% (0.15 g) by convective
heating. Decomposition: 128 8C without melting. IR (KBr)
Acknowledgments
Financial support from the Romanian Ministry of
Education, Research Youth and Sports (Grant ID PCCE
140/2008), as well as from the Sectorial Operational
Programs for Human Resources Development 2007–2013,
co-financed by the European Social Fund, under the project
No. POSDRU/107/1.5/S/76841 with the title ‘‘Modern
Doctoral Studies: Internationalization and Interdiscipli-
narity’’ is gratefully acknowledged.
n
max/cmꢃ1 2916, 1442, 624; MS (70 eV), m/z (%): 451 (100,
[M]+), 436 (24), 435 (39); 1H NMR (CDCl3)
3.42 (s, 3H, N–
d
CH3), 6.85–6.82 (m, 2H, H1, H9), 7.49–7.42 (m, 6H, Hc, Hd),
7.76–7.73 (m, 4H, Hb), 7.79 (s, 1H, H3a), 7.16(d, 2H, H4, H6,
JH
¼ 1:6), 8.27 (d, 2H, H2, H6, JH
¼ 8:6); 13C NMR
ꢃH
2
ꢃH
2
4
1
(75 MHz, CDCl3)
d 148.9, 145.5, 133.4, 129.9, 129.2, 129.2,
127.6, 125.9, 122.9, 121.7, 114.2, 35. 9; anal. calcd. for
33H50N2OS: C, 71.82; H, 4.69; N, 9.31; S, 7.10; O, 7.09;
C
found: C, 71.82; H, 4.71; N, 9.31; S, 7.12.
Appendix A. Supplementary data
5.3.13. (Z)-N-benzylidene-3,4-dinitroaniline oxide 6c
Light brown solid, yield 85% (0.24 g), mp 120–121 8C.
MS (70 eV), m/z (%): 287 (100, [M]+), 271 (65); 1H NMR
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.crci.2013.12.011.
(CDCl3)
d 7.55–7.53 (m, 3H, H3, H4, H5), 7.80–7.77 (m, 2H,
Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011

G Model
CRAS2C-3881; No. of Pages 7
H.I. Petkes et al. / C. R. Chimie xxx (2014) xxx–xxx
7
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Please cite this article in press as: Petkes HI, et al. Synthesis and antibacterial properties of new phenothiazinyl- and
phenyl-nitrones. C. R. Chimie (2014), http://dx.doi.org/10.1016/j.crci.2013.12.011