Novel 1,4-benzothiazine derivatives: synthesis, crystal structure, and anti-bacterial properties

Article abstract of DOI:10.1007/s11164-016-2499-6

In order to develop relatively small molecules as pharmacologically active molecules, novel 1,4-benzothiazine derivatives with triazole and oxazolidinone were synthesized. In this study, a series of 1,2,3-triazolylmethyl-1,4-benzothiazine derivatives were developed by exploiting a click chemistry reaction using a CuI-catalyzed Huisgen [3?+?2] cycloaddition. Starting from 2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one, a number of 1,4-benzothiazine derivatives were also synthesized using different alkylating agents to give a 4-(substituted)-2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one in good yields. The crystal and molecular structure of compound oxazolidin-2-one in basic benzothiazine was established by single-crystal X-ray diffraction. The newly synthesized products were subjected to in vitro biological evaluation. The result indicated that the compounds show convincing antibacterial activities against different microorganisms. All structures of the synthesized compounds were elucidated on the basis of spectral analyses and chemical reactions.

Full text of DOI:10.1007/s11164-016-2499-6

Res Chem Intermed
DOI 10.1007/s11164-016-2499-6
Novel 1,4-benzothiazine derivatives: synthesis, crystal
structure, and anti-bacterial properties
1
1,2
•
Nada Kheira Sebbar
1
•
•
Mohamed El Mehdi Mekhzoum
3
,2
El Mokhtar Essassi
4
Abdelfettah Zerzouf
4
•
5
•
Ahmed Talbaoui
Lahcen El Ammari
•
Youssef Bakri
•
Mohamed Saadi
5
Received: 28 December 2015 / Accepted: 29 February 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract In order to develop relatively small molecules as pharmacologically
active molecules, novel 1,4-benzothiazine derivatives with triazole and oxazolidi-
none were synthesized. In this study, a series of 1,2,3-triazolylmethyl-1,4-ben-
zothiazine derivatives were developed by exploiting a click chemistry reaction using
a CuI-catalyzed Huisgen [3 ? 2] cycloaddition. Starting from 2-(substituted)-3,4-
dihydro-2H-1,4-benzothiazi-3-one, a number of 1,4-benzothiazine derivatives were
also synthesized using different alkylating agents to give a 4-(substituted)-2-(sub-
stituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one in good yields. The crystal and
molecular structure of compound oxazolidin-2-one in basic benzothiazine was
established by single-crystal X-ray diffraction. The newly synthesized products
were subjected to in vitro biological evaluation. The result indicated that the
compounds show convincing antibacterial activities against different microorgan-
isms. All structures of the synthesized compounds were elucidated on the basis of
spectral analyses and chemical reactions.
&
El Mokhtar Essassi
emessassi@yahoo.fr; m.essassi@mascir.com
1
Laboratoire de Chimie Organique H e´ t e´ rocyclique URAC 21, P oˆ le de Comp e´ tence
Pharmacochimie, Facult e´ des Sciences, Universit e´ Mohammed V, Av. Ibn Battouta,
BP 1014, Rabat, Morocco
2
3
4
5
Moroccan Foundation for Advanced Science, Innovation and Research (MASCIR),
Rabat, Morocco
Laboratoire de Chimie Organique et Etudes Physico-chimique, ENS Takaddoum,
Rabat, Morocco
Laboratoire de Biochimie et Immunologie, Facult e´ des Sciences, Universit e´ Mohammed V,
Rabat, Morocco
Laboratoire de Chimie du Solide Appliqu e´ e, Facult e´ des Sciences, Universit e´ Mohammed V,
Avenue Ibn Battouta, BP 1014, Rabat, Morocco
123

N. K. Sebbar et al.
Keywords 1,4-Benzothiazine Á Click chemistry Á Oxazolidinone Á 1,2,3-Triazole Á
Antibacterial activity
Introduction
In recent years, heterocyclic compounds have received considerable attention due to
their significant importance in pharmacological and agricultural fields [1]. Notably,
nitrogen and sulfur-containing heterocyclic compunds are known to exhibit
excellent biological and pharmaceutical activities [2]. In fact, benzothiazine
derivatives have extensively been studied in different areas of chemistry, including
pharmaceutical and other chemical industries. The benzothiazine core has several
active sites, providing great responsiveness, making it an excellent heterocyclic
precursor in the synthesis of new heterocyclic systems. With respect to biological
applications, these derivatives are found to be potent anti-inflammatory, analgesic,
antimicrobial, anti-viral, herbicidal, fungicidal, and anticarcinogenic compounds
[
3–5]. These derivatives have also been reported as synthetic intermediates for other
drugs, as stabilizers in rubber vulcanization, corrosion inhibitors, and fading
preventers [6–9]. Recent studies have shown that benzothiazine derivatives have a
broad spectrum of action [10, 11]. Among their various biological activities,
benzothiazine derivatives have been studied widely, and several synthetic
approaches have been proposed [12] since their very first synthesis [13].
Alternatively, 1,3-dipolar cycloadditions form a subject of intensive research in
organic synthesis in view of their enormous synthetic applications [14]. In
particular, the cycloaddition between a terminal alkynes and azides. Historically,
triazolic compounds have proven themselves to be very important in medicinal
chemistry, as they have [15, 16] antitumor, anti-inflammation, antimicrobial,
antifungal, antithrombotic, antiplatelet, and antiviral [17] properties. 1,2,3-triazoles
have gained increased attention in the drug-discovery field since the introduction of
the ‘‘click chemistry’’ concept by Sharpless [18]. These types of compounds can
actively participate in hydrogen bonding and dipole–dipole interactions because of
their strong dipole moments and are extremely stable to hydrolysis and oxidative/
reductive conditions. Further, oxazolidinones represent a novel class of antibacterial
agents with significant activity against multidrug-resistant Gram-positive patho-
genic bacteria including methicillin-resistant Staphylococcus aureus (MRSA),
Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococci (VRE)
are of major concern. Many oxazolidinone derivatives are in clinical use, such as
linezolid eperezolid as antimicrobial agents [19]. Linezolid was the first oxazolidi-
none approved for the treatment of Gram-positive bacterial infections in humans.
Since linezolid, the many attractive traits of oxazolidinone series have encouraged
further research in this area, and also the literature reveals the existence of extensive
chemical programs [20]. Today, a large number of oxazolidinone derivatives with
diverse structural modifications have been reported in various patent reviews and
scientific literature [21–23]. The main target of these efforts is to extend the
spectrum of activity and reduction and/or elimination of toxic effects and potential
drug–drug interactions associated with monoamine oxidase (MAO) inhibition.
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
In general, the incorporation of two moieties increases biological activity of both,
and thus it was of value to synthesize some new heterocyclic derivatives having two
moieties in the same molecules. Considering these things, it is of our interest to
integrate both 1,4-benzothiazine, triazole pharmacophore, and oxazolidinone motif,
respectively, to generate a newer scaffold for biological evaluation. Herein, we will
describe new synthetic alternatives to derivatives of 1,4-benzothiazine, using
alkylation reactions and 1,3-dipolar cycloaddition with azide. A result evaluation of
the antibacterial activity will be made on some synthesized molecules.
Results and discussion
Synthesis
Initially, we prepared 1,4-benzothiazine 2 by condensation of 2-aminothiophenol 1
with methyl chloroacetate in the presence of excess potassium carbonate in DMF at
reflux. Thereafter, 3,4-dihydro-2H-1,4-benzothiazin-3-one 2 was subjected to the
action of benzaldehyde in the presence of an excess of sodium methylate in DMF.
This reaction thus leads to the formation of compound 3. The synthetic route to
2
-(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one 3 is described in
Scheme 1.
Given the presence of more reactive sites in the pattern of benzothiazine, this
heterocycle may engage in various types of reactions such as, N-alkylation,
electrophilic substitution, nitrating. In this respect, we were exclusively interested in
the reactions of N-alkylation of both compounds 2 and 3 by the action of alkylating
agents of choice, such as methyl chloroacetate, propargyl chloride, and 1-bro-
mobutane. The reactions will be under the conditions of phase transfer catalysis in
the presence of bromide tetra-n-butylammonium (TBAB) as catalyst and potassium
carbonate as base in DMF. These reactions enabled us to get the products N-
alkylated 4–8 with good yields (Scheme 2; Table 1). The structure of the compound
4
1
–8 [24–28], has been unambiguously characterized on the basis of spectral data H
Scheme 1 Preparation of 1,4-benzothiazine
benzothiazin-3-one 3. Reagents and conditions: (a) ClCH
b) benzaldehyde, CH ONa/DMF, reflux, 48 h
2
and 2-(phenylmethylidene)-3,4-dihydro-2H-1,4-
3
CO
2
CH
3
,
DMF/K
2
3
CO ,
rt. 24 h;
(
3
123

N. K. Sebbar et al.
Scheme 2 Synthetic route for the preparation of N-alkylated 4-8 compounds, (i) substituted alkynes
(CH
2
CO CH
2
3
Cl, CH
2
C:CH Cl, CH
2
2
(CH )
2
CH
3
2 3
Br), DMF, K CO , TBAB, rt, 24 h
Table 1 N-Alkyl derivatives 4-
produced via alkylation
reaction
0
Entry
R
R
Compounds Yield (%)
8
1
2
3
4
5
CH
2
2
CH
2
2
2
2
2
CO
2
CH
3
4
5
6
7
8
72
75
55
80
48
CH
CH
C:CH
C:CH
C=CHPh CH
C=CHPh CH
C=CHPh CH
CO
2
CH
3
(CH
2 2 3
) CH
Scheme 3 Preparation
of
(2Z)-4-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-2(phenylmethylidene)-3,4-
dihydro-2H-1,4-benzothiazin-3-one 9, (ii) DMF, K2CO3, TBAB, 80 °C, 6 h
1
3
NMR, C NMR. Thus, crystallographic analysis by X-ray diffraction, was
performed to confirm the exact structure of the compound 4, 7, and 8.
Following the method described by Alsubari et al. [29], a bond was formed
between the core benzothiazine and oxazolidinone motif. Thus, the action of two
equivalents of the hydrochloride of bis (2-chloroethyl) amine with the compound 3
under the conditions of transfer catalysis liquid–solid phase in DMF at 80 °C,
allowed us to isolate the product 9 (Scheme 3). In this reaction, potassium carbonate
simultaneously plays two roles; on the one hand, it ensured the deprotonation of the
nitrogen NH, and on the other hand, it acted as a carbonating agent favoring the
formation of the oxazolidinone.
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
NMR spectra
1 13
The structure of isolated product 9 was confirmed by H, C NMR spectroscopy.
1
The H NMR spectrum of the corresponding compound 9 exhibited four triplets,
arising from the methylene groups (d 3.30–3.65 NCH , 4.26 OCH ). The aromatic
2
2
protons of the benzothiazine ring system showed a multiplet in the region
3
1
(
7.06–7.64 ppm). The C NMR spectrum of 9, exhibited two signals at 158.4,
61.2 ppm for the carbonyl carbon of benzothiazine and oxazolidine ring,
1
respectively, and four signals at 41.4, 42.2, 44.9, 62.3 ppm for the methylene
groups. An X-ray crystallographic study of a single crystal of 9 confirmed the
structure deduced from NMR spectroscopic studies.
According to these results, a plausible mechanism for the formation of the
compound 9 was proposed. It is postulated that initial alkylation of the nitrogen
atom of the lactam functionality gave intermediates that underwent a nucleophilic
reaction involving potassium carbonate, and afterward, intramolecular cyclization
leads to the formation of the corresponding compound 9 (Scheme 4).
In further research of synthesized new, five-membered heterocyclic systems
obtained by 1,3-dipolar cycloaddition from 3-oxo-1,4-benzothiazine, we examined
the action of compound 5 with 1-azidomethyl-benzene, ethyl 2-azido acetate, and
2
-azidononane conditions in the click chemistry, which has led to regioselectively
Scheme 4 Plausible mechanism for formation of (2Z)-4-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-2-
phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one 9
(
123

N. K. Sebbar et al.
1
,4-triazoles 10–12 with high yields (Scheme 5; Table 2). The structures of 1,4-
1
13
triazoles 10–12 were established on the basis of spectral data of H NMR, C and
analysis by X-ray diffraction of a single crystal has allowed us to determine the
complete structure of compounds 10–11 [30, 31].
NMR spectra
In general, the 1,4-disubstituted-1H-1,2,3-triazoles can easily be distinguished from
the isomeric 1,5-disubstituted-1H-1,2,3-triazoles by the large 1-bond C–H coupling
1
constant in the gated decoupled C NMR spectrum. Depending on the substituents
3
within the triazole ring, The C signal of 1,4 appears at d & 120 ppm, whereas the
5
1
3
C signal of 1,5 appears at d & 133 ppm. In this respect, the C NMR signal of the
4
1
regiosmers has been obtained exclusively relative to 1,5-disubstituted triazoles. The
,4 isomer was more shielded than the 1,5 isomer [32]. In our case, the 1,4-
1
3
1
,4-disubstituted-1H-1,2,3-triazoles 10 show a characteristic
C signal at
d & 124.3 ppm for C , while the H triazol appears at d & 8 ppm (see support
5
information). Moreover, the regioselectivity outcome can be rationalized by
consideration of the substituent hindrance-demand features. It appears that the
highest regioselevity is in favor of the less sterically hindered 1,4-regioisomer.
Single-crystal X-ray analysis
The molecule of the title compound 9, C H N O S, is built up from two fused six-
2
0 18 2 3
membered rings linked to one phenyl via –CH– group and to oxazolidin-2-one
through –CH –CH – group as shown in Fig. 1. Furthermore, the oxazolidine ring
displays half chair conformation twisted on C(18)–N(2). The 1,4-benzothiazine
2
2
system is almost planar with the largest deviation from the mean plan being -0.067
˚
(
3)A at N(1) and makes dihedral angles of 17.01 (13)° and 8.88 (14)° with the
phenyl ring and the oxazolidine cycle, respectively. In the crystal, the molecules halt
together by C(16)–H(16B)ÁÁÁO(2) hydrogen bond forming inversion dimers as
shown in Fig. 2. The data have been assigned to the following deposition numbers.
CCDC 1433628.
The Crystal data, data collection and structure refinement details are summarized
in Table 3. The H atoms were located in a difference map and treated as riding with
Scheme 5 Synthesis of triazolylmethyl benzothiazinone derivatives 10–12. Reagents and conditions:
(
iii) substituted azides (R
1
–N ), CuSO
3
4
2 2
Á5H O, sodium ascorbate (5 % mol), H O/EtOH (1:1), rt, 10 h
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
Table 2 1,4-Disubstituted
Entry
R
1
–N
3
Compounds
Yield (%)
triazole derivatives 10–12 via
click chemistry
1
2
3
CH
2
2
Ph–N
3
10
11
12
86
84
78
CH
CO
2
Et–N
3
C
8
H
17–N
3
Fig. 1 Molecular structure of the title compound with the atom-labelling scheme. Displacement
ellipsoids are drawn at the 50 % probability level. H atoms are represented as small circles
˚
˚
C–H = 0.93 A (aromatic) and C–H = 0.97 A (methylene). All hydrogen with
U (H) = 1.2 U (aromatic and methylene) (Tables 4, 5, 6). Data collection:
iso
eq
APEX2; cell refinement: SAINT; data reduction: SAINT [33]; program(s) used to
solve structure and program(s) used to refine structure: SHELXL2013 [34];
molecular graphics: ORTEP-3 [35, 36]; software used to prepare material for
publication: PLATON [37] and publCIF [38].
Antibacterial activity
Microorganisms used
The synthesized compounds were evaluated for their in vitro antibacterial activity
against both Gram-positive bacteria: S. aureus ATCC 25923 and Streptococcus
fasciens ATCC 29212, and two Gram-negative bacteria: Escherichia coli ATCC
4
157 and Pseudomonas aeruginosa ATCC 27853. The strains used in this study are
widely encountered in various pathologies in humans and were obtained from the
Department of Microbiology, National Institute of Hygiene, Rabat, Morocco.
123

N. K. Sebbar et al.
Fig. 2 Perspective view of the structure of the title compound showing two molecules linked by
hydrogen bonds and forming inversion dimers
Bacterial culture
Starting with a culture of 18 h on Mueller–Hinton (MH) broth, a bactria carrying
suspension is used, incubated at 37 °C for 24 h. This was transplanted into a broth
(MH). This solution represents the bacterial inoculum which will be used for the
entire study.
Method gel diffusion
To test antibacterial activity, we used the technique of diffusion by mid agar (MH)
on a petri dish [39]. The medium was inoculated with a few milliliters of the
bacterial inoculum so as to cover the entire agar surface. The tests were performed
according to the method of Vincent (aromatogram). The latter was to remove the
filter paper discs impregnated by our products that were dissolved in 1 % DMSO on
the surface of the agar in the petri dishes previously seeded by inoculation. The
dishes were then incubated in an oven at 37° C for 24 h. Biological activity
manifested itself by the appearance of a halo of inhibition of microbial growth
around the discs containing the test product. The reading was performed by
measuring the diameter of inhibition observed.
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
Table 3 Crystal data, data collection, and structure refinement of crystal 9
C
20
H
18
N
2
O
3
S
F(000) = 768
= 1.377 Mg m
-
3
M
r
= 366.42
D
x
˚
Monoclinic, P2
1
/c
Mo Ka radiation, k = 0.71073 A
Cell parameters from 3626 reflections
h = 2.4–26.4°
l = 0.21 mm
T = 296 K
˚
a = 9.377 (2) A
˚
b = 20.090 (5) A
-1
˚
c = 10.133 (2) A
b = 112.146 (13)°
˚
V = 1768.1 (7) A
3
Block, colourless
Z = 4
0.36 9 0.31 9 0.26 mm
3626 Independent reflections
2898 Reflections with I [ 2r(I)
Bruker X8 APEX Diffractometer
Radiation source: fine-focus sealed tube
Graphite monochromator
Rint = 0.028
/
and x scans
Absorption correction: multi-scan
SADABS; Bruker [33])
min = 0.504, Tmax = 0.748
9,037 Measured reflections
hmax = 26.4°, hmin = 2.4°
h = -11 ? 11
(
T
k = -25 ? 25
1
l = -12 ? 12
Refinement on F2
0 Restraints
Least-squares matrix: full
2
Hydrogen site location: inferred from neighbouring sites
2
R[F [ 2r(F )] = 0.065
wR(F2) = 0.190
H-Atom parameters constrained
h
i
À
Á
2
2
2
w ¼ 1= r Fo þ ð0:0876PÞ þ 1:2706P
À
Á
2
o
2
where P ¼ F þ 2F =3
c
S = 1.05
(D/r)max \ 0.001
-3
˚
3
626 Reflections
35 Parameters
Dimax = 0.82 e A
-
3
˚
2
Dimin = - 0.64 e A
Minimum inhibitory concentration (MIC)
For MIC determination, we adopted the technique of sterile microtiter microplates
using the tetrazolium (MTT) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide as an indicator of sustainability. Into each well, we poured 100 lL of liquid
culture medium MH with 100 lL of the test product. Serial dilutions were then
performed. Each well was then inoculated with 10 lL of the bacterial suspension.
At the end of the incubation period at the appropriate temperature, 10 lL of MTT
(
0.4 mg/mL) was added to each well. The plates were reincubated for 30 min at 37°
C. After incubation time, wells where microbial growth occured showed a blue-
violet color. The MIC was then determined and corresponded to the lowest
concentration substance which produced no bacterial growth. The results of the
examination are shown in Fig. 3 and Table 7.
The results are presented in the form of antibiograms below:
This study allowed us to determine the MIC of some synthesized 1,4-
benzothiazine derivatives. The results of antibacterial activity of the products
123

N. K. Sebbar et al.
Table 4 Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters
(
2
˚
A )
Ã
U =Ueq
iso
x
y
z
C1
0.7381 (3)
0.6490 (3)
0.6653
0.79994 (13)
0.84203 (14)
0.8877
0.5945 (3)
0.6411 (3)
0.6425
0.0529 (6)
0.0637 (7)
0.076*
C2
H2
C3
0.5384 (3)
0.4784
0.81775 (17)
0.8464
0.6849 (4)
0.7145
0.0713 (8)
0.086*
H3
C4
0.5175 (4)
0.4437
0.75047 (18)
0.7333
0.6843 (4)
0.7156
0.0826 (10)
0.099*
H4
C5
0.6036 (3)
0.5876
0.70750 (16)
0.6619
0.6383 (4)
0.6398
0.0733 (9)
0.088*
H5
C6
0.7144 (3)
0.9205 (3)
0.9676 (3)
1.0809 (3)
1.1184
0.73160 (12)
0.70371 (13)
0.77442 (12)
0.78543 (13)
0.7468
0.5896 (3)
0.4993 (3)
0.4963 (3)
0.4474 (3)
0.4216
0.0515 (6)
0.0528 (6)
0.0483 (6)
0.0557 (6)
0.067*
C7
C8
C9
H9
C10
C11
H11
C12
H12
C13
H13
C14
H14
C15
H15
C16
H16A
H16B
C17
H17A
H17B
C18
H18A
H18B
C19
H19A
H19B
C20
N1
1.1567 (3)
1.1524 (4)
1.0959
0.84619 (13)
0.90819 (15)
0.9138
0.4266 (3)
0.4865 (3)
0.5440
0.0521 (6)
0.0638 (7)
0.077*
1.2322 (4)
1.2294
0.96153 (16)
1.0026
0.4607 (4)
0.5020
0.0759 (9)
0.091*
1.3149 (4)
1.3674
0.95455 (17)
0.9908
0.3754 (4)
0.3584
0.0770 (9)
0.092*
1.3202 (4)
1.3763
0.89433 (17)
0.8894
0.3153 (4)
0.2574
0.0778 (9)
0.093*
1.2419 (3)
1.2464
0.84073 (15)
0.7999
0.3406 (4)
0.2991
0.0677 (8)
0.081*
0.7535 (3)
0.7814
0.61539 (14)
0.5956
0.5200 (3)
0.4457
0.0587 (7)
0.070*
0.6429
0.6114
0.4922
0.070*
0.8340 (3)
0.9444
0.57949 (14)
0.5807
0.6580 (3)
0.6820
0.0621 (7)
0.075*
0.8123
0.6014
0.7336
0.075*
0.8518 (4)
0.9592
0.45677 (13)
0.4511
0.5967 (4)
0.6579
0.0697 (8)
0.084*
0.8437
0.4641
0.4996
0.084*
0.7554 (3)
0.7141
0.39787 (14)
0.3744
0.6068 (4)
0.5166
0.0656 (8)
0.079*
0.8168
0.3671
0.6799
0.079*
0.6508 (3)
0.7982 (3)
0.7818 (3)
0.9892 (3)
0.49179 (14)
0.68717 (10)
0.51007 (11)
0.65946 (9)
0.6605 (3)
0.5367 (3)
0.6457 (3)
0.4651 (3)
0.0571 (7)
0.0561 (6)
0.0619 (6)
0.0741 (7)
N2
O1
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
Table 4 continued
Ã
U =Ueq
iso
x
y
z
O2
O3
S1
0.6331 (2)
0.5619 (3)
0.87520 (13)
0.42524 (10)
0.52645 (12)
0.83914 (4)
0.6428 (2)
0.6887 (3)
0.54441 (13)
0.0660 (6)
0.0830 (7)
0.0916 (4)
2
Table 5 Atomic displacement parameters (A )
˚
1
1
22
33
U
12
U
13
23
U
U
U
U
C1
0.0578 (14)
0.0715 (18)
0.0626 (17)
0.0672 (18)
0.0669 (18)
0.0482 (13)
0.0539 (14)
0.0515 (13)
0.0534 (14)
0.0479 (13)
0.0733 (18)
0.094 (2)
0.0478 (14)
0.0509 (15)
0.074 (2)
0.0622 (15)
0.0783 (19)
0.088 (2)
-0.0004 (11)
0.0049 (13)
0.0142 (15)
0.0063 (16)
0.0014 (13)
0.0030 (10)
0.0019 (10)
-0.0011 (10)
-0.0002 (11)
-0.0026 (10)
-0.0169 (14)
-0.0213 (16)
-0.0214 (16)
-0.0117 (17)
-0.0041 (13)
-0.0054 (12)
-0.0030 (12)
-0.0032 (13)
-0.0066 (13)
0.0047 (12)
-0.0015 (9)
-0.0005 (10)
0.0014 (9)
0.0329 (12)
0.0391 (15)
0.0413 (16)
0.065 (2)
-0.0058 (11)
-0.0116 (13)
-0.0116 (16)
-0.001 (2)
C2
C3
C4
0.076 (2)
0.130 (3)
C5
0.0540 (16)
0.0464 (13)
0.0424 (13)
0.0403 (12)
0.0442 (13)
0.0482 (14)
0.0598 (16)
0.0551 (17)
0.0643 (19)
0.071 (2)
0.121 (3)
0.0602 (19)
0.0300 (12)
0.0358 (13)
0.0266 (11)
0.0350 (13)
0.0230 (12)
0.0320 (14)
0.0366 (19)
0.0414 (19)
0.0560 (19)
0.0480 (17)
0.0288 (13)
0.0284 (14)
0.0596 (18)
0.0411 (16)
0.0357 (13)
0.0430 (12)
0.0509 (13)
0.0716 (14)
0.0426 (11)
0.0684 (14)
0.1108 (8)
0.0024 (17)
C6
0.0671 (16)
0.0727 (16)
0.0582 (14)
0.0784 (17)
0.0621 (15)
0.0636 (16)
0.082 (2)
-0.0005 (11)
-0.0012 (11)
-0.0023 (10)
-0.0011 (12)
0.0051 (11)
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
N1
-0.0078 (13)
-0.0087 (15)
0.0072 (17)
0.084 (2)
0.090 (2)
0.082 (2)
0.099 (2)
0.0063 (18)
0.0691 (18)
0.0555 (14)
0.0604 (16)
0.0706 (18)
0.0692 (17)
0.0539 (14)
0.0586 (12)
0.0626 (13)
0.0776 (13)
0.0617 (11)
0.0790 (14)
0.1255 (8)
0.0553 (16)
0.0541 (15)
0.0541 (16)
0.0443 (14)
0.0463 (15)
0.0577 (16)
0.0400 (11)
0.0400 (11)
0.0415 (10)
0.0550 (11)
0.0821 (16)
0.0421 (4)
0.094 (2)
0.0006 (15)
0.0710 (17)
0.0745 (18)
0.116 (3)
-0.0083 (13)
-0.0091 (13)
-0.0103 (15)
-0.0075 (14)
0.0104 (13)
0.091 (2)
0.0704 (17)
0.0840 (15)
0.1006 (18)
0.1315 (19)
0.0931 (15)
0.1156 (19)
0.1577 (10)
-0.0032 (10)
-0.0018 (11)
-0.0058 (11)
0.0071 (10)
N2
O1
O2
-0.0104 (9)
0.0221 (12)
-0.0133 (4)
O3
0.0167 (13)
S1
-0.0191 (5)
tested showed the absence of growth inhibition for compound 2 in the four bacterial
strains. On the other hand, compound 3 obtained by substituting compound 2 with
the benzylidene group at position 2 resulted in an MIC = 125 lg/mL for S. aureus,
S. fasciens, P. aeruginosa and MIC = 250 lg/mL for E. coli.
In order to increase the inhibitory activity of compounds 2 and 3 we alkylated
those compounds with alkylating agents: propargyl chloride and bis (2-chloroethyl)
123

N. K. Sebbar et al.
Table 6 Geometric parameters
and hydrogen-bond geometry
C1–C6
1.389 (4)
1.391 (4)
1.739 (3)
1.362 (4)
0.9300
C12–H12
C13–C14
C13–H13
C14–C15
C14–H14
C15–H15
C16–N1
0.9300
A˚ , °) for (shelx)
(
C1–C2
1.363 (5)
0.9300
C1–S1
C2–C3
1.380 (4)
0.9300
C2–H2
C3–C4
1.365 (5)
0.9300
0.9300
C3–H3
1.493 (3)
1.500 (4)
0.9700
C4–C5
1.377 (4)
0.9300
C16–C17
C16–H16A
C16–H16B
C17–N2
C4–H4
C5–C6
1.394 (4)
0.9300
0.9700
C5–H5
1.468 (3)
0.9700
C6–N1
1.421 (3)
1.221 (3)
1.377 (3)
1.491 (3)
1.349 (3)
1.731 (2)
1.467 (4)
0.9300
C17–H17A
C17–H17B
C18–N2
C7–O1
0.9700
C7–N1
1.439 (3)
1.516 (4)
0.9700
C7–C8
C18–C19
C18–H18A
C18–H18B
C19–O2
C8–C9
C8–S1
0.9700
C9–C10
1.437 (3)
0.9700
C9–H9
C19–H19A
C19–H19B
C20–O3
C10–C15
C10–C11
C11–C12
C11–H11
C12–C13
C6–C1–C2
C6–C1–S1
C2–C1–S1
C3–C2–C1
C3–C2–H2
C1–C2–H2
C2–C3–C4
C2–C3–H3
C4–C3–H3
C3–C4–C5
C3–C4–H4
C5–C4–H4
C4–C5–C6
C4–C5–H5
C6–C5–H5
C1–C6–C5
C1–C6–N1
C5–C6–N1
O1–C7–N1
O1–C7–C8
1.391 (4)
1.393 (4)
1.387 (4)
0.9300
0.9700
1.200 (3)
1.343 (3)
1.351 (3)
C20–N2
C20–O2
1.369 (5)
120.3 (3)
124.3 (2)
115.4 (2)
121.4 (3)
119.3
C13–C14–H14
C15–C14–H14
C14–C15–C10
C14–C15–H15
C10–C15–H15
N1–C16–C17
N1–C16–H16A
120.1
120.1
121.7 (3)
119.1
119.1
119.3
109.7 (2)
109.7
118.6 (3)
120.7
C17–C16–H16A
N1–C16–H16B
C17–C16–H16B
H16A–C16–H16B
N2–C17–C16
109.7
120.7
109.7
121.4 (3)
119.3
109.7
108.2
119.3
110.1 (2)
109.6
120.8 (3)
119.6
N2–C17–H17A
C16–C17–H17A
N2–C17–H17B
C16–C17–H17B
H17A–C17–H17B
N2–C18–C19
109.6
119.6
109.6
117.5 (2)
122.0 (2)
120.5 (2)
119.0 (2)
119.7 (2)
109.6
108.2
101.3 (2)
111.5
N2–C18–H18A
C19–C18–H18A
111.5
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
Table 6 continued
N1–C7–C8
121.3 (2)
N2–C18–H18B
C19–C18–H18B
H18A–C18–H18B
O2–C19–C18
O2–C19–H19A
C18–C19–H19A
O2–C19–H19B
C18–C19–H19B
H19A–C19–H19B
O3–C20–N2
111.5
C9–C8–C7
116.3 (2)
121.8 (2)
121.76 (18)
132.9 (2)
113.6
111.5
C9–C8–S1
109.3
C7–C8–S1
105.7 (2)
110.6
C8–C9–C10
C8–C9–H9
110.6
C10–C9–H9
C15–C10–C11
C15–C10–C9
C11–C10–C9
C12–C11–C10
C12–C11–H11
C10–C11–H11
C13–C12–C11
C13–C12–H12
C11–C12–H12
C14–C13–C12
C14–C13–H13
C12–C13–H13
C13–C14–C15
D–HÁÁÁA
113.6
110.6
117.5 (2)
116.6 (2)
125.9 (2)
120.2 (3)
119.9
110.6
108.7
127.9 (3)
123.0 (3)
109.1 (2)
126.1 (2)
115.4 (2)
118.5 (2)
113.0 (2)
122.7 (2)
123.7 (2)
110.05 (19)
104.22 (12)
D–HÁÁÁA
160
O3–C20–O2
N2–C20–O2
119.9
C7–N1–C6
120.9 (3)
119.5
C7–N1–C16
C6–N1–C16
119.5
C20–N2–C18
C20–N2–C17
C18–N2–C17
C20–O2–C19
C8–S1–C1
119.8 (3)
120.1
120.1
119.9 (3)
D–H
HÁÁÁA
2.54
DÁÁÁA
3.467 (3)
a
Symmetry code: -x ? 1,
y ? 1, -z ? 1
a
C16–H16 BÁÁÁO2
0.97
-
amine hydrochloride. It is deducible that the presence of a prop-1-yn group in
compounds 5 and 6 gives the same activity against the four bacterial strains tested
with a MIC of 125 lg/mL for E. coli and an MIC of 250 lg/mL for S. aureus, S.
fasciens, and P. aeruginosa. However, compound 5 shows no activity against P.
aeruginosa. On the other hand, compound 9 also gives better activity with an MIC
of about 62.5 lg/mL for S. aureus, S. fasciens, and E. coli and 125 lg/mL for P.
aeruginosa. Indeed, for the three products containing 1,2,3-triazole 10–12 obtained
by cycloaddition reaction 1,3-dipolar, it is worth noting that compound 11 obtained
by cycloaddition with 2-ethyl azidoacetate exerted a strong inhibitory activity
during the treatment of different bacteria: CMI = 31.25 lg/mL for S. aureus, S.
fasciens, E. coli, and a CMI = 62.5 lg/mL for Pseudomonas.
On the other hand, it should be noted that the functionalized derivatives by ester
groups and benzene rings have the highest antibacterial coefficient (92 % of
pathogenic bacteria are sensitive).
This study is expected to take anti-inflammatory, antifungal, anti-parasitic, and
anti-cancer activities, because the literature gives a lot of interesting results on these
topics. Some other types of bacteria may possibly be tested by employing the same
method so as eventually to generalize the suggested investigation method.
123

N. K. Sebbar et al.
Fig. 3 The results of the antibacterial activity of the synthesized compounds 2–3, 5–6, and 9–12 towards
bacteria tested (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus
fasciens) are summarized in the table below. Chlor, Chloramphenicol (30 lg/mL); Amp, Ampicillin
(10 lg/mL); DMSO, dimethylsulfoxyde (1 %)
Table 7 Minimum Inhibitory Concentration (MIC) of the compounds 2–3, 5–6, and 9–12
Products CMI in lg/mL
Staphylococcus
aureus
Streptococcus
fasciens
Escherichia
coli
Pseudomonas
aeruginosa
2
3
5
6
9
1
1
1
–
–
–
–
125
250
250
62.5
125
31.25
62.5
1.875
125
250
250
62.5
125
31.25
62.5
3.75
250
125
125
62.5
125
31.25
62.5
15
125
–
250
125
250
62.5
125
7.5
0
1
2
Chlor
Experimental
Column chromatography was performed on silica gel 60 (Merck 230-400 mesh).
The reaction was followed by thin layer chromatography (TLC) Kiesegel 60F254
(
Merck). Melting points are taken using a Kofler bench. They are not corrected.
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
NMR spectra were recorded on a Bruker device type AC-300. Chemical shifts are
given in parts per million (ppm) and DMSO is used as solvent. key: s (singlet), d
(
doublet), t (triplet), m (multiplet). The analysis by X-ray diffraction was performed
on a Bruker APEXII diffractometer, equipped with a Kryo-Flex Bruker cooling
system.
3
,4-dihydro-2H-1,4-benzothiazin-3-one 2 Condensation of 2-aminothiophenol 1
0.047 mol) with chloro ethyl acetate (0.016 mol) in 50 mL of DMF, with a large
excess of K CO (0.02 mol). Then the reaction mixture is refluxed for 24 h. After
(
2
3
evaporating the DMF to dryness, the residue obtained is washed with distilled water
1
and then filtered. Yield: 85 %; mp = 176–178 °C; H-NMR (300 MHz, DMSO-
1
3
d ) d [ppm]: 3.43(s, 2H); 6.92–7.30(m, 4H, H ); 10.75(s, 1H; NH); C-NMR
6
ar
(
62.5 MHz, DMSO-d ) d [ppm]: 30.2(CH ); 117.7, 124.1, 127.4, 127.9 (CH );
6
2
ar
1
19.4, 137.8 (Cq); 165.8(C = O).
2
-(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one 3 A small amount
2.84 mmol) of the two compounds in 10 mL of DMF is added to an excess of
(
sodium methoxide (0.284 mmol) and benzaldehyde (6.24 mmol). The mixutre is
stirred to reflux for 48 h. After filtration of the salts, the filtrate is concentrated under
reduced pressure. The residue is purified on silica gel column and recrystallized
1
with hexane. Yield: 65 %; mp = 110–112 °C; H-NMR (300 MHz, DMSO-d ) d
6
1
ppm]: 7.78(s, 1H; = CH); 6.97–7.66 (m, 9H, H ); 11.02(s, 1H; NH); C-NMR
3
[
ar
(
62.5 MHz, DMSO-d ) d [ppm]: 115.3 (=CH); 117.21, 120.8, 123.7, 125.6, 127.5,
6
2
*129.3, 2*130.3 (CH ); 129.3, 131.1, 134.5, 134.7(Cq), 159.0 (C=O).
ar
General procedure for the alkylation
To a solution of (6.05 mmol) of 2-(substituted)-3,4-dihydro-2H-1,4-benzothiazin-3-
one 2 (3) in 25 mL of DMF, was added (7.26 mmol) of potassium carbonate, The
mixture is stirred magnetically for 5 min then added 0.3 mmol of bromide tetra-n-
butylammonium (BTBA) and 6.41 mmol reagent monohalo, then the mixture was
stirred magnetically for 24 h. After removal of salts by filtration, DMF was
evaporated under reduced pressure, and the residue obtained is dissolved in
dichloromethane. The remaining salts are extracted with distilled water, and the
mixture obtained is chromatographed on silica gel column (eluent ethyl acetate/
hexane (1/2)).
Methyl 2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl) acetate 4 Yield: 72 %;
1
mp = 128–130 °C; H-NMR (300 MHz, DMSO-d ) d [ppm]: 3.54 (s, 2H; CH );
6
2
1
3
3
.67 (s, 3H; OCH ); 4.69 (s, 2H; NCH ); 7.03–7.43 (m, 4H, H ); C-NMR
3 2 ar
(
62.5 MHz, DMSO-d ) d [ppm]: 30.6(CH ); 46.8(NCH ); 52.6(OCH ); 118.3,
6
2
2
3
1
24.0, 127.8, 128.5 (CH ); 123.2, 139.7 (Cq); 166.1, 169.4 (C=O).
ar
4
-(prop-2-yn-1-yl)-3,4-dihydro-2H-1,4-benzothiazin-3-one
1
5
Yield:
75 %;
mp = 219–220 °C; H-NMR (300 MHz, DMSO-d ) d [ppm]: 2.48 (t, 1H,–
C:CH, J = 1,8 Hz); 3.38 (s, 2H; CH ); 4.74 (d, 2H, NCH , J = 2.4 Hz);
7
6
2
2
1
3
.04–7.41 (m, 4H, Har); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 30.6(NCH );
6
2
123

N. K. Sebbar et al.
3
3.8(CH ); 74.9 (–C:CH); 118.4, 124.1, 127.7, 128.5 (CH ); 79.8, 123.3, 138.9
2
ar
(
Cq); 165.1(C=O).
(
2Z)-2-(phenylmethylidene)-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-1,4-benzothiazin-
1
3
-one
6
Yield: 55 %; mp = 130–132 °C; H-NMR (300 MHz, DMSO-d ) d
6
[
ppm]: 2.48(t, 1H, –C:CH, J = 1,8 Hz); 4.85 (d, 2H, NCH , J = 2,4 Hz); 7.84(s,
2
1
3
1
H; =CH); 7.09–7.66 (m, 9H, Har); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 34.9
6
(
NCH ); 75.4 (–C:CH); 126.8 (=CH); 117.8, 118.3, 124.4, 126.8, 2* 128.1, 129.1,
2
2
*129.7, 130.6 (CH ); 79.6, 134.4, 2*135.4, 135.8 (Cq), 165.1 (C=O).
ar
Methyl 2-[(2Z)-3-oxo-2-(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-4-yl]
1
acetate 7 Yield: 80 %; mp = 106–108 °C; H-NMR (300 MHz, DMSO-d ) d
6
[
ppm]: 3.75(s, 3H; OCH ); 4.85(s, 2H; NCH ); 7.08–7.70 (m, 9H, H ); 7.85(s,
3 2 ar
1
3
1
H; =CH); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 48.0 (NCH ); 53.10
6
2
(
OCH ); 118.25, 124.8, 127.20, 128.46, 129.46, 130.1, 131.0, 135.76 (CH );
18.6, 120.64, 134.81, 137.0 (Cq); 162.1, 169.7(C=O).
3
ar
1
(
2Z)-4-butyl-2-(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one 8 Yield:
1
4
CH , J = 7,2 Hz ; 1.35 (m, 2H; CH ); 1.61 (m, 2H; CH , J = 30 Hz); 4.07 (t, 2H;
1
NCH –, J = 7.5 Hz); 7.03–7.62 (m, 9H, H ); 7.78(s, 1H; = CH–C H ); C-NMR
8 %; mp = 89–90 °C; H-NMR (300 MHz, DMSO-d ) d [ppm]: 0.93 (t, 3H; –
6
3
)
2
2
3
2
ar
6 5
(
62.5 MHz, DMSO-d ) d [ppm]: 44.4 (NCH ); 19.9, 29.1 (CH ); 14.1 (–CH ); 120.9
6
2
2
3
(
=CH); 117.8, 124.0, 126.8, 128.0, 2*129.03, 129.02, 2*130.4 (CH ); 2*134.2,
34.6, 136.2 (Cq), 160.7 (C=O).
ar
1
Synthesis of oxazolidin-2-one in basic benzothiazine
Four eq of potassium carbonate, 0.2 eq of bromide tetra-n-butylammonium, and
2
.2 eq of bis (2-chloroethyl) amine hydrochloride were added to a solution of 0.2 g
of 2-(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one 3 in 20 mL of
DMF. The mixture was stirred magnetically at 80 °C for 6 h. After removal of salts
by filtration, DMF was evaporated under reduced pressure, and the residue obtained
was dissolved in dichloromethane. The remaining salts were extracted with distilled
water, and the mixture obtained was chromatographed on a silica gel column
(
eluent: ethyl acetate/ethanol: 4/1).
(
2Z)-4-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-2-(phenylmethylidene)-3,4-dihydro-2H-
1
1
,4-benzothiazin-3-one 9 Yield: 65 %; mp = 132–134 °C; H-NMR (300 MHz,
DMSO-d ) d [ppm]: 3.30–3.65 (m, 6H; NCH ); 4.26 (m, 2H, OCH ); 7.06–7.64 (m,
9
6
2
2
1
3
H, H ) 7.78(s, 1H, =CH–C H ); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 62.3
ar
6
5
6
(
OCH ); 41.4, 42.2, 44.9 (NCH ); 117.5 (=CH–C H ); 118.5, 120.7, 124.2, 126.9,
2 2 6 5
2
*128.0, 129.5, 2*130.4 (CH ); 2*134.3, 134.5, 136.1 (Cq); 158.4, 161.2 (C=O).
ar
Synthesis of triazolylmethyl benzothiazinone by Click Chemistry
-
In a flask, 10 mol of compound 5 and 2.5 9 10 azides prepared in 20 mL of
3
-3
-
ethanol is dissolved at room temperature. We add 0.5 9 10 mol of CuSO and
3
4
1
23

Novel 1,4-benzothiazine derivatives: synthesis, crystal…
-
3
1
0
mol of sodium ascorbate dissolved in 7 mL of distilled water. The mixture was
stirred for 24 h, and the reaction was monitored by TLC. The crude reaction was
purified by column chromatography on silica gel (ethyl acetate/hexane (3/1)) was
purified.
4
-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-2H-1,4-benzothiazin-3(4H)-one 10 Yield:
1
8
6 %; mp = 132–134 °C; H-NMR (300 MHz, DMSO-d ) d [ppm]: 3.53(s, 2H;
6
CH ); 5.12, 5.53(s, 4H, NCH ); 7.00–7.51 (m, 9H, H ); 8.00(s, 1H, =CH );
triazole
2
2
ar
1
3
C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 30.7 (CH ); 40.7, 53.2 (NCH ); 124.3
6
2
2
(
=CHtriazole); 118.7, 123.9, 127.7, 2*128.3, 128.4, 128.5, 2*129.2 (CH ); 136.4,
ar
1
39.8, 2*143.8 (Cq); 165.4 (C=O).
Ethyl2-{5-[(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl)methyl]-1H-1,2,3-triazol-1
1
yl}acetate 11 Yield: 84 %; mp = 139–141 °C; H-NMR (300 MHz, DMSO-d )
6
d [ppm]: 7.95(s, 1H, = CH triazole); 7.00–7.52 (m, 4H, H ); 5.32, 5.15 (s, 4H,
ar
NCH ); 3.54 (s, 2H; CH ); 4.12 (dd, 2H; OCH , J = 14.4 Hz); 1.17 (t, 2H; CH ,
1
2
2
2
3
3
J = 7.2 Hz); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 118.6 (=CHtriazole); 50.8,
6
3
0.7(NCH ); 30.7(CH ); 61.1(OCH ); 14.4(CH ); (123.9, 125.6, 127.7, 128.5)CH ;
2 2 2 3 ar
1
23.3, 139.8, 143.5 (Cq); 167.6, 165.4(C = O).
4
1
0
2
1
2
1
-[(1-octyl-1H-1,2,3-triazol-5-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-3-one
1
2
.81(t, 2H; CH , J = 6.9 Hz); 1.21–1.18(m, 10H; CH ); 1.72 (m, 2H; CH ); 4.26 (t,
Yield: 78 %; mp = 80–82 °C; H-NMR (300 MHz, DMSO-d ) d [ppm]:
6
3
2
2
H, NCH , J = 7.2 Hz); 5.11(S, 2H, NCH ); 6.99–7.49 (m, 4H, H ); 7.92(s,
2
2
ar
1
3
H, =CH triazole); C-NMR (62.5 MHz, DMSO-d ) d [ppm]: 14.4 (CH ); 22.5,
6
3
6.2, 28.7, 28.9, 30.0, 31.5 (CH ); (30.7) CH ; 2*49.7(NCH ); 118.7 (=CHtriazole);
2
2
2
23.8, 124.0, 127.6, 128.4 (CH ); 123.3, 139.8, 143.4 (Cq), 165.4 (C=O).
ar
Conclusion
In summary, a practical method for synthesizing new heterocyclic series of 3-oxo-
,4 benzothiazine using a condensation reaction with hydrochloride of bis (2-
1
chloroethyl) amine and alkylation reactions with various alkylating agents was
developed. Our interest also focused on the ‘‘click chemistry,’’ which is the
uncoordinated modern version of this cycloaddition. This reaction was catalyzed by
Cu (I) and form a 1,2,3-triazole heterocycles disubstituted in position 4 in a
1
13
regiospecific manner. Heterocycles obtained were identified by H NMR, C NMR,
and confirmed for certain products by X-ray. The synthesized products were
subjected to the evaluation of antibacterial activity. Several of the compounds tested
showed significant activity.
Acknowledgments The authors thank the Unit of Support for Technical and Scientific Research
(UATRS, CNRST) for the X-ray measurements and the University Mohammed V, Rabat, Morocco, for
the financial support.
123

N. K. Sebbar et al.
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