Efficient and convenient synthesis, characterization, and antimicrobial evaluation of some new tetracyclic 1,4-benzothiazines

Article abstract of DOI:10.1080/00397911.2015.1127383

In the present study, 20 new tetracyclic 1,4-benzothiazines (4a-4 t) were conveniently synthesized in good yields and characterized by different spectral and physical techniques. The in vitro antimicrobial evaluation of the synthesized benzothiazine derivatives was performed by serial dilution against two Gram-positive bacteria [Bacillus subtilis (MTCC 441) and Staphylococcus epidermidis (MTCC 6880)], two Gram-negative bacteria [Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424)], and two fungal strains [Candida albicans (MTCC 227) and Aspergillus Niger (MTCC 8189)]. The derivatives 4 l and 4 t were found to be more potent than standard drug, i.e., fluconazole, against A. Niger and C. albicans, respectively.

Full text of DOI:10.1080/00397911.2015.1127383

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient and Convenient Synthesis,
Characterization, and Antimicrobial Evaluation of
Some New Tetracyclic 1,4-Benzothiazines
Satbir Mor & Savita Nagoria
To cite this article: Satbir Mor & Savita Nagoria (2015): An Efficient and Convenient Synthesis,
Characterization, and Antimicrobial Evaluation of Some New Tetracyclic 1,4-Benzothiazines,
Synthetic Communications, DOI: 10.1080/00397911.2015.1127383
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1127383
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Date: 20 December 2015, At: 10:07

An efficient and convenient synthesis, characterization, and antimicrobial
evaluation of some new tetracyclic 1,4-benzothiazines
Satbir Mor1, Savita Nagoria1
1Department of Chemistry, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana, India
Address Correspondence to Satbir Mor E-mail: satbir_mor@yahoo.co.in
Abstract
In present study, a series of twenty new tetracyclic 1,4-benzothiazines (4a–4t) was
conveniently synthesized in high yields and characterized by employing different spectral
and physical techniques. The in vitro antimicrobial evaluation of the synthesized
benzothiazine derivatives was performed by serial dilution technique against four
bacterial strains, i.e., two Gram-positive bacteria viz. Bacillus subtilis (MTCC 441) and
Staphylococcus epidermidis (MTCC 6880) and two Gram-negative bacteria viz.
Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424), and two
fungal strains viz. Candida albicans (MTCC 227) and Aspergillus niger (MTCC 8189).
The derivatives 4l and 4t were found to be more potent than standard drug, i.e.,
Fluconazole against A. niger and C. albicans, respectively.
KEYWORDS: 2-Aminobenzenethiols; Antimicrobial; 1,4-Benzothiazines; Bromination
1

INTRODUCTION
Emerging infectious diseases and the increase in incidence of drug resistance among
pathogenic microorganisms have made the search for new antimicrobials inevitable for
the improvements in human well being, including quality of life, and to wealth creation
for individuals and nations. Consequently, the design as well as identification of potent
and novel structural leads remains a major challenge for molecular architectures and
medicinal chemistry researchers. 1,4-Benzothiazines undoubtedly constitute a privileged
class of bioactive molecules, as compounds bearing this structural motif acquire
remarkable biological activities and utilization as key structural template for the synthesis
of various natural products of pharmaceutical interest.[1] These scaffolds have immense
chemotherapeutic importance as antimicrobial,[2,3] antitumoral,[2,4] antidepressant,[5] anti-
inflammatory,[6] antiarrhythmic,[7] antidiabetic,[8] antihypertensive,[9] antirheumatic,[10]
antimalarial,[11] anti-HIV,[12] antitubercular,[13] agents, etc. Further, benzothiazines are
known to possess unique properties such as potassium channel openers,[14,15] steel
corrosion inhibitors,[16] photosensitizers[17] and dyes.[18] Also, such pharmacophores have
been found to elicit their role, as calcium ion antagonist,[19] lipoxygenase inhibitors,[20]
phosphodiesterase inhibitors,[21] neuroleptics,[22,23] antihistaminics,[24] antipsycotics,[25]
antioxidants,[26] cytostatic agents,[27] and Na+/H+ exchange inhibitors,[28] etc. In addition,
literature survey revealed that 1,4-benzothiazine is an ubiquitous motif which received
attention due to their occurrence in the nature as red hair pigments[29] and their
applications as precursors to thioesters for natural chemical ligation.[30] The multifarious
applications of 1,4-benzothiazine derivatives have led to the development of various
synthetic routes for their preparation,[31–34] however, the most convenient method for their
2

synthesis involves the treatment of dinucleophiles, i.e., 2-aminothiophenol or its
precursors with suitable α-halo ketones under appropriate reaction conditions. Prompted
from these findings and in continuation of our research program aimed at the synthesis
and biological evaluation of nitrogen and sulfur containing heterocyclic compounds,[35–38]
herein, we report an efficient and convenient synthesis, characterization and in vitro
antimicrobial evaluation of twenty new tetracyclic 1,4-benzothiazines (4a–4t).
RESULTS AND DISCUSSION
Chemistry
The synthetic route for the preparation of tetracyclic 1,4-benzothiazines (4a–4t) is
outlined in Scheme 1. The convenient, efficient and versatile synthesis of tetracyclic 1,4-
benzothiazines (4) began with phthalide as starting material. The key intermediates α-
haloketones, i.e., 2-aryl-2-bromo-1H-indene-1,3(2H)-diones (2) were synthesized by a
two step procedure that involves reacting phthalide with appropriate 4-substituted
benzaldehydes in the presence of sodium methoxide and ethylacetate to yield 2-aryl-1H-
indene-1,3(2H)-diones[39,40] (1) which upon subsequent bromination in Br2/chloroform
afforded the corresponding 2-aryl-2-bromo-1H-indene-1,3(2H)-diones (2) in high
yields.[41] The synthesis of 5-substituted 2-aminobenzenethiols (3) was accomplished in
good yields by base catalyzed hydrolytic fission of 6-substituted 2-aminobenzothiazoles
as described in the literature.[42–44] Finally, the target compounds (4a–4t) were achieved
in high yields (82–95%) by the condensation of equimolar quantities of 2-aryl-2-bromo-
1H-indene-1,3(2H)-diones (2) and appropriate 2-aminobenzenethiol/5-substituted 2-
aminobenzenethiols (3) in refluxing dry ethanol for 8–13 h.
3

The structures of all the newly synthesized 1,4-benzothiazines (4a–4t) were elucidated on
the basis of spectral (IR, 1H NMR, 13C NMR, COSY, DEPT, HSQC, HMBC and mass)
as well as analytical results. The IR spectra of all these compounds (4a–4t) displayed the
characteristic absorptions due to C=O stretching and C=N stretching in the regions at
1676–1697 cm-1 and 1645–1651 cm-1, respectively. The 1H NMR spectra of compounds
(4a–4t), in each case, exhibited a one-proton doublet in the region at δ 6.46–6.58 (J =
7.92–8.08 Hz) which was undoubtedly assigned to C4-H. The compounds with
substitution at C8, displayed a one-proton doublet in the region at δ 6.60–7.21 safely
assignable to C9-H with coupling constant (J) ranging from 1.36–2.88 Hz which is due to
meta coupling. The one-proton doublet (J = 7.44–7.68 Hz) exhibited in the region at δ
7.91–7.97 was easily assigned to C1-H. The most characteristic feature of 1H NMR
spectra of 1,4-benzothiazines (4a–4t) was a one-proton doublet (J = 8.44–9.32 Hz) in the
region at δ 9.04–9.18 due to C6-H. The signals due to the remaining aliphatic and
aromatic protons were observed in their expected regions (vide experimental). The salient
feature of 13C NMR spectra of 1,4-benzothiazines (4a–4t) was the signal observed in the
most downfield region at δ 164.80–165.22 which was indubitably assigned to C11.
Further, it is worthy to mention here that with the variation of R, the change in chemical
shift value of C8 signal was observed. The signals due to the remaining aliphatic and
aromatic carbons were observed in the expected regions (vide experimental). Further, the
mass spectral data and elemental analysis results of 1,4-benzothiazines (4a–4t) were also
found in good agreement with their molecular formulae (vide experimental).
4

In Vitro Antimicrobial Evaluation
All the synthesized 1,4-benzothiazine derivatives (4a–4t) were assessed for their in vitro
antimicrobial activity against two Gram-positive bacterial strains viz. Bacillus subtilis
(MTCC 441) and Staphylococcus epidermidis (MTCC 6880), two Gram-negative
bacterial strains viz. Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa
(MTCC 424), and two fungal strains viz. Candida albicans (MTCC 227) and Aspergillus
niger (MTCC 8189) by employing serial dilution technique.[45] Minimum inhibitory
concentrations (MIC) were expressed in terms of µmol/mL. Ciprofloxacin and
Fluconazole (Fig. 1) were used as reference drugs for antibacterial and antifungal
evaluation, respectively. The results of antibacterial evaluation summarized in Table 1
and Fig. 2 revealed that the derivatives 4a, 4f, 4i and 4n against B. subtilis; 4a, 4d, 4f, 4g,
4i, 4k, 4l, 4o and 4p against S. epidermidis; 4a, 4d, 4f, 4g, 4i, 4k, 4n, 4o, 4s and 4t
against E.coli, and 4g and 4h against P. aeruginosa were moderately active as compared
to the standard reference. However, all the tested derivatives were found to exhibit less
inhibitory activity as compared to reference drug, i.e., Ciprofloxacin. Further, the results
of antifungal evaluation presented in Table 2 and Fig. 3 revealed that derivatives 4a, 4f,
4j and 4p exhibited moderate activity against C. albicans as compared to reference drug,
i.e., Fluconazole. Similarly, compound 4h and 4r also possessed appreciable antifungal
activity against A. niger as compared to reference drug. Interestingly, the compounds 4t
against C. albicans and 4l against A. niger were found to be more potent than the
standard drug. Hence, 4t and 4l can be used as potential antifungal agents for further drug
development. Moreover, comparison of antibacterial and antifungal evaluation results
reveals that the antifungal activities are more prolific than antibacterial activities.
5

From the above antimicrobial results, following structure activity relationships (SAR)
may be inferred
1.
efficacy against S. epidermidis, E. coli and C. albicans.
2. The presence of electron withdrawing groups such as F at C4' of C10a-phenyl ring
The unsubstitution at C8 of 1,4-benzothiazine ring improved the antimicrobial
and Br at C8 and/or C4' positions enhanced the antimicrobial activity against all the tested
microbial strains except P. aeruginosa.
3.
phenyl ring increased the antimicrobial potency against all the tested microbial strains.
4. In some cases, presence of electron withdrawing NO2 at C4' of C10a-phenyl ring
In most of the cases, presence of electron donating ethyl group at C4' of C10a-
improved the antimicrobial activity against S. epidermidis, B. subtilis, E. coli and C.
albicans.
5.
In contrast to the above results, presence of electron withdrawing groups like
NO2, F and Br at C4' of C10a-phenyl ring lessen the antibacterial activity against P.
aeruginosa.
These results lead to the conclusion that there are different structural requirements for a
compound to be effective against different microbial strains. However, no general trend
toward structure activity relationship (SAR) has been established for antimicrobial
activity of the tested 1,4-benzotiazine derivatives (4).
CONCLUSION
6

Conclusively, we have accomplished the synthesis of a series of twenty new tetracyclic
1,4-benzothiazines (4a–4t) through an efficient chemical transformation. All the
synthesized 1,4-benzothiazines (4a–4t) have been investigated for their in vitro
antimicrobial activity. Most of the tested compounds exhibited moderate to good activity
towards Gram-positive and Gram-negative bacterial strains as well as the fungal strains.
Among the target compounds, 4l and 4t were found to be more potent than standard drug
against A. niger and C. albicans, respectively, which could be promising lead candidates
for further drug discovery against fungal infections. Further work in this direction is
continuing in our laboratory.
EXPERIMENTAL
Commercial reagents were utilized as received from suppliers without additional
purification. 2-Aminothiophenol was purchased from Sigma-Aldrich. All the synthesized
compounds were characterized by 1H NMR, 13C NMR, IR, ESI-MS and microanalysis.
All the melting points (°C) were recorded on electrothermal apparatus in open capillary
tubes and are uncorrected. Thin layer chromatography was used for monitoring the
progress of the reaction and ascertaining the purity of the synthesized compounds on pre-
coated TLC plates (Merck Keiselgel F254) using hexane-ethyl acetate solvent system of
different polarity and visualization was achieved by exposure to UV light. Columns were
packed as slurry of silica gel (60–120 mesh) in hexane. Initially, compounds were
adsorbed on silica gel in appropriate solvent and then loaded on column as slurry in
hexane. The FTIR spectra were scanned on IR Affinity-1 FTIR (Shimadzu)
spectrophotometer in KBr and wave numbers (ν) are reported in cm-1. Nuclear Magnetic
7

Resonance spectra (1H at 400 MHz and 13C at 100 MHz) were recorded on 400 MHz
Bruker AVANCE-III spectrometer using CDCl3 as solvent and tetramethylsilane (TMS)
as internal standard. DEPT (Distortionless Enhancement by Polarization Transfer) and
2D-NMR viz. COSY (correlation spectroscopy), HSQC (heteronuclear single-quantum
coherence) and HMBC (heteronuclear multiple bond correlation) spectra of compound 4b
were also recorded on 400 MHz Bruker AVANCE-III spectrometer. Chemical shifts (δ)
are reported in parts per million (ppm) and coupling constants (J) are expressed in Hertz
(Hz). Multiplicities in NMR signals are designated as s (singlet), d (doublet), dd (doublet
of doublet), t (triplet), q (quartet) and m (multiplet, for unresolved signals). Mass spectra
were scanned on Waters Quadrupole Detector (TDQ), Waters gtof micro Mass
spectrometer and Agilent 6410B Triple Quard LCMS spectrometer. Microanalyses were
performed on Thermo Scientific FLASH-2000 CHN analyser. All the synthesized
compounds were found in good agreement with the elemental analysis. Analytical results
for C, H and N were found to be within ± 0.4 % of the theoretical values. Nomenclature
of the compounds was assigned with the help of Chem Draw Ultra 12.0.
General Procedure For The Synthesis Of 2-Aryl-1H-Indene-1,3(2H)-Diones (1)
Condensation of equimolar quantities of phthalide and appropriate benzaldehyde under
the influence of sodium methoxide and ethylacetate led to the formation of 2-aryl-1H-
indene-1,3(2H)-dione (1).[39,40]
General Procedure For The Synthesis Of 2-Aryl-2-Bromo-1H-Indene-1,3(2H)-
Diones (2)
8

The 2-aryl-1H-indene-1,3(2H)-diones (1) upon bromination in Br2/chloroform furnished
the corresponding 2-aryl-2-bromo-1H-indene-1,3(2H)-diones (2).[41]
General Procedure For The Synthesis Of 5-Substituted-2-Aminobenzenethiols (3)
The reaction of potassium thiocyanate and bromine (generating thiocyanogen, [(SCN)2],
in situ) on appropriate anilines yielded the corresponding 6-substituted-2-
aminobenzothiazoles, which upon subsequent base catalyzed hydrolytic fission afforded
the corresponding 5-substituted 2-aminobenzenethiols (3) in good yields.[42–44]
Typical Procedure For The Synthesis Of 10a-(4-Nitrophenyl)Benzo[B]Indeno[1,2-
E][1,4]Thiazin-11(10ah)-One (4a)
2-(4-Nitrophenyl)-1H-indene-1,3(2H)-dione (1a) was synthesized by condensation of
equimolar quantities of phthalide and appropriate benzaldehyde under the influence of
sodium methoxide and ethylacetate.[39,40] The 2-(4-Nitrophenyl)-1H-indene-1,3(2H)-
diones (1a) upon bromination in Br2/chloroform furnished the corresponding 2-bromo-2-
(4-nitrophenyl)-1H-indene-1,3(2H)-dione (2a).[41] 2-Aminobenzenethiol (3a) required for
the synthesis of 1,4-benzothiazines was purchased from Sigma-Aldrich. A solution of
equimolar quantities of 2-bromo-2-(4-nitrophenyl)-1H-indene-1,3(2H)-dione (2a) and 2-
aminobenzenethiol (3a) in dry ethanol (30 mL) was heated at reflux on a water bath for
10 h. Thereafter, the reaction mixture was cooled to room temperature and solid thus
obtained was filtered, dried and purified on silica gel (60–120 mesh) column prepacked
in hexane. Elution of the column with hexane:ethylacetate (19:1, v/v) gave a
9

homogeneous residue, which upon crystallization from chloroform furnished 10a-(4-
Nitrophenyl)benzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-one (4a) in high yield (85%).
Spectral Data
Orange solid, yield 85%; mp 250–252 °C; IR (KBr, cm-1): νmax 3113, 3065 (aromatic C–
H), 1684 (C=O), 1647 (C=N), 1512 (asymmetric N–O stretch.), 1346 (symmetric N–O
stretch.); 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J = 8.44 Hz, H-6), 8.41 (d, 2H, J =
8.20 Hz, H-3', H-5'), 7.97 (d, 1H, J = 7.52 Hz, H-1), 7.73 (d, 2H, J = 8.20 Hz, H-2', H-6'),
7.55–7.09 (m, 5H, H-2, H-3, H-7, H-8, H-9), 6.48 (d, 1H, J = 7.92 Hz, H-4); 13C NMR
(100 MHz, CDCl3): δ 165.13 (C-11), 148.69 (C-4'), 141.47 (C-1'), 133.73 (C-5a), 131.87
(C-3), 131.09 (C-2', C-6'), 130.36 (C-4b), 129.03 (C-2), 128.56 (C-4a), 128.14 (C-7),
127.67 (C-11a), 125.77 (C-8), 125.61 (C-9), 124.93 (C-3', C-5'), 123.51 (C-1), 121.46 (C-
4), 119.51 (C-6), 119.15 (C-9a), 115.32 (C-10a); ESI-MS m/z: [M+H]+ calcd. for
C21H12N2O3S, 373.06; found, 373.14. Anal. calcd. for C21H12N2O3S: C, 67.73; H, 3.25; N,
7.52; found: C, 67.92; H, 3.48; N, 7.24.
General Procedure For In Vitro Antimicrobial Evaluation
All the newly synthesized twenty tetracyclic 1,4-benzothiazines (4a–4t) were screened
for their in vitro antimicrobial activity against two Gram-positive bacteria viz. B. subtilis
(MTCC 441) and S. epidermidis (MTCC 6880), two Gram-negative bacteria viz. E. coli
(MTCC 1652) and P. aeruginosa (MTCC 424), and two fungi viz. A. niger (MTCC
8189) and C. albicans (MTCC 227) by employing serial dilution technique.[45] Initially,
stock solutions were prepared by dissolving weighed amounts of synthesized compounds
10

in DMSO (1.0 mg of the test compound in 10 mL DMSO) to get a final concentration of
100 µg/mL. Fresh cultures were obtained by inoculation of respective microorganisms in
suitable media viz. nutrient broth for bacterial strains and potato dextrose broth for fungal
strains, followed by incubation at 37 ± 1 ºC for 24 h (all bacteria), 25 ± 1 ºC for 7 days
(A. niger) and 37 ± 1 ºC for 48 h (C. albicans). The stock solutions of the test compounds
were then serially diluted in test tubes containing 1 mL of sterile medium to get the
concentrations of 50–0.39 µg/mL. Then 100 µL of the respective microorganism in
sterile saline was inoculated to different dilutions of test compounds (each dilution in
triplicates). The inoculated test tubes were incubated at 37 ± 1 ºC for 24 h (bacteria), 25 ±
1 ºC for 7 days (A. niger) and 37 ± 1 ºC for 48 h (C. albicans). Ciprofloxacin and
Fluconazole were used as standard antibacterial and antifungal drugs, respectively, which
were also assessed under similar conditions for comparison with the tested compounds.
After incubation, microbial growth was monitored visually and spectrophotometrically
and the results were recorded in terms of Minimum Inhibitory Concentration (MIC,
µmol/mL). The data for the antibacterial activity are presented in Table 1 and Fig. 2, and
results of antifungal activity are depicted in Table 2 and Fig. 3.
SUPPLEMENTARY MATERIAL
Full experimental detail, characterization/spectral data, and 1H NMR, 13C NMR spectra
of all newly synthesized 1,4-benzothiazines (4a–4t) and 2D NMR spectra of 4b can be
accessed on the publisher’s website.
ACKNOWLEDGEMENTS
11

Authors wish to express their gratitude to University Grants Commission, New Delhi for
providing financial support. Authors are further grateful to Dr. Anil Kumar, Assistant
Professor, Department of Bio & Nano Technology, Guru Jambheshwar University of
Science & Technology, Hisar, for his assistance to carry out antimicrobial evaluation.
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Supplemental data for this article can be accessed on the publisher’s website.
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Table 1. In vitro antibacterial activity of 1,4-benzothiazines (4a–4t).
Compounds
Minimum Inhibitory Concentration (MIC)a
Gram-positive bacteria
Gram-negative bacteria
B. subtilisb S. epidermidisc E. colid P. aeruginosae
0.03357
0.01617
0.03106
0.02770
0.03072
0.01758
0.03383
0.03243
0.01439
0.03206
0.03619
0.03478
0.03330
0.01473
0.03291
0.03077
0.02974
0.02865
0.02576
0.01678
0.03235
0.03106
0.01385
0.03072
0.01758
0.01692
0.03243
0.01439
0.03206
0.01810
0.01739
0.03330
0.02946
0.01645
0.01538
0.02974
0.02865
0.02576
0.01678 0.03357
0.03235 0.03235
0.03106 0.03106
0.01385 0.02770
0.03072 0.03072
0.01758 0.03517
0.01692 0.01692
0.03243 0.01621
0.01439 0.05756
0.03206 0.06412
0.01810 0.03619
0.03478 0.03478
0.03330 0.06659
0.01473 0.02946
0.01645 0.03291
0.03077 0.03077
0.02974 0.02974
0.02865 0.02865
0.01288 0.05153
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
16

0.02836
0.00471
0.02836
0.00471
0.01418 0.02836
0.00471 0.00471
4t
Ciprofloxacin
a Unit: µmol/mL
b Bacillus subtilis (MTCC 441)
c Staphylococcus epidermidis (MTCC 6880)
d Escherichia coli (MTCC 1652)
e Pseudomonas aeruginosa (MTCC 424)
17

Table 2. In vitro antifungal activity of 1,4-benzothiazines (4a−4t).
Compounds Minimum Inhibitory Concentration (MIC)a
C. albicansb
0.0168
0.0323
0.0311
0.0554
0.0614
0.0176
0.0677
0.0324
0.0576
0.0160
0.0362
0.0348
0.0333
0.0295
0.0329
0.0154
0.0297
0.0573
0.0515
0.0018
A. nigerc
0.0336
0.0647
0.0621
0.0554
0.0614
0.0703
0.0677
0.0162
0.0288
0.0321
0.1448
0.0087
0.0333
0.0295
0.0658
0.0308
0.0595
0.0143
0.0515
0.0284
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
18

0.0102
0.0102
Fluconazole
a Unit: µmol/mL
b Candida albicans (MTCC 227)
c Aspergillus niger (MTCC 8189)
19

Scheme 1. The reaction sequence for the synthesis of 1,4-benzothiazines (4a–4t).
20

Fig. 1. Structures of Ciprofloxacin and Fluconazole.
21

Fig. 2. Graphical representation of in vitro antibacterial activity of 1,4-benzothiazines
(4a−4t).
22

Fig. 3. Graphical representation of in vitro antifungal activity of 1,4-benzothiazines
(4a−4t).
23